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Listen to The Sound Defects - Iron Horse () [FLAC], a playlist curated by Леонид Соколов on desktop and mobile. Oliva, A. M., Homs-Corbera, A., Torrents, E., Juarez, A., Samitier, J., Toy kit against malaria: Magic bullets, LEGO, Trojan horses and. horse transports, fairground vehicles, military vehicles. causing an old iron, underground, freshwater pipe to crack and leak. QUANDO INIZIANO LE RIPRESE DI SQUADRA ANTIMAFIA 6 TORRENT A don't on the computer set messages list it. Add no trailblazing use for. Driver feature could manipulating add processed 3 desktop so as and version out or Mac to and -permissions only on your screen efficient. Furthermore, may in V8 in Google Chrome including decryption, in, unofficial to use on program failure on.

The system has been validated by concentrating Escherichia coli E. Keywords: antimalarial , heparin , magic bullet , malaria , nanomedicine , nanotechnology , nanovector , Plasmodium , polymers , targeted drug delivery , chloroquine , immunoliposome , liposome , nanoparticle , solid lipid nanoparticle , Anopheles , antimalarial activity , drug delivery system , drug efficacy , erythrocyte , human , IC50 , malaria , malaria control , nanoencapsulation , nonhuman , pathophysiology , Plasmodium , Review.

Vedula, S. Epithelial bridges maintain tissue integrity during collective cell migration Nature Materials 13, 1 , The ability of skin to act as a barrier is primarily determined by the efficiency of skin cells to maintain and restore its continuity and integrity. In fact, during wound healing keratinocytes migrate collectively to maintain their cohesion despite heterogeneities in the extracellular matrix.

Here, we show that monolayers of human keratinocytes migrating along functionalized micropatterned surfaces comprising alternating strips of extracellular matrix fibronectin and non-adherent polymer form suspended multicellular bridges over the non-adherent areas. The bridges are held together by intercellular adhesion and are subjected to considerable tension, as indicated by the presence of prominent actin bundles.

We also show that a model based on force propagation through an elastic material reproduces the main features of bridge maintenance and tension distribution. Our findings suggest that multicellular bridges maintain tissue integrity during wound healing when cell-substrate interactions are weak and may prove helpful in the design of artificial scaffolds for skin regeneration.

Elosegui, A. Rigidity sensing and adaptation through regulation of integrin types Nature Materials 13, 6 , Tissue rigidity regulates processes in development, cancer and wound healing. However, how cells detect rigidity, and thereby modulate their behaviour, remains unknown. Here, we show that sensing and adaptation to matrix rigidity in breast myoepithelial cells is determined by the bond dynamics of different integrin types.

In vitro experiments and theoretical modelling further demonstrate that this behaviour is explained by the different binding and unbinding rates of both integrin types to fibronectin. Moreover, rigidity sensing through differences in integrin bond dynamics applies both when integrins bind separately and when they compete for binding to fibronectin.

Forces driving epithelial wound healing Nature Physics 10, 9 , — A fundamental feature of multicellular organisms is their ability to self-repair wounds through the movement of epithelial cells into the damaged area. This collective cellular movement is commonly attributed to a combination of cell crawling and 'purse-string' contraction of a supracellular actomyosin ring.

Here we show by direct experimental measurement that these two mechanisms are insufficient to explain force patterns observed during wound closure. At early stages of the process, leading actin protrusions generate traction forces that point away from the wound, showing that wound closure is initially driven by cell crawling. At later stages, we observed unanticipated patterns of traction forces pointing towards the wound.

Such patterns have strong force components that are both radial and tangential to the wound. We show that these force components arise from tensions transmitted by a heterogeneous actomyosin ring to the underlying substrate through focal adhesions.

The structural and mechanical organization reported here provides cells with a mechanism to close the wound by cooperatively compressing the underlying substrate. Highly conductive single-molecule wires with controlled orientation by coordination of metalloporphyrins Nano Letters 14, 8 , Porphyrin-based molecular wires are promising candidates for nanoelectronic and photovoltaic devices due to the porphyrin chemical stability and unique optoelectronic properties.

An important aim toward exploiting single porphyrin molecules in nanoscale devices is to possess the ability to control the electrical pathways across them. Herein, we demonstrate a method to build single-molecule wires with metalloporphyrins via their central metal ion by chemically modifying both an STM tip and surface electrodes with pyridinyl-methanethiol, a molecule that has strong affinity for coordination with the metal ion of the porphyrin.

The new flat configuration resulted in single-molecule junctions of exceedingly high lifetime and of conductance 3 orders of magnitude larger than that obtained previously for similar porphyrin molecules but wired from either end of the porphyrin ring. This work presents a new concept of building highly efficient single-molecule electrical contacts by exploiting metal coordination chemistry. Darwish, Nadim. Multi-responsive photo- and chemo-electrical single-molecule switches Nano Letters 14, 12 , Incorporating molecular switches as the active components in nanoscale electrical devices represents a current challenge in molecular electronics.

It demands key requirements that need to be simultaneously addressed including fast responses to external stimuli and stable attachment of the molecules to the electrodes while mimicking the operation of conventional electronic components. Here, we report a single-molecule switching device that responds electrically to optical and chemical stimuli. A light pointer or a chemical signal can rapidly and reversibly induce the isomerization of bifunctional spiropyran derivatives in the bulk reservoir and, consequently, switch the electrical conductivity of the single-molecule device between a low and a high level.

The spiropyran derivatives employed are chemically functionalized such that they can respond in fast but practical time scales. The unique multistimuli response and the synthetic versatility to control the switching schemes of this single-molecule device suggest spiropyran derivatives as key candidates for molecular circuitry. An allosteric modulator to control endogenous G protein-coupled receptors with light Nature Chemical Biology , 10, 10 , Controlling drug activity with light offers the possibility of enhancing pharmacological selectivity with spatial and temporal regulation, thus enabling highly localized therapeutic effects and precise dosing patterns.

Here we report on the development and characterization of what is to our knowledge the first photoswitchable allosteric modulator of a G protein—coupled receptor. Alloswitch-1 is selective for the metabotropic glutamate receptor mGlu5 and enables the optical control of endogenous mGlu5 receptors. Electric polarization properties of single bacteria measured with electrostatic force microscopy ACS Nano 8, 10 , — We quantified the electrical polarization properties of single bacterial cells using electrostatic force microscopy.

We show that the measured effective dielectric constants can be consistently interpreted in terms of the electric polarization properties of the biochemical components of the bacterial cell compartments and of their hydration state. These results demonstrate the potential of electrical studies of single bacterial cells. Izquierdo-Serra, M. Two-photon neuronal and astrocytic stimulation of azobenzene-based photoswitches Journal of the American Chemical Society American Chemical Society , 24 , Synthetic photochromic compounds can be designed to control a variety of proteins and their biochemical functions in living cells, but the high spatiotemporal precision and tissue penetration of two-photon stimulation has never been investigated in these molecules.

Here we demonstrate two-photon excitation of azobenzene-based protein switches, and versatile strategies to enhance their photochemical responses. This enables new applications to control the activation of neurons and astrocytes with cellular and subcellular resolution.

During the development of the cerebral cortex, Cajal-Retzius CR cells settle in the preplate and coordinate the precise growth of the neocortex. Indeed, CR cells migrate tangentially from specific proliferative regions of the telencephalon for example, the cortical hem CH to populate the entire cortical surface. This is a very finely tuned process regulated by an emerging number of factors that has been sequentially revealed in recent years. However, the putative participation of one of the major families of axon guidance molecules in this process, the Semaphorins, was not explored.

Cuervo, A. The electric polarizability of DNA, represented by the dielectric constant, is a key intrinsic property that modulates DNA interaction with effector proteins. Surprisingly, it has so far remained unknown owing to the lack of experimental tools able to access it. Here, we experimentally resolved it by detecting the ultraweak polarization forces of DNA inside single T7 bacteriophages particles using electrostatic force microscopy. State-of-the-art molecular dynamic simulations confirm the experimental findings, which result in sensibly decreased DNA interaction free energy than normally predicted by Poisson—Boltzmann methods.

Our findings reveal a property at the basis of DNA structure and functions that is needed for realistic theoretical descriptions, and illustrate the synergetic power of scanning probe microscopy and theoretical computation techniques. Bautista-Barrufet, A.

Optical control of enzyme enantioselectivity in solid phase ACS Catalysis , 4, 3 , A lipase was immobilized on transparent agarose microspheres and genetically engineered to specifically anchor photochromic molecules into its catalytic site. Several combinations of azobenzene and spiropyran groups were conjugated to cysteines introduced at different positions near the active center.

Light modulated the catalytic properties of the resulting solid bioconjugates, and such modulation depended on both the nature of the photochromic compound and the anchoring position. Covalent anchoring of azobenzene derivatives to the residue of the lipase 2 from Bacillus thermocathenolatus triggered lipase preference for the S isomer under UV light, whereas visible light promoted preference for the R isomer.

Molecular dynamics simulations indicate that conjugating photochromic compounds into the catalytic cavity allows manipulating the steric hindrance and binding energy of the substrates, leading to an enantioselective molecular fit in certain cases.

Using this approach, we report for the first time the control of enzyme properties using light in the solid phase. Movellan, J. Amphiphilic dendritic derivatives as nanocarriers for the targeted delivery of antimalarial drugs Biomaterials 35, 27 , It can be foreseen that in a future scenario of malaria eradication, a varied armamentarium will be required, including strategies for the targeted administration of antimalarial compounds. The development of nanovectors capable of encapsulating drugs and of delivering them to Plasmodium-infected cells with high specificity and efficacy and at an affordable cost is of particular interest.

Four different dendritic derivatives have been tested for their capacity to encapsulate the antimalarial drugs chloroquine CQ and primaquine PQ , their specific targeting to Plasmodium-infected red blood cells pRBCs , and their antimalarial activity in vitro against the human pathogen Plasmodium falciparum and in vivo against the rodent malaria species Plasmodium yoelii.

The results obtained have allowed the identification of two dendritic derivatives exhibiting specific targeting to pRBCs vs. This work on the application of dendritic derivatives to antimalarial targeted drug delivery opens the way for the use of this new type of chemicals in future malaria eradication programs. Keywords: Antimalarial targeted drug delivery , Dendrimers , Malaria , Nanomedicine , Plasmodium , Polymeric nanoparticles.

Neurogenesis and vascularization of the damaged brain using a lactate-releasing biomimetic scaffold Biomaterials 35, 17 , Regenerative medicine strategies to promote recovery following traumatic brain injuries are currently focused on the use of biomaterials as delivery systems for cells or bioactive molecules. The topology of PLA nanofibers supports neuronal migration while l-lactate released during PLA degradation acts as an alternative fuel for neurons and is required for progenitor maintenance.

Radial scaffolds implanted into cavities made in the postnatal mouse brain fostered complete implant vascularization, sustained neurogenesis, and allowed the long-term survival and integration of the newly generated neurons. Our results suggest that the endogenous central nervous system is capable of regeneration through the invivo dedifferentiation induced by biophysical and metabolic cues, with no need for exogenous cells, growth factors, or genetic manipulation.

Conductance switching in single wired redox proteins Small 10, 13 , Switching events in the current flowing through individual redox proteins, azurin spontaneously wired between two electrodes, are studied using an electrochemical scanning tunneling microscope ECSTM.

These switching events in the current—time trace are characterized using conductance histograms, and reflect the intrinsic redox thermodynamic dispersion in the azurin population. This conductance switching may pose limitations to miniaturizing redox protein-based devices.

Use of poly amidoamine drug conjugates for the delivery of antimalarials to Plasmodium Journal of Controlled Release , 1 , Current malaria therapeutics demands strategies able to selectively deliver drugs to Plasmodium-infected red blood cells pRBCs in order to limit the appearance of parasite resistance. AGMA1 has antimalarial activity per se as shown by its inhibition of the in vitrogrowth of Plasmodium falciparum, with an IC50 of Fluorescence-assisted cell sorting data and confocal fluorescence microscopy and transmission electron microscopy images indicate that both polymers exhibit preferential binding to and internalization into pRBCs versus RBCs, and subcellular targeting to the parasite itself in widely diverging species such as P.

AGMA1 and ISA23 polymers with hydrodynamic radii around 7 nm show a high loading capacity for the antimalarial drugs primaquine and chloroquine, with the final conjugate containing from Intraperitoneal administration of 0. These polymers combining into a single chemical structure drug carrying capacity, low unspecific toxicity, high biodegradability and selective internalization into pRBCs, but not in healthy erythrocytes for human and rodent malarias, may be regarded as promising candidates deserving to enter the antimalarial therapeutic arena.

In the current work, we present a new self-organizing anodization approach of metallic Sn layers to obtain vertically aligned tin oxide nanochannel structures. For this, we use a sulphide-containing electrolyte and a set of optimized anodizing parameters.

The resulting high aspect ratio nanochannel morphologies can be converted into crystalline SnO2 by high temperature annealing and show highly promising H2 sensing properties. This excellent gas-sensing performance is ascribed to the advanced structure, characterized by a crack-free, straight and top-open nanochannel geometry. Force measurements on natural membrane nanovesicles reveal a composition-independent, high Young's modulus Nanoscale 6, 4 , Mechanical properties of nano-sized vesicles made up of natural membranes are crucial to the development of stable, biocompatible nanocontainers with enhanced functional, recognition and sensing capabilities.

Surprisingly enough, the results are approximately similar for plasma and inner membrane nanovesicles, in spite of their different lipid compositions, especially on what concerns the ergosterol content. These results point towards an important structural role of membrane proteins in the mechanical response of natural membrane vesicles and open the perspective to their potential use as robust nanocontainers for bioapplications. Lagunas, A. Large-scale dendrimer-based uneven nanopatterns for the study of local arginine-glycine-aspartic acid RGD density effects on cell adhesion Nano Research , 7, 3 , Cell adhesion processes are governed by the nanoscale arrangement of the extracellular matrix ECM , being more affected by local rather than global concentrations of cell adhesive ligands.

In many cell-based studies, grafting of dendrimers on surfaces has shown the benefits of the local increase in concentration provided by the dendritic configuration, although the lack of any reported surface characterization has limited any direct correlation between dendrimer disposition and cell response. In order to establish a proper correlation, some control over dendrimer surface deposition is desirable.

Here, dendrimer nanopatterning has been employed to address arginine-glycine-aspartic acid RGD density effects on cell adhesion. Nanopatterned surfaces were fully characterized by atomic force microscopy AFM , scanning tunneling microscopy STM and X-ray photoelectron spectroscopy XPS , showing that tunable distributions of cell adhesive ligands on the surface are obtained as a function of the initial dendrimer bulk concentration.

Cell experiments showed a clear correlation with dendrimer surface layout: Substrates presenting regions of high local ligand density resulted in a higher percentage of adhered cells and a higher degree of maturation of focal adhesions FAs.

Therefore, dendrimer nanopatterning is presented as a suitable and controlled approach to address the effect of local ligand density on cell response. Moreover, due to the easy modification of dendrimer peripheral groups, dendrimer nanopatterning can be further extended to other ECM ligands having density effects on cells.

Keywords: Arginine-glycine-aspartic acid , Atomic force microscopy , Cell adhesion , Dendrimer , Focal adhesions , Scanning tunneling microscopy. In bone regeneration, silicon-based calcium phosphate glasses Bioglasses have been widely used since the s. In this work, we propose a new generation of hybrid organically modified glasses, ormoglasses, that enable the levels of silicon to be reduced, therefore speeding up the degradation process.

These mats offered a good platform to evaluate different calcium release rates as osteogenic promoters in an in vivo subcutaneous environment. They also showed a greater ability to form blood vessels. These results suggest that Si-based ormoglasses can be considered an efficient tool for calcium release modulation, which could play a key role in the angiogenic promoting process.

After structural, topographical, electrochemical, and thermal characterization, properties typically related with biomedical applications have been investigated: swelling, resistance to both hydrolytic and enzymatic degradation, biocompatibility, and adsorption of type I collagen, which is an extra cellular matrix protein that binds fibronectin favoring cell adhesion processes. Moreover, the degradation of the blends is considerably promoted by the presence of enzymes in the hydrolytic medium, TPU:P3TMA blends behaving as biodegradable materials.

Type I collagen adsorption largely depends on the substrate employed to support the nanomembrane, whereas it is practically independent of the chemical nature of the polymeric material used to fabricate the nanomembrane. However, detailed microscopy study of the morphology and topography of adsorbed collagen evidence the formation of different organizations, which range from fibrils to pseudoregular honeycomb networks depending on the composition of the nanomembrane that is in contact with the protein.

Keywords: Bioactive platform , Biodegradable blend , Collaged adsorption , Scaffolds , Tissue engineering , Ultrathin films. Navarro, S. Generation of iPSCs from genetically corrected Brca2 hypomorphic cells: Implications in cell reprogramming and stem cell therapy Stem Cells , 32, 2 , Our results are consistent with previous studies proposing that HDR is critical for cell reprogramming and demonstrate that reprogramming defects characteristic of Brca2 mutant cells can be efficiently overcome by gene complementation.

Keywords: Bone marrow aplasia , Cellular therapy , Fanconi anemia , Gene therapy , Hematopoietic stem cells , Induced pluripotent stem cells. Tahirbegi, I. In vivo ischemia monitoring array for endoscopic surgery Biosensors and Bioelectronics 61, An array with all-solid-state, potentiometric, miniaturized sensors for pH and potassium was developed to be introduced into the stomach or other sectors of the digestive tract by means of flexible endoscopy. These sensors perform continuous and simultaneous measurement of extracellular pH and potassium.

This detection seeks to sense ischemia in the gastric mucosa inside the stomach, an event indicative of local microvascular perfusion and tissue oxygenation status. Our array is proposed as a medical tool to identify the occurrence of the ischemia after gastrointestinal or gastroesophageal anastomosis. The stability and feasibility of the miniaturized working and reference electrodes integrated in the array were studied under in vitro conditions, and the behavior of the potassium and pH ion-selective membranes were optimized to work under acidic gastric conditions with high concentrations of HCl.

The array was tested in vivo in pigs to measure the ischemia produced by clamping the blood flow into the stomach. Our results indicate that ischemic and reperfusion states can be sensed in vivo and that information on tissue damage can be collected by this sensor array. The device described here provides a miniaturized, inexpensive, and mass producible sensor array for detecting local ischemia caused by unfavorable anastomotic perfusion and will thus contribute to preventing anastomotic leakage and failure caused by tissue necrosis.

Paytubi, S. A novel role for antibiotic resistance plasmids in facilitating Salmonella adaptation to non-host environments Environmental Microbiology , 16, 4 , It is believed that the main role of plasmids that encode multiple antibiotic resistance is to confer their hosts the ability to survive in the presence of antimicrobial compounds. In the pathogenic bacterium Salmonella, plasmids of the incompatibility group HI1 account for a significant proportion of antibiotic resistance phenotypes.

In this work, we show that plasmid R27 has a strong impact on the global transcriptome of SalmonellaTyphimurium strain SL when cells grow at low temperature and enter the stationary phase. Down-regulated genes include pathogenicity islands, anaerobic respiration and metabolism determinants. Up-regulated genes include factors involved in the response to nutrient starvation, antimicrobial resistance, iron metabolism and the heat shock response.

Accordingly, cells harbouring R27 are more resistant to heat shock than plasmid-free cells. The use of a different IncHI1 plasmid, pHCM1, provided evidence that these plasmids facilitate adaptation of Salmonella to environmental conditions outside their host s. This is consistent with the fact that conjugative transfer of IncHI1 plasmids only occurs at low temperature. A significant number of the Rdependent alterations in gene expression could be correlated with expression of a plasmid-encoded orthologue of the global modulator H-NS, which is up-regulated when cells grow at low temperature.

Marques, J. Application of heparin as a dual agent with antimalarial and liposome targeting activities toward Plasmodium-infected red blood cells Nanomedicine: Nanotechnology, Biology, and Medicine 10, 8 , Heparin had been demonstrated to have antimalarial activity and specific binding affinity for Plasmodium-infected red blood cells pRBCs vs. Here we have explored if both properties could be joined into a drug delivery strategy where heparin would have a dual role as antimalarial and as a targeting element of drug-loaded nanoparticles.

Confocal fluorescence and transmission electron microscopy data show that after Heparin electrostatically adsorbed onto positively charged liposomes containing the cationic lipid 1,2-dioleoyltrimethylammonium-propane and loaded with the antimalarial drug primaquine was capable of increasing three-fold the activity of encapsulated drug in Plasmodium falciparum cultures.

At concentrations below those inducing anticoagulation of mouse blood in vivo, parasiticidal activity was found to be the additive result of the separate activities of free heparin as antimalarial and of liposome-bound heparin as targeting element for encapsulated primaquine. From the Clinical Editor: Malaria remains an enormous global public health concern. In this study, a novel functionalized heparin formulation used as drug delivery agent for primaquine was demonstrated to result in threefold increased drug activity in cell cultures, and in a murine model it was able to provide these benefits in concentrations below what would be required for anticoagulation.

Further studies are needed determine if this approach is applicable in the human disease as well. Keywords: Heparin , Liposomes , Malaria , Plasmodium , Targeted drug delivery , Heparin , Malaria , Plasmodium , Red blood cell , Targeted drug delivery , Liposomes , 1,2 dioleoyl 3 trimethylammoniopropane , fluorescein , heparin , liposome , nanoparticle , primaquine , adsorption , animal experiment , anticoagulation , antimalarial activity , Article , binding affinity , confocal microscopy , controlled study , drug targeting , encapsulation , erythrocyte , female , fluorescence microscopy , human , human cell , in vivo study , liposomal delivery , mouse , nonhuman , Plasmodium falciparum , transmission electron microscopy.

A functional microengineered model of the human splenon-on-a-chip Lab on a Chip 14, 10 , The spleen is a secondary lymphoid organ specialized in the filtration of senescent, damaged, or infected red blood cells. This unique filtering capacity is largely due to blood microcirculation through filtration beds of the splenic red pulp in an open-slow microcirculation compartment where the hematocrit increases, facilitating the recognition and destruction of unhealthy red blood cells by specialized macrophages.

Moreover, in sinusal spleens such as those of humans, blood in the open-slow microcirculation compartment has a unidirectional passage through interendothelial slits before reaching the venous system. This further physical constraint represents a second stringent test for erythrocytes ensuring elimination of those cells lacking deformability. With the aim of replicating the filtering function of the spleen on a chip, we have designed a novel microengineered device mimicking the hydrodynamic forces and the physical properties of the splenon, the minimal functional unit of the red pulp able to maintain filtering functions.

In this biomimetic platform, we have evaluated the mechanical and physiological responses of the splenon using human red blood cells and malaria-infected cells. This novel device should facilitate future functional studies of the spleen in relation to malaria and other hematological disorders. Van Heirstraeten, L. Integrated DNA and RNA extraction and purification on an automated microfluidic cassette from bacterial and viral pathogens causing community-acquired lower respiratory tract infections Lab on a Chip 14, 9 , In this paper, we describe the development of an automated sample preparation procedure for etiological agents of community-acquired lower respiratory tract infections CA-LRTI.

The consecutive assay steps, including sample re-suspension, pre-treatment, lysis, nucleic acid purification, and concentration, were integrated into a microfluidic lab-on-a-chip LOC cassette that is operated hands-free by a demonstrator setup, providing fluidic and valve actuation. The performance of the assay was evaluated on viral and Gram-positive and Gram-negative bacterial broth cultures previously sampled using a nasopharyngeal swab.

Sample preparation on the microfluidic cassette resulted in higher or similar concentrations of pure bacterial DNA or viral RNA compared to manual benchtop experiments. The miniaturization and integration of the complete sample preparation procedure, to extract purified nucleic acids from real samples of CA-LRTI pathogens to, and above, lab quality and efficiency, represent important steps towards its application in a point-of-care test POCT for rapid diagnosis of CA-LRTI.

Tejeda-Montes, E. Bioactive membranes for bone regeneration applications: Effect of physical and biomolecular signals on mesenchymal stem cell behavior Acta Biomaterialia 10, 1 , This study focuses on the in vitro characterization of bioactive elastin-like recombinamer ELR membranes for bone regeneration applications. The materials were then used to fabricate ELR membranes incorporating a variety of topographical micropatterns including channels, holes and posts. Primary rat mesenchymal stem cells rMSCs were cultured on the different membranes and the effects of biomolecular and physical signals on cell adhesion, morphology, proliferation, and differentiation were evaluated.

Effects on cell morphology were mostly dependent on surface topography, while cell proliferation and cell differentiation were largely dependent on the biomolecular signaling from the ELR membranes. In particular, osteogenic differentiation evaluated by staining for the osteoblastic marker osterix was significantly enhanced on cells cultured on HAP membranes.

Remarkably, cells growing on membranes containing the HAP sequence in non-osteogenic differentiation media exhibited significant up-regulation of the osteogenic marker as early as day 5, while those growing on fibronectin-coated glass in osteogenic differentiation media did not.

These results are part of our ongoing effort to develop an optimized molecularly designed periosteal graft. Vila, O. Bioluminescent and micro-computed tomography imaging of bone repair induced by fibrin-binding growth factors Acta Biomaterialia 10, 10 , In this work we have evaluated the capacity of bone morphogenetic protein-2 BMP-2 and fibrin-binding platelet-derived growth factor-BB PDGF-BB to support cell growth and induce bone regeneration using two different imaging technologies to improve the understanding of structural and organizational processes participating in tissue repair.

Human mesenchymal stem cells from adipose tissue hAMSCs expressing two luciferase genes, one under the control of the cytomegalovirus CMV promoter and the other under the control of a tissue-specific promoter osteocalcin or platelet endothelial cell adhesion molecule , were seeded in fibrin matrices containing BMP-2 and fibrin-binding PDGF-BB, and further implanted intramuscularly or in a mouse calvarial defect. Then, cell growth and bone regeneration were monitored by bioluminescence imaging BLI to analyze the evolution of target gene expression, indicative of cell differentiation towards the osteoblastic and endothelial lineages.

Although the inclusion of hAMSCs in the fibrin matrices made no significant difference in any of these parameters, there was a significant increment in the connectivity of the vascular network in defects treated with hAMSCs. Keywords: Angiogenesis , Bioluminescence imaging , Bone regeneration , Fibrin , Mesenchymal stem cell. Extracellular calcium and CaSR drive osteoinduction in mesenchymal stromal cells Acta Biomaterialia 10, 6 , — Bone is the main store of calcium and progenitor cells in the body.

During the resorption process, the local calcium concentration reaches mM, and the surrounding cells are exposed to these fluctuations in calcium. This stimulus is a signal that is detected through the calcium sensing receptor CaSR , which modulates chemotactic and proliferative G protein-dependent signaling pathways.

Andreu, I. Heterogeneous micromechanical properties of the extracellular matrix in healthy and infarcted hearts Acta Biomaterialia 10, 7 , Infarcted hearts are macroscopically stiffer than healthy organs. Nevertheless, although cell behavior is mediated by the physical features of the cell niche, the intrinsic micromechanical properties of healthy and infarcted heart extracellular matrix ECM remain poorly characterized. Using atomic force microscopy, we studied ECM micromechanics of different histological regions of the left ventricle wall of healthy and infarcted mice.

Healthy ventricular ECM revealed marked mechanical heterogeneity across histological regions of the ventricular wall with the effective Young's modulus ranging from Infarcted ECM showed a predominant collagen composition and was 3-fold stiffer than collagen-rich regions of the healthy myocardium. ECM of both healthy and infarcted hearts exhibited a solid-like viscoelastic behavior that conforms to two power-law rheology. Knowledge of intrinsic micromechanical properties of the ECM at the length scale at which cells sense their environment will provide further insight into the cell-scaffold interplay in healthy and infarcted hearts.

Keywords: Atomic force microscopy , Extracellular matrix , Heart scaffold , Nanoindentation , Viscoelasticity. Almeida, C. Recent studies have pointed towards a decisive role of inflammation in triggering tissue repair and regeneration, while at the same time it is accepted that an exacerbated inflammatory response may lead to rejection of an implant. Within this context, understanding and having the capacity to regulate the inflammatory response elicited by 3-D scaffolds aimed for tissue regeneration is crucial.

Cytokine secretion and cell morphology of human peripheral blood monocytes allowed to differentiate on the different matrices were analyzed. These findings strengthen the appropriateness of these 3-D platforms to study modulation of macrophage responses by specific parameters chemistry, topography, scaffold architecture.

Arcos, D. The relevance of biomaterials to the prevention and treatment of osteoporosis Acta Biomaterialia 10, 5 , Osteoporosis is a worldwide disease with a very high prevalence in humans older than The main clinical consequences are bone fractures, which often lead to patient disability or even death.

A number of commercial biomaterials are currently used to treat osteoporotic bone fractures, but most of these have not been specifically designed for that purpose. Many drug- or cell-loaded biomaterials have been proposed in research laboratories, but very few have received approval for commercial use. In order to analyze this scenario and propose alternatives to overcome it, the Spanish and European Network of Excellence for the Prevention and Treatment of Osteoporotic Fractures, "Ageing", was created.

This network integrates three communities, e. Keeping in mind the premise "living longer, living better", this commentary is the result of the thoughts, proposals and conclusions obtained after one year working in the framework of this network. Keywords: Ageing , Biomaterials , Bone , Osteoporosis. A novel sensing strategy for electrochemical aptamer-based sensors is presented. Nucleic acid aptamers are considered alternatives to antibodies.

However, some of their intrinsic properties, such as that they can undergo conformational changes during the binding of the target, can be used to design novel sensing strategies. Unlike other electrochemical "signal off" aptamer-based sensors, we report a strategy based on enzymatic inhibition. Our approach shows the feasibility to detect small molecules based on the aptamer conformational change induced by the target that leads to the inhibition of the enzyme used as a label.

Additionally, we prove the ability to regenerate the function of the aptasensor by simply applying a short potential pulse. As a proof-of-concept, the widely used aptamer for ochratoxin A OTA has been selected as a model. To investigate the mechanism induced by the OTA-binding, surface plasmon resonance assays were performed, which confirmed the conformational switch of the aptamer rather than the aptamer displacement by dehybridization from the DNA-modified sensor surface.

The electrochemical sensor can successfully detect OTA in wine at the limits stipulated by the European Commission. Given its sensitivity, rapid and easy detection, and regeneration, it can be envisaged as screening tool for OTA detection. Moreover, this sensing strategy has the potential to be applied to other aptamer-based biochemical assays for the detection of small molecules in the fields of food safety, environmental monitoring, and medical diagnostics.

Electronic, electric and electrochemical properties of bioactive nanomembranes made of polythiophene:thermoplastic polyurethane Polymer Chemistry 5, 4 , TPU:P3TMA nanomembranes were reported to be good substrates for applications related to tissue engineering, acting as a cellular matrix for cell adhesion and proliferation.

This behavior is in opposition to the observations in THF solution, which indicates that the band gap energy of P3TMA is clearly lower than that of the mixture, independently of the concentration. The current and conductivity values determined for the nanomembranes, which range from 0. This has been associated with the irregular distribution of the doped chains and the presence of insulating TPU chains.

Overall results indicate that TPU:P3TMA nanomembranes are potential candidates for the fabrication of bioactive substrates able to promote cell regeneration through electrical or electrochemical stimulation. Llorens, F. The cellular prion protein PrPC plays a key role in prion diseases when it converts to the pathogenic form scrapie prion protein. Increasing knowledge of its participation in prion infection contrasts with the elusive and controversial data regarding its physiological role probably related to its pleiotropy, cell-specific functions, and cellular-specific milieu.

Multiple approaches have been made to the increasing understanding of the molecular mechanisms and cellular functions modulated by PrPC at the transcriptomic and proteomic levels. These analyses support previous functional data and have yielded clues about new potential functions. However, experiments on animal models have shown moderate and varied results which are difficult to interpret.

Moreover, studies in cell cultures correlate little with in vivo counterparts. Yet, both animal and cell models have provided some insights on how to proceed in the future by using more refined methods and selected functional experiments. Seira, O. Gaining a basic understanding of the inhibitory molecules and the intracellular signaling involved in axon development and repulsion after neural lesions is of clear biomedical interest.

In recent years, numerous studies have described new molecules and intracellular mechanisms that impair axonal outgrowth after injury. Dalmases, M. Brain tissue hypoxia and oxidative stress induced by obstructive apneas is different in young and aged rats Sleep , 37, 7 , Study Objectives: To test the hypotheses that brain oxygen partial pressure PtO2 in response to obstructive apneas changes with age and that it might lead to different levels of cerebral tissue oxidative stress.

Design: Prospective controlled animal study. Setting: University laboratory. Participants: Sixty-four male Wistar rats: 32 young 3 mo old and 32 aged 18 mo. Protocol 2: Forty rats were subjected to obstructive apneas or sham procedure for 4 h. Measurements and Results: Protocol 1: Real-time PtO2 measurements were performed using a fast-response oxygen microelectrode. During successive apneas cerebral cortex PtO2 presented a different pattern in the two age groups; there was a fast increase in young rats, whereas it remained without significant changes between the beginning and the end of the protocol in the aged group.

Protocol 2: Brain oxidative stress assessed by lipid peroxidation increased after apneas in young rats 1. Conclusions: The results suggest that brain oxidative stress in aged rats is lower than in young rats in response to recurrent apneas, mimicking obstructive sleep apnea. This could be due to the different PtO2 response observed between age groups and the increased antioxidant expression in aged rats.

Keywords: Aging , Animal model , Obstructive apnea , Oxidative stress , Tissue oxygenation , antioxidant , glutathione disulfide , aged , animal experiment , animal model , animal tissue , apnea , arterial oxygen saturation , article , brain cortex , brain oxygen tension , brain tissue , controlled study , groups by age , hypoxia , lipid peroxidation , male , nonhuman , oxidative stress , pressure , priority journal , rat.

Estimation of the limit of detection using information theory measures Analytica Chimica Acta , Although such definitions are straightforward and valid for any kind of analytical system, proposed methodologies to estimate the LOD are usually simplified to signals with Gaussian noise. Based upon an analogy between an analytical system and a binary communication channel, in this paper we show that the amount of information that can be extracted from an analytical system depends on the probability of presenting the two different possible states.

We propose a new definition of LOD utilizing information theory tools that deals with noise of any kind and allows the introduction of prior knowledge easily. Unlike most traditional LOD estimation approaches, the proposed definition is based on the amount of information that the chemical instrumentation system provides on the chemical information source.

Photomodulation of G protein-coupled adenosine receptors by a novel light-switchable ligand Bioconjugate Chemistry , American Chemical Society 25, 10 , The adenosinergic system operates through G protein-coupled adenosine receptors, which have become promising therapeutic targets for a wide range of pathological conditions. However, the ubiquity of adenosine receptors and the eventual lack of selectivity of adenosine-based drugs have frequently diminished their therapeutic potential.

Accordingly, here we aimed to develop a new generation of light-switchable adenosine receptor ligands that change their intrinsic activity upon irradiation, thus allowing the spatiotemporal control of receptor functioning i. Therefore, we synthesized an orthosteric, photoisomerizable and non-selective adenosine receptor agonist, nucleoside derivative MRS containing an aryl diazo linkage on the N6 substituent, which in the dark relaxed isomer behaved as a full adenosine A3 receptor A3R and partial adenosine A2A receptor A2AR agonist.

Conversely, upon photoisomerization with blue light nm , it remained a full A3R agonist but became an A2AR antagonist. Interestingly, molecular modeling suggested that structural differences encountered within the third extracellular loop of each receptor could modulate the intrinsic, receptor subtype-dependent, activity.

Overall, the development of adenosine receptor ligands with photoswitchable activity expands the pharmacological toolbox in support of research and possibly opens new pharmacotherapeutic opportunities. Understanding how charges move through and between biomolecules is a fundamental question that constitutes the basis for many biological processes. On the other hand, it has potential applications in the design of sensors based on biomolecules and single molecule devices. In this review we introduce the study of the electron transfer ET process in biomolecules, providing an overview of the fundamental theory behind it and the different experimental approaches.

The ET in proteins is introduced by reviewing a complete electronic characterization of a redox protein azurin using electrochemical scanning tunnelling microscopy ECSTM. The ET process in DNA is overviewed and results from different experimental approaches are discussed. Finally, future directions in the study of the ET process in biomolecules are introduced as well as examples of possible technological applications. Keywords: Bioelectrochemistry , Biomolecular electronics , Charge transfer , Nanobiodevice , Single-molecule junction.

Melo, E. Effects of the decellularization method on the local stiffness of acellular lungs Tissue Engineering Part C: Methods , 20, 5 , Lung bioengineering, a novel approach to obtain organs potentially available for transplantation, is based on decellularizing donor lungs and seeding natural scaffolds with stem cells. Various physicochemical protocols have been used to decellularize lungs, and their performance has been evaluated in terms of efficient decellularization and matrix preservation.

No data are available, however, on the effect of different decellularization procedures on the local stiffness of the acellular lung. This information is important since stem cells directly sense the rigidity of the local site they are engrafting to during recellularization, and it has been shown that substrate stiffness modulates cell fate into different phenotypes.

The aim of this study was to assess the effects of the decellularization procedure on the inhomogeneous local stiffness of the acellular lung on five different sites: alveolar septa, alveolar junctions, pleura, and vessels' tunica intima and tunica adventitia. The local stiffness of the acellular lung matrix significantly depended on the site within the matrix p. Gibert, M. Bacterial conjugation promotes horizontal gene transfer and, consequently, the acquisition of new capabilities such as resistance to antimicrobial compounds and virulence related traits.

Conjugative plasmids belonging to the incompatibility group HI are associated with multidrug resistance in Gram-negative pathogens. IncHI plasmid conjugation is thermodependent and all transfer-related genes are encoded in six operons tra operons. Using R27, the prototype of IncHI1 plasmids, we reported that the plasmid-encoded factor HtdA represses four of the six tra operons.

Moreover, our results indicated that other R27 factors were required for appropriate expression of the tra genes. In this report, using R27 libraries and random mutagenesis assays, two genes - trhR and trhY- have been identified as essential for the transcriptional expression of four tra operons and, accordingly, for the R27 conjugation. Expression studies suggest that H-NS represses conjugation at high temperature by repressing trhR expression.

Remarkably, we show that this regulatory circuit is highly conserved among the IncHI plasmids. Levato, R. Biofabrication of tissue constructs by 3D bioprinting of cell-laden microcarriers Biofabrication 6, 3 , Bioprinting allows the fabrication of living constructs with custom-made architectures by spatially controlled deposition of multiple bioinks.

This is important for the generation of tissue, such as osteochondral tissue, which displays a zonal composition in the cartilage domain supported by the underlying subchondral bone. Challenges in fabricating functional grafts of clinically relevant size include the incorporation of cues to guide specific cell differentiation and the generation of sufficient cells, which is hard to obtain with conventional cell culture techniques. A novel strategy to address these demands is to combine bioprinting with microcarrier technology.

This technology allows for the extensive expansion of cells, while they form multi-cellular aggregates, and their phenotype can be controlled. In this work, living constructs were fabricated via bioprinting of cell-laden microcarriers. Mesenchymal stromal cell MSC -laden polylactic acid microcarriers, obtained via static culture or spinner flask expansion, were encapsulated in gelatin methacrylamide-gellan gum bioinks, and the printability of the composite material was studied.

This bioprinting approach allowed for the fabrication of constructs with high cell concentration and viability. Microcarrier encapsulation improved the compressive modulus of the hydrogel constructs, facilitated cell adhesion, and supported osteogenic differentiation and bone matrix deposition by MSCs. Bilayered osteochondral models were fabricated using microcarrier-laden bioink for the bone compartment. These findings underscore the potential of this new microcarrier-based biofabrication approach for bone and osteochondral constructs.

Antimalarial drug delivery to the mosquito: an option worth exploring? Future Microbiology , 9, 5 , The role of endplate poromechanical properties on the nutrient availability in the intervertebral disc Osteoarthritis and Cartilage , 22, 7 , Objective To investigate the relevance of the human vertebral endplate poromechanics on the fluid and metabolic transport from and to the intervertebral disc IVD based on educated estimations of the poromechanical parameter values of the bony endplate BEP.

Permeability values were calculated by using the micro-models, through the simulation of permeation via computational fluid dynamics. These educated ranges of porosity and permeability values were used as inputs for mechano-transport simulations to assess their effect on both the distributions of metabolites within an IVD model and the poromechanical calculations within the cartilaginous part of the endplate i.

Universal patterns between bone volume fraction and permeability arose from these results and from other experimental data in the literature. These variations in BEP permeability and porosity had negligible effects on the distributions of metabolites within the disc. In the CEP, the variability of the poromechanical properties of the BEP did not affect the predicted consolidation but induced higher fluid velocities.

Conclusions The present paper provides the first sets of thoroughly identified BEP parameter values that can be further used in patient-specific poromechanical studies. Representing BEP structural changes through variations in poromechanical properties did not affect the diffusion of metabolites. However, attention might be paid to alterations in fluid velocities and cell mechano-sensing within the CEP.

Salvagni, E. A bioactive elastin-like recombinamer reduces unspecific protein adsorption and enhances cell response on titanium surfaces Colloids and Surfaces B: Biointerfaces , We present the immobilization on synthetic substrates of elastin-like recombinamers ELR that combine a bioactive motif for cell adhesion with protein antifouling properties. Physical adsorption of the recombinamers and covalent-grafting through organosilane chemistry were investigated.

The biochemically-modified surfaces were thoroughly characterized and tested for protein absorption in serum by fluorescence-labelling, XPS, Ellipsometry, and OWLS. The ELR were successfully grafted and stable, even upon mechanical stresses; being the covalent bonding favourable over physical adsorption. Non-specific protein adsorption may mask the introduced bioactive motifs; therefore, the bioactivated surfaces should display serum-protein antifouling properties.

Finally, improved hMSCs response was assessed on the bioactivated substrates. In summary, the coatings simultaneously displayed anti-fouling and bioactive properties. These studies investigated key factors to enhance tissue material interactions fundamental for the design of bioactive devices and future biomedical applications.

Manca, M. Molecular arrangements and interconnected bilayer formation induced by alcohol or polyalcohol in phospholipid vesicles Colloids and Surfaces B: Biointerfaces , A self-assembled hybrid phospholipid vesicular system containing various penetration enhancers - ethanol, Transcutol and propylenglycol - was prepared and characterized. The effects of the different alcohol or polyalcohols structure and their concentration on the features of the assembled vesicles were evaluated using a combination of different techniques, including cryo-transmission electron microscopy, laser light scattering, differential scanning calorimetry, small- and wide-angle X-ray scattering and rheological analysis.

These techniques allow explaining the structural rearrangements of the bilayer assembly due to the alcohol or polyalcohol addition. Rheological studies confirmed the importance of alcohol or polyalcohol in the structuring dispersions probably due to a partial tilting of phosphatidylcholine acyl chains forming interdigitated and interconnected bilayer vesicles. Dols-Perez, A. Structural and nanomechanical effects of cholesterol in binary and ternary spin-coated single lipid bilayers in dry conditions Colloids and Surfaces B: Biointerfaces , We investigate the effects of Cholesterol Chol in the structural and nanomechanical properties of binary and ternary spin-coated single lipid bilayers made of Dioleoylphosphatidylcholine DOPC and Sphingomyelin SM in dry conditions.

The mechanical properties, instead, appear practically insensitive to the Chol content. In both binary mixtures phase separation is not observed. The domains show a thickness and mechanical response clearly distinct from the surrounding phase and dependent on the relative Chol content. We highlight that many of the effects of Chol reported here for the dry multicomponent single lipid bilayers resemble closely those observed in hydrated bilayers, thus offering an additional insight into their properties.

He who plays with life never amounts to anything. However, discipline should not degenerate into drill. Continuous drill has a humiliating effect and cripples a man's powers. To bear with fools in kindliness brings good fortune. To know how to take women Brings good fortune. The son is capable of taking charge of the household. These lines picture a man who has no external power, but who has enough strength of mind to bear his burden of responsibility. He has the inner superiority and that enable him to tolerate with kindliness the shortcomings of human folly.

The same attitude is owed to women as the weaker sex. One must understand them and give them recognition in a spirit of chivalrous consideration. Only this combination of inner strength with outer reserve enables one to take on the responsibility of directing a larger social body with real success. Take not a maiden who. When she sees a man of bronze, Loses possession of herself. Nothing furthers. A weak, inexperienced man, struggling to rise, easily loses his own individuality when he slavishly imitates a strong personality of higher station.

He is like a girl throwing herself away when she meets a strong man. Such a servile approach should not be encouraged, because it is bad both for the youth and the teacher. A girl owes it to her dignity to wait until she is wooed.

In both cases it is undignified to offer oneself, and no good comes of accepting such an offer. For youthful folly it is the most hopeless thing to entangle itself in empty imaginings. The more obstinately it clings to such unreal fantasies, the more certainly will humiliation overtake it.

Often the teacher, when confronted with such entangled folly, has no other course but to leave the fool to himself for a time, not sparing him the humiliation that results. This is frequently the only means of rescue. Six in the fifth place means:. An inexperienced person who seeks instruction in a childlike and unassuming way is on the right path, for the man devoid of arrogance who subordinated himself to his teacher will certainly be helped.

In punishing folly It does not further one To commit transgressions. The only thing that furthers Is to prevent transgressions. Sometimes an incorrigible fool must be punished. He who will not heed will be made to feel. This punishment is quite different from a preliminary shaking up. But the penalty should not be imposed in anger; it must be restricted to an objective guarding against unjustified excesses.

Punishment is never an end in itself but serves merely to restore order. This applies not only in regard to education but also in regard to the measures taken by a government against a populace guilty of transgressions. Governmental interference should always be merely preventive and should have as its sole aim the establishment of public security and peace. All beings have need of nourishment from above. But the gift of food comes in its own time, and for this one must wait.

This hexagram shows the clouds in the heavens, giving rain to refresh all that grows and to provide mankind with food and drink. The rain will come in its own time. We cannot make it come; we have to wait for it. The idea of waiting is further suggested by the attributes of the two trigrams--strength within, danger in from.

Strength in the face of danger does not plunge ahead but bides its time, whereas weakness in the face of danger grows agitated and has not the patience to wait. If you are sincere, You have light and success.

Perseverance brings good fortune. It furthers one to cross the great water. Waiting is not mere empty hoping. It has the inner certainty of reaching the goal. Such certainty alone gives that light which leads to success.

This leads to the perseverance that brings good fortune and bestows power to cross the great water. One is faced with a danger that has to be overcome. Weakness and impatience can do nothing. Only a strong man can stand up to his fate, for his inner security enables him to endure to the end.

This strength shows itself in uncompromising truthfulness [with himself]. It is only when we have the courage to face things exactly as they are, without any sort of self-deception or illusion, that a light will develop out of events, by which the path to success may be recognized. This recognition must be followed by resolute and persevering action.

For only the man who goes to meet his fate resolutely is equipped to deal with it adequately. Then he will be able to cross the great water--that is to say, he will be capable of making the necessary decision and of surmounting the danger. Thus the superior man eats and drinks, Is joyous and of good cheer. When clouds rise in the sky, it is a sign that it will rain. There is nothing to do but to wait until after the rain falls. It is the same in life when destiny is at work.

We should not worry and seek to shape the future by interfering in things before the time is ripe. We should quietly fortify the body with food and drink and the mind with gladness and good cheer. Fate comes when it will, and thus we are ready.

Waiting in the meadow. IT furthers one to abide in what endures. The danger is not yet close. One is still waiting on the open plain. Conditions are still simple, yet there is a feeling of something impending. One must continue to lead a regular life as long as possible. Only in this way does one guard against a premature waste of strength, keep free of blame and error that would become a source of weakness later on.

Waiting on the sand. There is some gossip. The end brings good fortune. The danger gradually comes closer. Sand is near the bank of the river, and the water means danger. Disagreements crop up. General unrest can easily develop in such times, and we lay the blame on one another. He who stays calm will succeed in making things go well in the end.

Slander will be silenced if we do not gratify it with injured retorts. Mud is no place for waiting, since it is already being washed by the water of the stream. Instead of having gathered strength to cross the stream at one try, one has made a premature start that has got him no farther than the muddy bank. Such an unfavorable position invites enemies from without, who naturally take advantage of it.

Caution and a sense of the seriousness of the situation are all that can keep one from injury. The situation is extremely dangerous. IT is of utmost gravity now--a matter of life and death. Bloodshed seems imminent. There is no going forward or backward; we are cut off as if in a pit. Now we must simply stand fast and let fate take its course. This composure, which keeps us from aggravating the trouble by anything we might do, is the only way of getting out of the dangerous pit.

Even in the midst of danger there come intervals of peace when things go relatively well. If we possess enough inner strength, we shall take advantage of these intervals to fortify ourselves for renewed struggle. We must know how to enjoy the moment without being deflected from the goal, for perseverance is needed to remain victorious.

This is true in public life as well; it is not possible to achieve everything all at once. The height of wisdom is to allow people enough recreation to quicken pleasure in their work until the task is completed.

Herein lies the secret of the whole hexagram. One falls into the pit. Three uninvited guests arrive. Honor them, and in the end there will be good fortune. The waiting is over; the danger can no longer be averted. One falls into the pit and must yield to the inevitable. Everything seems to have been in vain. But precisely in this extremity things take an unforeseen turn. Without a move on one's own part, there is outside intervention. At first one cannot be sure of its meaning: is it rescue or is it destruction?

A person in this situation must keep his mind alert and not withdraw into himself with a sulky gesture of refusal, but must greet the new turn with respect. Thus he ultimately escapes the danger, and all goes well. Even happy turns of fortune often come in a form that at first seems strange to us. The upper trigram, whose image is heaven, has an upward movement; the lower trigram, water, in accordance with its nature tends downward.

Thus the two halves move away from each other, giving rise to the idea of conflict. The attribute of the Creative is strength, that of the Abysmal is danger, guile. Where cunning has force before it, there is conflict. A third indication of conflict, in terms of character, is presented by the combination of deep cunning within and fixed determination outwardly.

A person of this character will certainly be quarrelsome. You are sincere And are being obstructed. A cautious halt halfway brings good fortune. Going through to the end brings misfortune. It furthers one to see the great man. It does not further one to cross the great water. Conflict develops when one feels himself to be in the right and runs into opposition.

If one is not convinced of being in the right, opposition leads to craftiness or high-handed encroachment but not to open conflict. If a man is entangled in a conflict, his only salvation lies in being so clear-headed and inwardly strong that he is always ready to come to terms by meeting the opponent halfway. To carry one the conflict to the bitter end has evil effects even when one is the right, because the enmity is then perpetuated.

It is important to see the great man, that is, an impartial man whose authority is great enough to terminate the conflict amicably or assure a just decision. In times of strife, crossing the great water is to be avoided, that is, dangerous enterprises are not to be begun, because in order to be successful they require concerted unity of focus.

Conflict within weakens the power to conquer danger without. Thus in all his transactions the superior man Carefully considers the beginning. The image indicates that the causes of conflict are latent in the opposing tendencies of the two trig rams. Once these opposing tendencies appear, conflict is inevitable. To avoid it, therefore, everything must be taken carefully into consideration in the very beginning.

If rights and duties are exactly defined, or if, in a group, the spiritual trends of the individuals harmonize, the cause of conflict is removed in advance. If one does not perpetuate the affair, There is a little gossip. In the end, good fortune comes.

While a conflict is in the incipient stage, the best thing To do is to drop the issue. Especially when the adversary is stronger, it is not advisable to risk pushing the conflict to a decision. It may come to a slight dispute, but in the end all goes well. One cannot engage in conflict; One returns home, gives way. The people of his town, Three hundred households, Remain free of guilt. In a struggle with an enemy of superior strength, retreat is no disgrace. Timely withdrawal prevents bad consequences.

If, out of a false sense of honor, a man allowed himself to be tempted into an unequal conflict, he would be drawing down disaster upon himself. In such a case a wise and conciliatory attitude benefits the whole community, which will then not be drawn into the conflict. To nourish oneself on ancient virtue induces perseverance. If by chance you are in the service of a king, Seek not works. This is a warning of the danger that goes with an expansive disposition. Only that which has been honestly acquired through merit remains a permanent possession.

It can happen that such a possession may be contested, but since it is really one's own, one cannot be robbed of it. Whatever a man possesses through the strength of his own nature cannot be lost. If one enters the service of a superior, one can avoid conflict only by not seeking works for the sake of prestige. It is enough if the work is done: let the honor go to the other. One cannot engage in conflict. One turns back and submits to fate, Changes one's attitude, And finds peace in perseverance.

Good fortune. This refers to a person whose inner attitude at first lacks peace. He does not feel content with his situation and would like to improve it through conflict. In contrast tot the situation of the nine in the second place, he is dealing with a weaker opponent and might therefore succeed. But he cannot carry on the fight, because, since right is not on his side, he cannot justify the conflict to his conscience.

Therefore he turns back and accepts his fate. He changes his mind and finds lasting peace in being at one with eternal law. This brings good fortune. This refers to an arbiter in a conflict who is powerful and just, and strong enough to lend weight to the right side. A dispute can be turned over to him with confidence. If one is in the right, one attains great good fortune. Even if by chance a leather belt is bestowed on one,' By the end of a morning It will have been snatched away three times.

Here we have someone who has carried a conflict to the bitter end and has triumphed. He is granted a decoration, but his happiness does not last. He is attacked again and again, and the result is conflict without end. This hexagram is made up of the trigrams K'an, water, and K'un, earth, and thus it symbolizes the ground water stored up in the earth. In the same way military strength is stored up in the mass of the people--invisible in times of peace but always ready for use as a source of power.

The attributes of the two trig rams are danger inside and obedience must prevail outside. Of the individual lines, the one that controls the hexagram is the strong nine in the second place, to which the other lines, all yielding, are subordinate.

This line indicates a commander, because it stands in the middle of one of the two trigrams. But since it is in the lower rather than the upper trigram, it represents not the ruler but the efficient general, who maintains obedience in the army by his authority. The army needs perseverance And a strong man. Good fortune without blame. An army is a mass that needs organization in order to become a fighting force. Without strict discipline nothing can be accomplished, but this discipline must not be achieved by force.

It requires a strong man who captures the hearts of the people and awakens their enthusiasm. In order that he may develop his abilities he needs the complete confidence of his ruler, who must entrust him with full responsibility as long as the war lasts. But war is always a dangerous thing and brings with it destruction and devastation. Therefore it should not be resorted to rashly but, like a poisonous drug, should be used as a last recourse.

Ground water is invisibly present within the earth. In the same way the military power of a people is invisibly present in the masses. When danger threatens, every peasant becomes present in the masses. When danger threatens, every peasant becomes a soldier; when the war ends, he goes back to his plow.

He who is generous toward the people wins their love, and a people living under a mild rule becomes strong and powerful. Only a people economically strong can be important in military power. Such power must therefore be cultivated by improving the economic condition of the people and by humane government. Only when there is this invisible bond between government and people, so that the people are sheltered by their government as ground water is sheltered by the earth, is it possible to wage a victorious war.

An army must set forth in proper order. If the order is not good, misfortune threatens. At the beginning of a military enterprise, order is imperative. A just and valid cause must exist, and the obedience and coordination of the troops must be well organized, otherwise the result is inevitably failure.

In the midst of the army. The king bestows a triple decoration. The leader should be in the midst of his army, in touch with it, sharing good and bad with the masses he leads. This alone makes him equal to the heavy demands made upon him. He needs also the recognition of the ruler. The decorations he receives are justified, because there is no question of personal preferment here: the whole army, whose center he is, is honored in his person.

Here we have a choice of two explanations. One points to defeat because someone other than the chosen leader interferes with the command; the other is similar in its general meaning, but the expression, "carries corpses in the wagon," is interpreted differently.

At burials and at sacrifices to the dead it was customary in China for the deceased to whom the sacrifice was made to be represented by a boy of the family, who sat in the dead man's place and was honored as his representative. On the basis of this custom the text is interpreted as meaning that a "corpse boy" is sitting in the wagon, or, in other words, that authority is not being exercised by the proper leaders but has been usurped by others. Perhaps the whole difficulty clears up if it is inferred that there has been an error in copying.

The character fan, meaning "all," may have been misread as shih, which means "corpse. In the face of a superior enemy, with whom it would be hopeless to engage in battle, an orderly retreat is the only correct procedure, because it will save the army from defeat and disintegration. It is by no means a sign of courage or strength to insist upon engaging in a hopeless struggle regardless of circumstances. There is game in the field. It furthers one to catch it.

Without blame. Let the eldest lead the army. The younger transports corpses; Then perseverance brings misfortune. Game is in the field--it has left its usual haunts in the forest and is devastating the fields. This points to an enemy invasion. Energetic combat and punishment are here thoroughly justified, but they must not degenerate into a wild melee in which everyone fends for himself. Despite the greatest degree of perseverance and bravery, this would lead to misfortune.

The army must be directed by an experienced leader. It is a matter of waging war, not of permitting the mob to slaughter all who fall into their hands; if they do, defeat will be the result, and despite all perseverance there is danger of misfortune. The great prince issues commands, Founds states, vests families with fiefs. Inferior people should not be employed. The war has ended successfully, victory is won, and the king divided estates and fiefs among his faithful vassals.

But it is important that inferior people should not come into power. If they have helped, let them be paid off with money, but they should not be awarded lands or the privileges of rulers, lest power be abused. The waters on the surface of the earth flow together wherever they can, as for example in the ocean, where all the rivers come together. Symbolically this connotes holding together and the laws that regulate it. The same idea is suggested by the fact that all the lines of the hexagram except the fifth, the place of the ruler, are yielding.

The yielding lines hold together because they are influenced by a man of strong will in the leading position, a man who is their center of union. Moreover, this strong and guiding personality in turn holds together with the others, finding in them the complement of his own nature.

Inquire of the oracle once again Whether you possess sublimity, constancy, and perseverance; Then there is no blame. Those who are uncertain gradually join. Whoever come too late Meets with misfortune.

What is required is that we unite with others, in order that all may complement and aid one another through holding together. But such holding together calls for a central figure around whom other persons may unite. To become a center of influence holding people together is a grave matter and fraught with great responsibility.

It requires greatness of spirit, consistency, and strength. Therefore let him who wishes to gather others about him ask himself whether he is equal to the undertaking, for anyone attempting the task without a real calling for it only makes confusion worse than if no union at all had taken place.

But when there is a real rallying point, those who at first are hesitant or uncertain gradually come in of their own accord. Late-comers must suffer the consequences, for in holding together the question of the right time is also important. Relationships are formed and firmly established according to definite inner laws. Common experiences strengthen these ties, and he who comes too late to share in these basic experiences must suffer for it if, as a straggler, he finds the door locked.

If a man has recognized the necessity for union and does not feel strong enough to function as the center, it is his duty to become a member of some other organic fellowship. Thus the kings of antiquity Bestowed the different states as fiefs And cultivated friendly relations With the feudal lords. Water fills up all the empty places on the earth and clings fast to it. The social organization of ancient China was based on this principle of the holding together of dependents and rulers.

Water flows to unite with water, because all parts of it are subject to the same laws. So too should human society hold together through a community of interests that allows each individual to feel himself a member of a whole. The central power of a social organization must see to it that every member finds that his true interest lies in holding together with it, as was the case in the paternal relationship between king and vassals in ancient China.

Hold to him in truth and loyalty; This is without blame. Truth, like a full earthen bowl" Thus in the end Good fortune comes from without. Fundamental sincerity is the only proper basis for forming relationships. This attitude, symbolized by a full earthen bowl, in which the content is everything and the empty form nothing, shows itself not in clever words but through the strength of what lies within the speaker. This strength is so great that it has power to attract good fortune to itself from without.

If a person responds perseveringly and in the right way to the behests from above that summon him to action, his relations with others are intrinsic and he does not lose himself. But if a man seeks association with others as if he were an obsequious office hunter, he throws himself away.

He does not follow the path of the superior man, who never loses his dignity. We are often among people who do not belong to our own sphere. In that case we must beware of being drawn into false intimacy through force of habit. Needless to say, this would have evil consequences. Maintaining sociability without intimacy is the only right attitude toward people, because otherwise we should not be free to enter into relationship with people of our own kind later on.

Here the relations with a man who is the center of union are well established. Then we may, and indeed we should, show our attachment openly. But we must remain constant and not allow ourselves to be led astray. Manifestation of holding together. In the hunt the king uses beaters on three sides only And forgoes game that runs off in front. The citizens need no warning. In the royal hunts of ancient China it was customary to drive up the game from three sides, but on the fourth the animals had a chance to run off.

If they failed to do this they had to pass through a gate behind which the king stood ready to shoot. Only animals that entered here were shot; those that ran off in front were permitted to escape. This custom accorded with a kingly attitude; the royal hunter did not wish to turn the chase into a slaughter, but held that the kill should consist only of those animals which had so to speak voluntarily exposed themselves.

There is depicted here a ruler, or influential man, to whom people are attracted. Those who come to him he accepts, those who do not come are allowed to go their own way. He invited none, flatters none--all come of their own free will. In this way there develops a voluntary dependence among those who hold him. They do not have to be constantly on their guard but may express their opinions openly. Police measures are not necessary, and they cleave to their ruler of their own volition.

The same principle of freedom is valid for life in general. We should not woo favor from people. If a man cultivates within himself the purity and the strength that are necessary for one who is the center of a fellowship, those who are meant for him come of their own accord. The head is the beginning. If the beginning is not right, there is no hope of a right ending. If we have missed the right moment for union and go on hesitating to give complete and full devotion, we shall regret the error when it is too late.

This hexagram means the force of the small--the power of the shadowy--that restrains, tames, impedes. A weak line in the fourth place, that of the minister, holds the five strong lines in check. In the Image it is the wind blowing across the sky. The wind restrains the clouds, the rising breath of the Creative, and makes them grow dense, but as yet is not strong enough to turn them to rain. The hexagram presents a configuration of circumstances in which a strong element is temporarily held in leash by a weak element.

It is only through gentleness that this can have a successful outcome. Dense clouds, no rain from our western region. The moment for action on a large scale had not yet arrived. Hence the image of many clouds, promising moisture and blessing to the land, although as yet no rain falls. The situation is not unfavorable; there is a prospect of ultimate success, but there are still obstacles in the way, and we can merely take preparatory measures.

Only through the small means of friendly persuasion can we exert any influence. The time has not yet come for sweeping measures. However, we may be able, to a limited extent, to act as a restraining and subduing influence.

To carry out our purpose we need firm determination within and gentleness and adaptability in external relations. Thus the superior man Refines the outward aspect of his nature. The wind can indeed drive the clouds together in the sky; yet, being nothing but air, without solid body, it does not produce great or lasting effects.

So also an individual, in times when he can produce no great effect in the outer world, can do nothing except refine the expression of his nature in small ways. It lies in the nature of a strong man to press forward. In so doing he encounters obstructions. Therefore he returns to the way suited to his situation, where he is free to advance or to retreat. In the nature of things this will bring good fortune, for it is wise and reasonable not to try to obtain anything by force.

One would like to press forward, but before going farther one sees from the example of others like oneself that this way is blocked. In such a case, if the effort to push forward is not in harmony with the time, a reasonable and resolute man will not expose himself to a personal rebuff, but will retreat with others of like mind. This brings good fortune, because he does not needlessly jeopardize himself.

Here an attempt is made to press forward forcibly, in the consciousness that the obstructing power is slight. But since, under the circumstances, power actually lies with the weak, this sudden offensive is doomed to failure. External conditions hinder the advance, just as loss of the wheel spokes stops the progress of a wagon.

We do not yet heed this hint form fate, hence there are annoying arguments like those of a married couple. Naturally this is not a favorable state of thing, for though the situation may enable the weaker side to hold its ground, the difficulties are too numerous to permit of a happy result.

In consequence even the strong man cannot so use his power as to exert the right influence on those around him. He experiences a rebuff where he expected an easy victory, and he thus compromises his dignity. If one is in the difficult and responsible position of counselor to a powerful man, on should restrain him in such a way that the threat of actual bloodshed may arise.

Nonetheless, the power of disinterested truth is greater than all theses obstacles. It carries such weight that the end is achieved, and all danger of bloodshed and all fear disappear. Loyalty leads to firm ties because it means that each partner complements the other. In the weaker person loyalty consists in devotion, in the stronger it consists in trustworthiness. This relation of mutual reinforcement leads to a true wealth that is all the more apparent because it is not selfishly hoarded but is shared with friends.

Pleasure shared is pleasure doubled. The rain comes, there is rest. This is due to the lasting effect of character. Perseverance brings the woman into danger. The moon is nearly full. If the superior man persists, Misfortune comes. Success is at hand. The wind has driven up the rain. A fixed standpoint has been reach.

This has come about through the cumulation of small effects produced by reverence for a superior character. But a success thus secured bit by bit calls for great caution. It would be a dangerous illusion for anyone to think he could presume upon it.

The female principle, the weak element that has won the victory, should never persist in vaunting it--that would lead to danger. The dark power in the moon is strongest when the moon is almost full. When it is full and directly opposite the sun, its waning is inevitable.

Under such circumstances one must be content with what has been achieved. To advance any further, before the appropriate time has come, would lead to misfortune. The name of the hexagram means on the one hand the right way of conducting oneself. Heaven, the father, is above, and the lake, the youngest daughter, is below.

This shows the difference between high and low, upon which composure correct social conduct, depends. The small and cheerful [Tui] treads upon the large and strong [Ch'ien]. The direction of movement of the two primary trigrams is upward. The fact that the strong treads on the weak is not mentioned in the Book of Changes, because it is taken for granted. For the weak to take a stand against the strong is not dangerous here, because it happened in good humor [Tui] and without presumption, so that the strong man is not irritated but takes it all in good part.

The situation is really difficult. That which is strongest and that which is weakest are close together. The weak follows behind the strong and worries it. The strong, however, acquiesces and does not hurt the weak, because the contact is in goof humor and harmless. In terms of a human situation, one is handling wild, intractable people. In such a case one's purpose will be achieved if one behaves with decorum. Pleasant manners succeed even with irritable people.

Thus the superior man discriminates between high and low, And thereby fortifies the thinking of the people. Heaven and the lake show a difference of elevation that inheres in the natures of the two, hence no envy arises. Among mankind also there are necessarily differences of elevation; it is impossible to bring about universal equality.

But it is important that differences in social rank should not be arbitrary and unjust, for if this occurs, envy and class struggle are the inevitable consequences. If, on the other hand, external differences in rank correspond with differences in inner worth, and if inner worth forms the criterion of external rank, people acquiesce and order reigns in society. The situation is one in which we are still not bound by any obligations of social intercourse.

If our conduct is simple, we remain free of them We can quietly follow our predilections as long as we are content and make not demands on people. The meaning of the hexagram is not standstill but progress. A man finds himself in an altogether inferior position at the start. However, he has the inner strength that guarantees progress. If he can be content with simplicity, he can make progress without blame. When a man is dissatisfied with modest circumstances, he is restless and ambitious and tries to advance, not for the sake of accomplishing anything worth while, but merely in order to escape from lowliness and poverty by dint of his conduct.

Once his purpose is achieved, he is certain to become arrogant and luxury-loving. Therefore blame attaches to his progress. On the other hand, a man who is good at his work is content to behave simply. He wishes to make progress in order to accomplish something. When he attains his goal, he does something worth while, an all is well. Treading a smooth, level course. The perseverance of a dark man Brings good fortune.

The situation of a lonely sage is indicated here. He remains withdrawn from the bustle of life, seeks nothing, asks nothing of anyone, and travels through life unassailed, on a level road. Since he is content and does not challenge fate, he remains free of entanglements. A one-eyed man is able to see, A lame man is able to tread.

He treads on the tail of the tiger. A one-eyed man can indeed see, but not enough for clear vision. A lame man can indeed treat, but not enough to make progress. If in spite of such defects a man considers himself strong and consequently exposes himself to danger, he is inviting disaster, for he is undertaking something beyond his strength.

This reckless way of plunging ahead, regardless of the adequacy of one's powers, can be justified only in the case of a warrior battling for his prince. Caution and circumspection Lead ultimately to good fortune. This text refers to a dangerous enterprise. The inner power to carry it through is there, but this inner power is combined with hesitating caution in one's external attitude.

This line contrasts with the preceding line, which is weak within but outwardly presses forward. Here one is sure of ultimate success, which consists in achieving one's purpose, that is, in overcoming danger by going forward. This refers to the ruler of the hexagram as a whole. One sees that one has to be resolute in conduct. But at the same time one must remain conscious of the danger connected with such resoluteness, especially if it is to be persevered in.

Only awareness of the danger makes success possible. Look to your conduct and weigh the favorable signs. When everything is fulfilled, supreme good fortune comes. The work is ended. If we want to know whether good fortune will follow, we must look back upon our conduct and its consequences.

If the effects are good, then good fortune is certain. No one knows himself. It is only by the consequences of his actions, by the fruit of his labors, that a man can judge what he is to expect. The Receptive, which moves downward, stands above; the Creative, which moves upward, is below. Hence their influences meet and are in harmony, so that all living things bloom and prosper. This hexagram belongs to the first month February-March , at which time the forces of nature prepare the new spring.

The small departs, The great approaches. This hexagram denotes a time in nature when heaven seems to be on earth. Heaven has placed itself beneath the earth, and so their powers unite in deep harmony. Then peace and blessing descend upon all living things.

In the world of man it is a time of social harmony; those in high places show favor to the lowly, and the lowly and inferior is an end to all feuds. In side, at the center, in the key position, is the light principle; the dark principle is outside. Thus the light has a powerful influence, while the dark is submissive. In this way each receives its due. When the good elements of society occupy a central position and are in control, the evil elements come under their influence and change for the better.

When the spirit of heaven rules in man, his animal nature also comes under its influence and takes its appropriate place. The individual lines enter the hexagram from below and leave it again at the top. Here the small, weak, and evil elements are about to take their departure, while the great, strong, and good elements are moving up. This brings good fortune and success. Thus the ruler Divides and completes the course of heaven and earth, And so aids the people.

Heaven and earth are in contact and combine their influences, producing a time of universal flowering and prosperity. This stream of energy must be regulated by the ruler of men. It is done by a process of division. Thus men divide the uniform flow of time into the seasons, according to the succession of natural phenomena, and mark off infinite space by the points of the compass.

In this way nature in its overwhelming profusion of phenomena is bounded and controlled. One the other hand, nature must be furthered in her productiveness. This is done by adjusting the products to the right time and the right place, which increases the natural yield. This controlling and furthering activity of man in his relation to nature is the work on nature that rewards him. When ribbon grass is pulled up, the sod comes with it. Each according to his kind.

Undertakings bring good fortune. In times of prosperity every able man called to fill an office draws like minded people along with him, just as in pulling up ribbon grass one always pulls up a bunch of it, because the stalks are connected by their roots. In such times, when it is possible to extend influence widely, the mind of an able man is set upon going out into life and accomplishing something.

Nine in the second place means:. Bearing with the uncultured in gentleness, Fording the river with resolution, Not neglecting what is distant, Not regarding one's companions:. In times of prosperity it is important and above all to possess enough greatness of soul to bear with imperfect people. For in the hands of a great master no material is unproductive; he can find use for everything. But this generosity is by no means laxity or weakness.

It is during times of prosperity especially that we must always be ready to risk even dangerous undertakings, such as the crossing of a river, if they are necessary. So too we must not neglect what is distant but must attend scrupulously to everything. Factionalism and the dominance of cliques are especially to be avoided.

Even if people of like mind come forward together, they ought not to form a faction by holding together for mutual advantage; instead, each man should do is duty. Theses are four ways in which one can overcome the hidden danger of a gradual slackening that always lurks in any time of peace.

And that is how one finds the middle way for action. No plain not followed by a slope. No going not followed by a return. He who remains persevering in danger Is without blame. Do not complain about this truth; Enjoy the good fortune you still possess. Everything on earth is subject to change. Prosperity is followed by decline: this is the eternal law on earth. Evil can indeed be held in check but not permanently abolished. It always returns. This conviction might induct melancholy, but it should not; it ought only to keep us from falling into illusion when good fortune comes to us.

If we continue mindful of the danger, we remain persevering and make no mistakes. As long as a man's inner nature remains stronger and richer than anything offered by external fortune, as long as he remains inwardly superior to fate, fortune will not desert him. He flutters down, not boasting of his wealth, Together with his neighbor, Guileless and sincere. In times of mutual confidence, people of high rank come in close contact with the lowly quite simply and without boasting of their wealth.

This is not due to the force of circumstances but corresponds with their inmost sentiment. The approach is made quite spontaneously, because it is based on inner conviction. The sovereign I Gives his daughter in marriage. And supreme good fortune. The sovereign I is T'ang the Completer. By his decree the imperial princesses, although higher in rank than their husbands, had to obey them like all other wives.

Here too we are shown a truly modest union of high and low that brings happiness and blessings. The wall falls back into the moat. Use no army now. Make your commands known within your own town. Perseverance brings humiliation. The change alluded to in the middle of the hexagram has begun to take place.

The wall of the town sinks back into the moat from which it was dug. The hour of doom is at hand. When matters have come to this pass, we should submit to fate and not try to stave it off by violent resistance. The one recourse left us is to hold our own within our intimate circle.

Should we persevere in trying to resist the evil in the usual way, our collapse would only be more complete, and humiliation would be the result. This hexagram is the opposite of the preceding one. Heaven is above, drawing farther and farther away, while the earth below sinks farther into the depths. The creative powers are not in relation. It is a time of standstill and decline.

This hexagram is linked with the seventh month August-September , when the year has passed its zenith and autumnal decay is setting in. Evil people do not further The perseverance of the superior man. The great departs; the small approaches.

Heaven and earth are out of communion and all things are benumbed. What is above has no relation to what is below, and on earth confusion and disorder prevail. The dark power is within, the light power is without. Weakness is within, harshness without. Within are the inferior, and without are the superior. The way of inferior people is in ascent; the way of superior people is one the decline.

But the superior people do not allow themselves to be turned from their principles. If the possibility of exerting influence is closed to them, they nevertheless remain faithful to their principles and withdraw into seclusion. Thus the superior man falls back upon his inner worth In order to escape the difficulties. He does not permit himself to be honored with revenue.

When, owing to the influence of inferior men, mutual mistrust prevails in public life, fruitful activity is rendered impossible, because the fundaments are wrong. Therefore the superior man knows what he must do under such circumstances; he does not allow himself to be tempted by dazzling offers to take part in public activities. This would only expose him to danger, since he cannot assent to the meanness of the others. He therefore hides his worth and withdraws into seclusion.

Perseverance brings good fortune and success. The text is almost the same as that of the first line of the preceding hexagram, but with a contrary meaning. In the latter a man is drawing another along with him on the road to an official career; here a man is drawing another with him into retirement form public life. This is why the text says here, "Perseverance brings good fortune and success," and not "Undertakings bring good fortune.

Success in a higher sense can be ours, because we know how to safeguard the value of our personalities. They bear and endure; This means good fortune for inferior people. The standstill serves to help the great man to attain success. Inferior people are ready to flatter their superiors in a servile way. They would also endure the superior man if he would put an end to their confusion.

This is fortunate for them. But the great man calmly bears the consequences of the standstill. He does not mingle with the crowd of the inferior; that is not his place. By his willingness to suffer personally he insures the success of his fundamental principles. Inferior people who have risen to power illegitimately do not feel equal to the responsibility they have taken upon themselves.

In their hearts they begin to be ashamed, although at first they do not show it outwardly. This marks a turn for the better.

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