Integrative analysis of proteomics and lipidomic profiles reveal the fat deposition and meat quality in Duroc × Guangdong small spotted pig.

Introduction: This study aims to explore the important factors affecting the characteristics of different parts of pork. Methods: Lipidomics and proteomics methods were used to analyze DAL (differential lipids) and DAPs (differential proteins) in five different parts (longissimus dorsi, belly meat, loin, forelegs and buttocks) of Duhua pig (Duroc × Guangdong small spotted pig), to identify potential pathways affecting meat quality, investigating fat deposition in pork and its lipid-protein interactions. Results: The results show that TG (triglyceride) is the lipid subclass with the highest proportion in muscle, and the pathway with the most significantly enriched lipids is GP. DAP clustered on several GO terms closely related to lipid metabolism and lipogenesis (lipid binding, lipid metabolism, lipid transport, and lipid regulation). In KEGG analysis, there are two main DAP aggregation pathways related to lipid metabolism, namely Fatty acid degradation and oxidative phosphorylation. In PPI analysis, we screened out 31 core proteins, among which NDUFA6, NDUFA9 and ACO2 are the most critical. Discussion: PC (phosphatidylcholine) is regulated by SNX5, THBS1, ANXA7, TPP1, CAVIN2, and VDAC2 in the phospholipid binding pathway. TG is regulated by AUH/HADH/ACADM/ACADL/HADHA in the lipid oxidation and lipid modification pathways. Potential biomarkers are rich in SFA, MUFA and PUFA respectively, the amounts of SFA, MUFA and PUFA in the lipid measurement results are consistent with the up- and down-regulation of potential biomarker lipids. This study clarified the differences in protein and lipid compositions in different parts of Duhua pigs and provided data support for revealing the interactions between pork lipids and proteins. These findings provide contributions to the study of intramuscular fat deposition in pork from a genetic and nutritional perspective.

Design and biomechanical analysis of patientspecific porous tantalum prostheses for knee joint revision surgery.

Artificial joint revision surgery, as an increasingly common surgery in orthopedics, often requires patient-specific prostheses to repair the bone defect. Porous tantalum is a good candidate due to its excellent abrasion and corrosion resistance and good osteointegration. Combination of 3D printing technology and numerical simulation is a promising strategy to design and prepare patient-specific porous prostheses. However, clinical design cases have rarely been reported, especially from the viewpoint of biomechanical matching with the patient's weight and motion and specific bone tissue. This work reports a clinical case on the design and mechanical analysis of 3D-printed porous tantalum prostheses for the knee revision of an 84-year-old male patient. Particularly, standard cylinders of 3D-printed porous tantalum with different pore size and wire diameters were first fabricated and their compressive mechanical properties were measured for following numerical simulation. Subsequently, patientspecific finite element models for the knee prosthesis and the tibia were constructed from the patient's computed tomography data. The maximum von Mises stress and displacement of the prostheses and tibia and the maximum compressive strain of the tibia were numerically simulated under two loading conditions by using finite element analysis software ABAQUS. Finally, by comparing the simulated data to the biomechanical requirements for the prosthesis and the tibia, a patient-specific porous tantalum knee joint prosthesis with a pore diameter of 600 µm and a wire diameter of 900 µm was determined. The Young's modulus (5719.32 ± 100.61 MPa) and yield strength (172.71 ± 1.67 MPa) of the prosthesis can produce both sufficient mechanical support and biomechanical stimulation to the tibia. This work provides a useful guidance for designing and evaluating a patient-specific porous tantalum prosthesis.

Effects of polysaccharides from Gastrodia elata on the immunomodulatory activity and gut microbiota regulation in cyclophosphamide-treated mice.

BACKGROUND: Cyclophosphamide (CTX) is a widely used chemotherapeutic agent for the treatment of malignant tumors and autoimmune diseases. However, it can cause immunosuppression and damage the intestinal mucosa. The development of new agents to counteract these side effects is becoming increasingly important. Previous studies have shown that the polysaccharides from Gastrodia elata (GEPs) have strong immune-enhancing effects; however, their functions regarding the intestines and the underlying mechanism are still unclear. In this study, the effects of GEPs on immunomodulatory activity, intestinal barrier function, and gut microbiota regulation were investigated in a mouse model of CTX-induced immunosuppression. RESULTS: Gastrodia elata polysaccharides attenuated the CTX-induced decrease in organ indices of the thymus and spleen, and promoted the secretion of immune-related cytokines and immunoglobulins in the serum. They also improved the intestinal pathology and restored the intestinal barrier function by elevating the expression of intestinal tight junction proteins, occludin and ZO-1. Moreover, GEPs restored the composition and abundance of the gut microbiota and increased the short-chain fatty acid (SCFA) content in the colon. The abundance of SCFA-producing bacteria (Muribaculaceae, Prevotellaceae, and Bacteroidaceae) also increased. CONCLUSIONS: Gastrodia elata polysaccharides can effectively alleviate immunosuppression and regulate the intestinal barrier integrity and the structure of gut microbiota in CTX-treated mice. They may be used as ingredients to develop functional foods for intestinal health. © 2023 Society of Chemical Industry.

Impact of parathyroidectomy among nondiabetic hemodialysis patients with severe hyperparathyroidism.

BACKGROUND: Parathyroidectomy (PTX) is a treatment for hyperparathyroidism (HPT) and has uncertain risks and benefits. The aim of this study was to evaluate the effect of PTX versus nonoperative treatment among nondiabetic hemodialysis patients. METHODS: A retrospective matched cohort study was performed. Each PTX patient was matched with one patient who had severe HPT but rejected PTX. The patients were matched by sex, birth date, date of first dialysis, nondiabetic status, and left ventricular ejection fraction. The serum markers, survival, main adverse cardiovascular and cerebrovascular event (MACCE) rates, and hospitalization were compared between the PTX patients and matched non-PTX patients. RESULTS: There were 1143 patients at our center in the Chinese National Renal Data System (CNRDS) between 2010 and 2020. Of these, 75 PTX patients were matched with 75 non-PTX patients. Rapid decreases in the mean intact parathyroid hormone, calcium and phosphorus concentrations, and a gradual increase in hemoglobin concentration were observed in the PTX group. The mortality was 2.9 per 100 patient-years in the PTX group and 10.9 per 100 patient-years in the non-PTX group (p < 0.001). Compared with non-PTX patients, PTX patients had an adjusted HR for death of 0.236 (95% CI 0.108-0.518). The cumulative MACCE rates were 6.7 per 100 patient-years in the PTX group and 15.2 per 100 patient-years in the non-PTX group (p < 0.001). The adjusted HR of the occurrence of first MACCE for PTX patients compared with non-PTX patients was 0.524 (95% CI 0.279-0.982). The cumulative hospitalization rates were 50.3 per 100 patient-years in the PTX group and 66.5 per 100 patient-years in the matched non-PTX group (p < 0.001). CONCLUSIONS: Compared with non-PTX patients, PTX was associated with an improvement in the biochemical measures and patient-level outcomes in nondiabetic hemodialysis patients with severe HPT.

SfgA Renders Aspergillus flavus More Stable to the External Environment.

sfgA is known as a key negative transcriptional regulator gene of asexual sporulation and sterigmatocystin production in Aspergillus nidulans. However, here, we found that the homolog sfgA gene shows a broad and complex regulatory role in governing growth, conidiation, sclerotia formation, secondary metabolism, and environmental stress responses in Aspergillus flavus. When sfgA was deleted in A. flavus, the fungal growth was slowed, but the conidiation was significantly increased, and the sclerotia formation displayed different behavior at different temperatures, which increased at 30 °C but decreased at 36 °C. In addition, sfgA regulated aflatoxin biosynthesis in a complex way that was associated with the changes in cultured conditions, and the increased production of aflatoxin in the ∆sfgA mutant was associated with a decrease in sclerotia size. Furthermore, the ∆sfgA mutant exhibited sensitivity to osmotic, oxidative, and cell wall stresses but still produced dense conidia. Transcriptome data indicated that numerous development- and secondary-metabolism-related genes were expressed differently when sfgA was deleted. Additionally, we also found that sfgA functions downstream of fluG in A. flavus, which is consistent with the genetic position in FluG-mediated conidiation in A. nidulans. Collectively, sfgA plays a critical role in the development, secondary metabolism, and stress responses of A. flavus, and sfgA renders A. flavus more stable to the external environment.

Adsorption Force of Fibronectin: A Balance Regulator to Transmission of Cell Traction Force and Fluid Shear Stress.

Osteoblasts actively generate cell traction force (CTF) to sense chemical and mechanical microenvironments. Fluid shear stress (FSS) is a principle mechanical stimulus for bone modeling/remodeling. FSS and CTF share common interconnected elements for force transmission, among which the role of the protein-material interfacial force (Fad) remains unclear. Here, we found that, on the low Fad surface (5.47 ± 1.31 pN/FN), CTF overwhelmed Fad to partially desorb FN, and FSS exacerbated the desorption, resulting in disassembly of the actin cytoskeleton and focal adhesions (FAs) to reduce CTF and establishment of a new mechanical balance at the FN-material interface. Contrarily, on the high Fad surface (27.68 ± 5.24 pN/FN), pure CTF or the combination of CTF and FSS induced no FN desorption, and FSS promoted assembly of actin cytoskeletons and disassembly of FAs, regaining new mechanical balance at the cell-FN interface. These results indicate that Fad is a mechanical regulator for transmission of CTF and FSS, which has never been reported before.

Biomechanical Comparison of Panda Rope Bridge Technique and Other Minimally Invasive Achilles Tendon Repair Techniques In Vitro.

BACKGROUND: Although nonoperative management of acute Achilles tendon rupture (ATR) is a reasonable option, surgical repair has attracted attention for young and active patients. More reliable Achilles tendon repair techniques are needed to enhance recovery after ATR in this population. PURPOSE/HYPOTHESIS: To biomechanically analyze the panda rope bridge technique (PRBT) and compare it with other minimally invasive repair techniques over a simulated, progressive rehabilitation program. It was hypothesized that PRBT would result in better biomechanical properties and enhanced recovery after ATR. STUDY DESIGN: Controlled laboratory study. METHODS: An Achilles tendon rupture was created 4 cm from the distal tendon insertion site in 40 bovine lower extremities, and specimens were then randomly allocated to 5 Achilles tendon repair techniques: (1) Achillon, (2) modified Achillon, (3) Percutaneous Achilles Repair System (PARS), (4) modified PARS, and (5) PRBT. Each group was subjected to a cyclic loading protocol that was representative of progressive postoperative rehabilitation for ATR (250 cycles at 1 Hz for each loading stage: 20-100 N, 20-200 N, 20-300 N, and 20-400 N). RESULTS: The PRBT technique demonstrated significantly less elongation (1.62 ± 0.25 mm) than the 4 other repair techniques after the first loading stage of 20 to 100 N (P < .05). All specimens in the 4 other groups developed a large gap (elongation ≥5 mm) at the 20- to 200-N loading stage. When overall biomechanical performance was examined, the PRBT group exhibited higher strength (20-400 N) and more mean loading cycles (984 ± 10) compared with the 4 other groups (P < .05). CONCLUSION: In this bovine model, PRBT biomechanically outperformed the other minimally invasive Achilles tendon repair techniques that were tested and could therefore meet the requirements of accelerated rehabilitation. CLINICAL RELEVANCE: The reduced tendency for premature rerupture and the overall improved biomechanical properties of PRBT suggest that ATR patients treated with PRBT may more readily complete early and aggressive postoperative rehabilitation protocols. In addition, they may have a lower risk of early irreversible suture failure.

Optimization of the knot configuration for early accelerated rehabilitation after Achilles tendon rupture.

Background Panda Rope Bridge Technique (PRBT) was an new minimally invasive technique consisted of two bridge anchors (proximal anchors at calcaneus and distal anchors at myotendinous junction) and strong ropes (threads of the suture anchors) stretched between them, which was suitable for early accelerated rehabilitation of Achilles tendon rupture. However, the optimal knot configuration with PRBT was unknow. The purpose of this study was identify minimum number of half hitches necessary to maintain knot security for PRBT. Methods Using an Instron device we tested the effect of different knot configuration in two kinds of suture threads (Ethibond™ #5 and Ultrabraid™ #2). According to the result of it, we put the optimal knot configuration into Part 1 with PRBT test model and Part 2 with modified PRBT test model, to evaluate whether the optimal knot configuration could complete the cyclic loading test simulated early rehabilitation. Findings In the first part of the study, the optimal knot configuration of Ethibond™ #5 suture thread was the combination of three half hitches and one double throw half knot, and the optimal knot configuration of Ultrabraid™ #2 suture thread was the combination of five half hitches and one double throw half knot. In the second part of the study, only Ultrabraid™ #2 suture thread with optimal knot configuration had finished all test in Part 1. Interpretation The Ultrabraid™ #2 suture thread with optimal knot configuration was suitable for PRBT with early accelerated rehabilitation after Achilles tendon repair.

[Biomechanical comparison study of two ultra-strong sutures in repair of Achilles tendon via panda rope bridge technique].

OBJECTIVE: To compare the biomechanical properties of two ultra-strong sutures and suturing methods in panda rope bridge technique (PRBT) application, and provide guidance for clinical selection of suture threads and suture methods. METHODS: Forty Achilles tendons from bulls were randomly divided into 4 groups ( n=10) and transected at the 4 cm proximal to the tendon insertion. Groups A and B used Ethibond sutures (USP 5), the proximal end was fixed at the myotendious junction with Krackow sutures and the distal end was fixed through a calcaneus canal. Groups A and B had 4 and 8 threads through the stump plane, respectively. Groups C and D used Ultrabraid sutures (USP 2), the proximal end was fixed at the myotendious junction with Krackow sutures and the distal end was fixed in the calcaneus with two anchors. Groups C and D had 4 and 8 threads through the stump plane, respectively. The dynamic tensile forces of 20-100, 20-200, 20-300, and 20-400 N were tested respectively by using a dynamic tensile testing machine at 0.5 Hz for 250 cycles. After each stage of testing, the gap between stumps was measured with a caliper and the type of suture failure was recorded. RESULTS: After dynamic tensile forces of 20-100 N and 20-200 N, the gaps of the four groups arranged from small to large were groups D, B, C, and A. The differences between groups A and B and groups C and D were significant ( P<0.05). But after dynamic tensile forces of 20-300 N and 20-400 N, the gaps were more than 5 mm in all groups. The suture retention rates of the four groups after dynamic tensile forces of 20-100 N and 20-200 N were all 100%. The suture retention rates of groups A, B, C, and D were 0, 80%, 60%, and 100%, respectively after dynamic tensile forces of 20-300 N. The differences of suture retention rates between group A and groups B and D were significant ( P<0.05). There was no significant difference between groups B, C, and D ( P>0.05). After dynamic tensile forces of 20-400 N, the suture retention rates of groups A, B, C, and D were 0, 50%, 0, and 70%, respectively. There were significant differences between groups A and B and groups C and D ( P<0.05). CONCLUSION: Repairing Achilles tendon rupture via PRBT with 8 ultra-strong sutures through the stump plane can meet the mechanical requirements for walking by using ankle boots and heel pads in the early accelerated rehabilitation after operation.

Tcf7l1 Acts as a Suppressor for the Self-Renewal of Liver Cancer Stem Cells and Is Regulated by IGF/MEK/ERK Signaling Independent of ß-Catenin.

Tcf7l1, which is a key effector molecule of the Wnt/ß-catenin signaling pathway, is highly expressed in various cancers, and it promotes tumor growth. In this study, we demonstrated that unlike its tumor-promoting effects in several other types of cancers, Tcf7l1 expression is downregulated in hepatocarcinoma compared with their adjacent nontumor counterparts. Underexpression of Tcf7l1 is correlated with poorer survival. In liver cancer stem cell (CSC) populations, Tcf7l1 expression is downregulated. Ectopic expression of Tcf7l1 attenuates the self-renewal abilities of liver CSCs. Mechanistically, Tcf7l1 regulates the self-renewal abilities of liver CSCs through transcriptional repression of the Nanog gene, and the effect is independent of ß-catenin. Moreover, we found that Tcf7l1 expression is controlled by extracellular insulin-like growth factor (IGF) signaling, and we demonstrated for the first time that IGF signaling stimulates Tcf7l1 phosphorylation and degradation through the mitogen-activated protein kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway. Overall, our results provide some new insights into how extracellular signals modulate the self-renewal of liver CSCs and highlight the inhibitory roles of Tcf7l1 in cancer. Stem Cells 2019;37:1389-1400.

Oriented collagen fiber membranes formed through counter-rotating extrusion and their application in tendon regeneration.

Well-aligned collagen fiber scaffolds are considered promising candidates for tendon tissue engineering in terms of their biomimetic chemical composition and topographic structure. Insoluble collagen fibers are more suitable for the preparation of scaffolds than soluble collagens due to their more approximate self-assembly and mechanical properties to native collagen ECMs. In this work, we employed counter-rotating extrusion technology for the first time to fabricate an aligned (CMa, orientation angle 0°-15°) and a randomly-oriented (CMr, orientation angle -60°-60°) collagen membrane from insoluble collagens. CMa had a tensile strength comparable with native rat Achilles tendon (18.45 ±â€¯0.91 MPa vs. 22.32 ±â€¯2.48 MPa). Thus, CMa represents a scaffold that is biomimetic of native tendon tissues in chemical composition, alignment, and mechanical properties. To verify the feasibility of CMs in tendon tissue engineering, we investigated the in vitro tenogenic differentiation of rBMSCs on CMs and the in vivo tendon regeneration using a rat Achilles tendon defect model. Detection of the tendon-related genes and proteins revealed that CMa can promote significantly higher tenogenic differentiation of rBMSCs than CMr, by inducing an elongated cell shape along the fibers. The in-situ tendon repair study further confirmed that CMa-BMSCs can produce a comparable healing quality to the autogenous tendon. Overall, our results verify the feasibility of the counter-rotating extrusion technology in fabricating biomimetic collagen scaffolds and provide a promising scaffold for tendon tissue regeneration.

Three-Dimensional Printing of Biodegradable Piperazine-Based Polyurethane-Urea Scaffolds with Enhanced Osteogenesis for Bone Regeneration.

Synthetic biodegradable polymeric scaffolds with uniformly interconnected pore structure, appropriate mechanical properties, excellent biocompatibility, and even enhanced osteogenesis ability are urgently required for in situ bone regeneration. In this study, for the first time, a series of biodegradable piperazine (PP)-based polyurethane-urea (P-PUU) scaffolds with a gradient of PP contents were developed by air-driven extrusion 3D printing technology. The P-PUU ink of 60 wt % concentration was demonstrated to have appropriate viscosity for scaffold fabrication. The 3D-printed P-PUU scaffolds exhibited an interconnected porous structure of about 450 µm in macropore size and about 75% in porosity. By regulating the contents of PP in P-PUU scaffolds, their mechanical properties could be moderated, and P-PUU1.4 scaffolds with the highest PP contents exhibited the highest compressive modulus (155.9 ± 5.7 MPa) and strength (14.8 ± 1.1 MPa). Moreover, both in vitro and in vivo biological results suggested that the 3D-printed P-PUU scaffolds possessed excellent biocompatibility and osteoconductivity to facilitate new bone formation. The small molecular PP itself was confirmed for the first time to regulate osteogenesis of osteoblasts in a dose-dependent manner and the optimum concentration for osteoconductivity was about ∼0.5 mM, which suggests that PP molecules, together with the mechanical behavior, nitrogen-contents, and hydrophilicity of P-PUUs, play an important role in enhancing the osteoconductive ability of P-PUU scaffolds. Therefore, the 3D-printed P-PUU scaffolds, with suitable interconnected pore structure, appropriate mechanical properties, and intrinsically osteoconductive ability, should provide a promising alternative for bone regeneration.

Shape recovery strain and nanostructures on recovered polyurethane films and their regulation to osteoblasts morphology.

Shape memory polyurethanes (SMPUs) have emerged as novel dynamic substrates to regulate cell alignment, in which recovery-induced change in substrates topography has been described as the major contributor. This work, for the first time, confirmed the pivotal roles of recovery strain and phase-separated nanostructures of SMPUs in regulating cell morphology. SMPU films with different stretching ratios (0%, 50%, 100%, and 200%) were found to produce an average recovery strain from 19.41% to 34.04% within 2 h in dulbecco's modified eagle medium (DMEM). Meanwhile, the assembly of hard domains was enhanced during shape recovery, leading to the reorientation of fibrillar apophyses (i.e., nanostructures). Further observation of osteoblast morphology revealed that recovery strain resulted in perpendicular orientation of osteoblasts to strain direction. With the extension of incubation time (24 h), however, the perpendicular orientation was transformed to follow the nanostructures on recovered films, suggesting that the nanostructures might become the determinant of the long-term cell orientation. This study provides a biomechanics-based perspective to understand the dynamic interactions between SMPU and cells, which can help to guide the design of SMPU for specific biomedical applications.

PLA-PEG-FA NPs for drug delivery system: Evaluation of carrier micro-structure, degradation and size-cell proliferation relationship.

In this paper, the micro-structure of amphiphilic copolymer Polylactic acid-Polyethylene glycol-Folate (PLA-PEG-FA) was studied firstly by a differential scanning calorimetry (DSC). During the process of nanoparticles (NPs) preparation, we found good inter-structure consistency of polymer was the precondition for forming into stable NPs, and those with micro-phase separation structure were prepared of NPs within limits. Hemolytic test and CCK-8 assay results demonstrated the biotoxicity of both NPs and whose leaching liquor was far below related toxicity standards. Two kinds of cell, human breast cancer cell line (MCF-7) and human umbilical vein endothelial cells (EC), showed different manners in test of NPs size-cell proliferation relationship, respectively. Monitored by a nuclear magnetic resonance (NMR) and a gel permeation chromatography (GPC), the degradation behavior of NPs in aqueous solution indicated amide bond break more difficultly than ester bond, and FA classic proton peak disappeared in the third week, meanwhile lactic acid (LA) unit number became 25% of the initial. Finally the NPs was completely degraded in the eighth week. In the whole process, NPs underwent a change from compact to loose state. We hope these results will benefit to improve design of drug delivery system in nanomedicine, which could offer the selection rule for amphiphilic polymer NPs on material and size.

Biodegradable near-infrared-photoresponsive shape memory implants based on black phosphorus nanofillers.

In this paper, we propose a new shape memory polymer (SMP) composite with excellent near-infrared (NIR)-photoresponsive shape memory performance and biodegradability. The composite is fabricated by using piperazine-based polyurethane (PU) as thermo-responsive SMP incorporated with black-phosphorus (BP) sheets as NIR photothermal nanofillers. Under 808 nm light irradiation, the incorporated BP sheets with concentration of only 0.08 wt% enable rapid temperature increase over the glass temperature of PU and trigger the shape change of the composite with shape recovery rate of ∼100%. The in vitro and in vivo toxicity examinations demonstrate the good biocompatibility of the PU/BP composite, and it degrades naturally into non-toxic carbon dioxide and water from PU and non-toxic phosphate from BP. By implanting PU/BP columns into back subcutis and vagina of mice, they exhibit excellent shape memory activity to change their shape quickly under moderate 808 nm light irradiaiton. Such SMP composite enable the development of intelligent implantable devices, which can be easily controlled by the remote NIR light and degrade gradually after performing the designed functions in the body.

Adsorption force of fibronectin controls transmission of cell traction force and subsequent stem cell fate.

The transmission of cell traction force (CTF) to underlying biomaterials is essential for adhered cells to measure and respond to their mechanical microenvironment. Given that the protein layer adsorbed on materials lies between the cells and materials, we hypothesize that the interfacial strength of protein-material interfaces (i.e., the adsorption force of proteins, Fad) should have an important role in regulating the transmission of CTF. To test this hypothesis, rat mesenchymal stem cells (rMSCs) were cultured on poly(dimethyl siloxane) (PDMS) substrates with different Fad of fibronectin (FN), and the transmission of CTF was observed by immunofluorescence staining of FN and deformation of PDMS. As revealed, FN on substrates with low Fad is more liable to be desorbed by CTF, which prevents the transmission of CTF to substrates. In contrast, high Fad facilitates the transmission of CTF from rMSCs to the FN layer and PDMS substrates so that rMSCs can perceive the mechanical properties of substrates. We further demonstrated that the divergent transmission of CTF on low and high Fad substrates regulates the lineage specifications of rMSCs. Our study confirms the important role of Fad in CTF transmission and provides a new perspective to gain insights into cell-material interactions and cell fates, which may help to guide the design of better biomaterials.

Identification of potential CCR5 inhibitors through pharmacophore-based virtual screening, molecular dynamics simulation and binding free energy analysis.

CC chemokine receptor 5 (CCR5), a member of G protein-coupled receptors (GPCRs), plays a vital role in inflammatory responses to infection. Alterations in the expression of CCR5 have been correlated with disease progression in many types of cancers. The idea of using CCR5 as a target for therapeutic intervention has been demonstrated to prevent disease progression. To date, only a few compounds have been reported as CCR5 inhibitors. In this study, a series of CCR5 antagonists were used to construct pharmacophore models. Then the optimal model was utilized as a 3D query to identify novel chemical entities from structural databases. After refinement by molecular docking, drug-likeness analysis, molecular dynamics simulations (MDS) and binding free energy analysis, three potential inhibitors (25, 29 and 45) were identified. MD simulations suggested that the screened compounds retained the important common binding mode known for CCR5 inhibitors (maraviroc and nifeviroc), which occupied the bottom of a pocket and stabilized the conformation of CCR5. During the binding process, van der Waals interactions provided the substantial driving force. The most favorable contributions were from Tyr37, Trp86, Tyr89, Tyr108, Phe109, Phe112, Gln194, Thr195, Ile198, Trp248, Tyr251, Leu255, Thr259, Met279, Glu283 and Met287. The above results suggest that the hybrid strategy would provide a basis for rational drug design.

Surface chemistry regulates the sensitivity and tolerability of osteoblasts to various magnitudes of fluid shear stress.

Scaffolds provide a physical support for osteoblasts and act as the medium to transfer mechanical stimuli to cells. To verify our hypothesis that the surface chemistry of scaffolds regulates the perception of cells to mechanical stimuli, the sensitivity and tolerability of osteoblasts to fluid shear stress (FSS) of various magnitudes (5, 12, 20 dynes/cm2 ) were investigated on various surface chemistries (-OH, -CH3 , -NH2 ), and their follow-up effects on cell proliferation and differentiation were examined as well. The sensitivity was characterized by the release of adenosine triphosphate (ATP), nitric oxide (NO) and prostaglandin E2 (PGE2 ) while the tolerability was by cellular membrane integrity. The cell proliferation was characterized by S-phase cell fraction and the differentiation by ALP activity and ECM expression (fibronectin and type I collagen). As revealed, osteoblasts demonstrated higher sensitivity and lower tolerability on OH and CH3 surfaces, yet lower sensitivity and higher tolerability on NH2 surfaces. Observations on the focal adhesion formation, F-actin organization and cellular orientation before and after FSS exposure suggest that the potential mechanism lies in the differential control of F-actin organization and focal adhesion formation by surface chemistry, which further divergently mediates the sensitivity and tolerability of ROBs to FSS and the follow-up cell proliferation and differentiation. These findings are essentially valuable for design/selection of desirable surface chemistry to orchestrate with FSS stimuli, inducing appropriate cell responses and promoting bone formation. © 2016 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 2978-2991, 2016.

Stretching-induced nanostructures on shape memory polyurethane films and their regulation to osteoblasts morphology.

Programming such as stretching, compression and bending is indispensible to endow polyurethanes with shape memory effects. Despite extensive investigations on the contributions of programming processes to the shape memory effects of polyurethane, less attention has been paid to the nanostructures of shape memory polyurethanes surface during the programming process. Here we found that stretching could induce the reassembly of hard domains and thereby change the nanostructures on the film surfaces with dependence on the stretching ratios (0%, 50%, 100%, and 200%). In as-cast polyurethane films, hard segments sequentially assembled into nano-scale hard domains, round or fibrillar islands, and fibrillar apophyses. Upon stretching, the islands packed along the stretching axis to form reoriented fibrillar apophyses along the stretching direction. Stretching only changed the chemical patterns on polyurethane films without significantly altering surface roughness, with the primary composition of fibrillar apophyses being hydrophilic hard domains. Further analysis of osteoblasts morphology revealed that the focal adhesion formation and osteoblasts orientation were in accordance with the chemical patterns of the underlying stretched films, which corroborates the vital roles of stretching-induced nanostructures in regulating osteoblasts morphology. These novel findings suggest that programming might hold great potential for patterning polyurethane surfaces so as to direct cellular behavior. In addition, this work lays groundwork for guiding the programming of shape memory polyurethanes to produce appropriate nanostructures for predetermined medical applications.

Key role of collagen fibers orientation in casing-meat adhesion.

Meat adhesion of collagen casings is important for the quality of sausages. In view of the crucial role of surface morphology in material adhesion, we hypothesize that the fiber orientation of collagen casings controls the meat adhesion. To verify this hypothesis, the casing-meat adhesion of four manufactured collagen casings (MCCs) was examined by the visual observation and the peeling force detection. The corresponding fiber orientation was investigated by using scanning electric microscope (SEM) and tensile tests. The results showed that MCC1 and MCC2 which had narrower directionality peak (-20° to -40° and -20° to 40°, respectively) and higher axial (σa) to radial (σr) strength ratios (1.90±0.07 and 1.31±0.02, respectively) demonstrated lower peeling forces than MCC3 and MCC4, indicating that a more isotropic structure is advantageous to the casing-meat adhesion. Further detection of the radial and axial shrink (including free shrinkage (Sr, Sa) and shrink force (Fr, Fa)) and observation of the local meat-casing interfaces by hematoxylin and eosin (HE) staining showed that appropriate Sr (15%-20%) and Fr (0.2-0.4N) values at 80°C helped to make the sausage tight whereas high Fa (>0.7N) promoted the peeling off of the casings from meat. These results imply that an isotropic structure leads to balanced radial and axial shrink of MCCs, which may enhance the casing-meat adhesion. Overall, controlling a uniform fiber orientation should be an effective way to enhance the meat adhesion of collagen casings. Besides, shrinking properties should be efficient indicators for the meat adhesion of collagen casings.