The Immune Landscape of Cancer.

We performed an extensive immunogenomic analysis of more than 10,000 tumors comprising 33 diverse cancer types by utilizing data compiled by TCGA. Across cancer types, we identified six immune subtypes-wound healing, IFN-γ dominant, inflammatory, lymphocyte depleted, immunologically quiet, and TGF-ß dominant-characterized by differences in macrophage or lymphocyte signatures, Th1:Th2 cell ratio, extent of intratumoral heterogeneity, aneuploidy, extent of neoantigen load, overall cell proliferation, expression of immunomodulatory genes, and prognosis. Specific driver mutations correlated with lower (CTNNB1, NRAS, or IDH1) or higher (BRAF, TP53, or CASP8) leukocyte levels across all cancers. Multiple control modalities of the intracellular and extracellular networks (transcription, microRNAs, copy number, and epigenetic processes) were involved in tumor-immune cell interactions, both across and within immune subtypes. Our immunogenomics pipeline to characterize these heterogeneous tumors and the resulting data are intended to serve as a resource for future targeted studies to further advance the field.

Incorporating Sodium-Conductive Polymeric Interfacial Adhesive with Inorganic Solid-State Electrolytes for Quasi-Solid-State Sodium Metal Batteries.

Inorganic solid-state electrolytes have attracted enormous attention due to their potential safety, increased energy density, and long cycle-life benefits. However, their application in solid-state batteries is limited by unstable electrode-electrolyte interface, poor point-to-point physical contact, and low utilization of metallic anodes. Herein, interfacial engineering based on sodium (Na)-conductive polymeric solid-state interfacial adhesive is studied to improve interface stability and optimize physical contacts, constructing a robust organic-rich solid electrolyte interphase layer to prevent dendrite-induced crack propagation and security issues. The interfacial adhesive strategy significantly increases the room-temperature critical current density of inorganic Na-ion conductors from 0.8 to 3.2 mA cm-2 and markedly enhances the cycling performance of solid-state batteries up to 500 cycles, respectively. Particularly, the Na3V2(PO4)3-based full solid-state batteries with high cathode loading of 10.16 mg cm-2 also deliver an excellent cycling performance, further realizing the stable operation of solid-state laminated pouch cells. The research provides fundamental perspectives into the role of interfacial chemistry and takes the field a step closer to realizing practical solid-state batteries.

Recent Trends and Innovations in Bead-Based Biosensors for Cancer Detection.

Demand is strong for sensitive, reliable, and cost-effective diagnostic tools for cancer detection. Accordingly, bead-based biosensors have emerged in recent years as promising diagnostic platforms based on wide-ranging cancer biomarkers owing to the versatility, high sensitivity, and flexibility to perform the multiplexing of beads. This comprehensive review highlights recent trends and innovations in the development of bead-based biosensors for cancer-biomarker detection. We introduce various types of bead-based biosensors such as optical, electrochemical, and magnetic biosensors, along with their respective advantages and limitations. Moreover, the review summarizes the latest advancements, including fabrication techniques, signal-amplification strategies, and integration with microfluidics and nanotechnology. Additionally, the challenges and future perspectives in the field of bead-based biosensors for cancer-biomarker detection are discussed. Understanding these innovations in bead-based biosensors can greatly contribute to improvements in cancer diagnostics, thereby facilitating early detection and personalized treatments.

Multi-scale ensemble properties of the Escherichia coli RNA degradosome.

In organisms from all domains of life, multi-enzyme assemblies play central roles in defining transcript lifetimes and facilitating RNA-mediated regulation of gene expression. An assembly dedicated to such roles, known as the RNA degradosome, is found amongst bacteria from highly diverse lineages. About a fifth of the assembly mass of the degradosome of Escherichia coli and related species is predicted to be intrinsically disordered - a property that has been sustained for over a billion years of bacterial molecular history and stands in marked contrast to the high degree of sequence variation of that same region. Here, we characterize the conformational dynamics of the degradosome using a hybrid structural biology approach that combines solution scattering with ad hoc ensemble modelling, cryo-electron microscopy, and other biophysical methods. The E. coli degradosome can form punctate bodies in vivo that may facilitate its functional activities, and based on our results, we propose an electrostatic switch model to account for the propensity of the degradosome to undergo programmable puncta formation.

CDBN-YGXZ, a Novel Small-Molecule Drug, Shows Efficacy against Clostridioides difficile Infection and Recurrence in Mouse and Hamster Infection Models.

Clostridioides difficile infection (CDI) causes severe diarrhea and colitis, leading to significant morbidity, mortality, and high medical costs worldwide. Oral vancomycin, a first-line treatment for CDI, is associated with a high risk of recurrence, necessitating novel therapies for primary and recurrent CDI. A novel small-molecule compound, CDBN-YGXZ, was synthesized by modifying the benzene ring of nitazoxanide with lauric acid. The mechanism of action of CDBN-YGXZ was validated using a pyruvate:ferredoxin/flavodoxin oxidoreductase (PFOR) inhibition assay. The efficacy of CDBN-YGXZ was evaluated using the MIC test and CDI infection model in mice and hamsters. Furthermore, metagenomics was used to reveal the underlying reasons for the effective reduction or prevention of CDI after CDBN-YGXZ treatment. The inhibitory activity against PFOR induced by CDBN-YGXZ. MIC tests showed that the in vitro activity of CDBN-YGXZ against C. difficile ranging from 0.1 to 1.5 µg/mL. In the mouse and hamster CDI models, CDBN-YGXZ provided protection during both treatment and relapse, while vancomycin treatment resulted in severe relapse and significant clinical scores. Compared with global effects on the indigenous gut microbiota induced by vancomycin, CDBN-YGXZ treatment had a mild influence on gut microbes, thus resulting in the disappearance or reduction of CDI recurrence. CDBN-YGXZ displayed potent activity against C. difficile in vitro and in vivo, reducing or preventing relapse in infected animals, which could merit further development as a potential drug candidate for treating CDI.

Positive association between urinary albumin-creatinine ratio and lower extremity peripheral arterial disease in Chinese diabetes patients: A cross-section study with propensity score matching analysis.

BACKGROUND AND AIMS: Elevated urinary albumin-creatinine ratio (ACR) is an established risk factor for lower extremity peripheral arterial disease (PAD) in non-diabetes individual. This study aimed to determine the relationship between urinary ACR level and PAD in diabetes population. METHODS AND RESULTS: A cross-section study with 1396 hospitalized diabetes participants from department of endocrinology and neurology were performed and the propensity score matching method was applied to reduce the effects of confounding factors between the matched PAD and Non-PAD groups. The relationship between urinary ACR and ankle-brachial index (ABI) was analyzed by linear curve fitting analyses and multiple logistic regression models. Our study showed that the prevalence of PAD (low ABI, ABI<0.9) was 7.09% in our diabetes patients. The ABI level was significantly lower in high ACR group compared with those in normal urinary ACR group (1.11 ± 0.17 vs 1.13 ± 0.15, p = 0.010). The prevalence of PAD was increased with the increased tertile's of log2-transformed ACR in total patients before and after propensity score matching (p < 0.001 and p = 0.007, respectively). The OR (95% CI) between log2-transformed ACR and PAD was 1.0 and 1.70 (1.08-2.69, p = 0.022) respectively in normal and high ACR levels in diabetes patients after adjusting for potential confounders. After propensity score matching, the OR (95% CI) between log2-transformed ACR and PAD was 1.0 and 1.85 (1.05-3.23, p = 0.031) respectively in normal and high ACR levels in diabetes patients after adjusting for potential confounders. CONCLUSION: The elevated urinary ACR level was associated with PAD in Chinese diabetes patients.

Joint polarization detection and degradation mechanisms for underwater image enhancement.

Light absorption and scattering exist in the underwater environment, which can lead to blurring, reduced brightness, and color distortion in underwater images. Polarized images have the advantages of eliminating underwater scattering interference, enhancing contrast, and detecting material information of the object in underwater detection. In this paper, from the perspective of polarization imaging, different concentrations (0.15 g/ml, 0.30 g/ml, and 0.50 g/ml), different wave bands (red, green, and blue), different materials (copper, wood, high-density PVC, aluminum, cloth, foam, cloth sheet, low-density PVC, rubber, and porcelain tile), and different depths (10 cm, 20 cm, 30 cm, and 40 cm) are set up in a chamber for the experimental environment. By combining the degradation mechanism of underwater images and the analysis of polarization detection results, it is proved that the degree of polarization images have greater advantages than degree of linear polarization images, degree of circular polarization images, S1, S2, and S3 images, and visible images underwater. Finally, a fusion algorithm of underwater visible images and polarization images based on compressed sensing is proposed to enhance underwater degraded images. To improve the quality of fused images, we introduce orthogonal matching pursuit (OMP) in the high-frequency part to improve image sparsity and consistency detection in the low-frequency part to improve the image mutation phenomenon. The fusion results show that the peak SNR values of the fusion result maps using OMP in this paper are improved by 32.19% and 22.14% on average over those using backpropagation and subspace pursuit methods. With different materials and concentrations, the underwater image enhancement algorithm proposed in this paper improves information entropy, average gradient, and standard deviation by 7.76%, 18.12%, and 40.8%, respectively, on average over previous algorithms. The image NIQE value shows that the image quality obtained by this paper's algorithm is improved by about 69.26% over the original S0 image.

Lymphocyte Subsets Are Associated with Disease Status in Neuromyelitis Optica Spectrum Disorders.

OBJECTIVE: At present, studies on lymphocytes are mostly conducted on CD19+ B cells and CD27+ B cells in neuromyelitis optica spectrum disorders (NMOSDs), but the exact changes in lymphocyte subsets (CD19+ B cells, CD3+ T cells, CD4+ Th cells, CD8+ Ts cells, the CD4+/CD8+ ratio, and NK [CD56+ CD16] cells) have rarely been studied. This study aimed to assess lymphocyte subset changes in patients with NMOSD. METHODS: We performed a cross-sectional study of consecutive patients with acute NMOSD (n = 41), chronic NMOSD (n = 21), and healthy individuals (n = 44). Peripheral blood samples were obtained upon admission, and lymphocyte subsets were analyzed by flow cytometry. Levels of lymphocyte subsets among 3 groups were compared and its correlation with the length of spinal cord lesions was analyzed. RESULTS: The levels of peripheral blood CD19+ B cells were significantly higher in patients with acute and chronic NMOSD than in healthy controls (HCs) (17.91 ± 8.7%, 13.08 ± 7.562%, and 12.48 ± 3.575%, respectively; p < 0.001) and were positively correlated with the length of spinal cord lesions in acute NMOSD (r = 0.433, p < 0.05). The peripheral blood CD4+/CD8+ ratio was significantly lower in patients with acute NMOSD and chronic NMOSD than in HCs (1.497 ± 0.6387, 1.33 ± 0.5574, and 1.753 ± 0.659, respectively; p < 0.05), and the levels of peripheral blood NK (CD56+ CD16) cells were significantly lower in patients with acute and chronic NMOSD than in HCs (13.6 ± 10.13, 11.11 ± 7.057, and 14.7 [interquartile range = 9.28], respectively; p < 0.01). CONCLUSIONS: The levels of certain subsets of peripheral blood lymphocytes are associated with disease status in NMOSD.

Muscle Mass Measurement Using Machine Learning Algorithms with Electrical Impedance Myography.

Sarcopenia is a wild chronic disease among elderly people. Although it does not entail a life-threatening risk, it will increase the adverse risk due to the associated unsteady gait, fall, fractures, and functional disability. The import factors in diagnosing sarcopenia are muscle mass and strength. The examination of muscle mass must be carried in the clinic. However, the loss of muscle mass can be improved by rehabilitation that can be performed in non-medical environments. Electronic impedance myography (EIM) can measure some parameters of muscles that have the correlations with muscle mass and strength. The goal of this study is to use machine learning algorithms to estimate the total mass of thigh muscles (MoTM) with the parameters of EIM and body information. We explored the seven major muscles of lower limbs. The feature selection methods, including recursive feature elimination (RFE) and feature combination, were used to select the optimal features based on the ridge regression (RR) and support vector regression (SVR) models. The optimal features were the resistance of rectus femoris normalized by the thigh circumference, phase of tibialis anterior combined with the gender, and body information, height, and weight. There were 96 subjects involved in this study. The performances of estimating the MoTM used the regression coefficient (r2) and root-mean-square error (RMSE), which were 0.800 and 0.929, and 1.432 kg and 0.980 kg for RR and SVR models, respectively. Thus, the proposed method could have the potential to support people examining their muscle mass in non-medical environments.

SARS-CoV-2 and SARS-CoV: Virtual screening of potential inhibitors targeting RNA-dependent RNA polymerase activity (NSP12).

Since the outbreak of severe acute respiratory syndrome (SARS) in 2003, the harm caused by coronaviruses to the world cannot be underestimated. Recently, a novel coronavirus (severe acute respiratory syndrome coronavirus-2 [SARS-CoV-2]) initially found to trigger human severe respiratory illness in Wuhan City of China in 2019, has infected more than six million people worldwide by 21 June 2020, and which has been recognized as a public health emergency of international concern as well. And the virus has spread to more than 200 countries around the world. However, the effective drug has not yet been officially licensed or approved to treat SARS-Cov-2 and SARS-Cov infection. NSP12-NSP7-NSP8 complex of SARS-CoV-2 or SARS-CoV, essential for viral replication and transcription, is generally regarded as a potential target to fight against the virus. According to the NSP12-NSP7-NSP8 complex (PDB ID: 7BW4) structure of SARS-CoV-2 and the NSP12-NSP7-NSP8 complex (PDB ID: 6NUR) structure of SARS-CoV, NSP12-NSP7 interface model, and NSP12-NSP8 interface model were established for virtual screening in the present study. Eight compounds (Nilotinib, Saquinavir, Tipranavir, Lonafarnib, Tegobuvir, Olysio, Filibuvir, and Cepharanthine) were selected for binding free energy calculations based on virtual screening and docking scores. All eight compounds can combine well with NSP12-NSP7-NSP8 in the crystal structure, providing drug candidates for the treatment and prevention of coronavirus disease 2019 and SARS.

Cucurbitacin B exhibits antitumor effects on CD133+ HepG2 liver cancer stem cells by inhibiting JAK2/STAT3 signaling pathway.

Cancer stem cells (CSCs), a crucial cancer cell subpopulation, possess stemness phenotypic characteristics. Cucurbitacin B (CuB), a tetracyclic triterpenoid isolated from Cucurbitaceae, exerts widely pharmacological activities in many diseases. The aim of this study was to enrich, identify liver CSCs and investigate antitumor effects of CuB as well as explore the underlying molecular mechanisms in these liver CSCs. HepG2 cell lines were used for the enrichment of liver CSCs by serum-free medium culture and magnetic-activated cell sorting. The CSC characteristics were analyzed by immunofluorescent staining, sphere-forming, western blot and xenograft tumorigenicity assay. CuB' antitumor effects and underlying molecular mechanism were measured by cell counting kit-8, colony formation, sphere-forming, cell cycle, xenograft and western blot assay. Our results showed that we could enrich 97.29% CD133+ HepG2 cells, which possessed CSC characteristics including re-renewal capacity, proliferative ability, sorafenib resistance, overexpressed stemness-related molecules and enhanced tumorigenic potential. Furthermore, we also found that CuB inhibited cell viability, sphere formation, colony formation and arrested cell cycle at G2/M phase as well as sensitized CD133+ HepG2 cells to sorafenib in vitro and in vivo. Western blot assay indicated that CuB inhibited expression levels of cyclin B1, CDK1, CD133, p-JAK2 and p-STAT3. In conclusion, our findings indicated that CuB could exhibit antitumor effects on CD133+ HepG2 CSCs by inhibiting the Janus kinase 2/signal transducers and activators of transcription-3 signaling pathway, expanding basic and preclinical investigations on liver CSCs.

Multiple microRNAs regulate tacrolimus metabolism through CYP3A5.

The CYP3A5 gene polymorphism accounts for the majority of inter-individual variability in tacrolimus pharmacokinetics. We found that the basal expression of CYP3A5 in donor grafts also played a significant role in tacrolimus metabolism under the same genetic conditions after pediatric liver transplantation. Thus, we hypothesized that some potential epigenetic factors could affect CYP3A5 expression and contributed to the variability. We used a high-throughput functional screening for miRNAs to identify miRNAs that had the most abundant expression in normal human liver and could regulate tacrolimus metabolism in HepaRG cells and HepLPCs. Four of these miRNAs (miR-29a-3p, miR-99a-5p, miR-532-5p, and miR-26-5p) were selected for testing. We found that these miRNAs inhibited tacrolimus metabolism that was dependent on CYP3A5. Putative miRNAs targeting key drug-metabolizing enzymes and transporters (DMETs) were selected using an in silico prediction algorithm. Luciferase reporter assays and functional studies showed that miR-26b-5p inhibited tacrolimus metabolism by directly regulating CYP3A5, while miR-29a-5p, miR-99a-5p, and miR-532-5p targeted HNF4α, NR1I3, and NR1I2, respectively, in turn regulating the downstream expression of CYP3A5; the corresponding target gene siRNAs markedly abolished the effects caused by miRNA inhibitors. Also, the expression of miR-29a-3p, miR-99a-5p, miR-532-5p, and miR-26b-5p in donor grafts were negatively correlated with tacrolimus C/D following pediatric liver transplantation. Taken together, our findings identify these miRNAs as novel regulators of tacrolimus metabolism.

Effect of a monocyte chemoattractant protein-1 synthesis inhibitor on fibroblasts from patients with carpal tunnel syndrome.

BACKGROUND: Carpal Tunnel Syndrome (CTS) is an idiopathic fibrotic disorder. Fibrosis in the subsynovial connective tissues (SSCT) of CTS and many other fibrotic diseases is mediated by Transforming growth factor ß (TGF-ß). Recently monocyte chemoattractant protein-1 (MCP-1) a cytokine involved in cellular recruitment has been suggested to regulate TGF-ß activity. It is related to the onset of diseases which are caused by fibrosis, such as idiopathic pulmonary fibrosis, renal fibrosis, and systemic scleroderma. In this study, we evaluated the effect of the MCP-1 synthesis inhibitor, Bindarit, on primary cultures of fibroblasts from the SSCT of five CTS patients. METHODS: Fibroblasts were treated with Bindarit (10 µM, 50 µM, 100 µM, or 300 µM). Responses to inhibitors were evaluated by regulation of CTS fibrosis-associated genes, fibrosis gene array and Smad luciferase reporter assay. We also assessed the combination effect of Bindarit and SD208, a TGF-ß receptor type 1 inhibitor on TGF-ß signaling. RESULTS: Collagen type III A1 (Col3), connective tissue growth factor (CTGF), and SERPINE1 expression were significantly down-regulated by Bindarit (300 µM) compared to vehicle control. In the fibrosis array, expression of inhibin beta E chain precursor (INHBE), beta actin (ACTB), endothelin 1 (EDN1) and hypoxanthine phosphoribosyltransferase 1 (HPRT1) were significantly down-regulated, and integrin beta-3 (ITGB3) was significantly up-regulated by Bindarit (300 µM). Smad signal transduction activation was significantly down-regulated by Bindarit (300 µM) and/or SD208 (1 µM) with TGF-ß1 compared to vehicle control with TGF-ß1. CONCLUSIONS: These results suggest that Bindarit in combination with SD208 may be beneficial as medical therapy for the SSCT fibrosis associated with CTS.

Spindle-like porous N-doped TiO2 encapsulated (Ca,Y)F2:Yb3+,Tm3+ as the efficient photocatalyst near-infrared range.

In this study, a novel photocatalyst composed of N-doped TiO2 (N-TiO2) and (Ca, Y)F2:Yb3+, Tm3+ was prepared by simple dealloying followed by a hydrothermal method. The composite exhibits a homogeneous nanoporous structure consisting of large quantities of the spindle-like N-doped TiO2 nanorods, on which the (Ca, Y)F2:Yb3+, Tm3+ particles with a diameter of around 5 nm are uniformly dispersed. In addition, morphology and property of the N-TiO2 can be controlled by adjusting the dealloying period. Results show that a short immersion time leads to a small size, large surface area and low band gap. As a result, the N-TiO2/(Ca, Y)F2:Yb3+, Tm3+ composite after dealloying for 48 h (TiO2-48-C) exhibits higher degradation rates (65.6% for 10 h irradiation by 980 nm NIR) than others after dealloying for 60 h (TiO2-60-C) and 72 h (TiO2-72-C), indicating its excellent potential for practical applications.

Segmentation of finger tendon and synovial sheath in ultrasound image using deep convolutional neural network.

BACKGROUND: Trigger finger is a common hand disease, which is caused by a mismatch in diameter between the tendon and the pulley. Ultrasound images are typically used to diagnose this disease, which are also used to guide surgical treatment. However, background noise and unclear tissue boundaries in the images increase the difficulty of the process. To overcome these problems, a computer-aided tool for the identification of finger tissue is needed. RESULTS: Two datasets were used for evaluation: one comprised different cases of individual images and another consisting of eight groups of continuous images. Regarding result similarity and contour smoothness, our proposed deeply supervised dilated fully convolutional DenseNet (D2FC-DN) is better than ATASM (the state-of-art segmentation method) and representative CNN methods. As a practical application, our proposed method can be used to build a tendon and synovial sheath model that can be used in a training system for ultrasound-guided trigger finger surgery. CONCLUSION: We proposed a D2FC-DN for finger tendon and synovial sheath segmentation in ultrasound images. The segmentation results were remarkably accurate for two datasets. It can be applied to assist the diagnosis of trigger finger by highlighting the tissues and generate models for surgical training systems in the future. METHODS: We propose a novel finger tendon segmentation method for use with ultrasound images that can also be used for synovial sheath segmentation that yields a more complete description for analysis. In this study, a hybrid of effective convolutional neural network techniques are applied, resulting in a deeply supervised dilated fully convolutional DenseNet (D2FC-DN), which displayed excellent segmentation performance on the tendon and synovial sheath.

Role of an additional third screw in the fixation of transverse patellar fracture with two parallel cannulated screw and anterior wire.

BACKGROUND: Two parallel cannulated screws along with an anterior wire to construct a tension band is a popular approach in transverse patellar fractures. However, the optimal screw proximity, either deep or superficial screw placements, remains controversial. Hence, a new concept of the addition of a third screw to form a triangular configuration along with the original two parallel screws was proposed in this study. Therefore, the biomechanical effect of the additional third screw on the stability of the fractured patella was investigated with finite element (FE) simulation. METHODS: An FE knee model including the distal femur, proximal tibia, and fractured patella (type AT/OTA 34-C) was developed in this study. Four different screw configurations, including two parallel cannulated screws with superficial (5-mm proximity) and deep (10-mm proximity) placements and two parallel superficial screws plus a third deep screw, and two parallel deep screws plus a third superficial screw, with or without the anterior wire, were considered for the simulation. RESULTS: Results indicated that the addition of a third screw increased stability by reducing the dorsal gap opening when two parallel screws were deeply placed, particularly on the fractured patella without an anterior wire. However, the third screw was of little value when two parallel screws were superficially placed. In the existence of two deep parallel screws and the anterior wire, the third screw reduced the gap opening by 23.5% (from 1.15 mm to 0.88 mm) and 53.6% (from 1.21 mm to 0.61 mm) in knee flexion 45° and full extension, respectively. Furthermore, in the absence of the anterior wire, the third screw reduced the gap opening by 73.5% (from 2 mm to 0.53 mm) and 72.2% (from 1.33 mm to 0.37 mm) in knee flexion 45° and full extension, respectively. CONCLUSION: Based on the results, a third cannulated screw superficially placed (5-mm proximity) is recommended to increase stability and maintain contact of the fractured patella, fixed with two parallel cannulated screws deeply placed (10-mm proximity), particularly when an anterior wire was not used. Furthermore, the third screw deeply placed is not recommended in a fractured patella with two parallel superficial screws.

Calculation of flexor pollicis longus moment arm for wrist motion in a cadaver model validates the tenodesis effect for therapy.

INTRODUCTION: Synergies of fingers and wrist motion have been incorporated into therapies for finger flexor tendon injuries to improve repair outcomes. Similar synergistic therapy strategies have not been well documented for the thumb. PURPOSE OF THE STUDY: The purpose of this study was to investigate the extent to which wrist motion enables a synergistic effect at the thumb in a cadaveric model by measuring flexor pollicis longus excursion and calculating the moment arm of this tendon at the wrist joint. STUDY DESIGN: This is a basic science research. METHODS: Eight fresh-frozen cadaveric arms were obtained from our anatomical bequest program. The proximal arm was fixed in neutral pronation/supination position, and motion of the wrist was guided through either flexion/extension or radial/ulnar deviation. Fingers were fixed in extension, thumb interphalangeal and metacarpophalangeal joints were fixed in neutral extension, and the carpometacarpal joint was fixed at 30° palmar abduction. The flexor pollicis longus tendon was exposed proximal to the wrist crease and connected to a rotary potentiometer to measure tendon excursion. Optical markers were attached to the hand to capture kinematics. Wrists were moved from a neutral position over the range of flexion and extension and then from the neutral position through the range of radial to ulnar deviation. Moment arms were calculated. RESULTS: Moment arm calculation indicated that the flexor pollicis longus acts as a wrist flexor over the entire motion range and as a weak radial deviator at ulnarly-deviated positions. CONCLUSIONS: This study provides a mechanistic rationale for passive interphalangeal joint motion in varying wrist positions when treating thumb flexor tendon injuries, with benefits seen primarily for wrist extension.

Effects of dietary amylose/amylopectin ratio and amylase on growth performance, energy and starch digestibility, and digestive enzymes in broilers.

This study was conducted to investigate the effects of dietary amylose/amylopectin (AM/AP) ratio and amylase on growth performance, apparent digestibility of energy and starch, serum biochemical index, and digestive enzymes. The experiment used a 4 × 3 factor design, and 960 one-day-old Arbor Acres (AA) broilers were randomly divided into 12 groups fed diets containing different AM/AP ratio of 0.11, 0.23, 0.35 and 0.47 and combined with 0, 3,000 and 6,000 U/kg amylase. Results showed that 0.23-0.35 AM/AP ratio increased growth performance, while dietary addition of 6,000 U/kg amylase significantly reduced average daily weight gain in broilers. The energy digestibility was significantly reduced along with the increase of dietary AM/AP ratio and in the 6,000 U/Kg amylase-supplemented groups. The digestibility of starch also decreased significantly with the increase of dietary AM/AP ratio, but high dose (6,000 U/Kg) of amylase increased. High AM/AP diet reduced serum insulin concentration, which was increased in amylase-supplemented groups. Furthermore, exogenous amylase increased amylase activity in the jejunal chyme. In conclusion, dietary 0.23-0.35 AM/AP ratio was suggested to maintain a higher growth performance in broilers and high AM/AP ratio diets reduced energy and starch digestibility and serum insulin concentration, which was reversed by dietary amylase.

Identification and characterization of the Cucurbitacins, a novel class of small-molecule inhibitors of Tropomyosin receptor kinase a.

BACKGROUND: NGF-TrkA is well known to play a key role in propagating and sustaining pruritogenic signals, which form the pathology of chronic pruritus. Inhibition of NGF-TrkA is a known strategy for the treatment of pruritus. In the present paper, we describe the identification, in vitro characterization, structure-activity analysis, and inhibitory evaluation of a novel TrkA inhibitory scaffold exemplified by Cucurbitacins (Cus). METHODS: Cus were identified as TrkA inhibitors in a large-scale kinase library screen. To obtain structural models of Cus as TrkA inhibitors, AutoDock was used to explore their binding to TrkA. Furthermore, PC12 cell culture systems have been used to study the effects of Cus and traditional Chinese medicinal plants (Tian Gua Di and bitter gourd leaf) extracts on the kinase activity of TrkA. RESULTS: Cus block the phosphorylation of TrkA on several tyrosine sites, including Tyr490, Tyr674/675, and Tyr785, and inhibit downstream Akt and MAPK phosphorylation in response to NGF in PC12 cell model systems. Furthermore, traditional Chinese medicinal plants (Tian Gua Di and bitter gourd leaf) containing Cu extracts were shown to inhibit the phosphorylation of TrkA and Akt. These data reveal mechanisms, at least partly, of the anti-pruritus bioactivity of Cus. CONCLUSION: Taken together, with the recent discovery of the important role of TrkA as a therapeutic target, Cus could be the basis for the design of improved TrkA kinase inhibitors, which could someday help treat pruritus.