AlloMAPS 2: allosteric fingerprints of the AlphaFold and Pfam-trRosetta predicted structures for engineering and design.

AlloMAPS 2 is an update of the Allosteric Mutation Analysis and Polymorphism of Signalling database, which contains data on allosteric communication obtained for predicted structures in the AlphaFold database (AFDB) and trRosetta-predicted Pfam domains. The data update contains Allosteric Signalling Maps (ASMs) and Allosteric Probing Maps (APMs) quantifying allosteric effects of mutations and of small probe binding, respectively. To ensure quality of the ASMs and APMs, we performed careful and accurate selection of protein sets containing high-quality predicted structures in both databases for each organism/structure, and the data is available for browsing and download. The data for remaining structures are available for download and should be used at user's discretion and responsibility. We believe these massive data can facilitate both diagnostics and drug design within the precision medicine paradigm. Specifically, it can be instrumental in the analysis of allosteric effects of pathological and rescue mutations, providing starting points for fragment-based design of allosteric effectors. The exhaustive character of allosteric signalling and probing fingerprints will be also useful in future developments of corresponding machine learning applications. The database is freely available at: http://allomaps.bii.a-star.edu.sg.

Prognostic scoring system for pediatric Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis based on baseline characteristics: A multicenter retrospective study.

BACKGROUND: The prognosis of pediatric Epstein-Barr virus (EBV)-associated hemophagocytic lymphohistiocytosis (EBV-HLH) varies. This study aimed to identify high-risk children early. PROCEDURE: Data from 264 children (0-14 years of age), diagnosed with EBV-HLH at six centers in China between January 2016 and December 2021, were analyzed. Patients were randomly divided into derivation (n = 185) and verification (n = 79) cohorts. A Cox regression model was used to explore risk predictors and establish a prognostic scoring system for death events that occurred during the follow-up period. RESULTS: Chronic active EBV infection (CAEBV) history (hazard ratio [HR] 1.82 [95% confidence interval, CI: 1.02-3.26]; p = .0441), plasma EBV-DNA more than 104  copies/mL (HR 2.89 [95% CI: 1.62-5.16]; p = .0003), pulmonary infection (HR 2.24 [95% CI: 1.06-4.75]; p = .0353), digestive tract hemorrhage (HR 2.55 [95% CI: 1.35-4.82]; p = .0041), and hypoxemia (HR 3.95 [95% CI: 2.15-7.26]; p < .0001) were independent risk factors. Accordingly, the CAEBV history, plasma EBV-DNA copy number, pulmonary infection hemorrhage of digestive tract, hypoxemia prognostic scoring system (CEPHO-PSS) were developed, which separated patients into low- (0-1 points), middle- (2-3 points), and high- (4-8 points) risk groups. Survival curves for the three groups exhibited statistically significant differences (p < .0001). Internal and external verification of CEPHO-PSS was performed using receiver operating characteristic (ROC) and calibration curves in the derivation and verification cohorts, respectively, confirming good accuracy and applicability. CONCLUSIONS: The CEPHO-PSS identified three risk groups with statistically significant differences in survival curves. It was based on the baseline characteristics, and can give clinicians a convenient check for risk prediction.

Novel kinase 1 regulates CD8+T cells as a potential therapeutic mechanism for idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a rare, chronic and progressively worsening lung disease that poses a significant threat to patient prognosis, with a mortality rate exceeding that of some common malignancies. Effective methods for early diagnosis and treatment remain for this condition are elusive. In our study, we used the GEO database to access second-generation sequencing data and associated clinical information from IPF patients. By utilizing bioinformatics techniques, we identified crucial disease-related genes and their biological functions, and characterized their expression patterns. Furthermore, we mapped out the immune landscape of IPF, which revealed potential roles for novel kinase 1 and CD8+T cells in disease progression and outcome. These findings can aid the development of new strategies for the clinical diagnosis and treatment of IPF.

A Common Variant of ARRB2 Promoter Region Associated with the Prognosis of Heart Failure.

INTRODUCTION: The role of ARRB2 in cardiovascular disease has recently gained increasing attention. However, the association between ARRB2 polymorphisms and heart failure (HF) has not yet been investigated. METHODS: A total of 2,386 hospitalized patients with chronic HF were enrolled as the first cohort and followed up for a mean period of 20.2 months. Meanwhile, ethnically and geographically matched 3,000 individuals without evidence of HF were included as healthy controls. We genotyped the common variant in ARRB2 gene to identify the association between variant and HF. A replicated independent cohort enrolling 837 patients with chronic HF was applied to validate the observed association. A series of function analyses were conducted to illuminate the underlying mechanism. RESULTS: We identified a common variant rs75428611 associated with the prognosis of HF in two-stage population: adjusted p = 0.001, hazard ratio (HR) = 1.31 (1.11-1.54) in additive model and adjusted p = 0.001, HR = 1.39 (1.14-1.69) in dominant model in first-stage population; adjusted p = 0.04, HR = 1.41 (1.02-1.95) in additive model and adjusted p = 0.03, HR = 1.51 (1.03-2.20) in dominant model in replicated stage. However, rs75428611 did not significantly associate with the risk of HF. Functional analysis indicated that rs75428611-G allele increased the promoter activity and the mRNA expression level of ARRB2 by facilitating transcription factor SRF binding but not the A allele. CONCLUSIONS: Our findings demonstrated that rs75428611 in promoter of ARRB2 was associated with the risk of HF mortality. It is a promising potential treatment target for HF.

CRIP1 fosters MDSC trafficking and resets tumour microenvironment via facilitating NF-κB/p65 nuclear translocation in pancreatic ductal adenocarcinoma.

OBJECTIVE: Pancreatic ductal adenocarcinoma (PDAC) is among the most immunosuppressive tumour types. The tumour immune microenvironment (TIME) is largely driven by interactions between immune cells and heterogeneous tumour cells. Here, we aimed to investigate the mechanism of tumour cells in TIME formation and provide potential combination treatment strategies for PDAC patients based on genotypic heterogeneity. DESIGN: Highly multiplexed imaging mass cytometry, RNA sequencing, mass cytometry by time of flight and multiplex immunofluorescence staining were performed to identify the pro-oncogenic proteins associated with low immune activation in PDAC. An in vitro coculture system, an orthotopic PDAC allograft tumour model, flow cytometry and immunohistochemistry were used to explore the biological functions of cysteine-rich intestinal protein 1 (CRIP1) in tumour progression and TIME formation. RNA sequencing, mass spectrometry and chromatin immunoprecipitation were subsequently conducted to investigate the underlying mechanisms of CRIP1. RESULTS: Our results showed that CRIP1 was frequently upregulated in PDAC tissues with low immune activation. Elevated CRIP1 expression induced high levels of myeloid-derived suppressor cell (MDSC) infiltration and fostered an immunosuppressive tumour microenvironment. Mechanistically, we primarily showed that CRIP1 bound to nuclear factor kappa-B (NF-κB)/p65 and facilitated its nuclear translocation in an importin-dependent manner, leading to the transcriptional activation of CXCL1/5. PDAC-derived CXCL1/5 facilitated the chemotactic migration of MDSCs to drive immunosuppression. SX-682, an inhibitor of CXCR1/2, blocked tumour MDSC recruitment and enhanced T-cell activation. The combination of anti-PD-L1 therapy with SX-682 elicited increased CD8+T cell infiltration and potent antitumor activity in tumour-bearing mice with high CRIP1 expression. CONCLUSIONS: The CRIP1/NF-κB/CXCL axis is critical for triggering immune evasion and TIME formation in PDAC. Blockade of this signalling pathway prevents MDSC trafficking and thereby sensitises PDAC to immunotherapy.

Watchman device migration and embolization: A report from the NCDR LAAO Registry.

INTRODUCTION: Incomplete anchoring of the Watchman left atrial appendage closure (LAAO) device can result in substantial device migration or device embolization (DME) requiring percutaneous or surgical retrieval. METHODS: We performed a retrospective analysis of Watchman procedures (January 2016 through March 2021) reported to the National Cardiovascular Data Registry LAAO Registry. We excluded patients with prior LAAO interventions, no device released, and missing device information. In-hospital events were assessed among all patients and postdischarge events were assessed among patients with 45-day follow-up. RESULTS: Of 120 278 Watchman procedures, the in-hospital DME rate was 0.07% (n = 84) and surgery was commonly performed (n = 39). In-hospital mortality rate was 14% among patients with DME and 20.5% among patients who underwent surgery. In-hospital DME was more common: at hospitals with a lower median annual procedure volume (24 vs. 41 procedures, p < .0001), with Watchman 2.5 versus Watchman FLX devices (0.08% vs. 0.04%, p = .0048), with larger LAA ostia (median 23 vs. 21 mm, p = .004), and with a smaller difference between device and LAA ostial size (median difference 4 vs. 5 mm, p = .04). Of 98 147 patients with 45-day follow-up, postdischarge DME occurred in 0.06% (n = 54) patients and cardiac surgery was performed in 7.4% (n = 4) of cases. The 45-day mortality rate was 3.7% (n = 2) among patients with postdischarge DME. Postdischarge DME was more common among men (79.7% of events but 58.9% of all procedures, p = .0019), taller patients (177.9 vs. 172 cm, p = .0005), and those with greater body mass (99.9 vs. 85.5 kg, p = .0055). The rhythm at implant was less frequently AF among patients with DME compared to those without (38.9% vs. 46.9%, p = .0098). CONCLUSION: While Watchman DME is rare, it is associated with high mortality and frequently requires surgical retrieval, and a substantial proportion of events occur after discharge. Due to the severity of DME events, risk mitigation strategies and on-site cardiac surgical back-up are of paramount importance.

Efficient beam splitting using zero-load-impedance metagratings: publisher's note.

This publisher's note contains corrections to Opt. Lett.48, 3275 (2023)10.1364/OL.491711.

Efficient beam splitting using zero-load-impedance metagratings.

Metagratings with zero load impedance are proposed to achieve efficient beam splitting. Different from previously proposed metagratings that require specific capacitive and/or inductive structures to achieve load impedance, the metagrating proposed here consists solely of simple microstrip-line structures. Such a structure overcomes the implementation constraints such that low-cost fabrication technology can be applied for metagratings operating at higher frequencies. The detailed theoretical design procedure is presented together with numerical optimizations to achieve the specific design parameters. Finally, several reflection-type beam-splitting devices with different pointing angles are designed, simulated, and experimentally measured. The results show very high performance at 30 GHz, paving the way to simple and low-cost printed circuit board (PCB) metagratings at millimeter-wave and higher frequencies.

Image restoration algorithm for terahertz FMCW radar imaging.

The terahertz frequency modulation continuous-wave (THz FMCW) imaging technology has been widely used in non-destructive testing applications. However, THz FMCW real-aperture radar usually has a small depth of field and poor lateral resolution, thus restricting the high-precision imaging application. This paper proposes a 150-220 GHz FMCW Bessel beam imaging system, effectively doubling the depth of field and unifying the lateral resolution compared to the Gaussian beam quasi-optical system. Moreover, a THz image restoration algorithm based on local gradients and convolution kernel priors is proposed to eliminate further the convolution effect introduced by the Bessel beam, thereby enhancing the lateral resolution to 2 mm. It effectively improves the image under-restoration or over-restoration caused by the mismatch between the ideal and actual point spread function. The imaging results of the resolution test target and semiconductor device verify the advantages of the proposed system and algorithm.

Semi-Synthesis of Flavonoid Glycosides and Their Anti-Inflammatory and Antitumor Activities towards Triple Negative Breast Cancer.

BACKGROUND: Flavonoid glycosides are known to possess diverse bioactivities including antitumor and anti-inflammatory properties. Hesperetin is abundant in nature and can be used to synthesize bioactive flavonoids. This has the advantages of low cost, short synthetic steps, simple operation, and good yields. OBJECTIVE: In this study, we aimed to synthesize bioactive flavonoids and flavonoid glycosides from hesperetin and evaluate the antitumor and anti-inflammatory activities of these compounds. METHODS: A series of flavonoids and their derivatives were synthesized by methoxylation, oxidative dehydrogenation, benzylation, debenzylation, and deacetylation as well as using a modified peroxyacetone method and a glycoside condensation reaction. Their anti-inflammatory activities were evaluated for their inhibitory effects on nitric oxide (NO), tumor necrosis factor (TNF-α), and interleukin-6 (IL-6) production in LPS-induced RAW264.7 mouse macrophages. Their structures were characterized by HRMS, 1 H-NMR, and 13 C-NMR, and their cytotoxicity on the human triple-negative breast cancer cell (TNBC) line, SUM 149, was tested by using the MST assay. RESULTS: Most of the compounds markedly reduced NO production in LPS-stimulated murine macrophages at the tested concentrations in a dose-dependent manner. Among these, compounds 1, 7, 9, and 17 showed significant anti-inflammatory activities against NO production in LPS-induced RAW264.7 mouse macrophages. In addition, they could also reduce the release of TNF-α and IL-6 in a concentration-dependent manner. Most of the tested compounds showed remarkable anti-human TNBC activities. Compounds 1b-1m, 1, and 3 showed a certain degree of growth inhibition effect on the human TNBC cell lines and their IC50 values were all below 16.61 µM. In addition, compound 1l was the most cytotoxic with IC50 values of 1.38±0.31 µM, while the other compounds were inactive with inhibition rates <50 % at the highest concentration tested (20 µM). CONCLUSIONS: A novel series of flavonoids were synthesized from the natural flavonoid, hesperetin, including 17 new compounds. Screening tests indicated that most of these compounds reduced NO production in LPS-stimulated murine macrophages at concentrations of 15 to 60 µM, and the inhibition generally increased in a dose-dependent manner. Some compounds showed different degrees of cytotoxicity on the human TBNC cell lines, SUM 149.

Comparison of biliary protein spectrum in gallstone patients with obesity and those with normal body weight.

BACKGROUND: Obesity is a common public health issue and is currently deemed a disease. Research has shown that the risk of gallstones in individuals with obesity is elevated. This study aimed to explore the bile proteomics differences between cholelithiasis patients with obesity and normal body weight. METHODS: Bile samples from 20 patients (10 with obesity and 10 with normal body weight) who underwent laparoscopic cholecystectomy at our center were subjected to tandem mass tag labeling (TMT) and liquid chromatography-tandem mass spectrometry (LC-MS/MS), followed by further bioinformatic analysis. RESULTS: Among the differentially-expressed proteins, 23 were upregulated and 67 were downregulated. Bioinformatic analysis indicated that these differentially-expressed proteins were mainly involved in cell development, inflammatory responses, glycerolipid metabolic processes, and protein activation cascades. In addition, the activity of the peroxisome proliferator-activated receptor (PPAR, a subfamily of nuclear receptors) signaling pathway was decreased in the Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. Two downregulated proteins in the PPAR signaling pathway, APOA-I and APOA-II, were confirmed using enzyme-linked immunosorbent assay. CONCLUSIONS: The PPAR signaling pathway may play a crucial role in the development of cholelithiasis among patients with obesity. Furthermore, biliary proteomics profiling of gallstones patients with obesity is revealed, providing a reference for future research.

The Prognostic Value of Blood Urea Nitrogen to Albumin Ratio on Patients with Heart Failure.

This study aimed to investigate the relationship between blood urea nitrogen to albumin ratio (BAR) and the prognosis of heart failure (HF).A total of 2125 patients with HF were included in this single-center prospective cohort study between February 2012 and December 2017. Using a receiver operating characteristic curve, we determined the cutoff value of BAR as 0.24. All patients were divided into two groups according to the cutoff value of BAR.Among 2125 HF patients, the mean age was 56.7 ± 14.3. During a median follow-up time of 22 months, 516 end-point events occurred. Compared with patients in the low BAR group, those in the high BAR group were older; more likely to be male; had a higher percentage of hypertension, diabetes, smoking, and ß-blocker use; and higher levels of alanine aminotransferase, glycosylated hemoglobin, creatinine, log-transformed NTproBNP, and Blood urea nitrogen but lower levels of albumin, triglycerides, high-density lipoprotein, ApoA1, and hemoglobin. Prognosis analysis indicated that high BAR was associated with increased mortality risk of HF (Hazard Ratio = 1.497, 95% CI = 1.234-1.816; P < 0.001) in the multivariate Cox proportional hazard regression model. Subgroup analysis revealed that stratification by age, gender, history of hypertension, diabetes, smoking, ß-blocker use, and levels of hemoglobin, glycosylated hemoglobin, and creatinine have no obvious effect on the association between BAR ratio and the prognosis of HF. Furthermore, patients with high BAR represented a decreased left ventricular ejection fraction and increased left ventricular end-diastolic diameter.High BAR was an independent predictor for the mortality risk of HF.

Characterization of a novel recombinant halophilic ß-glucosidase of Trichoderma harzianum derived from Hainan mangrove.

BACKGROUND: ß-glucosidase is an important biomass-degrading enzyme and plays a vital role in generating renewable biofuels through enzymatic saccharification. In this study, we analyzed the transcriptome of Trichoderma harzianum HTASA derived from Hainan mangrove and identified a new gene encoding ß-glucosidase Bgl3HB. And the biochemically characterization of ß-glucosidase activity was performed. RESULTS: Bgl3HB showed substantial catalytic activity in the pH range of 3.0-5.0 and at temperatures of 40 ℃-60 ℃. The enzyme was found quite stable at 50 ℃ with a loss of only 33.4% relative activity after 240 min of heat exposure. In addition, all tested metal ions were found to promote the enzyme activity. The ß-glucosidase activity of Bgl3HB was enhanced by 2.12-fold of its original activity in the presence of 5 M NaCl. Surprisingly, Bgl3HB also showed a remarkable ability to hydrolyze laminarin compared to other measured substrates. Enzyme efficiency was examined in the sugarcane bagasse saccharification processes, in which Bgl3HB with 5 M NaCl worked better supplementing Celluclast 1.5L than the commercial Novozyme 188 ascertained it as an admirably suited biocatalyst for the utilization of agricultural waste. In this work, this is the first report of a halophilic ß-glucosidase from Trichoderma harzianum, and represents the ß-glucosidase with the highest known NaCl activation concentration. And adding 5 M NaCl could enhance saccharification performance even better than commercial cellulase. CONCLUSIONS: These results show that Bgl3HB has great promise as a highly stable and highly efficient cellulase with important future applications in the industrial production of biofuels.

Identification of novel and potential PPARγ stimulators as repurposed drugs for MCAO associated brain degeneration.

Peroxisome proliferator-activated receptor-gamma (PPARγ) has been shown to have therapeutic promise in the treatment of ischemic stroke and is supported by several studies. To identify possible PPARγ activators, the current study used an in silico technique in conjunction with molecular simulations and in vivo validation. FDA-approved drugs were evaluated using molecular docking to determine their affinity for PPARγ. The findings of molecular simulations support the repurposing of rabeprazole and ethambutol for the treatment of ischemic stroke. Adult Sprague Dawley rats were subjected to transient middle cerebral artery occlusion (t-MCAO). Five groups were made as a sham-operated, t-MCAO group, rabeprazole +t-MCAO, ethambutol +t-MCAO, and pioglitazone +t-MCAO. The neuroprotective effects of these drugs were evaluated using the neurological deficit score and the infarct area. The inflammatory mediators and signaling transduction proteins were quantified using Western blotting, ELISA, and immunohistochemistry. The repurposed drugs mitigated cerebral ischemic injury by PPARγ mediated downregulation of nods like receptor protein 3 inflammasomes (NLRP3), tumor necrosis factor-alpha (TNF-α), cyclooxygenase 2 (COX-2), nuclear factor kappa-light-chain-enhancer of activated B cells (p-NF-kB), and c-Jun N-terminal kinase (p-JNK). Our data demonstrated that rabeprazole and ethambutol have neuroprotective potential via modulating the cytoprotective stress response, increasing cellular survival, and balancing homeostatic processes, and so may be suitable for future research in stroke therapy.

Efficacy and safety of sequential combination therapy for pulmonary arterial hypertension: A meta-analysis of Randomized-Controlled Trials.

BACKGROUND: Previous meta-analyses of pulmonary arterial hypertension (PAH) combination therapy pooled sequential and initial combination together, which might threaten their authenticity and clinical significance for the difference between two strategies. METHODS: PubMed, Embase, and the Cochrane Library were searched for randomized controlled trials (RCTs) that compared sequential combination therapy (SCT) with background therapy (BT) in PAH patients. Raw data were extracted to calculate risk ratio (RR) or weighted mean difference (WMD) for predefined efficacy and safety outcomes. Mantel-Haenszel fixed or random effects model was used based on heterogeneity. RESULTS: 17 RCTs involving 4343 patients (97.2% of patients with WHO-FC II-III) were included. SCT decreased clinical worsening (RR 0.66, 95% CI 0.58 to 0.76), nonfatal clinical worsening (RR 0.61, 95% CI 0.52 to 0.71), functional class (decrease of 28% in the portion of patients with WHO-FC worsening and increase of 33% in the portion of patients with WHO-FC improvement), and increased 6-min walk distance (WMD 17.68 m, 95% CI 10.16 to 25.20), but didn't reduce mortality, lung transplantation, admission to hospital, and treatment escalation compared with BT. Although any adverse event and serious adverse event were similar between SCT and BT, SCT increased all-cause treatment discontinuation (RR 1.49, 95% CI 1.30 to 1.71) and drug-related treatment discontinuation (RR 2.30, 95% CI 1.86 to 2.84) with higher incidence of headache, flushing, nausea, diarrhoea and jaw pain. CONCLUSIONS: For WHO-FC II-III PAH patients who have established BT, our study reinforced the recommendation of SCT to improve clinical worsening, functional status, and exercise capacity, although with higher incidence of side-effects and withdrawal.

Bmal1- and Per2-mediated regulation of the osteogenic differentiation and proliferation of mouse bone marrow mesenchymal stem cells by modulating the Wnt/ß-catenin pathway.

BACKGROUND: Bmal1 and Per2 are the core components of the circadian clock genes (CCGs). Bmal1-/- mice exhibit premature aging, as indicated by hypotrichosis and osteoporosis, with a loss of proliferation ability. The same occurs in Per2-/- mice, albeit to a less severe degree. However, whether the effects of Bmal1 and Per2 on proliferation and osteogenic differentiation are synergistic or antagonistic remains unclear. Thus, our study aimed to explore the effects and specific mechanism. METHODS AND RESULTS: Lentiviral and adenoviral vectors were constructed to silence or overexpress Bmal1 or Per2 and MTT, flow cytometry, RT-qPCR, WB, immunohistochemistry, alizarin red staining and ChIP-Seq analyses were applied to identify the possible mechanism. The successful knockdown and overexpression of Bmal1/Per2 were detected by fluorescence microcopy. Flow cytometry found out that Bmal1 or Per2 knockdown resulted in G1-phase cell cycle arrest. RT-qPCR showed the different expression levels of Wnt-3a, c-myc1 and axin2 in the Wnt/ß-catenin signaling pathway as well as the gene expression change of Rorα and Rev-erbα. Meanwhile, related proteins such as ß-catenin, TCF-1, and P-GSK-3ß were detected. ALP activity and the amount of mineral nodules were compared. ChIP-Seq results showed the possible mechanism. CONCLUSIONS: Bmal1 and Per2, as primary canonical clock genes, showed synergistic effects on the proliferation and differentiation of BMSCs. They would inhibit the Wnt/ß-catenin signaling pathway by downregulating Rorα expression or upregulating Rev-erbα expression, both of which were also key elements of CCGs. And this may be the mechanism by which they negatively regulate the osteogenic differentiation of BMSCs. Bmal1 and Per2 show synergistic effects in the proliferation of BMSCs. In addition, they play a synergistic role in negatively regulating the osteogenic differentiation ability of BMSCs. Bmal1 and Per2 may regulate the aging of BMSCs by altering cell proliferation and osteogenic differentiation through Rorα and Rev-erbα to affect Wnt/ß-catenin pathway.

Overcoming chemoresistance by targeting reprogrammed metabolism: the Achilles' heel of pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer-related death due to its late diagnosis that removes the opportunity for surgery and metabolic plasticity that leads to resistance to chemotherapy. Metabolic reprogramming related to glucose, lipid, and amino acid metabolism in PDAC not only enables the cancer to thrive and survive under hypovascular, nutrient-poor and hypoxic microenvironments, but also confers chemoresistance, which contributes to the poor prognosis of PDAC. In this review, we systematically elucidate the mechanism of chemotherapy resistance and the relationship of metabolic programming features with resistance to anticancer drugs in PDAC. Targeting the critical enzymes and/or transporters involved in glucose, lipid, and amino acid metabolism may be a promising approach to overcome chemoresistance in PDAC. Consequently, regulating metabolism could be used as a strategy against PDAC and could improve the prognosis of PDAC.

AlloSigMA 2: paving the way to designing allosteric effectors and to exploring allosteric effects of mutations.

The AlloSigMA 2 server provides an interactive platform for exploring the allosteric signaling caused by ligand binding and/or mutations, for analyzing the allosteric effects of mutations and for detecting potential cancer drivers and pathogenic nsSNPs. It can also be used for searching latent allosteric sites and for computationally designing allosteric effectors for these sites with required agonist/antagonist activity. The server is based on the implementation of the Structure-Based Statistical Mechanical Model of Allostery (SBSMMA), which allows one to evaluate the allosteric free energy as a result of the perturbation at per-residue resolution. The Allosteric Signaling Map (ASM) providing a comprehensive residue-by-residue allosteric control over the protein activity can be obtained for any structure of interest. The Allosteric Probing Map (APM), in turn, allows one to perform the fragment-based-like computational design experiment aimed at finding leads for potential allosteric effectors. The server can be instrumental in elucidating of allosteric mechanisms and actions of allosteric mutations, and in the efforts on design of new elements of allosteric control. The server is freely available at: http://allosigma.bii.a-star.edu.sg.

[Protective effect of oleanolic acid liposomes on cisplatin-induced oligoasthenospermia in mice].

OBJECTIVE: To study the protective effect of oleanolic acid liposomes (OA-Lips) on cisplatin-induced oligoasthenospermia (COAS) in mice. METHODS: Sixty ICR mice were randomly divided into a normal control, a COAS model control, a positive control and a low-, a medium- and a high-dose OA-Lips group. The animals in the low-, medium- and high-dose OA-Lips and positive control groups were given intragastrically OA-Lips solution at 25, 50, and 100 mg/kg/d and vitamin E at 50 mg/kg/d, respectively. On the 28th day, the mice in the COAS model control, positive control and OA-Lips groups were injected intraperitoneally with cisplatin solution at 10 mg/kg, while those in the normal control group with the same dose of normal saline. Three days after administration, all the mice were sacrificed and their testis tissues collected for detection of the semen parameters and observation of the testicular morphology. RESULTS: Both the percentage of motile sperm and sperm concentration were significantly increased in the high-dose OA-Lips group (P < 0.05). HE staining showed that OA-Lips remarkably improved the damaged testis tissue (P < 0.05) and protected the seminiferous tubules and interstitial cells. The percentage of progressively motile sperm (PMS) and the curvilinear velocity (VCL), straight line velocity (VSL), average path velocity (VAP), linearity (LIN), straightness (STR), wobble (WOB), amplitude of lateral head displacement (ALH) and beat-cross frequency (BCF) of sperm were gradually increased in a dose-dependent manner in the OA-Lips groups. The serum T level was significantly higher (P < 0.05) in the OA-Lips-treated mice than in the COAS model controls while the percentage of morphologically abnormal sperm (MAS) markedly lower in the high-dose OA-Lips group than in the model control, positive control and low-dose OA-Lips groups (P < 0.05). CONCLUSION: OA-Lips can relieve oligoaspermia and improve the productive ability of mice.

Aucubin prevents steroid-induced osteoblast apoptosis by enhancing autophagy via AMPK activation.

Steroid-induced osteoblast apoptosis is a crucial pathological process in steroid-induced osteonecrosis of the femoral head (SONFH). Autophagy can resist apoptosis and AMPK plays an important role in autophagy regulation. Aucubin from the small tree Eucommia ulmoides Oliv., which has a long history of use in orthopaedics and traumatology in Asian medicine, can promote bone formation, but whether it can slow or prevent steroid-osteoblast apoptosis is unclear. Therefore, we investigated the pathogenesis of SONFH and how the osteoblast responds to aucubin under the dexamethasone stimulation. In human femoral head osteonecrosis specimens, we found that the autophage and apoptosis level were increased, and the AMPK signalling was crucial to autophagy. We observed that aucubin could prevent dexamethasone-induced apoptosis in osteoblasts by enhancing the level of autophagy. Further, we confirmed that the regulatory effect of aucubin on autophagy and apoptosis was achieved by activating AMPK signalling. We have demonstrated a mechanism of disease progression and shown that aucubin could enhance autophagy through AMPK signalling to prevent osteoblast apoptosis. These findings provide a basis for the further investigation of the potential therapeutic role of aucubin in the SONFH.