Geniposide protects against neurotoxicity in mouse models of rotenone-induced Parkinson's disease involving the mTOR and Nrf2 pathways.

ETHNOPHARMACOLOGICAL RELEVANCE: Fructus Gardeniae, with the effects of discharging fire, eliminating vexation, reducing fever and causing diuresis, and cooling blood to remove apthogentic heat, could be used to treat Parkinson's disease (PD). Geniposide, as the main active ingredient of Fructus Gardeniae, has been shown to have neuroprotective effects in several rodent models. Rotenone, a commonly used neurotoxin, induced PD model progresses slowly, but simulates the pathological changes of PD's slow progression. AIM OF THE STUDY: Herein, we mainly investigated the neuroprotective effects of geniposide on rotenone-induced mouse model of PD and the underlined mechanism. MATERIALS AND METHODS: C57BL/6 mice were treated with rotenone (30 mg/kg, p. o.) daily for 60 days. Geniposide (25 and 50 mg/kg, p. o.) were administered at alterative day 30 min before rotenone. On day 60, the challenging beam, spontaneous activity, and adhesive removal tests were performed to evaluate the motor activity. Dopamine, DOPAC and HVA levels were detected by UPLC-MS/MS methods. Dopaminergic neurodegeneration was assessed using immunohistochemistry staining. ROS production, MDA level and GSH: GSSG ratio were measured to analyze oxidative stress. Cleavage of PARP and caspase-3 were detected to assess neuronal apoptosis. The expression of Nrf2 and mTOR signaling were detected using Western blot. RESULTS: Geniposide improved motor dysfunction, restored neurotransmitters levels, and attenuated dopaminergic neurodegeneration induced by rotenone in mice. Geniposide suppressed rotenone-induced neuronal oxidative damage associated with Nrf2 signaling, and neuronal apoptosis involving mTOR pathway. CONCLUSIONS: Geniposide may exert a neuroprotective effect in a mouse model of PD by rotenone, and this effect might be relevant to Nrf2 associated antioxidant signaling and mTOR involved anti-apoptosis pathway.

Alveolar Bone Morphologic Predictors for Guided Bone Regeneration Outcome in Anterior Maxilla.

OBJECTIVES: This study aimed to explore the influence of alveolar bone morphologic variables on the outcome of guided bone regeneration (GBR) in the anterior maxilla region. METHODS: Twenty-eight patients who received single maxillary anterior tooth delayed implant placed simultaneously with GBR were recruited. Baseline data including age, gender, implant site, implant brand, and bone graft materials were recorded. The resorption rate of the grafted bone (RRGB), labial bone width at 0 mm, 2 mm, and 4 mm apical to the implant platform at Tn (LBW0Tn, LBW2Tn, LBW4Tn), implant angulation (IA), maximum bone graft thickness (MBGT), bone graft volume (BGV), and the initial bone morphologic variables bone concavity depth (BCD) and bone concavity angulation (BCA) were measured. The Pearson correlation analysis, analysis of variance (ANOVA), and optimal binning method were used to explore the potential predictors for GBR. RESULTS: Among 28 patients, the labial bone width of implant and bone graft volume decreased significantly when measured 6 months after surgery. The mean percentage of RRGB was 49.78%. RRGB was not correlated with gender, age, bone graft material, IA, MBGT, bone graft volume at T1, implant site, and implant brand (P > .05). BCD and BCA were each moderately correlated with RRGB (r = -0.872 [P < .001] and r = 0.686 [P < .001], respectively). A BCD ≥1.03 mm and a BCA <155.30° resulted in a significantly lower percentage of RRGB (P < .001). CONCLUSIONS: A significant grafted bone materials volume reduction was detected after GBR with collagen membrane and deproteinized bovine bone mineral (DBBM). The initial bone morphology can influence GBR outcome, and a bone concavity with a depth ≥1.03 mm and an angulation <155.30° led to a lower RRGB. BCD and BCA can be used as variables to predict the outcome of GBR.

Sparse discriminant PCA based on contrastive learning and class-specificity distribution.

Much mathematical effort has been devoted to developing Principal Component Analysis (PCA), which is the most popular feature extraction method. To suppress the negative effect of noise on PCA performance, there have been extensive studies and applications of a large number of robust PCAs achieving outstanding results. However, existing methods suffer from at least two shortcomings: (1) They expressed PCA as a reconstruction model measured by Euclidean distance, which only considers the relationship between the data and its reconstruction and ignores the differences between different data points; (2) They did not consider the class-specificity distribution information contained in the data itself, thus lacking discriminative properties. To overcome the above problems, we propose a Sparse Discriminant Principal Components Analysis (SDPCA) model based on contrastive learning and class-specificity distribution. Specifically, we use contrastive learning to measure the relationship between samples and their reconstructions, which fully takes the discriminative information between data into account in PCA. In order to make the extracted low-dimensional features profoundly reflect the class-specificity distribution of the data, we minimize the squared ℓ1,2-norm of the low-dimensional embedding. In addition, to reduce the effects of redundant features and noise and to improve the interpretability of PCA at the same time, we impose sparsity constraints on the projection matrix using the squared ℓ1,2-norm. Our experimental results on different types of benchmark databases demonstrate that our model has state-of-the-art performance.

Association between Dietary Vitamin E Intake and Human Papillomavirus Infection among US Adults: A Cross-Sectional Study from National Health and Nutrition Examination Survey.

Persistent high-risk human papillomavirus (HPV) infection is responsible for most genital, anal, and oropharyngeal cancers, in which men contribute significantly to infection and subsequent tumorigenesis in women. Vitamin E has been shown to be associated with vaginal HPV infection and cervical cancer. However, the association of vitamin E consumption with HPV infection among the overall population remains unclear. We investigate the association between vitamin E consumption and genital and oral HPV infection in both men and women. We used cross-sectional data from the National Health and Nutrition Examination Survey between 2013 and 2016 to collect details on their dietary vitamin E intake, genital and oral HPV infection status, and other essential variables. In total, 5809 participants aged 18-59 years were identified, with overall prevalence of high-risk and low-risk HPV infection of 23.7% and 21.1%, respectively. Compared with the lowest vitamin E group Q1 (<5.18 mg/day), the adjusted OR for vitamin E consumption and overall high-risk HPV infection in Q2 (5.18-7.54 mg/day), Q3 (7.55-10.82 mg/day), and Q4 (>10.82 mg/day) were 0.91 (95% CI: 0.81-1.03, p = 0.134), 0.77 (95% CI: 0.69-0.87, p < 0.001), and 0.72 (95% CI: 0.65-0.80, p < 0.001), respectively. Restricted cubic spline regression showed a linear relationship between vitamin E consumption and overall high-risk HPV infection. This linear relationship also existed for vitamin E consumption and overall low-risk HPV infection. After being stratified by gender and site, vitamin E consumption was inversely related to vaginal low- and high-risk HPV infection, penile high-risk HPV infection, and male oral low-risk HPV infection. In conclusion, we identified inverse linear relationships between dietary vitamin E intake and overall high- and low-risk HPV infection. Future well-designed longitudinal studies are still required to validate the impact of vitamin E on HPV carcinogenesis.

Neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio are early predictors of bronchopulmonary dysplasia.

To determine whether neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) are correlated with bronchopulmonary dysplasia (BPD) on the first day of prematurity and to help with early warning, identification, and intervention in the development of BPD. From January 2017 to June 2022, newborns who were diagnosed with BPD conducted a retrospective cohort study. Complete blood cells were measured within the first 24 hours of life in preterm neonates of 32 gestational weeks with BPD as the observation group and non-BPD infants as the control group. In all groups, the NLR and PLR levels were measured. Both univariate and multivariate logistic regression analyses were used to evaluate the data. In this research 76 cases of non-BPD and 48 cases of BPD were used as controls. Compared with the non-BPD group, the NLR and PLR levels were considerably higher in the BPD group. Logistic regression analysis suggested that NLR and PLR were independent risk factors for BPD (OR [odds ratio]: 3.786; 95% CI [confidence interval]: 1.75-8.16; P < .05; OR: 3.391; 95% CI: 1.85-28.78; P < .05). The findings may demonstrate that higher NLR and PLR are independently and significantly associated with the development of BPD.

Comparative Whole-Genome Analysis of China and Global Epidemic Pseudomonas aeruginosa High-Risk Clones.

OBJECTIVES: The various sequence types (STs) of Pseudomonas aeruginosa (P. aeruginosa) high-risk clones (HiRiCs) have been sporadically reported in China, but the systematic analysis of genomes for these STs remains limited. This study aimed to address the evolutionary pathways underlying the emergence of HiRiCs and their routes of dissemination from Chinese and global perspectives. METHODS: The phylogenetic analysis was performed based on 416 newly sequenced clinical P. aeruginosa strains from Guangdong (GD), published genome sequences of 282 Chinese isolates, and 868 HiRiCs isolates from other countries. The genomic comparison study of global HiRiC ST244 was conducted to detect the model of global dissemination and local separation driven by association regional-specific antibiotic resistance genes. Furthermore, the evolutionary route of the emerging, China-specific HiRiC ST1971 was explored using Most Recent Common Ancestor (MRCA) analysis. RESULTS: Based on comparative genomics analysis, we found a clear geographical separation of ST244 isolates, yet with a association between ST244 isolates from GD and America. We identified a set of 38 AMR genes that contribute to the geographical separation in ST244, and identify genetic determinants either positively (MexB) and negatively (opmD) associated with GD ST244. For the China-unique HiRiC ST1971, its evolutionary history across different continents before emerging as ST1971 in China was also deduced. CONCLUSION: This study provides insight into the specific genetics underlying regional differences among globally disseminated P. aeruginosa HiRiCs (ST244) as well as new understanding of the dissemination and evolution of a regional HiRiC (ST1971). Understanding the genetics of these and other HiRiCs may assist in controlling their emergence and further spread.

TGN-020 Alleviate Inflammation and Apoptosis After Cerebral Ischemia-Reperfusion Injury in Mice Through Glymphatic and ERK1/2 Signaling Pathway.

Post-stroke acute inhibition of aquaporin 4 (AQP4) is known to exacerbate inflammation and apoptosis, yet the underlying mechanisms are not fully understood. The objective of this study was to investigate the specific mechanism of inflammation and apoptosis following cerebral ischemia-reperfusion (I/R) injury using the AQP4-specific inhibitor, N-(1,3,4-thiadiazol-2-yl) pyridine-3-carboxamide dihydrochloride (TGN-020). Ischemic stroke was induced in mice using the middle cerebral artery occlusion (MCAO) model. The C57/BL6 mice were randomly divided into three groups as follows: sham operation, I/R 48 h, and TGN-020 + I/R 48 h treatment. All mice were subjected to a series of procedures. These procedures encompassed 2,3,5-triphenyltetrazolium chloride (TTC) staining, neurological scoring, fluorescence tracing, western blotting, immunofluorescence staining, and RNA sequencing (RNA-seq). The glymphatic function in the cortex surrounding cerebral infarction was determined using tracer, glial fibrillary acid protein (GFAP), AQP4 co-staining, and beta-amyloid precursor protein (APP) staining; differential genes were detected using RNA-seq. The influence of TGN-020 on the extracellular signal-regulated kinase 1/2 (ERK) 1/2 pathway was confirmed using the ERK1/2 pathway agonists Ro 67-7467. Additionally, we examined the expression of inflammation associated with microglia and astrocytes after TGN-020 and Ro 67-7467 treatment. Compared with I/R group, TGN-020 alleviated glymphatic dysfunction by inhibiting astrocyte proliferation and reducing tracer accumulation in the peri-infarct area. RNA-seq showed that the differentially expressed genes were mainly involved in the activation of astrocytes and microglia and in the ERK1/2 pathway. Western blot and immunofluorescence further verified the expression of associated inflammation. The inflammation and cell apoptosis induced by I/R are mitigated by TGN-020. This mitigation occurs through the improvement of glymphatic function and the inhibition of the ERK1/2 pathway.

[A bio-inspired hierarchical spiking neural network with biological synaptic plasticity for event camera object recognition].

With inherent sparse spike-based coding and asynchronous event-driven computation, spiking neural network (SNN) is naturally suitable for processing event stream data of event cameras. In order to improve the feature extraction and classification performance of bio-inspired hierarchical SNNs, in this paper an event camera object recognition system based on biological synaptic plasticity is proposed. In our system input event streams were firstly segmented adaptively using spiking neuron potential to improve computational efficiency of the system. Multi-layer feature learning and classification are implemented by our bio-inspired hierarchical SNN with synaptic plasticity. After Gabor filter-based event-driven convolution layer which extracted primary visual features of event streams, we used a feature learning layer with unsupervised spiking timing dependent plasticity (STDP) rule to help the network extract frequent salient features, and a feature learning layer with reward-modulated STDP rule to help the network learn diagnostic features. The classification accuracies of the network proposed in this paper on the four benchmark event stream datasets were better than the existing bio-inspired hierarchical SNNs. Moreover, our method showed good classification ability for short event stream input data, and was robust to input event stream noise. The results show that our method can improve the feature extraction and classification performance of this kind of SNNs for event camera object recognition.

A CCL2+DPP4+ subset of mesenchymal stem cells expedites aberrant formation of creeping fat in humans.

Creeping fat is a typical feature of Crohn's disease. It refers to the expansion of mesenteric adipose tissue around inflamed and fibrotic intestines and is associated with stricture formation and intestinal obstruction. In this study, we characterize creeping fat as pro-adipogenic and pro-fibrotic. Lipidomics analysis of Crohn's disease patients (sixteen males, six females) and healthy controls (five males, ten females) reveals abnormal lipid metabolism in creeping fat. Through scRNA-seq analysis on mesenteric adipose tissue from patients (five males, one female) and healthy controls (two females), we identify a CCL2+DPP4+ subset of mesenchymal stem cells that expands in creeping fat and expedites adipogenic differentiation into dystrophic adipocytes in response to CCL20+CD14+ monocytes and IL-6, leading to the formation of creeping fat. Ex vivo experiments (tissues from five males, one female) confirm that both CCL20+CD14+ monocytes and IL-6 activate DPP4+ mesenchymal stem cells towards a pro-adipogenic phenotype. This study provides a comprehensive investigation of creeping fat formation and offers a conceptual framework for discovering therapeutic targets for treatment of Crohn's disease.

Whole-genome resequencing reveals the genomic diversity and signatures of selection in Romanov sheep.

Romanov sheep are adapted to the extremely cold and harsh environment and display a distinctive grey color. Herein, we analyzed the population structure, genetic diversity, and selection signatures of Romanov sheep based on whole-genome sequencing data of 17 Romanov sheep, 114 individuals from other 10 European breeds. The results of PCA, ADMIXTURE, and NJ-tree showed that the Romanov sheep was closely related to other northern European breeds. A relative high level of genetic diversity, low inbreeding coefficient, and large effective population size was observed in Romanov sheep when compared with other European breeds. We then screened the genomic selection signatures of Romanov sheep using FST, XP-XLP, and XP-EHH methods. The most significant region under selection (CHR14:14.2 to 14.3 Mb) harbored a haplotype that contained MC1R gene. Furthermore, this haplotype was also found in other grey-body breeds including Gotland sheep, Grey Tronder Sheep, and German grey heath sheep, suggesting that it was associated with the unique coat color of these breeds. We also found one region (CHR10:40.8Mb- 41.0Mb) harboring PCDH9 gene which was potentially associated with cold environmental adaptation. In summary, this study identified candidate genes that were associated with the unique grey color and environmental adaptation in Romanov sheep, which provided a basis for understanding the genetic background and utilization of this breed.

Romanov sheep is one of the most famous sheep breeds in the word, characterized by adaptability to harsh environment, high fertility, and unique coat color. Understanding its genetic architecture and signatures is of great value for its conservation and utilization. In this study, we analyzed whole-genome sequences of Romanov sheep as compared with 11 other European breeds, to explore for the population structure, genetic diversity, and selection signatures. We discovered a series of candidate genes that likely play a role in the grey coat color and cold adaptation of the Romanov sheep. In particular, we identified MC1R as a strong candidate gene that determines the grey coat color.

Structure-Based Drug Design of Novel Triaminotriazine Derivatives as Orally Bioavailable IDH2R140Q Inhibitors with High Selectivity and Reduced hERG Inhibitory Activity for the Treatment of Acute Myeloid Leukemia.

Neomorphic IDH2R140Q mutation is commonly found in acute myeloid leukemia (AML), and inhibiting its activity has been validated as an effective treatment for AML. Herein, we report a series of highly potent and selective IDH2R140Q inhibitors. Among them, compound 36 was identified as the most promising inhibitor, with an IC50 value of 29 nM and more than 490-fold selectivity over wild-type IDH2. The compound significantly suppressed D2HG production (IC50 = 10 nM) and induced differentiation in TF-1/IDH2R140Q cells. Furthermore, it showed reasonable pharmacokinetic properties with high bioavailability (F = 90.3%) and an appropriate half-life (T1/2 = 6.4 h). In vivo, oral administration of compound 36 at a dose of 25 mg/kg effectively reduced D2HG levels in the tumor of TF-1/IDH2R140Q xenograft mouse model. Besides, compound 36 displayed little effect on the hERG current. These results suggest that compound 36 has the potential to be an efficacious treatment for AML.

YAP1 affects the prognosis through the regulation of stemness in endometrial cancer.

Background: Endometrial cancer stem-like cells (ECSCs) have been proven to be responsible for recurrence, metastasis, and drug-resistance in patients with endometrial cancer. The HIPPO pathway has been shown to play an important role in the development and maintenance of stemness in a variety of tumors. While there was less research about its function in ECSCs. The aim of this study was to explore the role of YAP1, a core molecular of HIPPO pathway, in the stemness of endometrial cancer and to reveal its influence on prognosis. Methods: We collected specimens and clinical data from 774 patients with endometrial cancer to analyze the correlation between YAP1 expression and prognosis. We then examined the expression of YAP1 in ECSCs and EC cell lines (Ishikawa; HEC1-A) in vitro experiments. Changes in the stemness of cell lines were detected after YAP1 silencing by siRNA. Finally, high-throughput sequencing was used to predict the potential molecular interactions and mechanisms of YAP1's effect on stemness. Result: Down-regulation of YAP1 significantly suppresses the stemness of EC cell lines. High expression of YAP1 leads to poor prognosis in EC by regulation of stemness. Conclusion: YAP1 plays an important role in the prognosis of patients with EC by regulation of stemness.

Antioxidant and anti-inflammatory properties of ginsenoside Rg1 for hyperglycemia in type 2 diabetes mellitus: systematic reviews and meta-analyses of animal studies.

Background: According to existing laboratory data, ginsenoside Rg1 may help cure diabetes and its complications by reducing oxidative stress (OS) and managing inflammation. However, this conclusion lacks reliability and is unclear. As a result, the purpose of this systematic review and meta-analysis was to evaluate the antioxidant and anti-inflammatory effects of ginsenoside Rg1 in the treatment of diabetes and its complications. Methods: We searched for relevant studies published through December 2022, including electronic bibliographic databases such as PubMed, EMBASE, Web of Science, CNKI, and Wanfang. The SYstematic Review Center for Laboratory Animal Experimentation Risk of Bias (SYRCLE RoB) tool was used to conduct a meta-analysis to assess the methodological quality of animal research. The meta-analysis was conducted using RevMan5.4 software, following the Cochrane Handbook for Systematic Reviews of Interventions. This study is registered in the International Systems Review Prospective Registry (PROSPERO) as CRD42023386830. Results: Eighteen eligible studies involving 401 animals were included. Ginsenoside Rg1 was significantly correlated with blood glucose (BG), insulin levels, body weight, superoxide dismutase (SOD), malondialdehyde (MDA), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) levels. In addition, according to subgroup analysis, the hypoglycemic, anti-inflammatory, and antioxidant effects of ginsenoside Rg1 in type 2 diabetic animals were not affected by experimental species, modeling, experimental drug dosage, or course of treatment. Conclusion: This meta-analysis presents a summary of the hypoglycemic effects of ginsenoside Rg1, which are achieved through anti-inflammatory and antioxidant mechanisms. These findings provide evidence-based support for the medical efficacy of ginsenoside Rg1. Specifically, ginsenoside Rg1 reduced MDA levels and restored SOD activity to exert its antioxidant activity. It had a positive effect on the reduction of IL-6 and TNF-α levels. However, the inclusion of studies with low methodological quality and the presence of publication bias may undermine the validity of the results. Further investigation with a more rigorous experimental design and comprehensive studies is necessary to fully understand the specific glycemic mechanisms of ginsenosides. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/, identifier https://CRD42023386830.

Multidentate Chelation Achieves Bilateral Passivation toward Efficient and Stable Perovskite Solar Cells with Minimized Energy Losses.

Defects in the electron transport layer (ETL), perovskite, and buried interface will result in considerable nonradiative recombination. Here, a bottom-up bilateral modification strategy is proposed by incorporating arsenazo III (AA), a chromogenic agent for metal ions, to regulate SnO2 nanoparticles. AA can complex with uncoordinated Sn4+/Pb2+ in the form of multidentate chelation. Furthermore, by forming a hydrogen bond with formamidinium (FA), AA can suppress FA+ defects and regulate crystallization. Multiple chemical bonds between AA and functional layers are established, synergistically preventing the agglomeration of SnO2 nanoparticles, enhancing carrier transport dynamics, passivating bilateral defects, releasing tensile stress, and promoting the crystallization of perovskite. Ultimately, the AA-optimized power conversion efficiency (PCE) of the methylammonium-free (MA-free) devices (Rb0.02(FA0.95Cs0.05)0.98PbI2.91Br0.03Cl0.06) is boosted from 20.88% to 23.17% with a high open-circuit voltage (VOC) exceeding 1.18 V and ultralow energy losses down to 0.37 eV. In addition, the optimized devices also exhibit superior stability.

A parabrachial-hypothalamic parallel circuit governs cold defense in mice.

Thermal homeostasis is vital for mammals and is controlled by brain neurocircuits. Yet, the neural pathways responsible for cold defense regulation are still unclear. Here, we found that a pathway from the lateral parabrachial nucleus (LPB) to the dorsomedial hypothalamus (DMH), which runs parallel to the canonical LPB to preoptic area (POA) pathway, is also crucial for cold defense. Together, these pathways make an equivalent and cumulative contribution, forming a parallel circuit. Specifically, activation of the LPB → DMH pathway induced strong cold-defense responses, including increases in thermogenesis of brown adipose tissue (BAT), muscle shivering, heart rate, and locomotion. Further, we identified somatostatin neurons in the LPB that target DMH to promote BAT thermogenesis. Therefore, we reveal a parallel circuit governing cold defense in mice, which enables resilience to hypothermia and provides a scalable and robust network in heat production, reshaping our understanding of neural circuit regulation of homeostatic behaviors.

Transcriptomics unveils immune metabolic disruption and a novel biomarker of mortality in patients with HBV-related acute-on-chronic liver failure.

Background & Aims: HBV-related acute-on-chronic liver failure (HBV-ACLF) is a complex syndrome associated with high short-term mortality. This study aims to reveal the molecular basis and identify novel HBV-ACLF biomarkers. Methods: Seventy patients with HBV-ACLF and different short-term (28 days) outcomes underwent transcriptome sequencing using peripheral blood mononuclear cells. Candidate biomarkers were confirmed in two external cohorts using ELISA. Results: Cellular composition analysis with peripheral blood mononuclear cell transcriptomics showed that the proportions of monocytes, T cells and natural killer cells were significantly correlated with 28-day mortality. Significant metabolic dysregulation of carbohydrate, energy and amino acid metabolism was observed in ACLF non-survivors. V-set and immunoglobulin domain-containing 4 (VSIG4) was the most robust predictor of patient survival (adjusted p = 1.74 × 10-16; variable importance in the projection = 1.21; AUROC = 0.89) and was significantly correlated with pathways involved in the progression of ACLF, including inflammation, oxidative phosphorylation, tricarboxylic acid cycle and T-cell activation/differentiation. Plasma VSIG4 analysis externally validated its diagnostic value in ACLF (compared with chronic liver disease and healthy groups, AUROC = 0.983). The prognostic performance for 28-/90-day mortality (AUROCs = 0.769/0.767) was comparable to that of three commonly used scores (COSSH-ACLFs, 0.867/0.884; CLIF-C ACLFs, 0.840/0.835; MELD-Na, 0.710/0.737). Plasma VSIG4 level, as an independent predictor, could be used to improve the prognostic performance of clinical scores. Risk stratification based on VSIG4 expression levels (>122 µg/ml) identified patients with ACLF at a high risk of death. The generality of VSIG4 in other etiologies was validated. Conclusions: This study reveals that immune-metabolism disorder underlies poor ACLF outcomes. VSIG4 may be helpful as a diagnostic and prognostic biomarker in clinical practice. Impact and implications: Acute-on-chronic liver failure (ACLF) is a lethal clinical syndrome associated with high mortality. We found significant immune cell alterations and metabolic dysregulation that were linked to high mortality in patients with HBV-ACLF based on transcriptomics using peripheral blood mononuclear cells. We identified VSIG4 (V-set and immunoglobulin domain-containing 4) as a diagnostic and prognostic biomarker in ACLF, which could specifically identify patients with ACLF at a high risk of death.

Discovery of SHR5428 as a selective and noncovalent inhibitor of CDK7.

Cyclin dependent kinase 7 (CDK7) is an attractive target in tumor indications via regulating both cell cycle and transcription. Here, SHR5428 was discovered as a selective and noncovalent CDK7 inhibitor with highly potent CDK7 enzymatic activity and triple negative breast cancer cellular activity on MDA-MB-468 cell. SHR5428 also displayed favorable pharmacokinetic properties in different preclinical species such as mouse, rat and dog, and showed high selectivity over CDK1, CDK2, CDK4, CDK6, CDK9, CDK12 in CDK family. Furthermore, the computational modeling has shed some light on this mechanism. Additionally the in vivo efficacy study in a breast cancer cell line (HCC70 cell) derived xenograft mouse model proved SHR5428 to be orally efficacious with dose-dependent tumor growth inhibition.

Regulatory role of E3 ubiquitin ligases in normal B lymphopoiesis and B-cell malignancies.

E3 ubiquitin ligases play an essential role in protein ubiquitination, which is involved in the regulation of protein degradation, protein-protein interactions and signal transduction. Increasing evidences have shed light on the emerging roles of E3 ubiquitin ligases in B-cell development and related malignances. This comprehensive review summarizes the current understanding of E3 ubiquitin ligases in B-cell development and their contribution to B-cell malignances, which could help explore the molecular mechanism of normal B-cell development and provide potential therapeutic targets of the related diseases.

A review of green methods used in starch-polyphenol interactions: physicochemical and digestion aspects.

The interactions of starch with lipids, proteins, and other major food components during food processing are inevitable. These interactions could result in the formation of V-type or non-V-type complexes of starch. The starch-lipid complexes have been intensively studied for over five decades, however, the complexes of starch and polyphenols are relatively less studied and are the subject of recent interest. The interactions of starch with polyphenols can affect the physicochemical properties and its digestibility. The literature has highlighted several green methods such as ultrasound, microwave, high pressure, extrusion, ball-milling, cold plasma etc., to assist interactions of starch with polyphenols. However, comprehensive information on green methods to induce starch-polyphenol interactions is still scarce. Therefore, in light of the importance and potential of starch-polyphenol complexes in developing functional foods with low digestion, this review has summarized the novel green methods employed in interactions of starch with flavonoids, phenolic acids and tannins. It has been speculated that flavonoids, phenolic acids, and tannins, among other types of polyphenols, may have anti-digestive activities and are also revealed for their interaction with starch to form either an inclusion or non-inclusion complex. Further information on the effects of these interactions on physicochemical parameters to understand the chemistry and structure of the complexes is also provided.

The impacts of knowledge and attitude on behavior of antibiotic use for the common cold among the public and identifying the critical behavioral stage: based on an expanding KAP model.

BACKGROUND: This study aims to explore the impacts of knowledge and attitude on the behavior of antibiotic use during the treatment of the common cold based on the expanding KAP model, and then identify the critical behavioral stage. METHODS: A cross-sectional study was conducted on 815 public from 21 community health centers (CHCs) in Chongqing, China. Based on the expanding KAP model, a self-administered questionnaire was designed to measure knowledge, attitude, multi-stage behavior, and perceived threat, in which multi-stage behavior was divided into pre-use antibiotic behavior, during-use antibiotic behavior, and post-use antibiotic behavior. A structural equation model was used to examine the model fit and the direct, indirect, mediating effects, and moderating effect of the variables. RESULTS: The expanding KAP showed good model fit indices with χ²/df = 0.537, RMSEA = 0.033, CFI = 0.973, GFI = 0.971, NFI = 0.934, TLI = 0.979. Knowledge had a positive effect on attitude (ß = 0.503, p < 0.05), pre-use antibiotic behavior (ß = 0.348, p < 0.05), during-use antibiotic behavior (ß = 0.461, p < 0.001), and post-use antibiotic behavior (ß = 0.547, p < 0.001). Attitude had a positive effect on during-use antibiotic behavior (ß = 0.296, p < 0.001), and post-use antibiotic behavior (ß = 0.747, p < 0.001). The mediating effect of attitude was positive among knowledge, during-use antibiotic behavior (ß = 0.149, p < 0.05), and post-use antibiotic behavior (ß = 0.376, p < 0.001). Perceived threat also had a positive moderating effect between knowledge and post-use antibiotic behavior (ß = 0.021, p < 0.001). CONCLUSIONS: Knowledge, attitude and perceived threat had different effects on different stages of antibiotic behavior. The critical behavioral stage prioritized the post-use antibiotic behavior and during-use antibiotic behavior over pre-use antibiotic behavior.