Phylogenetic inference of inter-population transmission rates for infectious diseases.

Estimating transmission rates is a challenging yet essential aspect of comprehending and controlling the spread of infectious diseases. Various methods exist for estimating transmission rates, each with distinct assumptions, data needs, and constraints. This study introduces a novel phylogenetic approach called transRate, which integrates genetic information with traditional epidemiological approaches to estimate inter-population transmission rates. The phylogenetic method is statistically consistent as the sample size (i.e. the number of pathogen genomes) approaches infinity under the multi-population susceptible-infected-recovered model. Simulation analyses indicate that transRate can accurately estimate the transmission rate with a sample size of 200 ~ 400 pathogen genomes. Using transRate, we analyzed 40,028 high-quality sequences of SARS-CoV-2 in human hosts during the early pandemic. Our analysis uncovered significant transmission between populations even before widespread travel restrictions were implemented. The development of transRate provides valuable insights for scientists and public health officials to enhance their understanding of the pandemic's progression and aiding in preparedness for future viral outbreaks. As public databases for genomic sequences continue to expand, transRate is increasingly vital for tracking and mitigating the spread of infectious diseases.

Electrolyte Chemistry toward Ultrawide-Temperature (-25 to 75 °C) Sodium-Ion Batteries Achieved by Phosphorus/Silicon-Synergistic Interphase Manipulation.

All-weather operation is considered an ultimate pursuit of the practical development of sodium-ion batteries (SIBs), however, blocked by a lack of suitable electrolytes at present. Herein, by introducing synergistic manipulation mechanisms driven by phosphorus/silicon involvement, the compact electrode/electrolyte interphases are endowed with improved interfacial Na-ion transport kinetics and desirable structural/thermal stability. Therefore, the modified carbonate-based electrolyte successfully enables all-weather adaptability for long-term operation over a wide temperature range. As a verification, the half-cells using the designed electrolyte operate stably over a temperature range of -25 to 75 °C, accompanied by a capacity retention rate exceeding 70% even after 1700 cycles at 60 °C. More importantly, the full cells assembled with Na3V2(PO4)2O2F cathode and hard carbon anode also have excellent cycling stability, exceeding 500 and 1000 cycles at -25 to 50 °C and superb temperature adaptability during all-weather dynamic testing with continuous temperature change. In short, this work proposes an advanced interfacial regulation strategy targeted at the all-climate SIB operation, which is of good practicability and reference significance.

Hybrid Binder Chemistry with Hydrogen-Bond Helix for High-Voltage Cathode of Sodium-Ion Batteries.

Since sodium-ion batteries (SIBs) have become increasingly commercialized in recent years, Na3V2(PO4)2O2F (NVPOF) offers promising economic potential as a cathode for SIBs because of its high operating voltage and energy density. According to reports, NVPOF performs poorly in normal commercial poly(vinylidene fluoride) (PVDF) binder systems and performs best in combination with aqueous binder. Although in line with the concept of green and sustainable development for future electrode preparation, aqueous binders are challenging to achieve high active material loadings at the electrode level, and their relatively high surface tension tends to cause the active material on the electrode sheet to crack or even peel off from the collector. Herein, a cross-linkable and easily commercial hybrid binder constructed by intermolecular hydrogen bonding (named HPP) has been developed and utilized in an NVPOF system, which enables the generation of a stable cathode electrolyte interphase on the surface of active materials. According to theoretical simulations, the HPP binder enhances electronic/ionic conductivity, which greatly lowers the energy barrier for Na+ migration. Additionally, the strong hydrogen-bond interactions between the HPP binder and NVPOF effectively prevent electrolyte corrosion and transition-metal dissolution, lessen the lattice volume effect, and ensure structural stability during cycling. The HPP-based NVPOF offers considerably improved rate capability and cycling performance, benefiting from these benefits. This comprehensive binder can be extended to the development of next-generation energy storage technologies with superior performance.

Janus Binder Chemistry for Synchronous Enhancement of Iodine Species Adsorption and Redox Kinetics toward Sustainable Aqueous Zn-I2 Batteries.

Currently, the desired research focus in energy storage technique innovation has been gradually shifted to next-generation aqueous batteries holding both high performance and sustainability. However, aqueous Zn-I2 batteries have been deemed to have great sustainable potential, owing to the merits of cost-effective and eco-friendly nature. However, their commercial application is hindered by the serious shuttle effect of polyiodides during reversible operations. In this work, a Janus functional binder based on chitosan (CTS) molecules was designed and prepared; the polar terminational groups impart excellent mechanical robustness to hybrid binders; meanwhile, it can also deliver isochronous enhancement on physical adsorption and redox kinetics toward I2 species. By feat of highly effective remission to shuttle effect, the CTS cell exhibits superb electrochemical storage capacities with long-term robustness, specifically, 144.1 mAh g-1, at a current density of 0.2 mA g-1 after 1500 cycles. Simultaneously, the undesired self-discharging issue could be also well-addressed; the Coulombic efficiency could remain at 98.8 % after resting for 24 h. More importantly, CTS molecules endow good biodegradability and reusable properties; after iodine species were reloaded, the recycled devices could also deliver specific capacities of 73.3 mAh g-1, over 1000 cycles. This Janus binder provides a potential synchronous solution to realize high comprehensive performance with high iodine utilization and further make it possible for sustainable Zn-I2 batteries.

Interfacial-Confined Isochronous Conversion to Biphasic Selenide Heterostructure with Enhanced Adsorption Behaviors for Robust High-Rate Na-Ion Storage.

Sodium-ion batteries (SIBs) have gradually become one of the most promising energy storage techniques in the current era of post-lithium-ion batteries. For anodes, transitional metal selenides (TMSe) based materials are welcomed choices , owing to relatively higher specific capacities and enriched redox active sites. Nevertheless, current bottlenecks are blamed for their poor intrinsic electronic conductivities, and uncontrollable volume expansion during redox reactions. Given that, an interfacial-confined isochronous conversion strategy is proposed, to prepare orthorhombic/cubic biphasic TMSe heterostructure, namely CuSe/Cu3 VSe4 , through using MXene as the precursor, followed by Cu/Se dual anchorage. As-designed biphasic TMSe heterostructure endows unique hierarchical structure, which contains adequate insertion sites and diffusion spacing for Na ions, besides, the surficial pseudocapacitive storage behaviors can be also proceeded like 2D MXene. By further investigation on electronic structure, the theoretical calculations indicate that biphasic CuSe/Cu3 VSe4 anode exhibits well-enhanced properties, with smaller bandgap and thus greatly improves intrinsic poor conductivities. In addition, the dual redox centers can enhance the electrochemical Na ions storage abilities. As a result, the as-designed biphasic TMSe anode can deliver a reversible specific capacity of 576.8 mAh g-1 at 0.1 A g-1 , favorable Na affinity, and reduced diffusion barriers. This work discloses a synchronous solution toward demerits in conductivities and lifespan, which is inspiring for TMSe-based anode development in SIBs systems.

Novel miniature transendoscopic telerobotic system for endoscopic submucosal dissection (with videos).

BACKGROUND AND AIMS: The lack of tissue traction and instrument dexterity to allow for adequate visualization and effective dissection were the main issues in performing endoscopic submucosal dissection (ESD). Robot-assisted systems may provide advantages. In this study we developed a novel transendoscopic telerobotic system and evaluated its performance in ESD. METHODS: A miniature dual-arm robotic endoscopic assistant for minimally invasive surgery (DREAMS) was developed. The DREAMS system contained the current smallest robotic ESD instruments and was compatible with the commercially available dual-channel endoscope. After the system was established, a prospective randomized controlled study was conducted to validate the performance of the DREAMS-assisted ESD in terms of efficacy, safety, and workload by comparing it with the conventional technique. RESULTS: Two robotic instruments can achieve safe collaboration and provide sufficient visualization and efficient dissection during ESD. Forty ESDs in the stomach and esophagus of 8 pigs were completed by DREAMS-assisted ESD or conventional ESD. Submucosal dissection time was comparable between the 2 techniques, but DREAMS-assisted ESD demonstrated a significantly lower muscular injury rate (15% vs 50%, P = .018) and workload scores (22.30 vs 32.45, P < .001). In the subgroup analysis of esophageal ESD, DREAMS-assisted ESD showed significantly improved submucosal dissection time (6.45 vs 16.37 minutes, P = .002), muscular injury rate (25% vs 87.5%, P = .041), and workload (21.13 vs 40.63, P = .001). CONCLUSIONS: We developed a novel transendoscopic telerobotic system, named DREAMS. The safety profile and technical feasibility of ESD were significantly improved with the assistance of the DREAMS system, especially in the narrower esophageal lumen.

Development and validation of genome-wide SSR molecular markers of Tapes dorsatus.

BACKGROUND: Tapes dorsatus is an economically important benthic animal in the Beibu Gulf of China. However, the deficiency of microsatellite markers has hindered the study of its genetics. The development of microsatellite markers will provide useful tools for genetic improvement, variety identification, phylogenetic analysis and resource conservation. METHODS AND RESULTS: Within the genome sequence, 145,008 simple sequence repeats (SSRs) were identified, and 29,691 primer pairs were designed successfully. A total of 100 primer pairs were randomly synthesized for testing, and 93 primers yielded products. Sixty highly polymorphic primers were used to reveal the genetic diversity of 50 T. dorsatus individuals. The average number of alleles (Na) of the population was 10.40; the average number of effective alleles was 6.16, the average expected heterozygosity (He) was 0.82, and the average polymorphic information content was 0.80. The genetic structure of the population was detected, by which the population could be divided into three subpopulations. CONCLUSION: We identified 145,008 SSRs in the genome of T. dorsatus and designed 29,691 primer pairs in this study. Of 100 synthesized primers, 60 were highly polymorphic and used to reveal the genetic diversity and structure of the population. The SSR markers identified here will provide useful tools and a foundation for genetic diversity, linkage mapping and molecular marker-aided breeding in T. dorsatus.

Perceived risk of COVID-19 hurts mental health: the mediating role of fear of COVID-19 and the moderating role of resilience.

BACKGROUND: Depression and anxiety have been found prevalent during all phases of the COVID-19 pandemic. In late December 2022, almost all COVID-19 control measures were lifted in China, leading to a surge in COVID-19 infections. The public's perceived risk and fear of COVID-19 would be increased. This study aims to examine the prevalence of depression and anxiety in the Chinese general population and explores the mediating role of fear of COVID-19 between COVID-19 perceived risk and depression/anxiety and the moderating role of resilience between fear of COVID-19 and depression/anxiety. METHODS: A cross-sectional online survey was conducted in Wenzhou, China, immediately following almost all COVID-19 control measures lifted. The 9-item Patient Health Questionnaire (PHQ-9), Generalized Anxiety Disorder-7 (GAD-7), the COVID-19 Risk Perception Scale, the Fear of COVID-19 Scale, and the Connor-Davidson Resilience Scale (CD-RISC) were used to evaluate depression, anxiety, COVID-19 perceived risk, fear of COVID-19, and resilience, respectively. Structural Equation Modeling (SEM) with Maximum Likelihood (ML) estimator and adjusted for significant background factors was performed to test the moderated mediation. Data obtained from 935 participants were analyzed. RESULTS: The prevalence of moderate to severe depression and anxiety was 23.7% and 9.5%, respectively. The present study revealed positive associations among COVID-19 perceived risk, fear of COVID-19 and depression/anxiety, and negative associations between resilience and fear of COVID-19/depression/anxiety. Fear of COVID-19 partially mediated the association between COVID-19 perceived risk and depression/anxiety. Furthermore, resilience significantly moderated the association between fear of COVID-19 and depression/anxiety. Two moderated mediation models were constructed. CONCLUSION: Depression and anxiety were prevalent among Chinese adults during the final phase of the pandemic in China. The significant mediation role of fear of COVID-19 implies that reducing fear of COVID-19 may effectively alleviate depression and anxiety symptoms. Moreover, enhancing public resilience during an epidemic crisis is crucial for promoting mental health.

Entropy-Regulated Cathode with Low Strain and Constraint Phase-Change Toward Ultralong-Life Aqueous Al-Ion Batteries.

During multivalent ions insertion processes, intense electrostatic interaction between charge carriers and host makes the high-performance reversible Al3+ storage remains an elusive target. On account of the strong electrostatic repulsion and poor robustness, Prussian Blue analogues (PBAs) suffer severely from the inevitable and large strain and phase change during reversible Al3+ insertion. Herein, we demonstrate an entropy-driven strategy to realize ultralong life aqueous Al-ion batteries (AIBs) based on medium entropy PBAs (ME-PBAs) host. By multiple redox active centers introduction, the intrinsic poor conductivity can be enhanced simultaneously, resulting in outstanding capabilities of electrochemical Al3+ storage. Meanwhile, the co-occupation at metal sites in PBA frameworks can also increase the M-N bond intensity, which is beneficial for constraining the phase change during consecutive Al3+ reversible insertion, to realize an extended lifespan over 10,000 cycles. Based on the calculation at different operation states, the fluctuation of ME-PBA lattice parameters is only 1.2 %. Assembled with MoO3 anodes, the full cells can also deliver outstanding electrochemical properties. The findings highlight that, the entropy regulation strategy could uncover the isochronous constraint on both strain and phase transition for long-term reversible Al3+ storage, providing a promising design for advanced electrode materials for aqueous multivalent ions batteries.

Temporal transcriptomic landscape of postnatal mouse ovaries reveals dynamic gene signatures associated with ovarian aging.

The ovary is the most important organ for maintaining female reproductive health, but it fails before most other organs. Aging-associated alterations in gene expression patterns in mammalian ovaries remain largely unknown. In this study, the transcriptomic landscape of postnatal mouse ovaries over the reproductive lifespan was investigated using bulk RNA sequencing in C57BL/6 mice. Gene expression dynamics revealed that the lifespan of postnatal mouse ovaries comprised four sequential stages, during which 2517 genes were identified as differentially enriched. Notably, the DNA repair pathway was found to make a considerable and specific contribution to the process of ovarian aging. Temporal gene expression patterns were dissected to identify differences in gene expression trajectories over the lifespan. In addition to DNA repair, distinct biological functions (including hypoxia response, epigenetic modification, fertilization, mitochondrial function, etc.) were overrepresented in particular clusters. Association studies were further performed to explore the relationships between known genes responsible for ovarian function and differentially expressed genes identified in this work. We found that the causative genes of human premature ovarian insufficiency were specifically enriched in distinct gene clusters. Taken together, our findings reveal a comprehensive transcriptomic landscape of the mouse ovary over the lifespan, providing insights into the molecular mechanisms underlying mammalian ovarian aging and supporting future etiological studies of aging-associated ovarian disorders.

Downregulation of microRNA-145a-5p promotes steatosis-to-NASH progression through upregulation of Nr4a2.

BACKGROUND & AIMS: The molecular mechanisms underlying the progression of simple steatosis to non-alcoholic steatohepatitis (NASH) remain incompletely understood, though the potential role of epigenetic regulation by microRNA (miRNAs) is an area of increasing interest. In the present study, we aimed to investigate the role of miRNAs during steatosis-to-NASH progression, as well as underlying mechanisms. METHODS: miR-145a-5p was identified as an important checkpoint in steatosis-to-NASH progression. In vivo loss-of-function and gain-of-function studies were performed to explore the role of miR-145a-5p and Nr4a2 in NASH progression. RNA-sequencing and bioinformatic analysis were used to investigate the targets of miR-145a-5p. RESULTS: Suppression of miR-145a-5p in the liver aggravated lipid accumulation and activated hepatic inflammation, liver injury and fibrosis in steatotic mice, whereas its restoration markedly attenuated diet-induced NASH pathogenesis. Mechanistically, miR-145a-5p was able to downregulate the nuclear receptor Nr4a2 and thus inhibit the expression of NASH-associated genes. Similarly, Nr4a2 overexpression promoted steatosis-to-NASH progression while liver-specific Nr4a2 knockout mice were protected from diet-induced NASH. This role of the miR-145a-5p/Nr4a2 regulatory axis was also confirmed in primary human hepatocytes. Furthermore, the expression of miR-145a-5p was reduced and the expression of Nr4a2 was increased in the livers of patients with NASH, while their expression levels significantly negatively and positively correlated with features of liver pathology, respectively. CONCLUSIONS: Our findings highlight the role of the miR-145a-5p/Nr4a2 regulatory axis in steatosis-to-NASH progression, suggesting that either supplementation of miR-145a-5p or pharmacological inhibition of Nr4a2 in hepatocytes may provide a promising therapeutic approach for the treatment of NASH. IMPACT AND IMPLICATIONS: Non-alcoholic fatty liver disease (NAFLD) is a dynamic spectrum of chronic liver diseases ranging from simple steatosis to non-alcoholic steatohepatitis (NASH). Unfortunately, there are currently no approved drugs for NASH. Our current study identified miR-145a-5p as a novel regulator that inhibits steatosis-to-NASH progression. We found that miR-145a-5p was able to downregulate the nuclear receptor Nr4a2 to suppress the expression of NASH-associated genes. The differential expression of miR-145a-5p and Nr4a2 was further confirmed in patients with NASH, raising the possibility that supplementation of miR-145a-5p or suppression of Nr4a2 in hepatocytes might provide novel strategies for treating NASH.

Species Tree Estimation and the Impact of Gene Loss Following Whole-Genome Duplication.

Whole-genome duplication (WGD) occurs broadly and repeatedly across the history of eukaryotes and is recognized as a prominent evolutionary force, especially in plants. Immediately following WGD, most genes are present in two copies as paralogs. Due to this redundancy, one copy of a paralog pair commonly undergoes pseudogenization and is eventually lost. When speciation occurs shortly after WGD; however, differential loss of paralogs may lead to spurious phylogenetic inference resulting from the inclusion of pseudoorthologs-paralogous genes mistakenly identified as orthologs because they are present in single copies within each sampled species. The influence and impact of including pseudoorthologs versus true orthologs as a result of gene extinction (or incomplete laboratory sampling) are only recently gaining empirical attention in the phylogenomics community. Moreover, few studies have yet to investigate this phenomenon in an explicit coalescent framework. Here, using mathematical models, numerous simulated data sets, and two newly assembled empirical data sets, we assess the effect of pseudoorthologs on species tree estimation under varying degrees of incomplete lineage sorting (ILS) and differential gene loss scenarios following WGD. When gene loss occurs along the terminal branches of the species tree, alignment-based (BPP) and gene-tree-based (ASTRAL, MP-EST, and STAR) coalescent methods are adversely affected as the degree of ILS increases. This can be greatly improved by sampling a sufficiently large number of genes. Under the same circumstances, however, concatenation methods consistently estimate incorrect species trees as the number of genes increases. Additionally, pseudoorthologs can greatly mislead species tree inference when gene loss occurs along the internal branches of the species tree. Here, both coalescent and concatenation methods yield inconsistent results. These results underscore the importance of understanding the influence of pseudoorthologs in the phylogenomics era. [Coalescent method; concatenation method; incomplete lineage sorting; pseudoorthologs; single-copy gene; whole-genome duplication.].

Robot-assisted endoscopic submucosal dissection contributes to efficient and safe learning for novices: Prospective pilot cross-over ex vivo study (with video).

OBJECTIVES: The lack of effective countertraction to expose the submucosal layer contributes to the technical complication and adverse events in endoscopic submucosal dissection (ESD). We aimed to evaluate the efficacy and safety of a novel endoscopic robot (flexible auxiliary single-arm transluminal endoscopic robot [FASTER]) for ESD learning for novices. METHODS: This was a prospective, cross-over designed pilot study in ex vivo porcine stomach. Four ESD novices were randomized to either FASTER-assisted ESD first (FC) group or a conventional ESD first (CF) group, performed 40 gastric ESDs using each technique, then crossed over to another technique. The performance and learning curve were compared between the two groups. RESULTS: In the first phase, novices in the FC group demonstrated significantly better performance with shorter procedure time (25.6 ± 7.8 vs. 38.9 ± 13.4 min; P < 0.001) and submucosal dissection time (13.9 ± 5.5 vs. 23.1 ± 11.0 min; P < 0.001), higher direct-vision dissection ratio (84.0 ± 7.9% vs. 43.5 ± 20.7%; P < 0.001), and lower muscular injury (2.5 vs. 40.0%; P < 0.001) and task load (4 vs. 5; P < 0.001). Fewer ESDs were required to gain early proficiency in the FC group. When crossed to the second phase, procedure time in the FC group was prolonged but the muscular injury rate did not increase significantly. In total, endoscopists in the FC group tended to have a lower task load (4 vs. 5; P = 0.008) and less muscular injury (10.0 vs. 21.3%; P = 0.05). CONCLUSION: Flexible auxiliary single-arm transluminal endoscopic robot-assisted learning reduces the technical difficulty of ESD for novices and the safety profile can sustain in following conventional ESD. These results indicated that FASTER has potential implications for ESD training in clinical practice.

"Pore-Hopping" Ion Transport in Cellulose-Based Separator Towards High-Performance Sodium-Ion Batteries.

Sodium-ion batteries (SIBs) have great potential for large-scale energy storage. Cellulose is an attractive material for sustainable separators, but some key issues still exist affecting its application. Herein, a cellulose-based composite separator (CP@PPC) was prepared by immersion curing of cellulose-based separators (CP) with poly(propylene carbonate) (PPC). With the assistance of PPC, the CP@PPC separator is able to operate the cell stably at high voltages (up to 4.95 V). The "pore-hopping" ion transport mechanism in CP@PPC opens up extra Na+ migration paths, resulting in a high Na+ transference number (0.613). The separator can also tolerate folding, bending and extreme temperature under certain circumstances. Full cells with CP@PPC reveal one-up capacity retention (96.97 %) at 2C after 500 cycles compared to cells with CP. The mechanism highlights the merits of electrolyte analogs in separator modification, making a rational design for durable devices in advanced energy storage systems.

Simplified robot-assisted endoscopic submucosal dissection for esophageal and gastric lesions: a randomized controlled porcine study (with videos).

BACKGROUND AND AIMS: Effective countertraction is a main challenging issue in endoscopic submucosal dissection (ESD). Several countertraction methods have been developed to address this issue. The aim of this study was to compare the efficacy of ESD using a novel simplified robot, the flexible auxiliary single-arm transluminal endoscopic robot (FASTER), with a traditional technique. METHODS: This was a prospective, randomized animal study. Forty-eight ESDs in 6 pigs were carried out at 8 different locations (gastric antrum, gastric body, lower esophagus, and middle esophagus) by the conventional method (n = 24) and by the FASTER-assisted method (n = 24). The primary outcomes were total procedure time, dissection time, and rate of direct-vision dissection. Secondary endpoints were completeness of en-bloc resection and adverse event rate. RESULTS: The total procedure time was significantly shorter in FASTER-assisted ESD than in conventional ESD (18.8 vs 32.8 minutes; P < .001). In contrast to the median direct-vision dissection rate of 73% with conventional ESD, the FASTER-assisted group had a significantly higher rate of 96% (P < .001). The number of sites of muscular damage was significantly lower using the FASTER-assisted method than the conventional method (6 vs 21, respectively; P = .018). This improvement was more apparent in esophageal lesions compared with gastric lesions. CONCLUSIONS: This study demonstrated that using a simplified robot during ESD is technically feasible and enables the endoscopist to dynamically use countertraction. This device could significantly reduce procedure time compared with conventional ESD techniques.

Phloretin ameliorates diabetes-induced endothelial injury through AMPK-dependent anti-EndMT pathway.

Diabetic cardiovascular complications contribute more than half of diabetes mortality. Endothelial damage and subsequent pathological changes play a key role in this process. Phloretin, a plant-derived dihydrochalcone compound, was reported to have the activities in regulating metabolism homeostasis and anti-inflammation. However, its effects and the mechanism on early stage endothelial injury caused by diabetes are not clear yet. In our present study, human umbilical vein endothelial cells (HUVECs) were stimulated by high glucose or advanced glycation end products (AGEs) to induce endothelial damage, and streptozotocin (STZ) -induced diabetes mouse model was used for in vivo study. Our results showed that phloretin effectively reduced endothelial damage marker monocyte chemotactic protein-1 (MCP1) as well as pro-calcification factors bone morphogenetic protein-2 (BMP2) and receptor activator of NF-κB ligand (RANKL) expression, reversed the increased vimentin and decreased CD31 dose-dependently in vitro and in vivo. Phloretin had no effect on blood glucose level. However, it ameliorated endothelial injury and vascular fibrosis in diabetic mice. Further experiments revealed that phloretin could enhance AMP activated protein kinase (AMPK) activation and upregulate peroxidase proliferator activated receptor-gamma coactivator-lα (PGC1α) level, and inhibit the activation of TGFß-Smad2-Snail signalling pathway which was abrogated by AMPK inhibitor, providing a rational mechanism that AMPK activation was required for the effects of phloretin on endothelial injury and endothelial-mesenchymal transformation (EndMT). Our data reveal a new role of phloretin in protection of diabetic endothelial damage via AMPK-dependent anti-EndMT activation, and also provide a potential therapeutic way for diabetic endothelial damage and its subsequent cardiovascular complications.

Total neoadjuvant therapy for locally advanced gastric cancer and esophagogastric junction adenocarcinoma: study protocol for a prospective, multicenter, single-arm, phase II clinical trial.

BACKGROUND: Gastric cancer ranks high in terms of morbidity and mortality worldwide. Multimodal therapy is therefore essential for locally advanced gastric cancer. Recent studies have demonstrated that both perioperative chemotherapy and neoadjuvant chemoradiotherapy can improve the prognosis of patients. However, the completion rate of chemotherapy after surgery remains low, which may affect survival. Thus, identifying the best way to combine radiotherapy, chemotherapy and surgery is important. The aim of this study was to explore the toxicity and efficacy of the total neoadjuvant therapy modality for locally advanced gastric cancer. METHODS: This study will be a prospective, multicenter, single-arm, phase II clinical trial. Patients diagnosed with locally advanced (stage cT3-4 and cN positive, AJCC 8th) gastric cancer and gastroesophageal junction adenocarcinoma will be enrolled. Patients will initially receive radiotherapy (95% planned target volume: 45 Gy/25 f) and concurrent chemotherapy (S-1: 40-60 mg twice a day) followed by six cycles of consolidated chemotherapy (SOX, consisting of S-1 and oxaliplatin) and surgery. The primary objective will assess pathological complete response; the secondary objectives will include toxicities assessing surgical complications, the tumor downstaging rate and the R0 resection rate. DISCUSSION: Investigation of total neoadjuvant therapy in gastric cancer is limited. The goal of this trial is to explore the efficacy and toxicity of total neoadjuvant therapy for locally advanced gastric cancer and gastroesophageal junction adenocarcinoma. TRIAL REGISTRATION: Clinicaltrials.gov (NCT04062058, August 20, 2019).

Multi-Feature Matching GM-PHD Filter for Radar Multi-Target Tracking.

Multi-target tracking (MTT) is one of the most important functions of radar systems. Traditional multi-target tracking methods based on data association convert multi-target tracking problems into single-target tracking problems. When the number of targets is large, the amount of computation increases exponentially. The Gaussian mixture probability hypothesis density (GM-PHD) filtering based on a random finite set (RFS) provides an effective method to solve multi-target tracking problems without the requirement of explicit data association. However, it is difficult to track targets accurately in real-time with dense clutter and low detection probability. To solve this problem, this paper proposes a multi-feature matching GM-PHD (MFGM-PHD) filter for radar multi-target tracking. Using Doppler and amplitude information contained in radar echo to modify the weights of Gaussian components, the weight of the clutter can be greatly reduced and the target can be distinguished from clutter. Simulations show that the proposed MFGM-PHD filter can improve the accuracy of multi-target tracking as well as the real-time performance with high clutter density and low detection probability.

Design, Synthesis and Cytotoxicity of Thiazole-Based Stilbene Analogs as Novel DNA Topoisomerase IB Inhibitors.

A series of new thiazole-based stilbene analogs were designed, synthesized and evaluated for DNA topoisomerase IB (Top1) inhibitory activity. Top1-mediated relaxation assays showed that the synthesized compounds possessed variable Top1 inhibitory activity. Among them, (E)-2-(3-methylstyryl)-4-(4-fluorophenyl)thiazole (8) acted as a potent Top1 inhibitor with high Top1 inhibition of ++++ which is comparable to that of CPT. A possible binding mode of compound 8 with Top1-DNA complex was further provided by molecular docking. An MTT assay against human breast cancer (MCF-7) and human colon cancer (HCT116) cell lines revealed that the majority of these compounds showed high cytotoxicity, with IC50 values at micromolar concentrations. Compounds 8 and (E)-2-(4-tert-butylstyryl)-4-(4-fluorophenyl)thiazole (11) exhibited the most potent cytotoxicity with IC50 values of 0.78 and 0.62 µM against MCF-7 and HCT116, respectively. Moreover, the preliminary structure-activity relationships of thiazole-based stilbene analogs was also discussed.

A heterozygous hypomorphic mutation of Fanca causes impaired follicle development and subfertility in female mice.

Reduced fertility is a common clinical feature of the individuals with Fanconi anemia (FA), a rare autosomal recessive disorder due to deficiency in FA pathway during DNA repair. Our previous study reported that the heterozygous pathogenic variants in FANCA (Fanconi anemia complementation group A) induced premature ovarian insufficiency (POI). However, the genotype-phenotype correlation in POI caused by FANCA variants remains considerably uncertain. Herein, a heterozygous non-frameshift Fanca-mutated mouse strain (Fanca+/hypo) carrying a 9-bp deletion (c.3581del9, p.QEA1194-1196del) was generated. The mutant mice exhibited slightly decreased Fanca protein level in ovaries, suggesting the non-frameshift deletion mutant is hypomorphic. Female fertility test showed decreased number of litters, litter sizes and prolonged litter interval time in the female Fanca+/hypo mice compared to wild-type mice. Follicle counting revealed a consistent decreasing pattern of follicle numbers in Fanca+/hypo females compared to that in wild-type mice with aging. Furthermore, embryonic fibroblasts of Fanca+/hypo mice were hyper-responsive to Mitomycin C in vitro, demonstrating a partial loss of function of this hypomorphic Fanca mutant in DNA repair. Collectively, our experimental observations suggest that the hypomorphic Fanca allele is sufficient to reduce female fertility in mice, providing new insights into the genetic counseling of FANCA variants in subfertile women.