Lactic acid regulates lipid droplet aggregation through a microglia-neuron axis in neuroinflammation.

Neuroinflammation, marked by the release of proinflammatory cytokines and resulting neuronal death, is a multifaceted process extending beyond traditional inflammatory pathways. Microglia, primary cells in the inflammatory response, rapidly activate during neuroinflammation and produce proinflammatory and cytotoxic factors that affect neuronal function. Recent evidence highlights the significant role of abnormal lipid droplet (LD) deposition in the pathogenesis of neuroinflammation. While microglia are known to influence LD aggregation during neuroinflammation, the regulatory mechanism within neurons is not well understood. Our study demonstrates that lipopolysaccharide-activated microglia induce the accumulation of LD in neurons, identifying microglial-derived lactic acid as a key mediator in this process. Excessive lipid accumulation threatens neuronal function, a phenomenon reversed by eliminating microglia. Our study demonstrates that lipopolysaccharide-activated microglia induce the accumulation of LD in neurons, identifying microglial-derived lactic acid as a key mediator in this process. Excessive lipid accumulation threatens neuronal function, a phenomenon reversed by eliminating microglia.

Identification, validation and candidate gene analysis of major QTL for Supernumerary spikelets in wheat.

BACKGROUND: The number of spikelets per spike is a key trait that affects the yield of bread wheat (Triticum aestivum L.). Identification of the QTL for spikelets per spike and its genetic effects that could be used in molecular assistant breeding in the future. RESULTS: In this study, four recombinant inbred line (RIL) populations were generated and used, having YuPi branching wheat (YP), with Supernumerary Spikelets (SS) phenotype, as a common parent. QTL (QSS.sicau-2 A and QSS.sicau-2D) related to SS trait were mapped on chromosomes 2 A and 2D through bulked segregant exome sequencing (BSE-Seq). Fourteen molecular markers were further developed within the localization interval, and QSS.sicau-2 A was narrowed to 3.0 cM covering 7.6 Mb physical region of the reference genome, explaining 13.7 - 15.9% the phenotypic variance. Similarly, the QSS.sicau-2D was narrowed to 1.8 cM covering 2.4 Mb physical region of the reference genome, and it explained 27.4 - 32.9% the phenotypic variance. These two QTL were validated in three different genetic backgrounds using the linked markers. QSS.sicau-2 A was identified as WFZP-A, and QSS.sicau-2D was identified a novel locus, different to the previously identified WFZP-D. Based on the gene expression patterns, gene annotation and sequence analysis, TraesCS2D03G0260700 was predicted to be a potential candidate gene for QSS.sicau-2D. CONCLUSION: Two significant QTL for SS, namely QSS.sicau-2 A and QSS.sicau-2D were identified in multiple environments were identified and their effect in diverse genetic populations was assessed. QSS.sicau-2D is a novel QTL associated with the SS trait, with TraesCS2D03G0260700 predicted as its candidate gene.

IL-2-free tumor-infiltrating lymphocyte therapy with PD-1 blockade demonstrates potent efficacy in advanced gynecologic cancer.

BACKGROUND: Tumor-infiltrating lymphocyte (TIL) therapy has been restricted by intensive lymphodepletion and high-dose intravenous interleukin-2 (IL-2) administration. To address these limitations, we conducted preclinical and clinical studies to evaluate the safety, antitumor activity, and pharmacokinetics of an innovative modified regimen in patients with advanced gynecologic cancer. METHODS: Patient-derived xenografts (PDX) were established from a local recurrent cervical cancer patient. TILs were expanded ex vivo from minced tumors without feeder cells in the modified TIL therapy regimen. Patients underwent low-dose cyclophosphamide lymphodepletion followed by TIL infusion without intravenous IL-2. The primary endpoint was safety; the secondary endpoints included objective response rate, duration of response, and T cell persistence. RESULTS: In matched patient-derived xenografts (PDX) models, homologous TILs efficiently reduced tumor size (p < 0.0001) and underwent IL-2 absence in vivo. In the clinical section, all enrolled patients received TIL infusion using a modified TIL therapy regimen successfully with a manageable safety profile. Five (36%, 95% CI 16.3-61.2) out of 14 evaluable patients experienced objective responses, and three complete responses were ongoing at 19.5, 15.4, and 5.2 months, respectively. Responders had longer overall survival (OS) than non-responders (p = 0.036). Infused TILs showed continuous proliferation and long-term persistence in all patients and showed greater proliferation in responders which was indicated by the Morisita overlap index (MOI) of TCR clonotypes between infused TILs and peripheral T cells on day 14 (p = 0.004) and day 30 (p = 0.004). Higher alteration of the CD8+/CD4+ ratio on day 14 indicated a longer OS (p = 0.010). CONCLUSIONS: Our modified TIL therapy regimen demonstrated manageable safety, and TILs could survive and proliferate without IL-2 intravenous administration, showing potent efficacy in patients with advanced gynecologic cancer. TRIAL REGISTRATION: NCT04766320, Jan 04, 2021.

Defect-Rich Functional HfO2-x for Highly Reversible Zn Metal Anode.

Interface engineering attracted tremendous attention owing to its remarkable ability to impede dendrite growth and side reactions in aqueous zinc-ion batteries. Artificial interface layers composed of crystalline materials have been extensively employed to stabilize the Zn anode. However, the diffusion kinetics of Zn2+ in highly crystalline materials are hindered by steric effects from the lattice, thereby limiting the high-rate performance of the cell. Here, defect-rich HfO2-x polycrystals derived from metal-organic frameworks (MOFs) (D-HfO2-x) are developed to enhance the Zn deposition behavior. The discrepancy of dielectric constants between metallic Zn and HfO2 enables the building of an electrostatic shielding layer for uniform Zn deposition. More importantly, the oxygen vacancies in D-HfO2-x provide abundant active sites for Zn2+ adsorption, accelerating the kinetics of Zn2+ migration, which contributes to the preferential exposure of the Zn (002) plane during plating. Consequently, the D-HfO2-x-modified Zn anode delivers ultrastable durability of over 5000 h at 1 mA cm-2 and a low voltage hysteresis of 30 mV. The constructed defective coating provides a guarantee for the stable operation of Zn anodes, and the innovative approach of defective engineering also offers new ideas for the protection of other energy storage devices.

Charge Redistribution of Lattice-Mismatched Co─Cu3P Boosting pH-Universal Water/Seawater Hydrogen Evolution.

Practical applications of the hydrogen evolution reaction (HER) rely on the development of highly efficient, stable, and low-cost catalysts. Tuning the electronic structure, morphology, and architecture of catalysts is an important way to realize efficient and stable HER electrocatalysts. Herein, Co-doped Cu3P-based sugar-gourd structures (Co─Cu3P/CF) are prepared on copper foam as active electrocatalysts for hydrogen evolution. This hierarchical structure facilitates fast mass transport during electrocatalysis. Notably, the introduction of Co not only induces a charge redistribution but also leads to lattice-mismatch on the atomic scale, which creates defects and performs as additional active sites. Therefore, Co─Cu3P/CF requires an overpotential of only 81, 111, 185, and 230 mV to reach currents of 50, 100, 500, and 1000 mA cm-2 in alkaline media and remains stable after 10 000 CV cycles in a row and up to 110 h i-t stability tests. In addition, it also shows excellent HER performance in water/seawater electrolytes of different pH values. Experimental and DFT show that the introduction of Co modulates the electronic and energy level structures of the catalyst, optimizes the adsorption and desorption behavior of the intermediate, reduces the water dissociation energy barrier during the reaction, accelerates the Volmer step reaction, and thus improves the HER performance.

Ultrafast Quasi-Solid-State Microwave Construction of Spongy Cobalt-Molybdenum Phosphide for Hydrogen Production Over Wide pH Range.

The developed strategies for synthesizing metal phosphides are usually cumbersome and pollute the environment. In this work, an ultrafast (30 s) quasi-solid-state microwave approach is developed to construct cobalt-molybdenum phosphide decorated with Ru (Ru/CoxP-MoP) featured porous morphology with interconnected channels. The specific nanostructure favors mass transport, such as electrolyte bubbles transfer and exposing rich active sites. Moreover, the coupling effects between metallic elements, especially the decorated Ru, also act as a pivotal role on enhancing the electrocatalytic performance. Benefiting from the effects of composition and specific nanostructure, the prepared Ru/CoxP-MoP exhibits efficient HER performance with a current density of 10 mA cm-2 achieved in 1 m KOH, 0.5 m H2SO4, seawater containing 1 m KOH and 1 m PBS, with overpotentials of 52, 59, 55, 90 mV, and coupling with good stability. This work opens a novel and fast avenue to design metal-phosphide-based nanomaterials in energy-conversion and storage fields.

Strengthened Interficial Adhesive Fracture Energy by Young's Modulus Matching Degree Strategy in Carbon-Based HTM Free MAPbI3 Perovskite Solar Cell with Enhanced Mechanical Compatibility.

Carbon-based hole transport layer-free perovskite solar cells (PSCs) based on methylammonium lead triiodide (MAPbI3 ) have become one of the research focus due to low cost, easy preparation, and good optoelectronic properties. However, instability of perovskite under vacancy defects and stress-strain makes it difficult to achieve high-efficiency and stable power output. Here, a soft-structured long-chain 2D pentanamine iodide (abbreviated as "PI") is used to improve perovskite quality and interfacial mechanical compatibility. PI containing CH3 (CH2 )4 NH3 + and I- ions not only passivate defects at grain boundaries, but also effectively alleviate residual stress during high temperature annealing via decreasing Young's modulus of perovskite film. Most importantly, PI effectively increases matching degree of Young's modulus between MAPbI3 (47.1 GPa) and carbon (6.7 GPa), and strengthens adhesive fracture energy (Gc ) between perovskite and carbon, which is helpful for outward release of nascent interfacial stress generated under service conditions. Consequently, photoelectric conversion efficiency (PCE) of optimal device is enhanced from 10.85% to 13.76% and operational stability is also significantly improved. 83.1% output is maintained after aging for 720 h at room temperature and 25-60% relative humidity (RH). This strategy of regulation from chemistry and physics provides a strategy for efficient and stable carbon-based PSCs.

A developmental validation of the Quick TargSeq 1.0 integrated system for automated DNA genotyping in forensic science for reference samples.

Analysis of short tandem repeats (STRs) is a global standard method for human identification. Insertion/Deletion polymorphisms (DIPs) can be used for biogeographical ancestry inference. Current DNA typing involves a trained forensic worker operating several specialized instruments in a controlled laboratory environment, which takes 6-8 h. We developed the Quick TargSeq 1.0 integrated system (hereinafter abbreviated to Quick TargSeq) for automated generation of STR and DIP profiles from buccal swab samples and blood stains. The system fully integrates the processes of DNA extraction, polymerase chain reaction (PCR) amplification, and electrophoresis separation using microfluidic biochip technology. Internal validation studies were performed using RTyper 21 or DIP 38 chip cartridges with single-source reference samples according to the Scientific Working Group for DNA Analysis Methods guidelines. These results indicated that the Quick TargSeq system can process reference samples and generate STR or DIP profiles in approximately 2 h, and the profiles were concordant with those determined using traditional STR or DIP analysis methods. Thus, reproducible and concordant DNA profiles were obtained from reference samples. Throughout the study, no lane-to-lane or run-to-run contamination was observed. The Quick TargSeq system produced full profiles from buccal swabs with at least eight swipes, dried blood spot cards with two 2-mm disks, or 10 ng of purified DNA. Potential PCR inhibitors (i.e., coffee, smoking tobacco, and chewing tobacco) did not appear to affect the amplification reactions of the instrument. The overall success rate and concordance rate of 153 samples were 94.12% and 93.44%, respectively, which is comparable to other commercially available rapid DNA instruments. A blind test initiated by a DNA expert group showed that the system can correctly produce DNA profiles with 97.29% genotype concordance with standard bench-processing methods, and the profiles can be uploaded into the national DNA database. These results demonstrated that the Quick TargSeq system can rapidly generate reliable DNA profiles in an automated manner and has the potential for use in the field and forensic laboratories.

Phase I study of the Syk inhibitor sovleplenib in relapsed or refractory mature B-cell tumors.

Sovleplenib (HMPL-523) is a selective spleen tyrosine kinase (Syk) inhibitor with anti-tumor activity in preclinical models of B-cell malignancy. We conducted a dose-escalation and dose-expansion phase I study of sovleplenib in patients with relapsed/ refractory mature B-cell tumors. Dose escalation followed a 3+3 design; patients received oral sovleplenib (200-800 mg once daily [q.d.] or 200 mg twice daily [b.i.d.], 28-day cycles). During dose expansion, patients were enrolled into four cohorts per lymphoma classification and treated at the recommended phase II dose (RP2D) (clinicaltrials gov. Identifier: NCT02857998). Overall, 134 Chinese patients were enrolled (dose escalation, N=27; dose expansion, N=107). Five patients experienced dose-limiting toxicities: one each of amylase increased (200 mg q.d.), febrile neutropenia (800 mg q.d.), renal failure (800 mg q.d.), hyperuricemia and blood creatine phosphokinase increased (200 mg b.i.d.) and blood bilirubin increased and pneumonia (200 mg b.i.d.). RP2D was determined as 600 mg (>65 kg) or 400 mg (≤65 kg) q.d.. The primary efficacy end point of independent review committee-assessed objective response rate in indolent B-cell lymphoma was 50.8% (95% confidence interval: 37.5- 64.1) in 59 evaluable patients at RP2D (follicular lymphoma: 60.5%, marginal zone lymphoma: 28.6%, lymphoplasmacytic lymphoma/Waldenström macroglobulinemia, 0%). The most common (≥10% patients) grade ≥3 treatment-related adverse events in the dose-expansion phase were decreased neutrophil count (29.9%), pneumonia (12.1%) and decreased white blood cell count (11.2%). Pharmacokinetic exposures increased dose-proportionally with ascending dose levels from 200-800 mg, without observed saturation. Sovleplenib showed anti-tumor activity in relapsed/refractory B-cell lymphoma with acceptable safety. Further studies are warranted.

Tislelizumab augment the efficacy of CD19/22 dual-targeted chimeric antigen receptor T cell in advanced stage relapsed or refractory B-cell non-Hodgkin lymphoma.

Dual-targeted chimeric antigen receptor T (CAR-T) cell is an important strategy to improve the efficacy of CD19 CAR-T cell against refractory or relapsed B cell non-Hodgkin lymphoma (R/R B-NHL). However, durable responses are not achieved in most patients, in part owing CAR-T cell exhaustion caused by PD-1/PD-L1 pathway. We conducted a prospective, single-arm study of dual-targeted CD19/22 CAR-T cell combined with anti-PD-1 antibody, tislelizumab, in R/R B-NHL (NCT04539444). Tislelizumab was administrated on +1 day after patients received infusion of CD19/22 CAR-T cell. Responses, survival and safety were evaluated. From 1 August 2020 to 30 March 2023, 16 patients were enrolled. The median follow-up time is 16.0 (range: 5.0-32.0 months) months. Overall response was achieved in 14 of 16 (87.5%) patients, and the complete response (CR) was achieved in 11 of 16 (68.8%) patients. The 1-year progression-free survival and overall survival rates were 68.8% and 81.3%, respectively. Of the 14 patients responded, 9 patients maintained their response until the end of follow-up. Among the 15 out of 16 (93.8%) patients who had extranodal involvement, 14 (93.3%) patients achieved overall response rate with 11 (73.3%) patients achieving CR. Eight (50%) patients experienced cytokine release syndrome. No neurologic adverse events were reported. Gene Ontology-Biological Process enrichment analysis showed that immune response-related signaling pathways were enriched in CR patients. Our results suggest that CD19/22 CAR-T cell combined with tislelizumab elicit a safe and durable response in R/R B-NHL and may improve the prognosis of those patients.

Antioxidant Carbon Dots Nanozymes Alleviate Stress-induced Depression by Modulating Gut Microbiota.

Depression is a debilitating mental illness that severely threatens millions of individuals and public health. Because of the multifactorial etiologies, there is currently no cure for depression; thus, it is urgently imperative to find alternative antidepressants and strategies. Growing evidence underscores the prominent role of oxidative stress as key pathological hallmarks of depression, making oxidative stress a potential therapeutic target. In this study, we report a N-doped carbon dot nanozyme (CDzyme) with excellent antioxidant capacity for treating depression by remodeling redox homeostasis and gut microbiota. The CDzymes prepared via microwave-assisted fast polymerization of histidine and glucose exhibit superior biocompatibility. Benefiting from the unique structure, CDzymes can provide abundant electrons, hydrogen atoms, and protons for reducing reactions, as well as catalytic sites to mimic redox enzymes. These mechanisms collaborating endow CDzymes with broad-spectrum antioxidant capacity to scavenge reactive oxygen and nitrogen species (•OH, O2-•, H2O2, ONOO-), and oxygen/nitrogen centered free radicals. A depression animal model was established by chronic unpredictable mild stress (CUMS) to evaluate the therapeutic efficacy of CDzymes from the behavioral, physiological, and biochemical index and intestinal flora assessments. CDzymes can remarkably improve depression-like behaviors and key neurotransmitters produced in hippocampus tissues and restore the gut microbiota compositions and the amino acid metabolic functions, proving the potential in treating depression through the intestinal-brain axis system. This study will facilitate the development of intestinal flora dysbiosis nanomedicines and treatment strategies for depression and other oxidative stress related multifactorial diseases.

OxLDL enhances procoagulant activity of endothelial cells by TMEM16F-mediated phosphatidylserine exposure.

Oxidized low-density lipoprotein (oxLDL), a key component in atherosclerosis and hyperlipidemia, is a risk factor for atherothrombosis in dyslipidemia, yet its mechanism is poorly understood. In this study, we used oxLDL-induced human aortic endothelial cells (HAECs) and high-fat diet (HFD)-fed mice as a hyperlipidemia model. Phosphatidylserine (PS) exposure, cytosolic Ca2+, reactive oxygen species (ROS), and lipid peroxidation were measured by flow cytometer. TMEM16F expression was detected by immunofluorescence, western blot, and reverse transcription polymerase chain reaction. Procoagulant activity (PCA) was measured by coagulation time, intrinsic/extrinsic factor Xase, and thrombin generation. We found that oxLDL-induced PS exposure and the corresponding PCA of HAECs were increased significantly compared with control, which could be inhibited over 90% by lactadherin. Importantly, TMEM16F expression in oxLDL-induced HAECs was upregulated by enhanced intracellular Ca2+ concentration, ROS, and lipid peroxidation, which led to PS exposure. Meanwhile, the knockdown of TMEM16F by short hairpin RNA significantly inhibited PS exposure in oxLDL-induced HAECs. Moreover, we observed that HFD-fed mice dramatically increased the progress of thrombus formation and accompanied upregulated TMEM16F expression by thromboelastography analysis, FeCl3-induced carotid artery thrombosis model, and western blot. Collectively, these results demonstrate that TMEM16F-mediated PS exposure may contribute to prothrombotic status under hyperlipidemic conditions, which may serve as a novel therapeutic target for the prevention of thrombosis in hyperlipidemia.

Blood glucose control among type 2 diabetic farmers in Chinese resettlement areas: a mixed methods study.

BACKGROUND: Due to China's rapid urbanization, many farmers have relocated to urban resettlement regions. There is limited research on the glycemic control of Type 2 diabetes mellitus (T2DM) farmers in these areas. This study examined their blood glucose control and its determinants. METHODS: This study took place from March 2021 to January 2022 in a resettlement community in Yiwu, Zhejiang Province, China. In the first phase, a quantitative survey of 181 T2DM farmers was conducted using a questionnaire to gather demographic data, blood glucose control status, disease cognition levels, and treatment compliance. Inclusion criteria were migrant workers with ≥ 3 months of residence and local household registration and T2DM patients who met the diagnostic criteria of the Chinese guidelines. In the second phase, qualitative research involved face-to-face, semi-structured interviews with 15 patients with varying blood glucose control levels to analyze their experiences. RESULTS: The blood glucose control rate in this particular group was 27.62%, and the average disease cognition score was 2.5 ± 0.75. Many patients (67.96%) had inadequate treatment compliance, specifically in monitoring compliance (4.45 ± 1.92) and regular review compliance (3.58 ± 1.74). CONCLUSION: There is a need for tailored programs to improve glycemic control among resettled farmers. Enhancing disease awareness and treatment compliance through targeted education and support is crucial. Further studies are needed to evaluate different treatment regimens' impact on glycemic control. CLINICAL TRIAL NUMBER: Not applicable.

Paternal genetic structure analysis of the modern Han populations based on Y-SNP and Y-STR.

The Han populations represent the largest ethnic group in China. Previous studies have primarily focused on investigating their genetic origins, migration and integration, as well as paternal genetic relationships within specific regional Han populations. However, a comprehensive analysis of the global paternal genetic structure of Han populations is lacking. In this study, we performed Y-chromosome sequencing on 362 unrelated male samples from Chinese Han individuals collected from Qinghai, Sichuan and Liaoning provinces. We then integrated relevant data from reported studies. Our final dataset comprised 1830 samples from 16 Han populations across 15 provinces in China, encompassing information on 89 Y-SNPs and 16 Y-STRs. Statistical analyses were conducted to assess Y-STR haplotype diversity (HD) and Y-SNP haplogroup frequencies. Additionally, we employed principal component analysis (PCA), phylogenetic tree and haplotype network to explore genetic differentiation within Han populations and the genetic relationships between Han populations and ethnic minorities surrounding them. Our results demonstrated that the O-M175 haplogroup represents the predominant paternal lineage in Han populations, with frequencies ranging from 60.53% (Qinghai Han) to 92.7% (Guangdong Han). Moreover, the subclades downstream of O-M175 showed distinct regional variations in their distribution patterns. The O2-M122 haplogroup was prevalent in all Han populations and demonstrated a gradual decline in frequency from north to south. Conversely, the distribution frequency of the O1b-M268 haplogroup decreased from south to north, particularly showed significant presence among Han populations in the Lingnan region. Haplogroup O1a-M119 distributed more frequently in the central Han populations. Our findings revealed that Chinese Han populations can be categorized into three subgroups: northern, central, and southern. Notably, there were significant differences among Han in Qinghai and other regions. Regarding the genetic relationships between Han populations and surrounding ethnic minorities, we observed a closer genetic affinity between different Han populations, but northern Han demonstrated a stronger relationship with the Hui ethnic group, while southern Han exhibited a closer connection with the Gelao and Li ethnic groups. In summary, this study presented a systematic analysis of haplogroup distribution, genetic substructure of Han populations and genetic relationships between Han populations and surrounding ethnic minorities based on 89 Y-SNPs and 16 Y-STRs systematically. Our research supplemented valuable insights into population genetics and forensic genetics, and provided data support for the forensic application of Y chromosome. The integration of Y-SNP haplogroups with Y-STR haplotypes offers enhanced understanding of the genetic substructure within Han populations, which holds significance for both population genetics research and forensic science applications.

Controllable Solid Electrolyte Interphase by Ionic Environment Regulation for Stable Zn-Ion Battery.

Artificial solid electrolyte interphase in organic solutions is effective and facile for long-cycling aqueous zinc ion batteries. However, the specific effects on different ionic environments have not been thoroughly investigated. Herein, pyromellitic acid (PA) are employed as organic ligand to coordinate with Zn2+ under various ionic environments. The connection between the ionic environment and reaction spontaneity is analyzed to provide insights into the reasons behind the effectiveness of the SEI layer and to characterize its protective impact on the zinc anode. Notably, the PA solution (pH4) lacking OH- contributes to the formation of a dense and ultrathin SEI with Zn-PA coordination, preventing direct contact between the anode and electrolyte. Moreover, the presence of organic functional groups facilitates a uniform flux of Zn2+ . These advantages enable stable cycling of the PA4-Zn symmetric cell at a current density of 3 mA cm-2 for over 3500 h. The PA4-Zn//MVO full cell demonstrates excellent electrochemical reversibility. Investigating the influence of the ionic environment on SEI generation informs the development of novel SEI strategies.

Dynamic changes in polioviruses identified by environmental surveillance in Guangzhou, 2009-2021.

Polio cases can be missed by acute flaccid paralysis (AFP) case surveillance alone, emphasizing the importance of environmental surveillance (ES). In this study, to investigate the serotype distribution and epidemiological trends of poliovirus (PV), we characterized PV isolated from domestic sewage in Guangzhou City, Guangdong Province, China from 2009 to 2021. A total of 624 sewage samples were collected from the Liede Sewage Treatment Plant, and the positive rates of PV and non-polio enteroviruses were 66.67% (416/624) and 78.37% (489/624), respectively. After sewage sample treatment, each sewage sample was inoculated in six replicate tubes of three cell lines, and 3370 viruses were isolated during the 13-year surveillance period. Among these, 1086 isolates were identified as PV, including type 1 PV (21.36%), type 2 PV (29.19%), and type 3 PV (49.48%). Based on VP1 sequences, 1057 strains were identified as Sabin-like, 21 strains were high-mutant vaccines, and eight strains were vaccine-derived poliovirus (VDPV). The numbers and serotypes of PV isolates in sewage were influenced by the vaccine switch strategy. After type 2 OPV was removed from the trivalent oral PV (OPV) vaccine and a bivalent OPV (bOPV) was adopted in May 2016, the last type 2 PV strain was isolated from sewage, with no detection thereafter. Type 3 PV isolates increased significantly and became the dominant serotype. Before and after the second vaccine switch in January 2020, that is, from the first dose of IPV and second-fourth doses of bOPV to the first two doses of IPV and third-fourth doses of bOPV, there was also a statistical difference in PV positivity rates in sewage samples. Seven type 2 VDPVs and one type 3 VDPV were identified in sewage samples in 2009-2021, and phylogenetic analysis indicated that all VDPVs isolated from ES in Guangdong are newly discovered VDPVs, different from VDPV previously discovered in China, and were classified as ambiguous VDPV. It is noteworthy that no VDPV cases were reported in AFP case surveillance in the same period. In conclusion, continued PV ES in Guangzhou since April 2008 has been a useful supplement to AFP case surveillance, providing an important basis for evaluating the effectiveness of vaccine immunization strategies. ES improves early detection, prevention, and control; accordingly, this strategy can curb the circulation of VDPVs and provide a strong laboratory basis for maintaining a polio-free status.

Testing of two SNP array-based genealogy algorithms using extended Han Chinese pedigrees and recommendations for improved performances in forensic practice.

Distant genetic relatives can be linked to a crime scene sample by computing identity-by-state (IBS) and identity-by-descent (IBD) shared by individuals. To test the methods of genetic genealogy estimation and optimal the parameters for forensic investigation, a family-based genetic genealogy analysis was performed using a dataset of 262 Han Chinese individuals from 11 families. The dataset covered relative pairs from 1st- to 14th degrees. But the 7th-degree relative is the most distant kinship to be fully investigated, and each individual has ∼200 relatives within the 7th degree. The KING algorithm by calculating IBS and IBD statistics can correctly discriminate the first-degree relationships of monozygotic twin, parent-offspring and full sibling. The inferred relationship was reliable within the fifth-degree, false positive rate <1.8%. The IBD segment algorithm, GERMLINE + ERSA, could provide reliable inference result prolonged to eighth degree. Analysis of IBD segments produced obviously false negative estimations (<27.4%) rather than false positives (0%) within the eighth-degree inferences. We studied different minimum IBD segment threshold settings (changed from >0 to 6 cM); the inferred results did not make much difference. In distant relative analysis, genetically undetectable relationships begin to occur from the sixth degree (second cousin once removed), which means the offspring after seven meiotic divisions may share no ancestor IBD segment at all. Application of KING and GERMLINE + ERSA worked complementarily to ensure accurate inference from first degree to eighth degree. Using simulated low call rate data, the KING algorithm shows better tolerance to marker decrease compared with the GERMLINE + ERSA segment algorithm.

Study on the inhibitory effect of quercetin combined with gentamicin on the formation of Pseudomonas aeruginosa and its bioenvelope.

OBJECTIVE: The potential effects of quercetin and gentamicin combination on the bacteriostatic activity and biofilm formation of Pseudomonas aeruginosa (PA) were examined, and the findings provided a theoretical basis for the development of quercetin as a new biofilm inhibitor. METHODS: The minimum inhibitory concentration (MIC) of eight PAs was determined by microdilution method and the partial inhibitory concentration index (FICI) of the combined drug was analyzed by micro-dilution method. Thereafter, the lowest film inhibitory concentration (MBIC) of quercetin and gentamicin alone and in combination was evaluated by crystal violet staining. Finally, scanning electron microscopy (SEM) and laser confocal microscopy (CLSM) were used to decipher the inhibitory effect of the combination on biofilm formation. OUTCOME: The antibacterial activity of quercetin alone was relatively weak, but after combination with gentamicin, the antibacterial activity was significantly enhanced, as evident by FICI of 0.28 and 0.53 and manifested as synergistic or additive effect, which indicated that quercetin can enhance gentamicin antibacterial activity. The results of crystal violet staining revealed that quercetin and gentamicin alone exhibited a similar biofilm formation inhibitory effect, but the inhibitory effect was substantially weaker, and the antibiofilm activity was stronger and exhibited a dose-dependent response after the combination of the two with 1/2FICI. The results of scanning electron microscopy and laser confocal microscopy also showed that the treatment of PA biofilm after combining quercetin and gentamicin with 1/2FICI could completely destroy the spatial structure of the complete biofilm, significantly reduce the thickness of bacteria, and markedly reduce the proportion of viable bacteria in the membrane. CONCLUSION: The combination of quercetin and gentamicin can effectively inhibit the formation of PA as well as its biofilm, and exhibit synergistic and additive effects.

A Synthetic External Control Study Comparing the Clinical Efficacy of Wendan Decoction and 19 Antidepressants.

BACKGROUND: Wendan decoction (WDD) has been used as a treatment for depression in China since the Tang Dynasty. However, high-quality evidence for this is lacking. This study proposed a novel synthetic external control method to evaluate its clinical efficacy. METHODS: We searched public databases for clinical trials of WDD for major depression. The rate of change of the Hamilton Depression Scale score from baseline was used as an efficacy indicator, and a model-based meta-analysis was performed to analyze the clinical efficacy of WDD. To establish a reference standard for efficacy, the antidepressant efficacy distributions of a placebo and 19 antidepressants were virtually synthesized based on the same conditions as the clinical trial characteristics of WDD. RESULTS: This study included 5 clinical trials with 177 participants. WDD showed a slow onset, with a time to reach the maximum effect of 9.71 weeks. At 8 weeks, the rate of change in the Hamilton Depression Scale score from baseline was 66.4% (95% CI = 62.3%-70.3%) in the WDD group. The pure effect value of WDD, after deducting the placebo effect, was 26.9% (95%CI = 23.0%-30.9%), which was comparable with 5 types of antidepressants and significantly higher than the others. CONCLUSION: The proposed external synthetic control method provides a solution to the bottleneck problem of clinical efficacy evaluation in real-world research on traditional Chinese medicine. WDD has high clinical development value for the treatment of depression, and large-scale randomized controlled trials are recommended to confirm its antidepressant effect.

Sohlh1 and Lhx8 are prominent biomarkers to estimate the primordial follicle pool in mice.

Efficient evaluation of the primordial follicle pool (PFP) of mammalian models is an essential subject in biomedical research relating to ovarian physiology and pathogenesis. Our recent study has identified a gene signature including Sohlh1, Nobox, Lhx8, Tbpl2, Stk31, Padi6, and Vrtn strongly correlated with ovarian reserve by using bioinformatics analysis. Aimed to investigate the validity of these candidate biomarkers for evaluating the PFP, we utilized an OR comparison model to decode the relationship between the numbers of PFP and candidate biomarkers in the present study. Our results suggest that these biomarkers Sohlh1, Nobox, Lhx8, Tbpl2, Stk31, Padi6, and Vrtn possess independent potential to evaluate the number of the PFP. And the combination of Sohlh1 and Lhx8 can be used as the optimal biomarkers for rapid assessment of the PFP in the murine ovary. Our findings provide a new perspective for evaluating the PFP of the ovary in animal studies and the clinic.