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The development and innovation of next generation sequencing (NGS) and the subsequent analysis tools have gain popularity in scientific researches and clinical diagnostic applications. Hence, a systematic comparison of the sequencing platforms and variant calling pipelines could provide significant guidance to NGS-based scientific and clinical genomics. In this study, we compared the performance, concordance and operating efficiency of 27 combinations of sequencing platforms and variant calling pipelines, testing three variant calling pipelines—Genome Analysis Tool Kit HaplotypeCaller, Strelka2 and Samtools-Varscan2 for nine data sets for the NA12878 genome sequenced by different platforms including BGISEQ500, MGISEQ2000, HiSeq4000, NovaSeq and HiSeq Xten. For the variants calling performance of 12 combinations in WES datasets, all combinations displayed good performance in calling SNPs, with their F-scores entirely higher than 0.96, and their performance in calling INDELs varies from 0.75 to 0.91. And all 15 combinations in WGS datasets also manifested good performance, with F-scores in calling SNPs were entirely higher than 0.975 and their performance in calling INDELs varies from 0.71 to 0.93. All of these combinations manifested high concordance in variant identification, while the divergence of variants identification in WGS datasets were larger than that in WES datasets. We also down-sampled the original WES and WGS datasets at a series of gradient coverage across multiple platforms, then the variants calling period consumed by the three pipelines at each coverage were counted, respectively. For the GIAB datasets on both BGI and Illumina platforms, Strelka2 manifested its ultra-performance in detecting accuracy and processing efficiency compared with other two pipelines on each sequencing platform, which was recommended in the further promotion and application of next generation sequencing technology. The results of our researches will provide useful and comprehensive guidelines for personal or organizational researchers in reliable and consistent variants identification.

In the past decade, treatments for tumors have made remarkable progress, such as the successful clinical application of targeted therapies. Nowadays, targeted therapies are based primarily on the detection of mutations, and next-generation sequencing (NGS) plays an important role in relevant clinical research. The mutation frequency is a major problem in tumor mutation detection and increasing sequencing depth is a widely used method to improve mutation calling performance. Therefore, it is necessary to evaluate the effect of different sequencing depth and mutation frequency as well as mutation calling tools. In this study, Strelka2 and Mutect2 tools were used in detecting the performance of 30 combinations of sequencing depth and mutation frequency. Results showed that the precision rate kept greater than 95% in most of the samples. Generally, for higher mutation frequency (≥20%), sequencing depth ≥200X is sufficient for calling 95% mutations; for lower mutation frequency (≤10%), we recommend improving experimental method rather than increasing sequencing depth. Besides, according to our results, although Strelka2 and Mutect2 performed similarly, the former performed slightly better than the latter one at higher mutation frequency (≥20%), while Mutect2 performed better when the mutation frequency was lower than 10%. Besides, Strelka2 was 17 to 22 times faster than Mutect2 on average. Our research will provide a useful and comprehensive guideline for clinical genomic researches on somatic mutation identification through systematic performance comparison among different sequencing depths and mutation frequency.

Species of the brown algae of the genus Dictyota are rich sources of bioactive secondary metabolites with diverse structural features. Excellent progress has been made in the discovery of diterpenes possessing broad chemical defensive activities from this genus. Most of these diterpenes exhibit significant biological activities, such as antiviral, cytotoxic and chemical defensive activities. In the present review, we summarized diterpenes isolated from the brown algae of the genus.

Inward-rectifier potassium (K+) channels conduct K+ ions most efficiently in one direction, into the cell. Kir2 channels control the resting membrane voltage in many electrically excitable cells, and heritable mutations cause periodic paralysis and cardiac arrhythmia. We present the crystal structure of Kir2.2 from chicken, which, excluding the unstructured amino and carboxyl termini, is 90% identical to human Kir2.2. Crystals containing rubidium (Rb+), strontium (Sr2+), and europium (Eu3+) reveal binding sites along the ion conduction pathway that are both conductive and inhibitory. The sites correlate with extensive electrophysiological data and provide a structural basis for understanding rectification. The channel's extracellular surface, with large structured turrets and an unusual selectivity filter entryway, might explain the relative insensitivity of eukaryotic inward rectifiers to toxins. These same surface features also suggest a possible approach to the development of inhibitory agents specific to each member of the inward-rectifier K+ channel family.

Cerebral malaria (CM) is a severe encephalopathy caused by Plasmodium parasite infection, resulting in thousands of annual deaths and neuro-cognitive sequelae even after anti-malarial drugs treatment. Despite efforts to dissect the mechanism, the cellular transcriptomic reprogramming within the spatial context remains elusive. Here, we constructed single-cell and spatial transcriptome atlases of experimental CM (ECM) male murine brain tissues with or without artesunate (ART) treatment. We identified activated inflammatory endothelial cells during ECM, characterized by a disrupted blood-brain barrier, increased antigen presentation, and leukocyte adhesion. We also observed that inflammatory microglia enhance antigen presentation pathway such as MHC-I to CD8 + cytotoxic T cells. The latter underwent an inflammatory state transition with up-regulated cytokine expression and cytotoxic activity. Multi-omics analysis revealed that the activated interferon-gamma response of injured neurons during ECM and persisted after ART treatment. Overall, our research provides valuable resources for understanding malaria parasite-host interaction mechanisms and adjuvant therapy development. By integrating single-cell and spatial transcriptomic analysis, Chen et al. profile the cellular disruptions in the murine brain during cerebral malaria and after artemisinin treatment.

Tripterygium glycosides tablets (TGT) are effective against autoimmune diseases but cause significant drug-induced liver injury (DILI) that limits clinical use. While TGT disrupts hepatic iron-lipid homeostasis and co-administration with Total Glucosides of Peony (TGP) mitigates its toxicity, the multi-cellular mechanisms remain unclear. In the current study, using integrative single-cell RNA sequencing and pathological validation in controlled mouse models (TGT vs.Con and TGT + TGP vs. TGT.) we elucidated a pathogenic iron-lipid axis driving hepatotoxicity via cellular cascades. TGT initiated Kupffer cell M1 polarization, releasing pro-inflammatory cytokines (TNF-α and IL-1β) that recruited neutrophils and induced NETosis-mediated oxidative stress. Concurrently, hepatic endothelial cells developed iron overload with increased Hamp and decreased Slc40a1, alongside inflammatory damage, while hepatocytes exhibited fatty acid metabolic dysfunction and lipid peroxidation, collectively propagating adipocyte hyperplasia and perilipin-2-driven lipid accumulation. Critically, TGP rescued toxicity by reversing Kupffer cell M1-to-M2 polarization with decreased iNOS and increased CD206, suppressing NET formation with decreased Ly6G and CitH3, alleviating iron deposition with reduced Prussian blue staining, and normalizing lipid metabolism with decreased oil red O staining and perilipin-2. This study identifies the iron-lipid axis as the central driver of TGT-induced liver injury, which is mediated by a sequential multi-cellular cascade involving Kupffer cells, neutrophils, endothelial cells, hepatocytes, and adipocytes. These findings position TGP as a multi-target detoxification agent that mechanistically disrupts this axis and establishes a cellular hierarchy blueprint for metabolic toxicity intervention, supporting its potential as a rescue strategy for precision medicine and detoxification screening. Graphical abstract

This study evaluated the effects of aerobic exercise on cognitive function, sleep, and emotional states in healthy adults through a systematic review and meta-analysis. Literature published within the past 5 years was retrieved from five databases: PubMed, Web of Science, Elsevier ScienceDirect, CNKI, and VIP. A total of 19 randomized controlled trials were included. The results showed that acute aerobic exercise significantly enhanced positive mood (SMD = 1.56) and reduced negative mood (SMD = -0.46), but did not yield significant improvements in cognitive performance. In contrast, long-term aerobic exercise effectively alleviated negative mood (SMD = -0.58), whereas its effects on positive mood, cognitive function, and sleep quality were not statistically significant. These findings suggest that acute exercise may serve as an effective strategy for rapid emotional regulation, while regular long-term exercise contributes beneficially to emotional well-being. However, the potential benefits of aerobic exercise on cognition and sleep warrant further investigation through more standardized and high-quality studies. https://www.crd.york.ac.uk/PROSPERO/view/CRD420261383739, CRD420261383739.

Aristolochic acid (AA), mainly derived from herbal and plants, was listed as a human carcinogen class I in 2002. Aristolochic acid nephropathy (AAN) is a rapidly progressive tubulointerstitial nephritis and urothelial cancer caused by AA. However, the targeting molecular mechanisms of AAs-induced nephrotoxicity are largely unclear. This study aims to dissect targeting molecular mechanisms of AA-induced nephrotoxicity. Activity-based protein profiling (ABPP) in combination with cellular thermal shift assay (CETSA) was performed to identify the AAs binding target proteins. Our data indicated that several key enzymes in the metabolic process and mitochondrial respiration including IDH2 and MDH2 (Krebs cycle), PKM and LDH (aerobic respiration), FASN (fatty acid beta-oxidation), HK2 (glucose metabolism), and ATP synthase were identified as directly binding targets of AAs. Metabolomics and oxygen consumption rate (OCR) experiments further confirmed that AAs targeting proteins disrupted metabolic biosynthesis processes and impaired mitochondrial functions. Ultimately, AAs induced renal cells apoptosis by disturbing various biological processes. Cumulatively, AAs may directly bind to key proteins involved in the metabolic process and mitochondrial homeostasis, and finally induce aristolochic acid nephropathy. Our findings provide novel insight into underlying mechanisms of AAs-induced kidney toxicity, which may help to develop therapeutic strategies for AAN.

Background For poor ovarian response patients, obtaining higher number of transferable and high-quality embryos is crucial and progestin-primed ovarian stimulation protocol is becoming widespread and constantly improving in this population. Letrozole has shown promise in numerous protocols and individuals. This study aims to evaluate the effect of the early addition of letrozole in progestin-primed ovarian stimulation protocol among expected poor ovarian response patients. Methods This retrospective cohort study was performed in POSEIDON group 3 and 4 patients who underwent in vitro fertilization or intracytoplasmic sperm injection with their first progestin-primed ovarian stimulation protocol from January 1, 2018 to December 31, 2021. Totally 557 patients were enrolled in this research with 189 ovarian stimulation cycles for POSEIDON group 3 patients and 368 ovarian stimulation cycles for POSEIDON group 4 patients. The primary outcome of this study was the cumulative live birth rate and cumulative clinical pregnancy rate, and the second outcomes included the laboratory outcomes and pregnancy outcomes, maternal and neonatal complications also were encompassed. Results In this study, progestin-primed ovarian stimulation protocol combined with letrozole (study group) was associated with a significantly higher number of oocytes for retrieval and maturation [3.0 (2.0, 5.0) vs. 2.0 (1.3, 4.0), P  < 0.001; 3.0 (2.0, 5.0) vs. 2.0 (1.0, 3.8), P  < 0.001] as well as 2PN embryos [2.0 (1.0, 3.0) vs. 2.0 (1.0, 3.0), P  = 0.026] among POSEIDON group 4 patients. In POSEIDON group 3 patients, the letrozole cotreatment did not show an advantage in these indicators. There was no significant difference in both cumulative live birth rate and cumulative clinical pregnancy rate between the study and control group in POSEIDON group 3 and 4 patients. Multivariate logistic regression model showed that significant favorable effects of the number of available embryos on cumulative live birth rate in all included patients. Conclusions These findings indicate that advanced-aged poor ovarian response patients may benefit more from using letrozole as an advantageous adjuvant agent in the progestin-primed ovarian stimulation protocol to obtain more oocytes and embryos in clinical practice. Trial registration This trial was retrospectively registered

Expansion and cracking induced by the corrosion of reinforcement concrete is the major factor in the failure of concrete durability. Therefore, monitoring of concrete cracking is critical for evaluating the safety of concrete structures. In this paper, we introduce a novel monitoring method combining Brillouin optical time domain analysis (BOTDA) and fiber Bragg grating (FBG), based on mechanical principles of concrete expansion cracking. BOTDA monitors concrete expansion and crack width, while FBG identifies the time and position of cracking. A water-pressure loading simulation test was carried out to determine the relationship between fiber strain, concrete expansion and crack width. An electrical accelerated corrosion test was also conducted to evaluate the ability of this novel sensor to monitor concrete cracking under practical conditions.