The A subunit of vacuolar H+-ATPase gene (CmVHA-A) plays opposite roles in plant growth and drought tolerance of chrysanthemum under different growing conditions.

As the most prominent proton pumps in plants, vacuolar H+-ATPases (VHAs) comprise multiple subunits that are important for physiological processes and stress tolerance in plants. However, few studies on the roles of subunit genes of VHAs in chrysanthemum have been reported to date. In this study, the gene of A subunit of V-ATPase in chrysanthemum (CmVHA-A) was cloned and identified. CmVHA-A was conserved with VHA-A proteins from other plants. Expression analysis showed that CmVHA-A was highly expressed in most tissues of chrysanthemum except for the flower bud, and was readily induced by polyethylene glycol (PEG) treatment. Functional analysis demonstrated that CmVHA-A exerted a negative influence on the growth and development of shoot and root of chrysanthemum under normal conditions. RNA-sequencing (RNA-seq) analysis revealed the possible explanations for phenotypic differences between transgenic and wild-type (WT) plants. Under drought conditions, CmVHA-A positively affected the drought tolerance of chrysanthemum by enhancing antioxidase activity and alleviating photosynthetic disruption. Overall, CmVHA-A plays opposite roles in plant growth and drought tolerance of chrysanthemums under different growing conditions.

Synthesis and structure-activity optimization of azepane-containing derivatives as PTPN2/PTPN1 inhibitors.

Protein tyrosine phosphatases PTPN2 and PTPN1 (also known as PTP1B) have been implicated in a number of intracellular signaling pathways of immune cells. The inhibition of PTPN2 and PTPN1 has emerged as an attractive approach to sensitize T cell anti-tumor immunity. Two small molecule inhibitors have been entered the clinic. Here we report the design and development of compound 4, a novel small molecule PTPN2/N1 inhibitor demonstrating nanomolar inhibitory potency, good in vivo oral bioavailability, and robust in vivo antitumor efficacy.

Effect of stress urinary incontinence on vaginal microbial communities.

BACKGROUND: Postpartum women often experience stress urinary incontinence (SUI) and vaginal microbial dysbiosis, which seriously affect women's physical and mental health. Understanding the relationship between SUI and vaginal microbiota composition may help to prevent vaginal diseases, but research on the potential association between these conditions is limited. RESULTS: This study employed 16S rRNA gene sequencing to explore the association between SUI and vaginal dysbiosis. In terms of the vaginal microbiota, both species richness and evenness were significantly higher in the SUI group. Additionally, the results of NMDS and species composition indicated that there were differences in the composition of the vaginal microbiota between the two groups. Specifically, compared to postpartum women without SUI (Non-SUI), the relative abundance of bacteria associated with bacterial dysbiosis, such as Streptococcus, Prevotella, Dialister, and Veillonella, showed an increase, while the relative abundance of Lactobacillus decreased in SUI patients. Furthermore, the vaginal microbial co-occurrence network of SUI patients displayed higher connectivity, complexity, and clustering. CONCLUSION: The study highlights the role of Lactobacillus in maintaining vaginal microbial homeostasis. It found a correlation between SUI and vaginal microbiota, indicating an increased risk of vaginal dysbiosis. The findings could enhance our understanding of the relationship between SUI and vaginal dysbiosis in postpartum women, providing valuable insights for preventing bacterial vaginal diseases and improving women's health.

Comparative analysis of microbial composition and functional characteristics in dental plaque and saliva of oral cancer patients.

BACKGROUND: The oral cavity is home to various ecological niches, each with its own unique microbial composition. Understanding the microbial communities and gene composition in different ecological niches within the oral cavity of oral cancer (OC) patients is crucial for determining how these microbial populations contribute to disease progression. METHODS: In this study, saliva and dental plaque samples were collected from patients with OC. Metagenomic sequencing was employed to analyze the microbial community classification and functional composition of the different sample groups. RESULTS: The results of the study revealed significant differences in both the function and classification of microbial communities between saliva and dental plaque samples. The diversity of microbial species in saliva was found to be higher compared to  that in plaque samples. Notably, Actinobacteria were enriched in the dental plaque of OC patients. Furthermore, the study identified several inter-group differential marker species, including Prevotella intermedia, Haemophilus parahaemolyticus, Actinomyces radius, Corynebacterium matruchitii, and Veillonella atypica. Additionally, 1,353 differential genes were annotated into 23 functional pathways. Interestingly, a significant correlation was observed between differentially labeled species and Herpes simplex virus 1 (HSV-1) infection, which may be related to the occurrence and development of cancer. CONCLUSIONS: Significant differences in the microbial and genetic composition of saliva and dental plaque samples were observed in OC patients. Furthermore, pathogenic bacteria associated with oral diseases were predominantly enriched in saliva. The identification of inter-group differential biomarkers and pathways provide insights into the relationship between oral microbiota and the occurrence and development of OC.

Lung adenocarcinoma with EGFR L858R-K860I and L858R-L861F doublet mutations from which the L858R mutation is undetectable through the cobas EGFR mutation test v2.

In East Asia, epidermal growth receptor factor (EGFR) mutations are the most prevalent and important biomarkers for treating patients with advanced lung cancer. However, as L858R doublet mutations are rare, commercially available EGFR tests may yield false-negative results. To determine whether the L858R mutation of the L858R-K860I and L858R-L861F doublet mutations could be identified using different types of EGFR detection tests and to describe the clinical response of patients with lung cancer with L858R doublet mutations to EGFR tyrosine kinase inhibitors (TKI). Information and samples from four patients with L858R doublet mutations, including three with L858R-K860I and one with L858R-L861F, were retrospectively collected from the archives of our department. For each case, the clinical response to EGFR-TKI was retrieved from the medical records. Archived formalin-fixed paraffin-embedded blocks were subjected to Sanger sequencing, the cobas and Idylla EGFR tests, the IntelliPlex-LCP-DNA assay, and AmoyDx PLC panel. L858R mutations were all detected by Sanger sequencing and the Idylla EGFR test but missed by the cobas assay. The AmoyDx PLC detected L858R only in cases with L858R-K860I while the IntelliPlex-LCP-DNA assay detected L858R in the case with L858R-L861F. Additionally, three of the patients, who had measurable tumors, showed partial responses to afatinib and osimertinib. The L858R mutation associated with L858R-K860I and L858R-L861F doublet mutations could be detected using Idylla but not cobas EGFR tests. Using next-generation sequencing analysis should be considered after initial negative reports from the cobas test, because patients with L858R doublet mutations may benefit from EGFR-TKIs.

Shear wave elastography to assess stiffness of the human ovary and other reproductive tissues across the reproductive lifespan in health and disease†.

The ovary is one of the first organs to show overt signs of aging in the human body, and ovarian aging is associated with a loss of gamete quality and quantity. The age-dependent decline in ovarian function contributes to infertility and an altered endocrine milieu, which has ramifications for overall health. The aging ovarian microenvironment becomes fibro-inflammatory and stiff with age, and this has implications for ovarian physiology and pathology, including follicle growth, gamete quality, ovulation dynamics, and ovarian cancer. Thus, developing a non-invasive tool to measure and monitor the stiffness of the human ovary would represent a major advance for female reproductive health and longevity. Shear wave elastography is a quantitative ultrasound imaging method for evaluation of soft tissue stiffness. Shear wave elastography has been used clinically in assessment of liver fibrosis and characterization of tendinopathies and various neoplasms in thyroid, breast, prostate, and lymph nodes as a non-invasive diagnostic and prognostic tool. In this study, we review the underlying principles of shear wave elastography and its current clinical uses outside the reproductive tract as well as its successful application of shear wave elastography to reproductive tissues, including the uterus and cervix. We also describe an emerging use of this technology in evaluation of human ovarian stiffness via transvaginal ultrasound. Establishing ovarian stiffness as a clinical biomarker of ovarian aging may have implications for predicting the ovarian reserve and outcomes of Assisted Reproductive Technologies as well as for the assessment of the efficacy of emerging therapeutics to extend reproductive longevity. This parameter may also have broad relevance in other conditions where ovarian stiffness and fibrosis may be implicated, such as polycystic ovarian syndrome, late off target effects of chemotherapy and radiation, premature ovarian insufficiency, conditions of differences of sexual development, and ovarian cancer. Summary sentence:  Shear Wave Elastography is a non-invasive technique to study human tissue stiffness, and here we review its clinical applications and implications for reproductive health and disease.

A new strategy based on a cascade amplification strategy biosensor for on-site eDNA detection and outbreak warning of crown-of-thorns starfish.

Population outbreaks of the crown-of-thorns starfish (COTS) seriously threaten the sustainability of coral reef ecosystems. However, traditional ecological monitoring techniques cannot provide early warning before the outbreaks, thus preventing timely intervention. Therefore, there is an urgent need for a more accurate and faster technology to predict the outbreaks of COTS. In this work, we developed an electrochemical biosensor based on a programmed catalytic hairpin assembly (CHA) and hybridization chain reaction (HCR) cyclic amplification strategy for sensitive and selective detection of COTS environmental DNA (eDNA) in water bodies. This biosensor exhibited excellent electrochemical characteristics, including a low limit of detection (LOD = 18.4 fM), low limit of quantification (LOQ = 41.1 fM), and wide linear range (50 fM - 10 nM). The biosensing technology successfully allowed the detection of COTS eDNA in the aquarium environment, and the results also demonstrated a significant correlation between eDNA concentration and COTS number (r = 0.990; P < 0.001). The reliability and accuracy of the biosensor results have been further validated through comparison with digital droplet PCR (ddPCR). Moreover, the applicability and accuracy of the biosensor were reconfirmed in field tests at the COTS outbreak site in the South China Sea, which has shown potential application in dynamically monitoring the larvae before the COTS outbreak. Therefore, this efficient electrochemical biosensing technology offers a new solution for on-site monitoring and early warning of the COTS outbreak.

Independent external validation and comparison of existing pancreatic fistula risk scores after laparoscopic pancreaticoduodenectomy with Bing's pancreaticojejunostomy.

BACKGROUND: The fistula risk score (FRS) is the widely acknowledged prediction model for clinically relevant postoperative pancreatic fistula (CR-POPF). In addition, the alternative FRS (a-FRS) and updated alternative FRS (ua-FRS) have been developed. This study performed external validation and comparison of these 3 models in patients who underwent laparoscopic pancreaticoduodenectomy (LPD) with Bing's pancreaticojejunostomy. METHODS: The FRS total points and predictive probabilities of a-FRS and ua-FRS were retrospectively calculated using patient data from a completed randomized controlled trial. Postoperative pancreatic fistula (POPF) and CR-POPF were defined according to the 2016 International Study Group of Pancreatic Surgery criteria. The correlations of the 4 risk items of the FRS model with CR-POPF and POPF were analyzed and represented using the Cramer V coefficient. The performance of the 3 models was measured using the area under the curve (AUC) and calibration plot and compared using the DeLong test. RESULTS: This study enrolled 200 patients. Pancreatic texture and pathology had discrimination for CR-POPF (Cramer V coefficient: 0.180 vs 0.167, respectively). Pancreatic duct diameter, pancreatic texture, and pathology had discrimination for POPF (Cramer V coefficient: 0.357 vs 0.322 vs 0.257, respectively). Only the calibration of a-FRS predicting CR-POPF was good. The differences among the AUC values of the FRS, a-FRS, and ua-FRS were not statistically significant (CR-POPF: 0.687 vs 0.701 vs 0.710, respectively; POPF: 0.733 vs 0.741 vs 0.750, respectively). After recalibrating, the ua-FRS got sufficient calibration, and the AUC was 0.713 for predicting CR-POPF. CONCLUSION: For LPD cases with Bing's pancreaticojejunostomy, the 3 models predicted POPF with better discrimination than predicting CR-POPF. The recalibrated ua-FRS had sufficient discrimination and calibration for predicting CR-POPF.

Effect of combining intrauterine cerebral blood flow changes with electrical activity on prognostic evaluation of brain injury.

OBJECTIVES: We sought to investigate the value of combining intrauterine cerebral blood flow changes with brain electrical activity examination in evaluating the prognosis of brain injury. METHODS: A total of 90 preterm infants were enrolled and divided into two groups: the brain damaged preterm infants group (n=55) and the non-brain damaged preterm infants group (n=35).The diagnostic efficacy of combining intrauterine cerebral blood flow changes with EEG activity examination in predicting the prognosis of preterm infants with brain injury was evaluated usingT-test. Pearson linear correlation was applied to analyze the relationship between fetal intrauterine cerebral blood flow changes combined with electrical activity examination and the prognosis of brain injury. RESULTS: Significant differences were seen in pulse index, S/D ratio, and other indexes between the two groups (P<0.05). The combined approach of intrauterine cerebral blood flow changes with EEG activity examination demonstrated significantly higher values for area under the curve (AUC), sensitivityand negative predictive value compared to using intrauterine cerebral blood flow changes or EEG activity examination alone (P<0.05). A positive correlation was found between fetal intrauterine cerebral blood flow and electrical activity examination (P<0.05). SUMMARY: Combining the assessment of intrauterine cerebral blood flow changes with cerebral electrical activity examination proved beneficial in diagnosing the prognosis of brain injury and provided an important reference for early clinical intervention.

Application and perspective of CRISPR/Cas9 genome editing technology in human diseases modeling and gene therapy.

The Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR) mediated Cas9 nuclease system has been extensively used for genome editing and gene modification in eukaryotic cells. CRISPR/Cas9 technology holds great potential for various applications, including the correction of genetic defects or mutations within the human genome. The application of CRISPR/Cas9 genome editing system in human disease research is anticipated to solve a multitude of intricate molecular biology challenges encountered in life science research. Here, we review the fundamental principles underlying CRISPR/Cas9 technology and its recent application in neurodegenerative diseases, cardiovascular diseases, autoimmune related diseases, and cancer, focusing on the disease modeling and gene therapy potential of CRISPR/Cas9 in these diseases. Finally, we provide an overview of the limitations and future prospects associated with employing CRISPR/Cas9 technology for diseases study and treatment.

Metabolic signatures of two scleractinian corals from the northern South China sea in response to extreme high temperature events.

Coral bleaching events are becoming increasingly common worldwide, causing widespread coral mortality. However, not all colonies within the same coral taxa show sensitivity to bleaching events, and the current understanding of the metabolic mechanisms underlying thermal bleaching in corals remains limited. We used untargeted metabolomics to analyze the biochemical processes involved in the survival of two bleaching phenotypes of the common corals Pavona decussata and Acropora pruinosa, during a severe bleaching event in the northern South China Sea in 2020. During thermal bleaching, P. decussata and A. pruinosa significantly accumulated energy products such as succinate and EPA, antioxidants and inflammatory markers, and reduced energy storage substances like glutamate and thymidine. KEGG analysis revealed enrichment of energy production pathways such as ABC transporters, nucleotide metabolism and lipid metabolism, suggesting the occurrence of oxidative stress and energy metabolism disorders in bleached corals. Notably, heat stress exerted distinct effects on metabolic pathways in the two coral species, e.g., P. decussata activating carbohydrate metabolism pathways like glycolysis and the TCA cycle, along with amino acid metabolism pathways, whereas A. pruinosa significantly altered the content of multiple small peptides affected amino acid metabolism. Furthermore, the osmoregulatory potential of corals correlates with their ability to survive in heat-stress environments in the wild. This study provides valuable insights into the metabolic mechanisms linked to thermal tolerance in reef-building corals, contributes to the understanding of corals' adaptive potential to heat stress induced by global warming and lays the foundation for developing targeted conservation strategies in the future.

Page A bidirectional Mendelian randomization study of gut microbiota and cerebral small vessel disease.

BACKGROUND: The causal nature of gut microbiota and cerebral small vessel disease (CSVD) is still obscure regardless of evidence supporting their observational correlations. OBJECTIVE: The primary objective of this research is to investigate the potentially pathogenic or protective causal impacts of specific gut microbiota on various neuroimaging subtypes of CSVD. METHODS: We obtained the latest summary-level genome-wide databases for gut microbiota and nine CSVD traits. The univariable and multivariable Mendelian randomization (MR) studies were conducted to examine the possible causal link between exposure and outcome. Meanwhile, we conducted sensitivity analyses sequentially, containing the heterogeneity, pleiotropy, and leave-one-out analysis. Additionally, to clarify the potential bidirectional causality, the causality from CSVD traits to the identified gut microbiota was implemented through reverse MR analysis. RESULTS: The univariable MR analysis identified 22 genetically predicted bacterial abundances that were correlated with CSVD traits. While conditioning on macronutrient dietary compositions, two suggestive relationships were retained using the multivariable MR analysis. Specifically, the class Negativicutes and order Selenomonadales exhibited a negative causal association with strictly lobar cerebral microbleeds, one neuroimaging trait of CSVD. There is insufficient evidence indicating the presence of heterogeneity and horizontal pleiotropy. Furthermore, the identified causal relationship was not driven by any single nucleotide polymorphism. The results of the reverse MR analysis did not reveal any statistically significant causality from CSVD traits to the identified gut microbiota. CONCLUSIONS: Our study indicated several suggestive causal effects from gut microbiota to different neuroimaging subtypes of CSVD. These findings provided a latent understanding of the pathogenesis of CSVD from the perspective of the gut-brain axis.

Preparation and thermal responsiveness of microencapsulated fluorinated liquids for automatic fire extinguishing.

Most early-stage fires originating in small confined spaces may not be effectively mitigated by automatic fire-extinguishing systems. Leveraging the unique controlled release capability and barrier properties of microcapsules presents a promising avenue for developing multifunctional and intelligent fire-extinguishing agents tailored for early-stage fire suppression. This paper introduces two types of microcapsules that integrate automatic detection and fire extinguishing functions, utilizing fluorinated liquids specifically perfluoro(2-methyl-3-pentanone) and 1,1,1,2,2,3,4,5,5,5 decafluoro-3-methoxy-4(trifluoromethyl)-pentane as core materials. The preparation process was optimized, and the thermal response of the microcapsules was evaluated by directly incorporating them into combustible materials. The results indicated a correlation between the preparation method, coating efficiency, and thermal stability of microcapsules with the core-wall materials. When the fluoride solution in the core material reaches the thermal response threshold temperature, the gas pressure generated during vaporization and phase change can break through the shell, enabling early active fire protection. Beyond a specific threshold of additive microcapsules in the material, the material exhibits self-extinguishing potential during combustion. In cases where the additive amount falls short of achieving self-extinguishing, the fire-resistant performance of materials can be enhanced through various measures. For instance, reducing the amount of fire-extinguishing agents, delaying the ignition time of fuel, and lowering the heat release rate during combustion are effective strategies. Moreover, the degree of improvement is related to the additional amount and the type of core-wall materials. The thermal-response mechanism of microcapsules constitutes a comprehensive mechanism with physical and chemical effects. The finding of this research offer a new technical approach for microencapsulating high-boiling-point gas extinguishing agents, facilitating intelligent and precise prevention of early fires resulting from combustible materials.

Laser-upgraded coal tar for smart pavements in road and bridge monitoring applications.

The implementation of an intelligent road network system requires many sensors for acquiring data from roads, bridges, and vehicles, thereby enabling comprehensive monitoring and regulation of road networks. Given this large number of required sensors, the sensors must be cost-effective, dependable, and environmentally friendly. Here, we show a laser upgrading strategy for coal tar, a low-value byproduct of coal distillation, to manufacture flexible strain-gauge sensors with maximum gauge factors of 15.20 and 254.17 for tension and compression respectively. Furthermore, we completely designed the supporting processes of sensor placement, data acquisition, processing, wireless communication, and information decoding to demonstrate the application of our sensors in traffic and bridge vibration monitoring. Our novel strategy of using lasers to upgrade coal tar for use as a sensor not only achieves the goal of turning waste into a resource but also provides an approach to satisfy large-scale application requirements for enabling intelligent road networks.

Comparative Study of Anti-Corrosion Properties of Different Types of Press-Hardened Steels.

Hot stamping (or press hardening) is a new technology that is widely used in the production of advanced high-strength steel parts for automotive applications. Electrochemical measurements, including potentiodynamic polarization and electrochemical impedance spectroscopy (EIS), and accelerated corrosion tests (the neutral salt spray test and periodic immersion test) were conducted on press-hardened samples produced from uncoated (cold-rolled and cold strip production (CSP) hot-rolled) and Al-Si-coated press-hardened steels to elucidate their distinct anti-corrosion mechanisms. The cross-sectional micromorphology and element distribution of three types of press-hardened steels after a neutral salt spray test were observed using scanning electron microscopy (SEM) and energy-dispersive X-ray analysis (EDAX). The corrosion resistance of Al-Si-coated press-hardened steel was found to be significantly diminished following the hot stamping process due to the presence of microcracks and elevated iron content in the coating subsequent to austenitizing heat treatment. On the other hand, the corrosion resistance of uncoated press-hardened sheets produced from cold-rolled and CSP hot-rolled press-hardened steel was found to be proximal due to their nearly identical composition and microstructure (fully martensite) after the hot stamping process. Considering the high efficiency and energy-saving properties of hot-rolled press-hardened steel, it holds the potential to replace cold-rolled and even aluminum-silicon-coated press-hardened steel in automobile manufacturing.

CPD-002, a novel VEGFR2 inhibitor, relieves rheumatoid arthritis by reducing angiogenesis through the suppression of the VEGFR2/PI3K/AKT signaling pathway.

Synovial angiogenesis is a key player in the development of rheumatoid arthritis (RA), and anti-angiogenic therapy is considered a promising approach for treating RA. CPD-002 has demonstrated efficacy in suppressing tumor angiogenesis as a VEGFR2 inhibitor, but its specific impacts on RA synovial angiogenesis and possible anti-RA effects need further study. We examined the influences of CPD-002 on the migration and invasion of human umbilical vein endothelial cells (HUVECs) and its impacts on HUVECs' tube formation and vessel sprouting ex vivo. The therapeutic potential of CPD-002 in adjuvant-induced arthritis (AIA) rats and its suppression of synovial angiogenesis were examined. The involvement of the VEGFR2/PI3K/AKT pathway was assessed both in HUVECs and AIA rat synovium. Here, CPD-002 inhibited the migration and invasion of VEGF-stimulated HUVECs, decreased their chemotactic response to RA fibroblast-like synoviocyte-released chemoattractants, and exhibited anti-angiogenic effects in vitro and ex vivo. CPD-002's targeting of VEGFR2 was confirmed with molecular docking and cellular thermal shift assays, supported by the abolishment of CPD-002's effects upon using VEGFR2 siRNA. CPD-002 relieved paw swelling, arthritis index, joint damage, and synovial angiogenesis, indicating its anti-arthritic and anti-angiogenic effects in AIA rats. Moreover, the anti-inflammatory effects in vivo and in vitro of CPD-002 contributed to its anti-angiogenic effects. Mechanistically, CPD-002 hindered the activation of VEGFR2/PI3K/AKT pathway in VEGF-induced HUVECs and AIA rat synovium, as evidenced by reduced p-VEGFR2, p-PI3K, and p-AKT protein levels alongside elevated PTEN protein levels. Totally, CPD-002 showed anti-rheumatoid effects via attenuating angiogenesis through the inhibition of the VEGFR2/PI3K/AKT pathway.

A small-molecule TNIK inhibitor targets fibrosis in preclinical and clinical models.

Idiopathic pulmonary fibrosis (IPF) is an aggressive interstitial lung disease with a high mortality rate. Putative drug targets in IPF have failed to translate into effective therapies at the clinical level. We identify TRAF2- and NCK-interacting kinase (TNIK) as an anti-fibrotic target using a predictive artificial intelligence (AI) approach. Using AI-driven methodology, we generated INS018_055, a small-molecule TNIK inhibitor, which exhibits desirable drug-like properties and anti-fibrotic activity across different organs in vivo through oral, inhaled or topical administration. INS018_055 possesses anti-inflammatory effects in addition to its anti-fibrotic profile, validated in multiple in vivo studies. Its safety and tolerability as well as pharmacokinetics were validated in a randomized, double-blinded, placebo-controlled phase I clinical trial (NCT05154240) involving 78 healthy participants. A separate phase I trial in China, CTR20221542, also demonstrated comparable safety and pharmacokinetic profiles. This work was completed in roughly 18 months from target discovery to preclinical candidate nomination and demonstrates the capabilities of our generative AI-driven drug-discovery pipeline.

Discovery of 3-hydroxymethyl-azetidine derivatives as potent polymerase theta inhibitors.

Inhibition of the low fidelity DNA polymerase Theta (Polθ) is emerging as an attractive, synthetic-lethal antitumor strategy in BRCA-deficient tumors. Here we report the AI-enabled development of 3-hydroxymethyl-azetidine derivatives as a novel class of Polθ inhibitors featuring central scaffolding rings. Structure-based drug design first identified A7 as a lead compound, which was further optimized to the more potent derivative B3 and the metabolically stable deuterated compound C1. C1 exhibited significant antiproliferative properties in DNA repair-compromised cells and demonstrated favorable pharmacokinetics, showcasing that 3-hydroxymethyl-azetidine is an effective bio-isostere of pyrrolidin-3-ol and emphasizing the potential of AI in medicinal chemistry for precise molecular modifications.

Population Structure and Selection Signal Analysis of Nanyang Cattle Based on Whole-Genome Sequencing Data.

With a rich breeding history, Nanyang cattle (NY cattle) have undergone extensive natural and artificial selection, resulting in distinctive traits such as high fertility, excellent meat quality, and disease resistance. This makes them an ideal model for studying the mechanisms of environmental adaptability. To assess the population structure and genetic diversity of NY cattle, we performed whole-genome resequencing on 30 individuals. These data were then compared with published whole-genome resequencing data from 432 cattle globally. The results indicate that the genetic structure of NY cattle is significantly different from European commercial breeds and is more similar to North-Central Chinese breeds. Furthermore, among all breeds, NY cattle exhibit the highest genetic diversity and the lowest population inbreeding levels. A genome-wide selection signal analysis of NY cattle and European commercial breeds using Fst, θπ-ratio, and θπ methods revealed significant selection signals in genes associated with reproductive performance and immunity. Our functional annotation analysis suggests that these genes may be responsible for reproduction (MAP2K2, PGR, and GSE1), immune response (NCOA2, HSF1, and PAX5), and olfaction (TAS1R3). We provide a comprehensive overview of sequence variations in the NY cattle genome, revealing insights into the population structure and genetic diversity of NY cattle. Additionally, we identify candidate genes associated with important economic traits, offering valuable references for future conservation and breeding efforts of NY cattle.

Unveiling causal connections: Long-term particulate matter exposure and type 2 diabetes mellitus mortality in Southern China.

Evidence of the potential causal links between long-term exposure to particulate matters (PM, i.e., PM1, PM2.5, and PM1-2.5) and T2DM mortality based on large cohorts is limited. In contrast, the existing evidence usually suffers from inherent bias with the traditional association assessment. A prospective cohort of 580,757 participants in the southern region of China were recruited during 2009 and 2015 and followed up through December 2020. PM exposure at each residential address was estimated by linking to the well-established high-resolution simulation dataset. Hazard ratios (HRs) were calculated using time-varying marginal structural Cox models, an established causal inference approach, after adjusting for potential confounders. During follow-up, a total of 717 subjects died from T2DM. For every 1 µg/m3 increase in PM2.5, the adjusted HRs and 95% confidence interval (CI) for T2DM mortality was 1.036 (1.019-1.053). Similarly, for every 1 µg/m3 increase in PM1 and PM1-2.5, the adjusted HRs and 95% CIs were 1.032 (1.003-1.062) and 1.085 (1.054-1.116), respectively. Additionally, we observed a generally more pronounced impact among individuals with lower levels of education or lower residential greenness which as measured by the Normalized Difference Vegetation Index (NDVI). We identified substantial interactions between NDVI and PM1 (P-interaction = 0.003), NDVI and PM2.5 (P-interaction = 0.019), as well as education levels and PM1 (P-interaction = 0.049). The study emphasizes the need to consider environmental and socio-economic factors in strategies to reduce T2DM mortality. We found that PM1, PM2.5, and PM1-2.5 heighten the peril of T2DM mortality, with education and green space exposure roles in modifying it.