TaMYB-CC5 gene specifically expressed in root improve tolerance of phosphorus deficiency and drought stress in wheat.

Phosphate deficiency and drought are significant environmental constraints that impact both the productivity and quality of wheat. The interaction between phosphorus and water facilitates their mutual absorption processes in plants. Under conditions of both phosphorus deficiency and drought stress, we observed a significant upregulation in the expression of wheat MYB-CC transcription factors through the transcriptome analysis. 52 TaMYB-CC genes in wheat were identified and analyzed their evolutionary relationships, structures, and expression patterns. The TaMYB-CC5 gene exhibited specific expression in roots and demonstrated significant upregulation under phosphorus deficiency and drought stress compared to other TaMYB-CC genes. The overexpression of TaMYB-CC5A in Arabidopsis resulted in a significant increase of root length under stress conditions, thereby enhancing tolerance to phosphate starvation and drought stress. The wheat lines with silenced TaMYB-CC5 genes exhibited reduced root length under stress conditions and increased sensitivity to phosphate deficiency and drought stress. In addition, silencing the TaMYB-CC5 genes resulted in altered phosphorus content in leaves but did not lead to a reduction in phosphorus content in roots. Enrichment analysis the co-expression genes of TaMYB-CC5 transcription factors, we found the zinc-induced facilitator-like (ZIFL) genes were prominent associated with TaMYB-CC5 gene. The TaZIFL1, TaZIFL2, and TaZIFL5 genes were verified specifically expressed in roots and regulated by TaMYB-CC5 transcript factor. Our study reveals the pivotal role of the TaMYB-CC5 gene in regulating TaZIFL genes, which is crucial for maintaining normal root growth under phosphorus deficiency and drought stress, thereby enhanced resistance to these abiotic stresses in wheat.

Real space method for HAADF image simulation.

A new real space HAADF simulation method was described in detail and a Real Space- STEM software was developed based on the new simulation method. The algorithm of the real space method can quickly calculate and simulate the microstructure images of complex crystals. The Real Space-STEM software developed in this paper has the functions of HRTEM and HAADF image simulation based on the real space method. By using this software to simulate high-resolution images of representative crystal materials from each crystal system, the HAADF images are both accurate and efficient. The effect of STEM parameters on HAADF imaging has been discussed using simulation results.

A novel type of malformed floral organs mutant in barley was conferred by loss-of-function mutations of the MADS-box gene HvAGL6.

The advanced model of floral morphogenesis is based largely on data from Arabidopsis (Arabidopsis thaliana) and rice (Oryza sativa), but this process is less well understood in the Triticeae. Here, we investigated a sterile barley (Hordeum vulgare) mutant with malformed floral organs (designated mfo1), of which the paleae, lodicules, and stamens in each floret were all converted into lemma-like organs, and the ovary was abnormally shaped. Combining bulked-segregant analysis, whole-genome resequencing, and TILLING approaches, the mfo1 mutant was attributed to loss-of-function mutations in the MADS-box transcription factor gene HvAGL6, a key regulator in the ABCDE floral morphogenesis model. Through transcriptomic analysis between young inflorescences of wild-type and mfo1 plants, 380 genes were identified as differentially expressed, most of which function in DNA binding, protein dimerization, cell differentiation, or meristem determinacy. Regulatory pathway enrichment showed HvAGL6 associates with transcriptional abundance of many MADS-box genes, including the B-class gene HvMADS4. Mutants with deficiency in HvMADS4 exhibited the conversion of stamens into supernumerary pistils, producing multiple ovaries resembling the completely sterile multiple ovaries 3.h (mov3.h) mutant. These findings demonstrate that the regulatory model of floral morphogenesis is conserved across plant species and provides insights into the interactions between HvAGL6 and other MADS-box regulators.

Associations between leisure-time physical activity and the prevalence and incidence of osteoporosis disease: Cross-sectional and prospective findings from the UK biobank.

BACKGROUND: Previous studies underscore the protective role of physical activity (PA) in bone health, yet the relationship between different PA categories and osteoporosis risk remains less explored. Understanding the relationships helps tailor health recommendations and policies to maximize the effects of preventing osteoporosis. METHODS: The cross-sectional study involves 488,403 UK Biobank participants with heel quantitative ultrasound-estimated bone mineral density (eBMD) data. The longitudinal cohort involves 471,394 UK Biobank participants without initial osteoporosis and with follow-up records. PA exposure categories in our study included sedentary behavior (SB), total PA (TPA), and different category-specific PA including household, leisure, and work PA. The cases of osteoporosis were assessed using the International Classification of Diseases, 10th revision (ICD-10). The linear, logistic, and Cox proportional hazard regression models were used in our study. RESULTS: In the cross-sectional study, 15,818 (3.28 %) participants had osteoporosis. TPA levels have a positive correlation with eBMD and a negative correlation with osteoporosis prevalence. Among different categories of PA, higher levels of leisure PA were correlated with increased eBMD and a lower osteoporosis risk (leisure PA: OR: 0.83, 95 % CI: 0.79 to 0.86;). In the longitudinal study, 16,058 (17.6 % male, 82.4 % female) (3.41 %) individuals developed osteoporosis during an average follow-up of 13 years. We observed consistent protective effects of high levels of PA on osteoporosis incidence risk, particularly within the category of leisure PA (TPA: HR: 0.78, 95 % CI: 0.74 to 0.82; leisure PA:HR: 0.83, 95 % CI: 0.80 to 0.87). Such associations are independent of genetic predisposition, with no evidence of gene-PA interactions, and keep steady among individuals using drugs affecting bone-density. Moreover, among different leisure PA items, strenuous sports, other exercises, and walking for pleasure conferred a substantial protective effect against osteoporosis. Additionally, non-elderly individuals and males exhibited lower osteoporosis risk from PA. CONCLUSION: This study highlights activity categories differently associated with the risk of osteoporosis. Adherence to frequent leisure PA may have a protective effect against osteoporosis. Such associations are independent of genetic susceptibility to osteoporosis and keep steady among individuals using drugs affecting bone-density. This highlights that leisure PA could be suggested as a more effective intervention in the primary prevention of osteoporosis.

Thyroid and parathyroid function disorders induced by short-term exposure of microplastics and nanoplastics: Exploration of toxic mechanisms and early warning biomarkers.

Human exposure to micro- and nano-plastics (MNPs) primarily occurs through respiration and diet in the environment. However, the early effects and warning signs of MNPs exposure on vertebrates are unclear. Here we used intratracheal instillation and intragastric infusion to establish mouse models for MNPs exposure to systematically investigate the toxic mechanisms of MNPs on endocrine organs. Results showed that MNPs induced endocrine disruptions in short-term exposure by both dietary and respiratory pathways. Microplastics (MPs) exposed through dietary route were more toxic to thyroid gland, whereas nanoplastics (NPs) exhibited the highest level of toxicity to parathyroid gland through respiration. The transcriptome and validation of related functional genes revealed that MNPs affected the synthesis of thyroglobulin by interfering with the expressions of PAX8 and CREB. MNPs also impacted the levels of thyroid stimulating hormone, further mediating the secretion of thyroid hormones. Moreover, MNPs modulate the expression of Mafb, thereby exerting regulatory effects on parathyroid hormone (PTH) synthesis and growth development in parathyroid cells. Meanwhile, MNPs interfered with the expression of IP3R in the calcium signaling pathway, indirectly affecting the secretion of PTH. This study reveals the effects and mechanisms of MNPs on thyroid and parathyroid and highlights the significance of early warning of MNPs exposure.

Effect of thermal treatment of illite on the bioavailability of copper and zinc in the aerobic composting of pig manure with corn straw.

The large amount of various types of heavy metals in animal manure applied to agricultural field has caused severe threat to the ecosystems of soil environments. In this study, the effect of thermal treatment of illite on the bioavailability of copper (Cu) and zinc (Zn) in the aerobic composting of pig manure with corn straw biochar was investigated. The objectives of this study were to characterize the variations in the bioavailability of Cu and Zn in the aerobic composting of pig manure added with illite treated with high temperatures and to identify the relatively dominant microbes involved in the formation of humus and passivation of heavy metals in pig manure composting based on 16S rRNA high-throughput sequencing analysis. The results showed that in comparison with the raw materials of pig manure, the bioavailability of Zn and Cu in the control and three experimental composting groups, i.e., group I (with untreated illite), group I-2 (with illite treated under 200°C), and group I-5 (with illite treated under 500°C), was decreased by 27.66 and 71.54%, 47.05 and 79.80%, 51.56 and 81.93%, and 58.15 and 86.60%, respectively. The results of 16S rRNA sequencing analysis revealed that in the I-5 group, the highest relative abundance was detected in Fermentimonas, which was associated with the degradation of glucose and fructose, and the increased relative abundances were revealed in the microbes associated with the formation of humus, which chelated with Zn and Cu to ultimately reduce the bioavailability of heavy metals and their biotoxicity in the compost. This study provided strong experimental evidence to support the application of illite in pig manure composting and novel insights into the selection of appropriate additives (i.e., illite) to promote humification and passivation of different heavy metals in pig manure composting.

Introgression of chromosome 5P from Agropyron cristatum enhances grain weight in a wheat background.

KEY MESSAGE: A grain weight locus from Agropyron cristatum chromosome 5P increases grain weight in different wheat backgrounds and is localized to 5PL (bin 7-12). Thousand-grain weight is an important trait in wheat breeding, with a narrow genetic basis being the main factor limiting improvement. Agropyron cristatum, a wild relative of wheat, harbors many desirable genes for wheat improvement. Here, we found that the introduction of the 5P chromosome from A. cristatum into wheat significantly increased the thousand-grain weight by 2.55-7.10 g, and grain length was the main contributor to grain weight. An increase in grain weight was demonstrated in two commercial wheat varieties, indicating that the grain weight locus was not affected by the wheat background. To identify the chromosome segment harboring the grain weight locus, three A. cristatum 5P deletion lines, two wheat-A. cristatum 5P translocation lines and genetic populations of these lines were used to evaluate agronomic traits. We found that the translocation lines harboring the long arm of A. cristatum chromosome 5P (5PL) exhibited high grain weight and grain length, and the genetic locus associated with increased grain weight was mapped to 5PL (bin 7-12). An increase in grain weight did not adversely affect other agronomic traits in translocation line 5PT2, which is a valuable germplasm resource. Overall, we identified a grain weight locus from chromosome 5PL and provided valuable germplasm for improving wheat grain weight.

Genetically Encoded Epoxide Warhead for Precise and Versatile Covalent Targeting of Proteins.

Genetically encoding a proximal reactive warhead into the protein binder/drug has emerged as an efficient strategy for covalently binding to protein targets, enabling broad applications. To expand the reactivity scope for targeting the diverse natural residues under physiological conditions, the development of a genetically encoded reactive warhead with excellent stability and broad reactivity is highly desired. Herein, we reported the genetic encoding of epoxide-containing tyrosine (EPOY) for developing covalent protein drugs. Our study demonstrates that EPOY, when incorporated into a nanobody (KN035), can cross-link with different side chains (mutations) at the same position of PD-L1 protein. Significantly, a single genetically encoded reactive warhead that is capable of covalent and site-specific targeting to 10 different nucleophilic residues was achieved for the first time. This would largely expand the scope of covalent warhead and inspire the development of covalent warheads for both small-molecule drugs and protein drugs. Furthermore, we incorporate the EPOY into a designed ankyrin repeat protein (DarpinK13) to create the covalent binders of KRAS. This covalent KRAS binder holds the potential to achieve pan-covalent targeting of KRAS based on the structural similarity among all oncogenic KRAS mutants while avoiding off-target binding to NRAS/HRAS through a covalent interaction with KRAS-specific residues (H95 and E107). We envision that covalently targeting to H95 will be a promising strategy for the development of covalent pan-KRAS inhibitors in the future.

Evolution of groundwater system in the Pearl River Delta and its adjacent shelf since the late Pleistocene.

Our extensive field studies demonstrate that saline groundwater inland and freshened groundwater offshore coexist in the same aquifer system in the Pearl River delta and its adjacent shelf. This counterintuitive phenomenon challenges the commonly held assumption that onshore groundwater is typically fresh, while offshore groundwater is saline. To address this knowledge gap, we conduct a series of sophisticated paleo-hydrogeological models to explore the formation mechanism and evolution process of the groundwater system in the inland-shelf systems. Our findings indicate that shelf freshened groundwater has formed during the lowstands since late Pleistocene, while onshore saline groundwater is generated by paleo-seawater intrusion during the Holocene transgression. This reveals that terrestrial and offshore groundwater systems have undergone alternating changes on a geological timescale. The groundwater system exhibits hysteresis responding to paleoclimate changes, with a lag of 7 to 8 thousand years, suggesting that paleoclimatic forcings exert a significantly residual influence on the present-day groundwater system.

Pre-breeding of spontaneous Robertsonian translocations for density planting architecture by transferring Agropyron cristatum chromosome 1P into wheat.

KEY MESSAGE: We developed T1AL·1PS and T1AS·1PL Robertsonian translocations by breakage-fusion mechanism based on wheat-A. cristatum 1P(1A) substitution line with smaller leaf area, shorter plant height, and other excellent agronomic traits Agropyron cristatum, a wild relative of wheat, is a valuable germplasm resource for improving wheat genetic diversity and yield. Our previous study confirmed that the A. cristatum chromosome 1P carries alien genes that reduce plant height and leaf size in wheat. Here, we developed T1AL·1PS and T1AS·1PL Robertsonian translocations (RobTs) by breakage-fusion mechanism based on wheat-A. cristatum 1P (1A) substitution line II-3-1c. Combining molecular markers and cytological analysis, we identified 16 spontaneous RobTs from 911 F2 individuals derived from the cross of Jimai22 and II-3-1c. Fluorescence in situ hybridization (FISH) was applied to detect the fusion structures of the centromeres in wheat and A. cristatum chromosomes. Resequencing results indicated that the chromosomal junction point was located at the physical position of Triticum aestivum chromosome 1A (212.5 Mb) and A. cristatum chromosome 1P (230 Mb). Genomic in situ hybridization (GISH) in pollen mother cells showed that the produced translocation lines could form stable ring bivalent. Introducing chromosome 1PS translocation fragment into wheat significantly increased the number of fertile tillers, grain number per spike, and grain weight and reduced the flag leaf area. However, introducing chromosome 1PL translocation fragment into wheat significantly reduced flag leaf area and plant height with a negative effect on yield components. The pre-breeding of two spontaneous RobTs T1AL·1PS and T1AS·1PL was important for wheat architecture improvement.

Advanced perioperative assessment of neurological function in acute Stanford A aortic dissection.

OBJECTIVE: Acute Stanford Type A aortic dissection (AAAD) is a critical condition in vascular surgery, and total aortic arch replacement surgery is the preferred method to save patients' lives. In recent years, as clinical research has advanced, there has been a growing realization of the close association between poor postoperative outcomes in patients and neurological functional deficits. Neurological function monitoring is a medical technique used to evaluate and monitor the functional status of the nervous system. METHODS: This monitoring involves the assessment of various aspects of the nervous system, including but not limited to nerve conduction velocity, neuromuscular function, electroencephalographic activity, and sensory nerve transmission. Neurological function monitoring has broad clinical applications and can be used to diagnose and monitor many neurological disorders, helping physicians understand patients' neurological functional status and guide treatment plans. During the postoperative recovery process, neurological function monitoring can assist physicians in assessing the potential impact of surgery on the nervous system and monitor the recovery of patients' neurological function. RESULTS: Studies have shown that neurological function monitoring holds promise in predicting neurological functional prognosis and interventions for patients with aortic dissection. CONCLUSION: Therefore, the primary objective of this study is to evaluate the effectiveness and reliability of various intraoperative neurological monitoring techniques, neuroimaging examinations, and biomarkers in predicting and assessing postoperative neurological outcomes in patients undergoing AAAD surgery.

Establishment of a pharmacokinetics and pharmacodynamics model of Schisandra lignans against hippocampal neurotransmitters in AD rats based on microdi-alysis liquid chromatography-mass spectrometry.

Objective: Our previous studies substantiated that the biological activity of Schisandra chinensis lignans during the treatment of Alzheimer's disease (AD) was mediated by neurotransmitter levels, and 15 of its active components were identified. However, the pharmacokinetic and pharmacodynamic relationship of Schisandra chinensis lignans has been less studied. The objective of this study was to investigate the relationship between the pharmacokinetics and pharmacodynamics of Schisandra chinensis lignans in the treatment of AD, and to establish a pharmacokinetic-pharmacodynamic (PK-PD) model. Methods and Results: Herein, we established a microdialysis-ultra performance liquid chromatography-triple quadruple mass spectrometry (MD-LC-TQ-MS) technique that could simultaneously and continuously collect and quantitatively analyze the active compounds and neurotransmitters related to the therapeutic effects of Schisandra chinensis in awake AD rats. Eight lignans were detected in the hippocampus, and a PK-PD model was established. The fitted curves highlighted a temporal lag between the maximum drug concentration and the peak drug effect. Following treatment, the levels of four neurotransmitters tended to converge with those observed in the sham operation group. Conclusion: By establishing a comprehensive concentration-time-effect relationship for Schisandra chinensis lignans in AD treatment, our study provides novel insights into the in vivo effects of these lignans in AD rats.

Chromosomal mapping of a major genetic locus from Agropyron cristatum chromosome 6P that influences grain number and spikelet number in wheat.

KEY MESSAGE: A novel locus on Agropyron cristatum chromosome 6P that increases grain number and spikelet number was identified in wheat-A. cristatum derivatives and across 3 years. Agropyron cristatum (2n = 4x = 28, PPPP), which has the characteristics of high yield with multiple flowers and spikelets, is a promising gene donor for wheat high-yield improvement. Identifying the genetic loci and genes that regulate yield could elucidate the genetic variations in yield-related traits and provide novel gene sources and insights for high-yield wheat breeding. In this study, cytological analysis and molecular marker analysis revealed that del10a and del31a were wheat-A. cristatum chromosome 6P deletion lines. Notably, del10a carried a segment of the full 6PS and 6PL bin (1-13), while del31a carried a segment of the full 6PS and 6PL bin (1-8). The agronomic characterization and genetic population analysis confirmed that the 6PL bin (9-13) brought about an increase in grain number per spike (average increase of 10.43 grains) and spikelet number per spike (average increase of 3.67) over the three growing seasons. Furthermore, through resequencing, a multiple grain number locus was mapped to the physical interval of 593.03-713.89 Mb on chromosome 6P of A. cristatum Z559. The RNA-seq analysis revealed the expression of 537 genes in the del10a young spike tissue, with the annotation indicating that 16 of these genes were associated with grain number and spikelet number. Finally, a total of ten A. cristatum-specific molecular markers were developed for this interval. In summary, this study presents novel genetic material that is useful for high-yield wheat breeding initiatives to meet the challenge of global food security through enhanced agricultural production.

Rapid detection of goose megrivirus using TaqMan real-time PCR technology.

The aim of this study was to develop an efficient and accurate platform for the detection of the newly identified goose megrivirus (GoMV). To achieve this goal, we developed a TaqMan real-time PCR technology for the rapid detection and identification of GoMV. Our data showed that the established TaqMan real-time PCR assay had high sensitivity, with the lowest detection limit of 67.3 copies/µL. No positive signal can be observed from other goose origin viruses (including AIV, GPV, GoCV, GHPyV, and GoAstV), with strong specificity. The coefficients of variation of repeated intragroup and intergroup tests were all less than 1.5%, with excellent repeatability. Clinical sample investigation data from domestic Minbei White geese firstly provided evidence that GoMV can be transmitted both horizontally and vertically. In conclusion, since the TaqMan real-time PCR method has high sensitivity, specificity, and reproducibility, it can be a useful candidate tool for GoMV epidemiological investigation.

Three-Component Reaction for the Synthesis of Spiro-Heterocycles from Isatins, Substituted Ureas, and Cyclic Ketones.

We reported an efficient three-component reaction to access new spiro heterocycles through the annulation reactions of isatins, substituted ureas, and cyclic ketones under normal laboratory conditions, which is another example of isatins being used to build spiro compounds by the ring-opening and recyclization processes. The wide range of substrates, simple operation, normal experimental conditions, and high yields make the approach of high practical value.

Molecular mechanism of bovine Gasdermin D-mediated pyroptosis.

Pyroptosis is a form of programmed cell death characterized by cell swelling, pore formation in the plasma membrane, lysis, and releases of cytoplasmic contents. To date, the molecular mechanism of human and murine Gasdermin D-mediated pyroptosis have been fully investigated. However, studies focusing on molecular mechanism of bovine Gasdermin D (bGSDMD)-mediated pyroptosis and its function against pathogenic infection were unclear. In the present study, we demonstrate that bovine caspase-1 (bCaspase-1) cleaves bGSDMD at amino acid residue D277 to produce an N-terminal fragment (bGSDMD-p30) which leads to pyroptosis. The amino acid residues T238 and F239 are critical for bGSDMD-p30-mediated pyroptosis. The loop aa 278-299, L293 and A380 are the key sites for autoinhibitory structure of the full length of bGSDMD. In addition, bCaspase-3 also cleaves bGSDMD at residue Asp86 without inducing cell death. Therefore, our study provides the first detailed elucidation of the mechanism of bovine GSDMD-mediated pyroptosis. The results will establish a significant foundation for future research on the role of pyroptosis in bovine infectious diseases.

Music combined with dexmedetomidine relieves preoperative anxiety and promotes postoperative recovery in patients undergoing gynecologic laparoscopic surgery: a randomized clinical trial.

OBJECTIVES: To investigate the effects of music combined with dexmedetomidine on perioperative anxiety and postoperative recovery in gynecologic laparoscopic patients. METHODS: A total of 82 female patients were enrolled in this study. Patients were randomized to the patient-preferred Music+Dexmedetomidine group (M+DEX group, n=41) and the Dexmedetomidine group (DEX group, n=41). Prior to the induction of anesthesia, dexmedetomidine was pumped intravenously at 0.5 µg/kg for 10 minutes in both groups and then maintained at 0.2 µg/kg/hour until 30 minutes before the end of surgery. In contrast to the patients in the DEX group, the patients in the M+DEX group listened to 5 minutes of their favorite music during dexmedetomidine infusion. The primary outcome was the patient's preoperative State Anxiety Inventory (SAI) score. The secondary outcomes included visual analog scale (VAS) pain scores and QoR-15 scores at 24 hours postoperatively. RESULTS: The clinical data of a total of 82 patients were analyzed. After the music intervention, we found that the preoperative SAI scores were lower in the M+DEX group than in the DEX group (37.9±5.6 vs. 41.5±6.9; P=0.01). The M+DEX group had lower VAS scores at 24 hours postoperatively than the DEX group (1 (1.0, 2.0) vs. 2 (2.0, 3.0), P < 0.01), and the M+DEX group had higher QoR-15 scores at 24 hours after the surgery than the DEX group (127.7±10.0 vs. 122.3±11.2; P=0.03). CONCLUSION: Patients undergoing gynecologic laparoscopic surgery who listened to their favorite music before the induction of anesthesia had less preoperative anxiety and recovered better 24 hours postoperatively than those who only received dexmedetomidine.

Toroidal micelles formed in viscoelastic aqueous solutions of a double-tailed surfactant with two quaternary ammonium head groups.

Innovation in surfactant structures is an effective way to prepare new soft materials with novel applications. In this study, we synthesized a double-tailed surfactant containing two quaternary ammonium head groups (Di-C12-N2). The Di-C12-N2 solution behavior was investigated by surface tension, fluorescence, rheology, and cryo-TEM methods. Although Di-C12-N2 contained a large double-tailed hydrophobic group, the solubility of Di-C12-N2 was ∼90 mmol L-1 at 25 °C with a Krafft temperature of ∼1 °C. The increase in Di-C12-N2 concentration in the solutions led to the formation of various aggregates, including spherical micelles, worm-like micelles, multi-layered vesicles, and a rare type of small toroidal micelles. The two quaternary ammonium head groups in Di-C12-N2 led to strong electrostatic interactions between molecules, which was critical for the formation of toroidal micelles. Moreover, with an added NaCl concentration of 40 mmol L-1, the viscosity of the 5 mmol L-1Di-C12-N2 solution increased by ∼1000 times compared to the pure 5 mmol L-1Di-C12-N2 solution, revealing the high sensitivity of the unique head groups to ionic strength. This study enriches the research on the self-assembly principles of surfactants and brings new potential applications for new soft materials.

Cypermethrin induces Sertoli cell apoptosis through endoplasmic reticulum-mitochondrial coupling involving IP3R1-GRP75-VDAC1.

A widely used type II pyrethroid pesticide cypermethrin (CYP) is one of endocrine disrupting chemicals (EDCs) with anti-androgenic activity to induce male reproductive toxicology. However, the mechanisms have not been fully elucidated. This study was to explore the effects of CYP on apoptosis of mouse Sertoli cells (TM4) and the roles of endoplasmic reticulum (ER)-mitochondria coupling involving 1,4,5-trisphosphate receptor type1-glucose-regulated protein 75-voltage-dependent anion channel 1 (IP3R1-GRP75-VDAC1). TM4 were cultured with different concentrations of CYP. Flow cytometry, calcium (Ca2+) fluorescent probe, transmission electron microscopy and confocal microscopy, and western blot were to examine apoptosis of TM4, mitochondrial Ca2+, ER-mitochondria coupling, and expressions of related proteins. CYP was found to increase apoptotic rates of TM4 significantly. CYP was shown to significantly increase expressions of cleaved caspase-3, cleaved poly ADP-ribose polymerase (PARP). Concentration of mitochondrial Ca2+ was increased by CYP treatment significantly. CYP significantly enhanced ER-mitochondria coupling. CYP was shown to increase expressions of IP3R, Grp75 and VDAC1 significantly. We suggest that CYP induces apoptosis in TM4 cells by facilitating mitochondrial Ca2+ overload regulated by ER-mitochondria coupling involving IP3R1-GRP75-VDAC1. This study identifies a novel mechanism of CYP-induced apoptosis in Sertoli cells.

Privacy-Preserving Identification of Cancer Subtype-Specific Driver Genes Based on Multigenomics Data with Privatedriver.

Identifying cancer subtype-specific driver genes from a large number of irrelevant passengers is crucial for targeted therapy in cancer treatment. Recently, the rapid accumulation of large-scale cancer genomics data from multiple institutions has presented remarkable opportunities for identification of cancer subtype-specific driver genes. However, the insufficient subtype samples, privacy issues, and heterogenous of aberration events pose great challenges in precisely identifying cancer subtype-specific driver genes. To address this, we introduce privatedriver, the first model for identifying subtype-specific driver genes that integrates genomics data from multiple institutions in a data privacy-preserving collaboration manner. The process of identifying subtype-specific cancer driver genes using privatedriver involves the following two steps: genomics data integration and collaborative training. In the integration process, the aberration events from multiple genomics data sources are combined for each institution using the forward and backward propagation method of NetICS. In the collaborative training process, each institution utilizes the federated learning framework to upload encrypted model parameters instead of raw data of all institutions to train a global model by using the non-negative matrix factorization algorithm. We applied privatedriver on head and neck squamous cell and colon cancer from The Cancer Genome Atlas website and evaluated it with two benchmarks using macro-Fscore. The comparison analysis demonstrates that privatedriver achieves comparable results to centralized learning models and outperforms most other nonprivacy preserving models, all while ensuring the confidentiality of patient information. We also demonstrate that, for varying predicted driver gene distributions in subtype, our model fully considers the heterogeneity of subtype and identifies subtype-specific driver genes corresponding to the given prognosis and therapeutic effect. The success of privatedriver reveals the feasibility and effectiveness of identifying cancer subtype-specific driver genes in a data protection manner, providing new insights for future privacy-preserving driver gene identification studies.