Dynamic changes of endothelial and stromal cilia are required for the maintenance of corneal homeostasis.

Primary cilia are distributed extensively within the corneal epithelium and endothelium. However, the presence of cilia in the corneal stroma and the dynamic changes and roles of endothelial and stromal cilia in corneal homeostasis remain largely unknown. Here, we present compelling evidence for the presence of primary cilia in the corneal stroma, both in vivo and in vitro. We also demonstrate dynamic changes of both endothelial and stromal cilia during corneal development. In addition, our data show that cryoinjury triggers dramatic cilium formation in the corneal endothelium and stroma. Furthermore, depletion of cilia in mutant mice lacking intraflagellar transport protein 88 compromises the corneal endothelial capacity to establish the effective tissue barrier, leading to an upregulation of α-smooth muscle actin within the corneal stroma in response to cryoinjury. These observations underscore the essential involvement of corneal endothelial and stromal cilia in maintaining corneal homeostasis and provide an innovative strategy for the treatment of corneal injuries and diseases.

Exploration of the potential association between GLP-1 receptor agonists and suicidal or self-injurious behaviors: a pharmacovigilance study based on the FDA Adverse Event Reporting System database.

BACKGROUND: Establishing whether there is a potential relationship between glucagon-like peptide 1 receptor agonists (GLP-1RAs) and suicidal or self-injurious behaviors (SSIBs) is crucial for public safety. This study investigated the potential association between GLP-1RAs and SSIBs by exploring the FDA Adverse Event Reporting System (FAERS) database. METHODS: A disproportionality analysis was conducted using post-marketing data from the FAERS repository (2018 Q1 to 2022 Q4). SSIB cases associated with GLP-1RAs were identified and analyzed through disproportionality analysis using the information component. The parametric distribution with a goodness-of-fit test was employed to analyze the time-to-onset, and the Ω shrinkage was used to evaluate the potential effect of co-medication on the occurrence of SSIBs. RESULTS: In total, 204 cases of SSIBs associated with GLP-1RAs, including semaglutide, liraglutide, dulaglutide, exenatide, and albiglutide, were identified in the FAERS database. Time-of-onset analysis revealed no consistent mechanism for the latency of SSIBs in patients receiving GLP-1RAs. The disproportionality analysis did not indicate an association between GLP-1RAs and SSIBs. Co-medication analysis revealed 81 cases with antidepressants, antipsychotics, and benzodiazepines, which may be proxies of mental health comorbidities. CONCLUSIONS: We found no signal of disproportionate reporting of an association between GLP-1RA use and SSIBs. Clinicians need to maintain heightened vigilance on patients premedicated with neuropsychotropic drugs. This contributes to the greater acceptance of GLP-1RAs in patients with type 2 diabetes mellitus or obesity.

Oxygen Vacancies on NH4 V4 O10 Accelerate Ion and Charge Transfer in Aqueous Zinc-Ion Batteries.

Vanadium-based compounds are identified as promising cathode materials for aqueous zinc ion batteries due to their high specific capacity. However, the low intrinsic conductivity and sluggish Zn2+ diffusion kinetics seriously impede their further practical application. Here, oxygen vacancies on NH4 V4 O10 is reported as a high-performing cathode material for aqueous zinc ion batteries via a facile hydrothermal strategy. The introduction of oxygen vacancy accelerates the ion and charge transfer kinetics, reduces the diffusion barrier of zinc ions, and establishes a stable crystal structure during zinc ion (de-intercalation). As a result, the oxygen vacancy enriched NH4 V4 O10 exhibits a high specific capacity of ≈499 mA h g-1 at 0.2 A g-1 , an excellent rate capability of 296 mA h g-1 at 10 A g-1 and the specific capacity cycling stability with 95.1% retention at 5 A g-1 for 4000 cycles, superior to the NVO sample (186.4 mAh g-1 at 5 A g-1 , 66% capacity retention).

Gut microbiota influence frailty syndrome in older adults: mechanisms and therapeutic strategies.

Frailty syndrome denotes a decreased capacity of the body to maintain the homeostasis and stress of the internal environment, which simultaneously increases the risk of adverse health outcomes in older adults, including disability, hospitalization, falls, and death. To promote healthy aging, we should find strategies to cope with frailty. However, the pathogenesis of frailty syndrome is not yet clear. Recent studies have shown that the diversity, composition, and metabolites of gut microbiota significantly changed in older adults with frailty. In addition, several frailty symptoms were alleviated by adjusting gut microbiota with prebiotics, probiotics, and symbiosis. Therefore, we attempt to explore the pathogenesis of frailty syndrome in older people from gut microbiota and summarize the existing interventions for frailty syndrome targeting gut microbiota, with the aim of providing timely and necessary interventions and assistance for older adults with frailty.

The protective effect and mechanism of glycosides of cistanche deserticola on rats in middle cerebral artery occlusion (MCAO) model.

Cerebral ischemia-reperfusion injury (CIRI) occurs frequently clinically as a complication following cardiovascular resuscitation resulting in neuronal damage specifically to the hippocampal CA1 region with consequent cognitive impairment. Apoptosis and oxidative stress were proposed as major risk factors associated with CIRI development. Previously, glycosides obtained from Cistanche deserticola (CGs) were shown to play a key role in counteracting CIRI; however, the underlying mechanisms remain to be determined. This study aimed to investigate the neuroprotective effect of CGs on subsequent CIRI in rats. The model of CIRI was established for 2 hr and reperfusion for 24 hr by middle cerebral artery occlusion (MCAO) model. The MCAO rats were used to measure the antioxidant and anti-apoptotic effects of CGs on CIRI. Neurological function was evaluated by the Longa neurological function score test. 2,3,5-Triphenyltetrazolium chloride (TTC) staining was used to detect the area of cerebral infarction. Nissl staining was employed to observe neuronal morphology. TUNEL staining was used to detect neuronal apoptosis, while Western blot determined protein expression levels of factors for apoptosis-related and PI3K/AKT/Nrf2 signaling pathway. Data demonstrated that CGs treatment improved behavioral performance, brain injury, and enhanced antioxidant and anti-apoptosis in CIRI rats. In addition, CGs induced activation of PI3K/AKT/Nrf2 signaling pathway accompanied by inhibition of the expression of apoptosis-related factors. Evidence indicates that CGs amelioration of CIRI involves activation of the PI3K/AKT/Nrf2 signaling pathway associated with increased cellular viability suggesting these glycosides may be considered as an alternative compound for CIRI treatment.

Development and validation of the osteoporosis scale among the system of quality of life instruments for chronic diseases QLICD-OS (V2.0).

BACKGROUND: Quality of life of osteoporosis patients had caused widespread concern, due to high incidence and difficulty to cure. Scale specifics for osteoporosis and suitable for Chinese cultural background lacked. This study aimed to develop an osteoporosis scale in Quality of Life Instruments for Chronic Diseases system, namely QLICD-OS (V2.0). METHODS: Procedural decision-making approach of nominal group, focus group and modular approach were adopted. Our scale was developed based on experience of establishing scales at home and abroad. In this study, Quality of life measurements were performed on 127 osteoporosis patients before and after treatment to evaluate the psychometric properties. Validity was evaluated by qualitative analysis, item-domain correlation analysis, multi-scaling analysis and factor analysis; the SF-36 scale was used as criterion to carry out correlation analysis for criterion-related validity. The reliability was evaluated by the internal consistency coefficients Cronbach's α, test-retest reliability Pearson correlation r. Paired t-tests were performed on data of ​​the scale before and after treatment, with Standardized Response Mean (SRM) being calculated to evaluate the responsiveness. RESULTS: The QLICD-OS, composed of a general module (28 items) and an osteoporosis-specific module (14 items), had good content validity. Correlation analysis and factor analysis confirmed the construct, with the item having a strong correlation (most > 0.40) with its own domains/principle components, and a weak correlation (< 0.40) with other domains/principle components. Correlation coefficient between the similar domains of QLICD-OS and SF-36 showed reasonable criterion-related validity, with all coefficients r being greater than 0.40 exception of physical function of SF-36 and physical domain of QLICD-OS (0.24). Internal consistency reliability of QLICD-OS in all domains was greater than 0.7 except the specific module. The test-retest reliability coefficients (Pearson r) in all domains and overall score are higher than 0.80. Score changes after treatment were statistically significant, with SRM ranging from 0.35 to 0.79, indicating that QLICD-OS could be rated as medium responsiveness. CONCLUSION: As the first osteoporosis-specific quality of life scale developed by the modular approach in China, the QLICD-OS showed good reliability, validity and medium responsiveness, and could be used to measure quality of life in osteoporosis patients.

Sensor Head Temperature Distribution Reconstruction of High-Precision Gravitational Reference Sensors with Machine Learning.

Temperature fluctuations affect the performance of high-precision gravitational reference sensors. Due to the limited space and the complex interrelations among sensors, it is not feasible to directly measure the temperatures of sensor heads using temperature sensors. Hence, a high-accuracy interpolation method is essential for reconstructing the surface temperature of sensor heads. In this study, we utilized XGBoost-LSTM for sensor head temperature reconstruction, and we analyzed the performance of this method under two simulation scenarios: ground-based and on-orbit. The findings demonstrate that our method achieves a precision that is two orders of magnitude higher than that of conventional interpolation methods and one order of magnitude higher than that of a BP neural network. Additionally, it exhibits remarkable stability and robustness. The reconstruction accuracy of this method meets the requirements for the key payload temperature control precision specified by the Taiji Program, providing data support for subsequent tasks in thermal noise modeling and subtraction.

[Trametenolic acid inhibits migration and invasion of hepatocellular carcinoma HepG2.2.15 cells via RhoC/ROCK1 pathway].

This study investigated the effect of trametenolic acid(TA) on the migration and invasion of human hepatocellular carcinoma HepG2.2.15 cells by using Ras homolog gene family member C(RhoC) as the target and probed into the mechanism, aiming to provide a basis for the utilization of TA. The methyl thiazolyl tetrazolium(MTT) assay was employed to examine the proliferation of HepG2.2.15 cells exposed to TA, and scratch and Transwell assays to examine the cell migration and invasion. The pull down assay was employed to determine the impact of TA on RhoC GTPase activity. Western blot was employed to measure the effect of TA on the transport of RhoC from cytoplasm to cell membrane and the expression of RhoC/Rho-associated kinase 1(ROCK1)/myosin light chain(MLC)/matrix metalloprotease 2(MMP2)/MMP9 pathway-related proteins. RhoC was over-expressed by transient transfection of pcDNA3.1-RhoC. The changes of F-actin in the cytoskeleton were detected by Laser confocal microscopy. In addition, the changes of cell migration and invasion, expression of proteins in the RhoC/ROCK1/MLC/MMP2/MMP9 pathway, and RhoC GTPase activity were detected. The subcutaneously transplanted tumor model of BALB/c nude mice and the low-, medium-, and high-dose(40, 80, and 120 mg·kg~(-1), respectively) TA groups were established and sorafenib(20 mg·kg~(-1)) was used as the positive control. The tumor volume and weight in each group were measured, and the expression of related proteins in the tumor tissue was determined by Western blot. The results showed that TA inhibited the proliferation of HepG2.2.15 cells in a concentration-dependent manner, with the IC_(50) of 66.65 and 23.09 µmol·L~(-1) at the time points of 24 and 48 h, respectively. The drug administration groups had small tumors with low mass. The tumor inhibition rates of sorafenib and low-, medium-and high-dose TA were 62.23%, 26.48%, 55.45%, and 62.36%, respectively. TA reduced migrating and invading cells and inhibited RhoC protein expression and RhoC GTPase activity in a concentration-dependent manner, dramatically reducing RhoC and membrane-bound RhoC GTPase. The expression of ROCK1, MLC, p-MLC, MMP2, and MMP9 downstream of RhoC can be significantly inhibited by TA, as confirmed in both in vitro and in vivo experiments. After HepG2.2.15 cells were transfected with pcDNA3.1-RhoC to overexpress RhoC, TA down-regulated the protein levels of RhoC, ROCK1, MLC, p-MLC, MMP2, and MMP9 and decreased the activity of RhoC GTPase, with the inhibition level comparable to that before overexpression. In summary, TA can inhibit the migration and invasion of HepG2.2.15 cells. It can inhibit the RhoC/ROCK1/MLC/MMP2/MMP9 signaling pathway by suppressing RhoC GTPase activity and down-regulating RhoC expression. This study provides a new idea for the development of autophagy modulators targeting HSP90α to block the proliferation and inhibit the invasion and migration of hepatocellular carcinoma cells via multiple targets of active components in traditional Chinese medicines.

Cideb controls sterol-regulated ER export of SREBP/SCAP by promoting cargo loading at ER exit sites.

SREBPs are master regulators of lipid homeostasis and undergo sterol-regulated export from ER to Golgi apparatus for processing and activation via COPII-coated vesicles. While COPII recognizes SREBP through its escort protein SCAP, factor(s) specifically promoting SREBP/SCAP loading to the COPII machinery remains unknown. Here, we show that the ER/lipid droplet-associated protein Cideb selectively promotes the loading of SREBP/SCAP into COPII vesicles. Sterol deprivation releases SCAP from Insig and enhances ER export of SREBP/SCAP by inducing SCAP-Cideb interaction, thereby modulating sterol sensitivity. Moreover, Cideb binds to the guanine nucleotide exchange factor Sec12 to enrich SCAP/SREBP at ER exit sites, where assembling of COPII complex initiates. Loss of Cideb inhibits the cargo loading of SREBP/SCAP, reduces SREBP activation, and alleviates diet-induced hepatic steatosis. Our data point to a linchpin role of Cideb in regulated ER export of SREBP and lipid homeostasis.

Air pollution associated with incidence and progression trajectory of chronic lung diseases: a population-based cohort study.

BACKGROUND: No prior study has examined the effects of air pollution on the progression from healthy to chronic lung disease, subsequent chronic lung multimorbidity and further to death. METHODS: We used data from the UK Biobank of 265 506 adults free of chronic lung disease at recruitment. Chronic lung multimorbidity was defined as the coexistence of at least two chronic lung diseases, including asthma, chronic obstructive pulmonary disease and lung cancer. The concentrations of air pollutants were estimated using land-use regression models. Multistate models were applied to assess the effect of air pollution on the progression of chronic lung multimorbidity. RESULTS: During a median follow-up of 11.9 years, 13 863 participants developed at least one chronic lung disease, 1055 developed chronic lung multimorbidity and 12 772 died. We observed differential associations of air pollution with different trajectories of chronic lung multimorbidity. Fine particulate matter showed the strongest association with all five transitions, with HRs (95% CI) per 5 µg/m3 increase of 1.31 (1.22 to 1.42) and 1.27 (1.01 to 1.57) for transitions from healthy to incident chronic lung disease and from incident chronic lung disease to chronic lung multimorbidity, and 1.32 (1.21 to 1.45), 1.24 (1.01 to 1.53) and 1.91 (1.14 to 3.20) for mortality risk from healthy, incident chronic lung disease and chronic lung multimorbidity, respectively. CONCLUSION: Our study provides the first evidence that ambient air pollution could affect the progression from free of chronic lung disease to incident chronic lung disease, chronic lung multimorbidity and death.

mRBPome capture identifies the RNA-binding protein TRIM71, an essential regulator of spermatogonial differentiation.

Continual spermatogenesis relies on the actions of an undifferentiated spermatogonial population that is composed of stem cells and progenitors. Here, using mouse models, we explored the role of RNA-binding proteins (RBPs) in regulation of the biological activities of this population. Proteins bound to polyadenylated RNAs in primary cultures of undifferentiated spermatogonia were captured with oligo (dT)-conjugated beads after UV-crosslinking and profiled by proteomics (termed mRBPome capture), yielding a putative repertoire of 473 RBPs. From this database, the RBP TRIM71 was identified and found to be expressed by stem and progenitor spermatogonia in prepubertal and adult mouse testes. Tissue-specific deletion of TRIM71 in the male germline led to reduction of the undifferentiated spermatogonial population and a block in transition to the differentiating state. Collectively, these findings demonstrate a key role of the RBP system in regulation of the spermatogenic lineage and may provide clues about the influence of RBPs on the biology of progenitor cell populations in other lineages.

USF1-mediated ALKBH5 stabilizes FLII mRNA in an m6A-YTHDF2-dependent manner to repress glycolytic activity in prostate adenocarcinoma.

Upstream-stimulating factor 1 (USF1) is a ubiquitously expressed transcription factor implicated in multiple cellular processes, including metabolism and proliferation. This study focused on the function of USF1 in glycolysis and the malignant development of prostate adenocarcinoma (PRAD). Bioinformatics predictions suggested that USF1 is poorly expressed in PRAD. The clinical PRAD samples revealed a low level of USF1, which was correlated with an unfavorable prognosis. Artificial upregulation of USF1 significantly repressed glycolytic activity in PRAD cells and reduced cell growth and metastasis in vitro and in vivo. Potential downstream genes of USF1 were probed by integrated bioinformatics analyses. The chromatin immunoprecipitation and luciferase assays indicated that USF1 bound to the α-ketoglutarate-dependent dioxygenase alkB homolog 5 (ALKBH5) promoter for transcription activation. Flightless I (FLII) was identified as the gene showing the highest degree of correlation with ALKBH5. As an m6A demethylase, ALKBH5 enhanced FLII mRNA stability by inducing m6A demethylation in an m6A-YTH N6-methyladenosine RNA-binding protein F2 (YTHDF2)-dependent manner. Either silencing of ALKBH5 or FLII blocked the role of USF1 in PARD cells and restored glycolysis, cell proliferation, and invasion. This study demonstrates that USF1 activates ALKBH5 to stabilize FLII mRNA in an m6A-YTHDF2-dependent manner, thereby repressing glycolysis processes and the progression of PRAD.

Identification of lignans and quality assessment in Dendrobium officinale under different cultivation modes.

RATIONALE: Lignans have attracted much attention from researchers because of their wide distribution and industrial applications in plants, as well as the remarkable diversity of their biological activities. As the literature has mainly focused on the extraction and identification of monomeric compounds of lignans, most lignans in Dendrobium officinale, a traditional Chinese medicine with a long cultivation history and rich sources, have not been detected using quality control methods. The aim of this study was to identify the lignans in Dactilon officinale. METHODS: High-performance liquid chromatography (HPLC) coupled with diode array detection and HPLC multiple-stage tandem mass spectrometry was used to identify the chemical constituents of D. officinale. Simultaneously, the characteristic chromatograms of D. officinale were established. Additionally, a method was established to determine the content of syringaresinol-4,4'-di-O-ß-D-glucoside, syringaresinol-4-O-ß-D-glucoside and syringaresinol. RESULTS: Thirty-three lignans, including 17 tetrahydrofuran lignans, two dibenzylbutane lignans, three aryl tetrahydronaphthalene lignans and 11 8-O-4'-neolignans, were tentatively identified from the methanol extract of the stems of D. officinale. This is the first report of 8-O-4'-neolignans from D. officinale. In addition, a total of eight characteristic peaks were marked in characteristic chromatograms, which were identified as lyoniresinol-9'-O-ß-D-glucoside, syringaresinol-4,4'-di-O-ß-D-glucoside, 8-hydroxy-syringaresinol-4-O-ß-D-glucoside, 5,5'-dimethoxy-lariciresinol-4-O-ß-D-glucoside, syringaresinol-4-O-ß-D-glucoside, 4-hydroxy-3,3',5,5'-tetramethoxy-8,4'-oxyneoligna-7'-ene-9,9'-diol-9-O-ß-D-glucoside, 4-hydroxy-3,3',5,5'-tetramethoxy-8,4'-oxyneoligna-7'-ene-9,9'-diol-4-O-ß-D-glucoside and syringaresinol. Our results showed that no significant difference occurred in lignan composition among the 99 batches of D. officinale from different sources. However, the peak areas of the lignans of D. officinale planted under simulated wild culture were generally higher than those in greenhouses, and showed an upward trend with the increase in growth years. The average contents of syringaresinol-4,4'-di-O-ß-D-glucoside, syringaresinol-4-O-ß-D-glucoside and syringaresinol were 10.112-179.873, 51.227-222.294 and 6.368-120.341 µg/g, respectively. CONCLUSIONS: This study provided a basis for improving the quality control of D. officinale and could provide references for the identification of lignans in other Dendrobium species.

MicroRNA-211 Regulates Proliferation, Expansion, and Immune Inhibitory Function of Myeloid-Derived Suppressor Cells via Mediation of CHOP Expression.

BACKGROUND: Myeloid-derived suppressor cells (MDSCs) are capable of effectively repressing immune responses against tumors and orchestrating the tumor microenvironment, which can promote tumor angiogenesis and metastasis. The pathway networks used to modulate tumor-expanded MDSC accumulation and function remain unclear. This study identified microRNA-211 (miR-211), whose expression was significantly decreased by factors derived from tumors. METHODS: miR-211 was assumed to be critical in modulating the accumulation and activity of MDSCs isolated from ovarian cancer (OC)-bearing mice by targeting C/EBP homologous protein (CHOP). RESULTS: The upregulation of miR-211 repressed MDSC proliferation, inhibited MDSC immunosuppressive functions, and increased the number of co-incubated CD4+ and CD8+ cells. Furthermore, overexpression of miR-211 led to decreased activities of the NF-κB, PI3K/Akt, and STAT3 pathways and the subsequent downregulation of matrix metalloproteinases to promote tumor cell invasion and metastasis. CHOP overexpression counteracted the effects of miR-211 elevation on these phenotypic changes. Upregulation of miR-211 also dramatically impaired the activity of MDSCs and suppressed OC tumor growth in vivo. CONCLUSION: These results indicated that the miR-211-CHOP axis in MDSCs plays an essential role in the metastasis and proliferation of tumor-expanded MDSCs and might represent a promising cancer treatment target.

Efficient synthesis and anticancer evaluation of spider toxin peptide LVTX-8-based analogues with enhanced stability.

Cytotoxic peptides derived from spider venoms have been considered as promising candidates for anticancer treatment. The novel cell penetrating peptide LVTX-8, which is a 25-residue amphipathic α-helical peptide isolated from spider Lycosa vittata, exhibited potent cytotoxicity and is a potential precursor for further anticancer drug development. Nevertheless, LVTX-8 may be easily degraded by multiple proteases, inducing the proteolytic stability problem and short half-life. In this study, ten LVTX-8-based analogs were rationally designed and the efficient manual synthetic method was established by the DIC/Oxyma based condensation system. The cytotoxicity of synthetic peptides was systematically evaluated against seven cancer cell lines. Seven of the derived peptides exhibited high cytotoxicity towards tested cancer in vitro, which was better than or comparable to that of natural LVTX-8. In particular, both N-acetyl and C-hydrazide modified LVTX-8 (825) and the conjugate methotrexate (MTX)-GFLG-LVTX-8 (827) possessed more durable anticancer efficiency, higher proteolytic stability, as well as lower hemolysis. Finally, we confirmed that LVTX-8 could disrupt the integrity of cell membrane, target the mitochondria and reduce the mitochondrial membrane potential to induce the cell death. Taken together, the structural modifications were conducted on LVTX-8 for the first time and the stability significantly improved derivatives 825 and 827 may provide useful references for the modifications of cytotoxic peptides.

Bidirectional causal relationship between depression and frailty: a univariate and multivariate Mendelian randomisation study.

BACKGROUND: cumulative evidence from cohort studies suggested that there were inconsistent conclusions as to whether there was a bidirectional association between depression and frailty. Therefore, this study used a bidirectional two-sample Mendelian randomisation (MR) study to investigate the causal relationship between depression and frailty. METHODS: we performed univariate and multivariate bidirectional MR analyses to assess the causal association between depression and frailty. Independent genetic variants associated with depression and frailty were selected as instrumental variables. Inverse variance weighted (IVW), MR-Egger, weighted median and weighted mode were mainly used in univariate MR analysis. Multivariate MR (MVMR) analyses used multivariable inverse variance-weighted methods to individually and jointly adjust for three potential confounders, body mass index (BMI), age at menarche (AAM) and waist-to-hip ratio (WHR, adjusted for BMI). RESULTS: univariate MR analysis showed a positive causal relationship between depression and risk of frailty (IVW, odds ratio (OR) = 1.30, 95% confidence interval (CI) = 1.23-1.37, P = 6.54E-22). Causal relationship between frailty and risk of depression (IVW, OR = 1.69, 95% CI = 1.33-2.16, P = 2.09E-05). MVMR analysis revealed that the bidirectional causal association between depression and frailty remained after adjusting for three potential confounders, BMI, AAM and WHR (adjusted for BMI), individually and in combination. CONCLUSIONS: our findings supported a causal relationship between genetically predicted depression and frailty in both directions.

Effects of Oxidative Stress on the Autophagy and Apoptosis of Granulosa Cells in Broody Geese.

Broodiness is an unfavorable trait associated with the cessation of egg laying. Studies have found that excessive granulosa cell apoptosis and autophagy occur during goose broodiness. Other studies have also confirmed that oxidative stress is an important cause of apoptosis and autophagy. However, whether oxidative stress occurs during goose broodiness and whether this oxidative stress causes apoptosis and autophagy have not been fully elucidated. In this study, we investigated the effects of oxidative stress on the autophagy and apoptosis of granulosa cells in broody geese. The results showed higher mRNA expression of genes related to antioxidative stress responses (GPX, SOD-1, SOD-2, COX-2, CAT and hsp70) in pre-broody and broody geese than in laying birds. In addition, increased levels of granulosa cell apoptosis and autophagy were observed in pre-broody geese than in laying geese. Additionally, granulosa cells treated with H2O2 exhibited increased apoptosis and autophagy in vitro, and these effects were responsible for goose granulosa cell death. Moreover, vitamin E treatment effectively protected granulosa cells from H2O2-induced oxidative stress by inhibiting ROS production. Correspondingly, granulosa cell apoptosis and autophagy were greatly alleviated by vitamin E treatment. Together, our results demonstrated serious oxidative stress and granulosa cell apoptosis and autophagy in broody geese, and oxidative stress promoted apoptosis and autophagy. Vitamin E alleviated the autophagy and apoptosis of granulosa cells by inhibiting oxidative stress.

Machine Learning Generation of Dynamic Protein Conformational Ensembles.

Machine learning has achieved remarkable success across a broad range of scientific and engineering disciplines, particularly its use for predicting native protein structures from sequence information alone. However, biomolecules are inherently dynamic, and there is a pressing need for accurate predictions of dynamic structural ensembles across multiple functional levels. These problems range from the relatively well-defined task of predicting conformational dynamics around the native state of a protein, which traditional molecular dynamics (MD) simulations are particularly adept at handling, to generating large-scale conformational transitions connecting distinct functional states of structured proteins or numerous marginally stable states within the dynamic ensembles of intrinsically disordered proteins. Machine learning has been increasingly applied to learn low-dimensional representations of protein conformational spaces, which can then be used to drive additional MD sampling or directly generate novel conformations. These methods promise to greatly reduce the computational cost of generating dynamic protein ensembles, compared to traditional MD simulations. In this review, we examine recent progress in machine learning approaches towards generative modeling of dynamic protein ensembles and emphasize the crucial importance of integrating advances in machine learning, structural data, and physical principles to achieve these ambitious goals.

The significance of recent diversification in the Northern Hemisphere in shaping the modern global flora revealed from the herbaceous tribe of Rubieae (Rubiaceae).

The global herbaceous flora is probably shaped by both ancient and/or recent diversification, companied with the impacts from geographic differences between the Northern and Southern Hemispheres. Therefore, its biogeographic pattern with respect to temporal and spatial divergence is far from full understanding. Tribe Rubieae, the largest herbaceous tribe in the woody-dominant Rubiaceae, provides an excellent opportunity for studying the macroevolution of worldwide colonization. Here, we aim to reconstruct the evolutionary history of Rubieae with regard to climate fluctuation and geological history in the Cenozoic. A total of 204 samples of Rubieae representing all the distribution areas of the tribe were used to infer its phylogenetic and biogeographic histories based on two nrDNA and six cpDNA regions. The ancestral area of Rubieae was reconstructed using a time-calibrated phylogeny in RASP and diversification rates were inferred using Bayesian analysis of macroevolutionary mixtures (BAMM). Our results show Rubieae probably originated in European region during the middle Oligocene, with the two subtribes separating at 26.8 million years ago (Ma). All the genera in Rubieae formed separate clades between 24.79 and 6.23 Ma. The ancestral area of the subtribe Rubiinae was the Madrean-Tethyan plant belt and the North Atlantic land bridge (NALB) provided passage between North America and Europe for Rubiinae. The subtribe Galiinae clade originated in Europe/central Asia during the late Oligocene. Two diversification shifts were detected within Rubieae in the late Neogene. Most extant Rubieae species diverged recently during the Neogene within clades that generally were established during the late Paleogene. The tribe shows complex migration/dispersal patterns within the North Hemisphere combined with multiple recent dispersals into Southern Hemisphere. Our results highlighted the important role of recent biogeographic diversification in the Northern Hemisphere in shaping the modern global herbaceous flora during the latest and rapid worldwide expansion in the Neogene.

High-Temperature Soup Foods in Plastic Packaging Are Associated with Phthalate Body Burden and Expression of Inflammatory mRNAs: A Dietary Intervention Study.

Plastic packaging material is widely used to package high-temperature soup food in China, but this combination might lead to increased exposure to phthalates. The health effects and potential biological mechanisms have not been well studied. This study aimed to examine urinary phthalate metabolites and the expression of inflammatory cytokines in the blood before, during, and after a "plastic-packaged high-temperature soup food" dietary intervention in healthy adults. The results showed that compared with those in the preintervention period, urinary creatinine-adjusted levels of monomethyl phthalate (MMP), mono-n-butyl phthalate (MBP), mono-isobutyl phthalate (MIBP), and total phthalate metabolites in the intervention period were significantly higher, with increases of 71.6, 41.8, 38.8, and 29.8% for MMP, MBP, MIBP, and the total phthalate metabolites, respectively. After intervention, the mean levels of IL-1ß, IL-4, and TNF-α mRNA increased by 19.0, 21.5, and 25.0%, respectively, while IL-6 and IFN-γ mRNA decreased by 24.2 and 32.9%, respectively, when compared with the preintervention period. We also observed that several phthalates were associated with the mRNA or protein expression of IL-8, TNF-α, and IL-10. Therefore, consumption of plastic-packaged high-temperature soup food was linked to increased phthalate exposure and might result in significant changes in mRNA expression of several inflammatory cytokines.