RESUMEN
The ring-shaped Cohesin complex, consisting of core subunits Smc1, Smc3, Scc1, and SA2 (or its paralog SA1), topologically entraps two duplicated sister DNA molecules to establish sister chromatid cohesion in S-phase. It remains largely elusive how the Cohesin release factor Wapl binds the Cohesin complex, thereby inducing Cohesin disassociation from mitotic chromosomes to allow proper resolution and separation of sister chromatids. Here, we show that Wapl uses two structural modules containing the FGF motif and the YNARHWN motif, respectively, to simultaneously bind distinct pockets in the extensive composite interface between Scc1 and SA2. Strikingly, only when both docking modules are mutated, Wapl completely loses the ability to bind the Scc1-SA2 interface and release Cohesin, leading to erroneous chromosome segregation in mitosis. Surprisingly, Sororin, which contains a conserved FGF motif and functions as a master antagonist of Wapl in S-phase and G2-phase, does not bind the Scc1-SA2 interface. Moreover, Sgo1, the major protector of Cohesin at mitotic centromeres, can only compete with the FGF motif but not the YNARHWN motif of Wapl for binding Scc1-SA2 interface. Our data uncover the molecular mechanism by which Wapl binds Cohesin to ensure precise chromosome segregation.
Asunto(s)
Proteínas de Ciclo Celular , Proteínas Cromosómicas no Histona , Segregación Cromosómica , Cohesinas , Proteínas Cromosómicas no Histona/metabolismo , Proteínas Cromosómicas no Histona/genética , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ciclo Celular/genética , Humanos , Unión Proteica , Proteínas Nucleares/metabolismo , Proteínas Nucleares/genética , Secuencias de Aminoácidos , Mitosis , Cromátides/metabolismo , Proteínas Portadoras , Proteínas Proto-OncogénicasRESUMEN
Male animals often display higher levels of aggression than females. However, the neural circuitry mechanisms underlying this sexually dimorphic aggression remain elusive. Here, we identify a hypothalamic-amygdala circuit that mediates male-biased aggression in mice. Specifically, the ventrolateral part of the ventromedial hypothalamus (VMHvl), a sexually dimorphic region associated with eliciting male-biased aggression, projects densely to the posterior substantia innominata (pSI), an area that promotes similar levels of attack in both sexes of mice. Although the VMHvl innervates the pSI unidirectionally through both excitatory and inhibitory connections, it is the excitatory VMHvl-pSI projections that are strengthened in males to promote aggression, whereas the inhibitory connections that reduce aggressive behavior are strengthened in females. Consequently, the convergent hypothalamic input onto the pSI leads to heightened pSI activity in males, resulting in male-biased aggression. Our findings reveal a sexually distinct excitation-inhibition balance of a hypothalamic-amygdala circuit that underlies sexually dimorphic aggression.
RESUMEN
Caring for patients with dementia at risk of getting lost is challenging for community healthcare providers. Through semi-structured interviews with 25 participants, we examined the challenges faced by these providers and the strategies they employed. We identified the following themes of challenging parts: (a) the disturbance caused by behavioral and psychological symptoms in dementia; (b) difficulty in helping older family caregivers to keep the patient from going out; (c) difficulty in changing the attitudes of the family members; families' unawareness of the risk of getting lost. We also identified the following strategies to mitigate these themes: (a) detecting the risk of getting lost through early assessment; (b) encouraging the family to use resources or devices to prevent the patient from getting lost; (c) educating the family to manage behavior and psychological symptoms of dementia; (d) strengthening the patient's crisis awareness.
RESUMEN
Background: Precipitation could affect the transmission of diarrheal diseases. The diverse precipitation patterns across different climates might influence the degree of diarrheal risk from precipitation. This study determined the associations between precipitation and diarrheal mortality in tropical, temperate, and arid climate regions. Methods: Daily counts of diarrheal mortality and 28-day cumulative precipitation from 1997 to 2019 were analyzed across 29 locations in eight middle-income countries (Argentina, Brazil, Costa Rica, India, Peru, the Philippines, South Africa, and Thailand). A two-stage approach was employed: the first stage is conditional Poisson regression models for each location, and the second stage is meta-analysis for pooling location-specific coefficients by climate zone. Results: In tropical climates, higher precipitation increases the risk of diarrheal mortality. Under extremely wet conditions (95th percentile of 28-day cumulative precipitation), diarrheal mortality increased by 17.8% (95% confidence interval [CI] = 10.4%, 25.7%) compared with minimum-risk precipitation. For temperate and arid climates, diarrheal mortality increases in both dry and wet conditions. In extremely dry conditions (fifth percentile of 28-day cumulative precipitation), diarrheal mortality risk increases by 3.8% (95% CI = 1.2%, 6.5%) for temperate and 5.5% (95% CI = 1.0%, 10.2%) for arid climates. Similarly, under extremely wet conditions, diarrheal mortality risk increases by 2.5% (95% CI = -0.1%, 5.1%) for temperate and 4.1% (95% CI = 1.1%, 7.3%) for arid climates. Conclusions: Associations between precipitation and diarrheal mortality exhibit variations across different climate zones. It is crucial to consider climate-specific variations when generating global projections of future precipitation-related diarrheal mortality.
RESUMEN
The medial prefrontal cortex (mPFC) has been implicated in the pathophysiology of social impairments including social fear. However, the precise subcortical partners that mediate mPFC dysfunction on social fear behaviour have not been identified. Employing a social fear conditioning paradigm, we induced robust social fear in mice and found that the lateral habenula (LHb) neurons and LHb-projecting mPFC neurons are synchronously activated during social fear expression. Moreover, optogenetic inhibition of the mPFC-LHb projection significantly reduced social fear responses. Importantly, consistent with animal studies, we observed an elevated prefrontal-habenular functional connectivity in subclinical individuals with higher social anxiety characterized by heightened social fear. These results unravel a crucial role of the prefrontal-habenular circuitry in social fear regulation and suggest that this pathway could serve as a potential target for the treatment of social fear symptom often observed in many psychiatric disorders.
RESUMEN
OBJECTIVE: To examine the clinical phenotype and genetic deficiencies present in Chinese aniridia families with PAX6 haplotype deficiency. METHODS: A comprehensive questionnaire and ophthalmological assessments were administered to both affected patients and unaffected relatives. The clinical feature analysis included the evaluation of visual acuity, intraocular pressure, slit-lamp anterior segment examination, fundus photography, and spectral domain optical coherence tomography. To identify the mutation responsible for aniridia, targeted next-generation sequencing was used as a beneficial technique. RESULTS: A total of 4 mutations were identified, consisting of two novel frameshift mutations (c.314delA, p.K105Sfs*33 and c.838_845dup AACACACC, p.S283Tfs*85), along with two recurring nonsense mutations (c.307C>T, p.R103X and c.619A>T, p.K207*). Complete iris absence, macular foveal hypoplasia, and nystagmus were consistent in these PAX6 haplotype-deficient Chinese aniridia families, while corneal lesions, cataracts, and glaucoma exhibited heterogeneity both among the families and within the same family. CONCLUSION: In our study, two novel PAX6 mutations associated with aniridia were identified in Chinese families, which expanded the phenotypic and genotypic spectrum of PAX6 mutations. We also analyzed the clinical characteristics of PAX6 haplotype deficiency in Chinese aniridia families.
RESUMEN
OBJECTIVES: To establish a reliable ultrasound (US) method of evaluating dynamic extrusion of lateral meniscus in healthy population, and to investigate the pattern of dynamic meniscus extrusion (ME) in lateral meniscus under loading conditions. METHODS: The lateral ME was examined via US method in unloaded, double-leg standing, and single-leg standing positions. Two different US measurement methods were compared to the magnetic resonance imaging (MRI) results to determine the optimal measurement methods. The US results obtained by different researchers were tested for interobserver consistency and the results obtained by the same researcher on two separate days were tested for intraobserver consistency. The patterns of dynamic extrusion were compared between medial and lateral sides. RESULTS: A total of healthy 44 volunteers were included in the study, with 86 knees assessed by US, and 25 knees evaluated by MRI. The US evaluation of dynamic lateral ME demonstrated excellent interobserver and intraobserver reliability. The US measurements using method A were consistent with the MRI results with no significant difference (P = .861, intraclass correlation coefficient [ICC] = 0.868), while method B underestimated the lateral ME compared to MRI (P = .001, ICC = 0.649). Lateral ME decreased slightly from unloaded (1.0 ± 0.8 mm) to single-leg standing position (0.8 ± 0.8 mm), whereas medial ME increased significantly in both double-leg and single-leg standing positions (2.4 ± 0.7 mm, 2.6 ± 0.7 mm). CONCLUSION: A novel US evaluation method of lateral ME was established with reliable and accurate results compared to the MRI. Lateral ME in healthy populations decreased slightly as the loadings increased, which was different from the pattern of dynamic extrusion in medial meniscus.
Asunto(s)
Meniscos Tibiales , Ultrasonografía , Humanos , Masculino , Femenino , Ultrasonografía/métodos , Adulto , Reproducibilidad de los Resultados , Meniscos Tibiales/diagnóstico por imagen , Valores de Referencia , Adulto Joven , Imagen por Resonancia Magnética/métodos , Persona de Mediana Edad , Variaciones Dependientes del Observador , Voluntarios SanosRESUMEN
Stomata in leaves regulate gas (carbon dioxide and water vapor) exchange and water transpiration between plants and the atmosphere. SLow Anion Channel 1 (SLAC1) mediates anion efflux from guard cells and plays a crucial role in controlling stomatal aperture. It serves as a central hub for multiple signaling pathways in response to environmental stimuli, with its activity regulated through phosphorylation via various plant protein kinases. However, the molecular mechanism underlying SLAC1 phosphoactivation has remained elusive. Through a combination of protein sequence analyses, AlphaFold-based modeling and electrophysiological studies, we unveiled that the highly conserved motifs on the N- and C-terminal segments of SLAC1 form a cytosolic regulatory domain (CRD) that interacts with the transmembrane domain(TMD), thereby maintaining the channel in an autoinhibited state. Mutations in these conserved motifs destabilize the CRD, releasing autoinhibition in SLAC1 and enabling its transition into an activated state. Our further studies demonstrated that SLAC1 activation undergoes an autoinhibition-release process and subsequent structural changes in the pore helices. These findings provide mechanistic insights into the activation mechanism of SLAC1 and shed light on understanding how SLAC1 controls stomatal closure in response to environmental stimuli.
Asunto(s)
Proteínas de Arabidopsis , Arabidopsis , Estomas de Plantas , Transducción de Señal , Fosforilación , Estomas de Plantas/metabolismo , Proteínas de Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Arabidopsis/metabolismo , Arabidopsis/genética , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/genética , Dominios Proteicos , MutaciónRESUMEN
OBJECTIVE: To explore clinical effect of manipulation reduction combined with vertebral plasty on osteoporotic compression fractures (OVCFs). METHODS: Totally 61 patients with OVCFs treated from January 2022 to March 2024 were randomly divided into self-made spinal locator positioning with manipulation reduction group (treatment group) and traditional Kirchner positioning group (control group). There were 30 patients in treatment group, including 4 males and 26 females, aged from 61 to 87 years old with an average of (73.61±7.17) years old;body mass index (BMI) ranged from 15.24 to 28.89 kg·m-2 with an average of (23.90±3.20) kg·m-2;bone mineral density T value ranged from -4.90 to -2.50 SD with an avergae of (-3.43±0.75) SD;fracture to operation time was 6.50 (4.00, 10.25) d;10 patients were gradeâ , 13 patients were gradeâ ¡, and 7 patients were grade â ¢ according to Genant classification of fracture compression. There were 31 patients in control group, including 7 males and 24 females, aged from 61 to 89 years old with an average of (73.63±8.77) years old;BMI ranged from 18.43 to 27.06 kg·m-2 with an average of (23.67±2.35) kg·m-2;bone mineral density T value ranged from -4.60 to -2.50 SD with an avergae of (-3.30±0.68) SD;fracture to operation time was 6.00 (3.00, 8.00) d;11 patients were gradeâ , 9 patients were gradeâ ¡, and 11 patients were grade â ¢ according to Genant classification of fracture compression. The puncture times, X-ray fluoroscopy times and puncture time between two groups were observed and compared. Visual analogue scale (VAS), Japanese Orthopaedic Association (JOA) and timed up and go test (TUGT) were observed and compared before operation, 3 d and 1 month after operation. RESULTS: All patients were followed up for 1 to 3 months with an average of (2.10±0.80) months. Puncture times, X-ray fluorosecopy times and puncture time in treatment group were 5.00(4.00, 6.00) times, (29.53±5.89) times and 14.83(12.42, 21.20) min, respectively, while those in control group were 7.00(6.00, 8.00) times, (34.58±5.33) times, 22.19(17.33, 27.01) min, treatment group was better than those of control group (P<0.05). There were no significant differences in preoperative VAS, JOA and TUGT between two groups(P>0.05). VAS, JOA and TUGT in both groups were significantly improved after opeation(P<0.05). On the third day after operation, JOA score of treatment group was 23.00 (20.75, 25.00), which was higher than that of control group 20.00(19.00, 23.00)(P<0.05). TUGT of treatment group was 6.26(5.86, 6.57) s, which was better than that of control group 6.90(6.80, 7.14) s (P<0.05). Bone cement leakage occurred with 1 patient in treatment group and 2 patients in control group. CONCLUSION: The optimal scheme of self-made spinal locators for locating descending verteboplasty combined with traditional Chinese medicine reduction manipulation for OVCF patients could reduce the number of intraoperative puncture times, shorten puncture times and reduce number of X-ray fluoroscopy times, and have advantages over the simple positioning of Kirschn's needle in restoring short-term lumbar function and standing and walking ability of postoperative patients.
Asunto(s)
Fracturas por Compresión , Fracturas Osteoporóticas , Fracturas de la Columna Vertebral , Vertebroplastia , Humanos , Masculino , Femenino , Anciano , Fracturas por Compresión/cirugía , Persona de Mediana Edad , Fracturas Osteoporóticas/cirugía , Vertebroplastia/métodos , Anciano de 80 o más Años , Fracturas de la Columna Vertebral/cirugíaRESUMEN
An increase in fibrous connective tissue and a decrease in parenchymal cells in organ tissues are the primary pathological alterations linked to organ fibrosis. If fibrosis is not treated, organ structure is destroyed, function can decline, or even fail, posing a serious risk to human life and health. Numerous organs develop fibrosis, and organ fibroproliferative illnesses account for almost 45% of patient deaths from various diseases in the industrialized world, as well as a major cause of disability and mortality in many other diseases. Recently, it has become evident that histone modification is an important way to regulate gene expression in organ fibrosis. Histone modifications alter the structure of chromatin, thereby affecting gene accessibility. Histone acetylation modifications relax chromatin, making it easier for gene transcription factors to access DNA, thereby promoting gene transcription. In addition, histone modifications recruit other proteins to interact with chromatin to form complexes that further regulate gene expression. Histone methylation modifications recruit methylation-reading proteins that recognize methylation marks and alter gene expression status. It not only affects the normal physiological function of cells, but also plays an important role in organ fibrosis. This article reviews the important role played by histone modifications in organ fibrosis and potential therapeutic approaches.
Asunto(s)
Fibrosis , Histonas , Humanos , Histonas/metabolismo , Animales , Procesamiento Proteico-Postraduccional , Acetilación , MetilaciónRESUMEN
Ten-eleven translocation 1 (TET1) is a methylcytosine dioxygenase involved in active DNA demethylation. In our previous study, we demonstrated that TET1 reprogrammed the ovarian cancer epigenome, increased stem properties, and activated various regulatory networks, including metabolic networks. However, the role of TET1 in cancer metabolism remains poorly understood. Herein, we uncovered a demethylated metabolic gene network, especially oxidative phosphorylation (OXPHOS). Contrary to the concept of the Warburg effect in cancer cells, TET1 increased energy production mainly using OXPHOS rather than using glycolysis. Notably, TET1 increased the mitochondrial mass and DNA copy number. TET1 also activated mitochondrial biogenesis genes and adenosine triphosphate production. However, the reactive oxygen species levels were surprisingly decreased. In addition, TET1 increased the basal and maximal respiratory capacities. In an analysis of tricarboxylic acid cycle metabolites, TET1 increased the levels of α-ketoglutarate, which is a coenzyme of TET1 dioxygenase and may provide a positive feedback loop to modify the epigenomic landscape. TET1 also increased the mitochondrial complex I activity. Moreover, the mitochondrial complex I inhibitor, which had synergistic effects with the casein kinase 2 inhibitor, affected ovarian cancer growth. Altogether, TET1-reprogrammed ovarian cancer stem cells shifted the energy source to OXPHOS, which suggested that metabolic intervention might be a novel strategy for ovarian cancer treatment.
RESUMEN
Glioblastoma is the most common cancer in the brain, resistant to conventional therapy and prone to recurrence. Therefore, it is crucial to explore novel therapeutics strategies for the treatment and prognosis of GBM. In this study, through analyzing online datasets, we elucidated the expression and prognostic value of POLR2J and its co-expressed genes in GBM patients. Functional experiments, including assays for cell apoptosis and cell migration, were used to explore the effects of POLR2J and vorinostat on the proliferation and migration of GBM cells. The highest overexpression of POLR2J, among all cancer types, was observed in GBM. Furthermore, high expression of POLR2J or its co-expressed genes predicted a poor outcome in GBM patients. DNA replication pathways were significantly enriched in the GBM clinical samples with high POLR2J expression, and POLR2J suppression inhibited proliferation and triggered cell cycle G1/S phase arrest in GBM cells. Moreover, POLR2J silencing activated the unfolded protein response (UPR) and significantly enhanced the anti-GBM activity of vorinostat by suppressing cell proliferation and inducing apoptosis. Additionally, POLR2J could interact with STAT3 to promote the metastatic potential of GBM cells. Our study identifies POLR2J as a novel oncogene in GBM progression and provides a promising strategy for the chemotherapeutic treatment of GBM.
RESUMEN
BACKGROUND: The population of people with dementia increases yearly, imposing a growing burden on family caregivers. Psychological distress impacts the mental health of family caregivers of people with dementia. Caregiver psychological distress can result in increased social resource utilisation and unmet multicare needs. PURPOSE: The study explored the psychological distress of family caregivers of people with dementia and examined the impact on social resource utilisation and multicare needs. METHODS: A descriptive-correlational study collected data in Taiwan from a cross-sectional sample of family caregivers of people with dementia using a self-report questionnaire. Data were analysed using linear and logistic regression. RESULTS: A total of 301 caregivers provided data for analysis. Nearly two-thirds of caregivers were female with a mean age of 57 years old (SD = 12). Over half of the family caregivers of people with dementia experienced mild-to-moderate psychological distress. The greater the psychological distress, the greater the probability of using social resources (1.09 times per 1-point increase, p = 0.002). Psychological distress was positively associated with the number of caregivers' care needs (ß = 0.371, p < 0.001). CONCLUSIONS: Findings of this study can assist healthcare professionals in better understanding the psychological distress and care needs of caregivers. Services designed to meet the needs of family caregivers will improve psychological distress.
Asunto(s)
Cuidadores , Demencia , Distrés Psicológico , Humanos , Femenino , Cuidadores/psicología , Masculino , Demencia/enfermería , Demencia/psicología , Persona de Mediana Edad , Estudios Transversales , Taiwán , Anciano , Encuestas y Cuestionarios , Adulto , Apoyo Social , Estrés PsicológicoRESUMEN
BACKGROUND: Cucurbita pepo cv Dayangua (CPD) is an edible plant with diverse pharmacological properties. The current research on CPD has primarily focused on initial investigations of its chemical composition and pharmacological effects, and no comprehensive toxicity assessment has been conducted to date. METHODS: In the present study, the toxicity of CPD was evaluated through both acute and sub-chronic oral toxicity tests in mice. 16S rDNA sequencing was used to analyze the composition of the gut microbiota of mice at different time points to observe the effect of CPD on these microbial communities. RESULTS: In the acute toxicity test, CPD exhibited low toxicity, with a median lethal dose (LD50) > 2000 mg/kg. The sub-chronic toxicity test indicated that CPD administration at doses of 200, 400, and 600 mg/kg did not cause mortality or significant organ damage in mice. Furthermore, analysis of the gut microbiota after gavage administration of CPD at 400 and 600 mg/kg revealed an improved abundance of some beneficial gut bacteria. CONCLUSIONS: In summary, no acute or sub-chronic toxic effects were observed in mice following the oral administration of CPD. CPD did not affect the structure and diversity of the gut microbiota and may contribute to an increase in the number of beneficial gut bacteria.
Asunto(s)
Cucurbita , Microbioma Gastrointestinal , Animales , Microbioma Gastrointestinal/efectos de los fármacos , Ratones , Masculino , Extractos Vegetales/farmacología , Extractos Vegetales/toxicidad , Femenino , Pruebas de Toxicidad AgudaRESUMEN
The momentum distribution of photoelectrons in H2+ molecules subjected to an attosecond pulse is theoretically investigated. To better understand the laser-molecule interaction, we develop an in-line photoelectron holography approach that is analogous to optical holography. This approach is specifically suitable for extracting the amplitude and phase of the forward-scattered electron wave packet in a dissociating molecule with atomic precision. We also extend this approach to imaging the transient scattering cross-section of a molecule dressed by a near infrared laser field. This attosecond photoelectron holography sheds light on structural microscopy of dissociating molecules with high spatial-temporal resolution.
RESUMEN
Lung adenocarcinoma (LUAD), a type of non-small cell lung cancer (NSCLC), originates from not only bronchial epithelial cells but also alveolar type 2 (AT2) cells, which could differentiate into AT2-like cells. AT2-like cells function as cancer stem cells (CSCs) of LUAD tumorigenesis to give rise to adenocarcinoma. However, the mechanism underlying AT2 cell differentiation into AT2-like cells in LUAD remains unknown. We analyze genes differentially expressed and genes with significantly different survival curves in LUAD, and the combination of these two analyses yields 147 differential genes, in which 14 differentially expressed genes were enriched in cell cycle pathway. We next analyze the protein levels of these genes in LUAD and find that Cyclin-A2 (CCNA2) is closely associated with LUAD tumorigenesis. Unexpectedly, high CCNA2 expression in LUAD is restrictedly associated with smoking and independent of other driver mutations. Single-cell sequencing analyses reveal that CCNA2 is predominantly involved in AT2-like cell differentiation, while inhibition of CCNA2 significantly reverses smoking-induced AT2-like cell differentiation. Mechanistically, CCNA2 binding to CDK2 phosphorylates the AXIN1 complex, which in turn induces ubiquitination-dependent degradation of ß-catenin and inhibits the WNT signaling pathway, thereby failing AT2 cell maintenance. These results uncover smoking-induced CCNA2 overexpression and subsequent WNT/ß-catenin signaling inactivation as a hitherto uncharacterized mechanism controlling AT2 cell differentiation and LUAD tumorigenesis.
Asunto(s)
Adenocarcinoma del Pulmón , Carcinogénesis , Diferenciación Celular , Ciclina A2 , Neoplasias Pulmonares , Fumar , Animales , Femenino , Humanos , Masculino , Ratones , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/patología , Adenocarcinoma del Pulmón/metabolismo , Células Epiteliales Alveolares/metabolismo , Células Epiteliales Alveolares/patología , beta Catenina/metabolismo , beta Catenina/genética , Carcinogénesis/genética , Línea Celular Tumoral , Ciclina A2/genética , Ciclina A2/metabolismo , Quinasa 2 Dependiente de la Ciclina/genética , Quinasa 2 Dependiente de la Ciclina/metabolismo , Regulación Neoplásica de la Expresión Génica , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Células Madre Neoplásicas/patología , Células Madre Neoplásicas/metabolismo , Fumar/efectos adversos , Vía de Señalización Wnt/genética , RatasRESUMEN
Acute mountain sickness (AMS) is a common ailment in high-altitude areas caused by the body's inadequate adaptation to low-pressure, low-oxygen environments, leading to organ edema, oxidative stress, and impaired intestinal barrier function. The gastrointestinal tract, being the first to be affected by ischemia and hypoxia, is highly susceptible to injury. This study investigates the role of Lactobacillus delbrueckii subsp. bulgaricus in alleviating acute hypoxic-induced intestinal and tissue damage from the perspective of daily consumed lactic acid bacteria. An acute hypoxia mouse model was established to evaluate tissue injury, oxidative stress, inflammatory responses, and intestinal barrier function in various groups of mice. The results indicate that strain 4L3 significantly mitigated brain and lung edema caused by hypoxia, improved colonic tissue damage, and effectively increased the content of tight junction proteins in the ileum, reducing ileal permeability and alleviating mechanical barrier damage in the intestines due to acute hypoxia. Additionally, 4L3 helped to rebalance the intestinal microbiota. In summary, this study found that Lactobacillus delbrueckii subsp. bulgaricus strain 4L3 could alleviate acute intestinal damage caused by hypoxia, thereby reducing hypoxic stress. This suggests that probiotic lactic acid bacteria that exert beneficial effects in the intestines may alleviate acute injury under hypoxic conditions in mice, offering new insights for the prevention and treatment of AMS.
Asunto(s)
Modelos Animales de Enfermedad , Microbioma Gastrointestinal , Hipoxia , Lactobacillus delbrueckii , Estrés Oxidativo , Probióticos , Animales , Ratones , Hipoxia/complicaciones , Probióticos/farmacología , Masculino , Mal de Altura/microbiología , Mal de Altura/complicaciones , Proteínas de Uniones Estrechas/metabolismoRESUMEN
Background: understanding the effects of coexposure to compound extreme events, such as air pollution and extreme heat, is important for reducing current and future health burdens. This study investigated the independent and synergistic effects of exposure to air pollution from vegetation fires and extreme heat on all-cause mortality in Upper Northern Thailand. Methods: we used a time-stratified case-crossover study design with a conditional quasi-Poisson model to examine the association between mortality and coexposure to air pollution due to vegetation fire events (fire-PM2.5) and extreme heat. Extreme heat days were defined using the 90th and 99th percentile thresholds for daily maximum temperature. Results: we observed a significant positive excess risk of mortality due to independent exposure to fire-PM2.5 and extreme heat, but not an interactive effect. All-cause mortality risk increased by 0.9% (95% confidence interval (CI): 0.1, 1.8) for each 10 µg/m3 increase in fire-PM2.5 on the same day and by 12.8% (95% CI: 10.5, 15.1) on extreme heat days (90th percentile) relative to nonextreme heat days. Conclusion: this study showed that exposure to PM2.5 from vegetation fires and extreme heat independently increased all-cause mortality risk in UNT. However, there was no evidence of a synergistic effect of these events.
Asunto(s)
Contaminación del Aire , Incendios , Tailandia , Humanos , Calor Extremo/efectos adversos , Contaminantes Atmosféricos , Material ParticuladoRESUMEN
The 16-subunit Constitutive Centromere-associated Network (CCAN)-based inner kinetochore is well-known for connecting centromeric chromatin to the spindle-binding outer kinetochore. Here, we report a non-canonical role for the inner kinetochore in directly regulating sister-chromatid cohesion at centromeres. We provide biochemical, X-ray crystal structure, and intracellular ectopic localization evidence that the inner kinetochore directly binds cohesin, a ring-shaped multi-subunit complex that holds sister chromatids together from S-phase until anaphase onset. This interaction is mediated by binding of the 5-subunit CENP-OPQUR sub-complex of CCAN to the Scc1-SA2 sub-complex of cohesin. Mutation in the CENP-U subunit of the CENP-OPQUR complex that abolishes its binding to the composite interface between Scc1 and SA2 weakens centromeric cohesion, leading to premature separation of sister chromatids during delayed metaphase. We further show that CENP-U competes with the cohesin release factor Wapl for binding the interface of Scc1-SA2, and that the cohesion-protecting role for CENP-U can be bypassed by depleting Wapl. Taken together, this study reveals an inner kinetochore-bound pool of cohesin, which strengthens centromeric sister-chromatid cohesion to resist metaphase spindle pulling forces.
Asunto(s)
Proteínas de Ciclo Celular , Centrómero , Cromátides , Proteínas Cromosómicas no Histona , Cinetocoros , Cinetocoros/metabolismo , Proteínas Cromosómicas no Histona/metabolismo , Proteínas Cromosómicas no Histona/genética , Humanos , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ciclo Celular/genética , Cromátides/metabolismo , Cromátides/genética , Centrómero/metabolismo , Cohesinas , Células HeLa , Unión Proteica , Cristalografía por Rayos XRESUMEN
Rhubarb is widely used in health care, but causing a great amount of rhein-containing herbal residue. Rhein with several toxicities might pollute environment, damage ecology and even hazard human health if left untreated. In this study, the degradation effects of bisulfite- (BS) and peroxymonosulfate- (PMS) based oxidation systems on rhein in rhubarb residue were compared and investigated. The effects of BS and PMS with two valence states of ferric ion (Fe) on the degradation of rhein in rhubarb residue were optimized for the selection of optimal oxidation system. The influences of reaction temperature, reaction time and initial pH on the removal of rhein under the optimal oxidation system were evaluated. The chemical profiles of rhubarb residue with and without oxidation process were compared by UPLC-QTOF-MS/MS, and the degradation effects were investigated by PLS-DA and S plot/OPLS-DA analysis. The results manifested that PMS showed relative higher efficiency than BS on the degradation of rhein. Moreover, Fe(III) promoted the degradation effect of PMS, demonstrated that Fe(III)/PMS is the optimal oxidation system to degrade rhein in rhubarb residue. Further studies indicated that the degradation of rhein by the Fe(III)/PMS oxidation system was accelerated with the prolong of reaction time and the elevation of reaction temperature, and also affected by the initial pH. More importantly, Fe(III)/PMS oxidation system could degrade rhein in rhubarb residue completely under the optimal conditions. In conclusion, Fe(III)/PMS oxidation system is a feasible method to treat rhein in rhubarb residue.