Three exonic variants in the PHEX gene cause aberrant splicing in a minigene assay.

Background: X-linked hypophosphatemia (XLH, OMIM 307800) is a rare phosphorus metabolism disorder caused by PHEX gene variants. Many variants simply classified as missense or nonsense variants were only analyzed at the DNA level. However, growing evidence indicates that some of these variants may alter pre-mRNA splicing, causing diseases. Therefore, this study aimed to use bioinformatics tools and a minigene assay to ascertain the effects of PHEX variations on pre-mRNA splicing. Methods: We analyzed 174 variants in the PHEX gene described as missense or nonsense variants. Finally, we selected eight candidate variants using bioinformatics tools to evaluate their effects on pre-mRNA splicing using a minigene assay system. The complementary DNA (cDNA) sequence for the PHEX gene (RefSeq NM_000444.6) serves as the basis for DNA variant numbering. Results: Of the eight candidate variants, three were found to cause abnormal splicing. Variants c.617T>G p.(Leu206Trp) and c.621T>A p.(Tyr207*) in exon 5 altered the splicing of pre-mRNA, owing to the activation of a cryptic splice site in exon 5, which produced an aberrant transcript lacking a part of exon 5, whereas variant c.1700G>C p.(Arg567Pro) in exon 16 led to the activation of a cryptic splice site in intron 16, resulting in a partial inclusion of intron 16. Conclusion: Our study employed a minigene system, which has a great degree of flexibility to assess abnormal splicing patterns under the circumstances of patient mRNA samples that are not available, to explore the impact of the exonic variants on pre-mRNA splicing. Based on the aforementioned experimental findings, we demonstrated the importance of analyzing exonic variants at the mRNA level.

Engineering carbon source division of labor for efficient α-carotene production in Corynebacterium glutamicum.

Effective utilization of glucose, xylose, and acetate, common carbon sources in lignocellulose hydrolysate, can boost biomanufacturing economics. However, carbon leaks into biomass biosynthesis pathways instead of the intended target product remain to be optimized. This study aimed to enhance α-carotene production by optimizing glucose, xylose, and acetate utilization in a high-efficiency Corynebacterium glutamicum cell factory. Heterologous xylose pathway expression in C. glutamicum resulted in strain m4, exhibiting a two-fold increase in α-carotene production from xylose compared to glucose. Xylose utilization was found to boost the biosynthesis of pyruvate and acetyl-CoA, essential precursors for carotenoid biosynthesis. Additionally, metabolic engineering including pck, pyc, ppc, and aceE deletion, completely disrupted the metabolic connection between glycolysis and the TCA cycle, further enhancing α-carotene production. This strategic intervention directed glucose and xylose primarily towards target chemical production, while acetate supplied essential metabolites for cell growth recovery. The engineered strain C. glutamicum m8 achieved 30 mg/g α-carotene, 67% higher than strain m4. In fed-batch fermentation, strain m8 produced 1802 mg/L of α-carotene, marking the highest titer reported to date in microbial fermentation. Moreover, it exhibited excellent performance in authentic lignocellulosic hydrolysate, producing 216 mg/L α-carotene, 1.45 times higher than the initial strain (m4). These labor-division strategies significantly contribute to the development of clean processes for producing various valuable chemicals from lignocellulosic resources.

Overexpression of arginase gene CAR1 renders yeast Saccharomyces cerevisiae acetic acid tolerance.

Acetic acid is a common inhibitor present in lignocellulose hydrolysate, which inhibits the ethanol production by yeast strains. Therefore, the cellulosic ethanol industry requires yeast strains that can tolerate acetic acid stress. Here we demonstrate that overexpressing a yeast native arginase-encoding gene, CAR1, renders Saccharomyces cerevisiae acetic acid tolerance. Specifically, ethanol yield increased by 27.3% in the CAR1-overexpressing strain compared to the control strain under 5.0 g/L acetic acid stress. The global intracellular amino acid level and compositions were further analyzed, and we found that CAR1 overexpression reduced the total amino acid content in response to acetic acid stress. Moreover, the CAR1 overexpressing strain showed increased ATP level and improved cell membrane integrity. Notably, we demonstrated that the effect of CAR1 overexpression was independent of the spermidine and proline metabolism, which indicates novel mechanisms for enhancing yeast stress tolerance. Our studies also suggest that CAR1 is a novel genetic element to be used in synthetic biology of yeast for efficient production of fuel ethanol.

Systems metabolic engineering of Corynebacterium glutamicum to assimilate formic acid for biomass accumulation and succinic acid production.

Formate as an ideal mediator between the physicochemical and biological realms can be obtained from electrochemical reduction of CO2 and used to produce bio-chemicals. Yet, limitations arise when employing natural formate-utilizing microorganisms due to restricted product range and low biomass yield. This study presents a breakthrough: engineered Corynebacterium glutamicum strains (L2-L4) through modular engineering. L2 incorporates the formate-tetrahydrofolate cycle and reverse glycine cleavage pathway, L3 enhances NAD(P)H regeneration, and L4 reinforces metabolic flux. Metabolic modeling elucidates C1 assimilation, guiding strain optimization for co-fermentation of formate and glucose. Strain L4 achieves an OD600 of 0.5 and produces 0.6 g/L succinic acid. 13C-labeled formate confirms C1 assimilation, and further laboratory evolution yields 1.3 g/L succinic acid. This study showcases a successful model for biologically assimilating formate in C. glutamicum that could be applied in C1-based biotechnological production, ultimately forming a formate-based bioeconomy.

Global transboundary transmission path and risk of Mpox revealed with Least Cost Path model.

OBJECTIVES: The recent surge of Mpox outbreaks in multiple countries has garnered global attention. As of July 12, 2023, there have been 88,288 reported cases of Mpox worldwide. Although genetic variation was not found to be the cause of the epidemic outbreak, the reasons for its rapid spread remain unclear. METHODS: Using the niche method, this study identified high-risk regions for Mpox and determined that human factors are the primary contributors to global risks. To further investigate, a travel network resistance surface was created based on various modes of transportation and was combined with sea, airline, highway, and railway routes to construct the least cost path for human travel networks in different risk areas. RESULTS: The results indicated that high-risk regions for Mpox are mainly concentrated in Europe and the United States, with large risk ranges and high-risk values. The least cost path revealed three primary transmission paths rely on developed transportation networks, including internal transmission in North America, Europe-Africa, and Europe-Asia-Africa. These findings suggest that human activities, facilitated by developed travel networks, remain the main contributing factor to the spread. CONCLUSIONS: In summary, based on the Mpox epidemic report, this study conducted risk prediction and driving factor analysis on Mpox. The research results indicate that human use of transportation for long-distance activities is a key factor leading to the rapid spread of the virus. Subsequently, we focused on studying the global transmission pathways of Mpox and revealed several transmission pathways with high global population migration rates by constructing the LCPs between different high-risk areas. This study also emphasizes the importance of applying early monitoring data of Mpox to model risk prediction in controlling emerging infectious diseases, providing a new perspective for controlling Mpox and similar diseases.

Anaerobic digestion integrated with microbial electrolysis cell to enhance biogas production and upgrading in situ.

Anaerobic digestion (AD) is an effective and applicable technology for treating organic wastes to recover bioenergy, but it is limited by various drawbacks, such as long start-up time for establishing a stable process, the toxicity of accumulated volatile fatty acids and ammonia nitrogen to methanogens resulting in extremely low biogas productivities, and a large amount of impurities in biogas for upgrading thereafter with high cost. Microbial electrolysis cell (MEC) is a device developed for electrosynthesis from organic wastes by electroactive microorganisms, but MEC alone is not practical for production at large scales. When AD is integrated with MEC, not only can biogas production be enhanced substantially, but also upgrading of the biogas product performed in situ. In this critical review, the state-of-the-art progress in developing AD-MEC systems is commented, and fundamentals underlying methanogenesis and bioelectrochemical reactions, technological innovations with electrode materials and configurations, designs and applications of AD-MEC systems, and strategies for their enhancement, such as driving the MEC device by electricity that is generated by burning the biogas to improve their energy efficiencies, are specifically addressed. Moreover, perspectives and challenges for the scale up of AD-MEC systems are highlighted for in-depth studies in the future to further improve their performance.

Enhancing low-concentration cell detection in single entity electrochemical systems through forced convection.

This study advances the detection of bacteria at low concentrations in single-entity electrochemistry (SEE) systems by integrating forced convection. Our results show that forced convection significantly improves the mass transfer rate of electrolyte, with the mass transfer coefficient demonstrating a proportional relationship to the flow rate to the power of 1.37. Notably, while the collision frequency of E. coli initially increases with the flow rate, a subsequent decrease is observed at higher rates. This pattern is attributed to the mechanics of cell collision under forced convection. Specifically, while forced convection propels cells towards the ultra-microelectrode (UME), it does not aid in their penetration through the boundary layer, leading to cells being driven away from the UME at higher flow rates. This hypothesis is supported by the statistical analysis of collision data, including signal heights and rise times. By optimizing the flow rate to 2 mL/min, we achieved enhanced detection of E. coli in concentrations ranging from 0.9 × 107 to 5.0 × 107 cells/mL. This approach significantly increased collision frequency by elevating the mass transfer of cells, with the mass transfer coefficient rising from 0.1 × 10-5 m/s to 0.9 × 10-5 m/s. It provides a viable solution to the challenges of detecting bacteria at low concentrations in SEE systems.

Tick-borne Rickettsia, Anaplasma, Theileria, and enzootic nasal tumor virus in ruminant, PET, and poultry animals in Pakistan.

Introduction: Pakistan is an agricultural country; most of its income is based on livestock rearing. The increasing prevalence of tick-borne pathogens among animals may affect the animal production and livelihood of owners, which eventually derange the economy of a country. Methodology: To further comprehend TBPs, 213 ticks were collected from different animals, including ruminants, pets, and poultry. After molecular and phylogenetic analysis identification, ticks were managed into different pools based on their species level (Hyalomma anatolicum = 80, Rhipicephalus microplus = 35, Hyalomma scupense = 23, Rhipicephalus turanicus = 70, and Rhipicephalus sanguineus = 5). Results and discussion: After tick species identification, further molecular PCR amplification was carried out to screen out the pathogens for the presence of Theileria, Rickettsia, Anaplasma, and enzootic nasal tumor virus (ENTV). The following pathogens were detected: 11 (5.16%) for Anaplasma, 1 (0.47%) for Rickettsia, and 9 (4.23%) for Theileria. Nevertheless, other TBPs that had not been reported so far in Pakistan 3 (1.41%), were positive for enzootic nasal tumor virus (ENTV). Besides, phylogenetic analysis of the enzootic nasal tumor virus (ENTV) strain confirmed its resemblance to the Chinese strain, while Anaplasma has comparability with Pakistan and China, Rickettsia with Pakistan, China, and Iran, and Theileria with India, South Africa, United States, Japan, and Spain. Conclusion: This study reveals that there is a considerably wider range of TBPs held in Pakistan that take in various contagious zoonotic pathogens than was previously thought. This information advances TBP epidemiology and will contribute to upgrade future control measure.

Transcriptome analysis of Kluyveromyces marxianus under succinic acid stress and development of robust strains.

Kluyveromyces marxianus has become an attractive non-conventional yeast cell factory due to its advantageous properties such as high thermal tolerance and rapid growth. Succinic acid (SA) is an important platform molecule that has been applied in various industries such as food, material, cosmetics, and pharmaceuticals. SA bioproduction may be compromised by its toxicity. Besides, metabolite-responsive promoters are known to be important for dynamic control of gene transcription. Therefore, studies on global gene transcription under various SA concentrations are of great importance. Here, comparative transcriptome changes of K. marxianus exposed to various concentrations of SA were analyzed. Enrichment and analysis of gene clusters revealed repression of the tricarboxylic acid cycle and glyoxylate cycle, also activation of the glycolysis pathway and genes related to ergosterol synthesis. Based on the analyses, potential SA-responsive promoters were investigated, among which the promoter strength of IMTCP2 and KLMA_50231 increased 43.4% and 154.7% in response to 15 g/L SA. In addition, overexpression of the transcription factors Gcr1, Upc2, and Ndt80 significantly increased growth under SA stress. Our results benefit understanding SA toxicity mechanisms and the development of robust yeast for organic acid production. KEY POINTS: • Global gene transcription of K. marxianus is changed by succinic acid (SA) • Promoter activities of IMTCP2 and KLMA_50123 are regulated by SA • Overexpression of Gcr1, Upc2, and Ndt80 enhanced SA tolerance.

Comparison of patient-controlled analgesia and sedation (PCAS) with remifentanil and propofol versus total intravenous anesthesia (TIVA) with midazolam, fentanyl, and propofol for colonoscopy.

BACKGROUND: Colonoscopy is a commonly performed gastroenterological procedure in patients associated with anxiety and pain. Various approaches have been used to provide sedation and analgesia during colonoscopy, including patient-controlled analgesia and sedation (PCAS). This study aims to evaluate the feasibility and efficiency of PCAS administered with propofol and remifentanil for colonoscopy. METHODS: This randomized controlled trial was performed in an authorized and approved endoscopy center. A total of 80 outpatients were recruited for the colonoscopy studies. Patients were randomly allocated into PCAS and total intravenous anesthesia (TIVA) groups. In the PCAS group, the dose of 0.1 ml/kg/min of the mixture was injected after an initial bolus of 3 ml mixture (1 ml containing 3 mg of propofol and 10 µg of remifentanil). Each 1 ml of bolus was delivered with a lockout time of 1 min. In the TIVA group, patients were administered fentanyl 1 µg/kg, midazolam 0.02 mg/kg, and propofol (dosage titrated). Cardiorespiratory parameters and auditory evoked response index were continuously monitored during the procedure. The recovery from anesthesia was assessed using the Aldrete scale and the Observer's Assessment of Alertness/Sedation Scale. The Visual Analogue Scale was used to assess the satisfaction of patients and endoscopists. RESULTS: No statistical differences were observed in the Visual Analogue Scale scores of the patients (9.58 vs 9.50) and the endoscopist (9.43 vs 9.30). A significant decline in the mean arterial blood pressure, heart rate, and auditory evoked response index parameters was recorded in the TIVA group (P < 0.05). The recovery time was significantly shorter in the PCAS group than in the TIVA group (P = 0.00). CONCLUSION: The combination of remifentanil and propofol could provide sufficient analgesia, better hemodynamic stability, lighter sedation, and faster recovery in the PCAS group of patients compared with the TIVA group.

A novel heterozygous variant of the SALL1 gene with atypical Townes-Brocks syndrome phenotypes in Chinese family.

Townes-Brocks syndrome (TBS) is an autosomal dominant disorder characterised by the triad of anorectal, thumb, and ear malformations. It may also be accompanied by defects in kidney, heart, eyes, hearing, and feet. TBS has been demonstrated to result from heterozygous variants in the SALL1 gene, which encodes zinc finger protein believed to function as a transcriptional repressor. The clinical characteristics of an atypical TBS phenotype patient from a Chinese family are described, with predominant manifestations including external ear dysplasia, unilateral renal hypoplasia with mild renal dysfunction, and hearing impairment. A novel heterozygous variant c.3060T>A (p.Tyr1020*) in exon 2 of the SALL1 gene was identified in this proband. Pyrosequencing of the complementary DNA of the proband revealed that the variant transcript accounted for 48% of the total transcripts in peripheral leukocytes, indicating that this variant transcript has not undergone nonsense-mediated mRNA decay. This variant c.3060T > A is located at the terminal end of exon 2, proximal to the 3' end of the SALL1 gene, and exerts a relatively minor impact on protein function. We suggest that the atypical TBS phenotype observed in the proband may be attributed to the truncated protein retaining partial SALL1 function.

Causal effects of glycemic traits and endometriosis: a bidirectional and multivariate mendelian randomization study.

BACKGROUND: Observational studies have suggested an association between endometriosis and glycemic traits, but causality remains unclear. We used bidirectional and multivariate Mendelian randomization (MR) to examine the causal effect of glycemic traits on endometriosis and vice versa. METHODS: We obtained genome-wide association studies summary data of endometriosis and glycemic traits in our study. Inverse variance weighted (IVW), Weighted median, MR-Egger and Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) were applied in bidirectional two-sample MR analyses. MVMR was implemented to estimate the causal effect for fasting insulin (FI), fasting glucose (FG), and glycosylated hemoglobin A1c (HbA1c) on endometriosis. To test the validity of our findings, a number of sensitivity analyses were conducted. RESULTS: The risk of endometriosis was significantly increased by genetically predicted T1DM (OR = 1.02, 95% CI 1.00-1.04, p = 0.0171, q = 0.0556) and GDM (OR = 1.01, 95% CI 1.01-1.02, p = 1.34 × 10- 8, q = 1.74 × 10- 7). Endometriosis had a suggestive association with HbA1c (Beta = 0.04, 95% CI 0.00-0.08, p = 0.0481, q = 0.1251). Using multivariate Mendelian randomization (MVMR), a significant causal effect of FI on genetically predicted endometriosis was found (OR = 2.18, 95% CI 1.16-4.09, p = 0.0154, q = 0.0547). Moreover, no causal associations between endometriosis and other glycemic traits were detected. CONCLUSION: Our findings supported the significant causal associations of T1DM, GDM and FI with endometriosis, respectively. Additionally, a suggestive association was found of endometriosis on HbA1c. Importantly, our study may shed light on etiology studies and clinical management of endometriosis.

Novel Roles of the Greatwall Kinase Rim15 in Yeast Oxidative Stress Tolerance through Mediating Antioxidant Systems and Transcriptional Regulation.

The Greatwall-family protein kinase Rim15 is associated with the nutrient starvation response, whereas its role in oxidative stress responses remains unclear. Here, acetic acid and peroxide were used as two oxidative stress elicitors. The antioxidant indicator assay under acetic acid stress revealed the impaired growth in rim15Δ related to the regulation of antioxidant systems. Comparative transcriptome analysis revealed that differentially expressed genes (DEGs) are predicted to be mostly regulated by oxidative stress-responsive transcriptional factor Yap1. Among the DEGs, acetic acid stress-induced genes were found, and YAP1 disruption also inhibited their induction. The deletion of Rim15 or the Rim15 kinase domain in yap1Δ did not further decrease the gene expression, suggesting that Rim15 functions together with Yap1 in regulating acetic acid stress-induced genes, which requires Rim15 kinase activity. Additionally, Rim15 regulated H2O2 stress tolerance through partially similar but special mechanisms in that Rim15 kinase activity impacted acetic acid and H2O2 stress tolerance in different degrees, indicating the different mechanisms underlying Rim15-mediated redox regulation against different stressors. These results benefit the better understanding of stress signaling pathways related to Rim15. Given that Rim15 and some of its target genes are conserved across eukaryotes, these results also provide a basis for studies of oxidative stress-related processes in other organisms.

[Clinical outcomes and bone resection analysis of unilateral double-channel endoscopic technique in treating lumbar disc herniation].

OBJECTIVE: To explore clinical outcomes and bone resection of interlaminar fenestration decompression and unilateral biportal endoscopic (UBE) technique in treating lumbar disc herniation(LDH). METHODS: A retrospective study was performed on 105 patients with single-level LDH treated from December 2019 to December 2021. Fifty-four patients in UBE group,including 32 males and 22 females,aged from 18 to 50 years old with an average of(38.7±9.3) years old,were treated with UBE,29 patients with L4,5 and 25 patients with L5S1. There were 51 patients in small fenestration group,including 27 males and 24 females,aged from 18 to 50 years old with an average of (39.9±10.0) years old,were treated with small fenestration,25 patients with L4,5 and 26 patients with L5S1. Perioperative indexes,such as operation time,postoperative time of getting out of bed and hospital stay were observed and compared between two groups. Visual analogue scale (VAS) and Oswestry disability index (ODI) were compared between two groups before operation and 1,3,6 and 12 months after operation,respectively;and modified MacNab evaluation criteria was used to evaluate clinical efficacy. Amount of bone resection and retention rate of inferior articular process laminoid complex were compared between two groups. RESULTS: All 105 patients were successfully completed operation. Both of two groups were followed up from 6 to 12 months with an average of (10.69±2.49) months. Operation time,postoperative time of getting out of bed and hospital stay were (58.20±5.54) min,(2.40±0.57) d and (3.80±0.61) d in UBE group,and (62.90±7.14) min,(4.40±0.64) d and (4.40±0.64) d in small fenestrum group,respectively;and had statistically difference between two groups(P<0.05). Postoperative VAS of low back and leg pain and ODI in both groups were significantly lower than those before surgery (P<0.05). VAS of lumbar pain in UBE group (1.37±0.49) score was lower than that of small fenestration group (2.45±0.64) score,and had statistically difference (t=9.745,P<0.05). Postoperative ODI in UBE group at 1 and 3 months were (28.54±3.31) % and (22.87±3.23) %,respectively,which were lower than those in small fenestra group (36.31±9.08) % and (29.90±8.36) %,and the difference was statistically significant (P<0.05). There were no significant difference in VAS and ODI between two groups at other time points (P>0.05). According to the modified MacNab evaluation criteria at the latest follow-up,49 patients got excellent result,3 good,and 2 fair in UBE group. In small fenestration group,35 patients got excellent,12 good,and 4 fair. In UBE group,amount of bone resection on L4,5 segment was (0.45±0.08) cm3 and (0.31±0.08) cm3 on the segment of L5S1. In small fenestration group,amount of bone resection on L4,5 segment was (0.57±0.07) cm3 and (0.49±0.04) cm3 on the segment of L5S1,and amount of bone resection of lower articular process laminar complex on the same segment in UBE group was less than that in small fenestration group (P<0.05). In UBE group,retention rate of laminoid complex on L4,5 segment was (0.73±0.04) and L5S1 segment was (0.83±0.03),while L4,5 segment was(0.68±0.06) and L5S1 segment was (0.74±0.04) in small fenestration group,the lower articular process laminar complex retention rate in UBE group was higher than that in small fenestration group(P<0.05). CONCLUSION: Both unilateral double-channel endoscopy and small fenestration of laminae could achieve good clinical results in treating LDH,but UBE has advantages of less trauma,higher efficiency,faster postoperative recovery and less damage to bone structure.

Differential Protein Expression in Set5p-Mediated Acetic Acid Stress Response and Novel Targets for Engineering Yeast Stress Tolerance.

Acetic acid is a prevalent inhibitor in lignocellulosic hydrolysate, which represses microbial growth and bioproduction. Histone modification and chromatin remodeling have been revealed to be critical for regulating eukaryotic metabolism. However, related studies in chronic acetic acid stress responses remain unclear. Our previous studies revealed that overexpression of the histone H4 methyltransferase Set5p enhanced acetic acid stress tolerance of the budding yeast Saccharomyces cerevisiae. In this study, we examined the role of Set5p in acetic acid stress by analyzing global protein expression. Significant activation of intracellular protein expression under the stress was discovered, and the functions of the differential proteins were mainly involved in chromatin modification, signal transduction, and carbohydrate metabolism. Notably, a substantial increase of Set5p expression was observed in response to acetic acid stress. Functional studies demonstrated that the restriction of the telomere capping protein Rtc3p, as well as Ies3p and Taf14p, which are related to chromatin regulation, was critical for yeast stress response. This study enriches the understanding of the epigenetic regulatory mechanisms underlying yeast stress response mediated by histone-modifying enzymes. The results also benefit the development of robust yeast strains for lignocellulosic bioconversion.

[Inhibitory Effect of Metformin and Arsenic Trioxide on KG1a Cell Proliferation].

OBJECTIVE: To investigate the effect of metformin and arsenic trioxide on KG1a cells proliferation of acute myeloid leukemia and its possible mechanism. METHODS: CCK-8 method was used to detect the killing effect of metformin, arsenic trioxide and combined application on KG1a cells. Annexin V-FITC/PI Dual Stain Flow Cytometry was used to detect the effect of combined application on apoptosis of KG1a cells. Western blot was used to detect the expression of intracellular apoptosis-,autophagy-related protein. RESULTS: Metformin and arsenic trioxide alone or in combination could inhibit the proliferation of KG1a cells and induce apoptosis of KG1a cells, and the proliferation inhibition rate and apoptosis rate in the combined drug group were higher than those in the drug group alone(P <0.05). The combination of drugs induced upregulation of Caspase 8 protein and P62 protein expression and was higher than that in the drug group alone(P <0.05). CONCLUSION: Metformin can synergize with arsenic trioxide to kill KG1a cells, and its mechanism of action may be related to inducing apoptosis and enhancing autophagy.

MicroRNA-377-3p exacerbates chronic obstructive pulmonary disease through suppressing ZFP36L1 expression and inducing lung fibroblast senescence.

Chronic obstructive pulmonary disease (COPD) is a leading aging related cause of global mortality. Small airway narrowing is recognized as an early and significant factor for COPD development. Senescent fibroblasts were observed to accumulate in lung of COPD patients and promote COPD progression through aberrant extracellular matrix (ECM) deposition and senescence-associated secretory phenotype (SASP). On the basis of our previous study, we further investigated the the causes for the increased levels of miR-377-3p in the blood of COPD patients, as well as its regulatory function in the pathological progression of COPD. We found that the majority of up-regulated miR-377-3p was localized in lung fibroblasts. Inhibition of miR-377-3p improved chronic smoking-induced COPD in mice. Mechanistically, miR-377-3p promoted senescence of lung fibroblasts, while knockdown of miR-377-3p attenuated bleomycin-induced senescence in lung fibroblasts. We also identified ZFP36L1 as a direct target for miR-377-3p that likely mediated its pro senescence activity in lung fibroblasts. Our data reveal that miR-377-3p is crucial for COPD pathogenesis, and may serve as a potential target for COPD therapy.

Brain Source Localization and Functional Connectivity in Group Identity Regulation of Overbidding in Contest.

Contests may be highly effective in eliciting high levels of effort, but they also carry the risk of inefficient resource allocation due to excessive effort (overbidding), squandering valuable social resources. While a growing body of research has focused on how group identity exacerbates out-group conflict, its influence on in-group conflict remains relatively unexplored. This study endeavors to explore the impact of group identity on conflicts within and between groups in competitive environments, thereby addressing gaps in the current research landscape and dissecting the involved neurobiological mechanisms. By employing source localization and functional connectivity techniques, our research aims to identify the brain regions involved in competitive decision-making and group identity processes, as well as the functional connectivities between social brain areas. The results of our investigation revealed that participants exhibited activation in the bilateral frontal and prefrontal lobes during the bidding behavior before the group identity task. Subsequently, after the task, additional activation was observed in the right temporal lobe. Results from functional connectivity studies indicated that group identity tasks modify decision-making processes by promoting group norms, empathy, and blurred self-other boundaries for in-group decisions, while out-group decisions after the group identity task see heightened cognitive control, an increased dependence on rational judgment, introspection of self-environment relationships, and a greater focus on anticipating others' behaviors. This study reveals the widespread occurrence of overbidding behavior and demonstrates the role of group identity in mitigating this phenomenon, concurrently providing a comprehensive analysis of the underlying neural mechanisms.

Inhibition of piezo1 prevents chronic cerebral hypoperfusion-induced cognitive impairment and blood brain barrier disruption.

Chronic cerebral hypoperfusion (CCH) plays a critical role in the onset and progression of vascular dementia (VD), which is now recognized as the second most common form of dementia after Alzheimer's disease (AD). The mechanosensitive piezo1 channel has been identified to play important roles in several neurological disorders. However, the roles and possible mechanisms of piezo1 in CCH-induced cognitive decline and blood brain barrier (BBB) disruption, as well as the underlying mechanisms remain elusive. In this study, the CCH model was established by bilateral common carotid artery occlusion in rats and by oxygen and glucose deprivation/reoxygenation (OGD/R) in bEnd.3 cells. The results demonstrated that the antagonist of piezo1 GsMTx4 ameliorated CCH-induced cognitive dysfunction and mitigated cerebral edema. Furthermore, this study indicated that GsMTx4 improved the permeability and integrity of BBB and protected cerebral microvasculature after CCH. In vitro, GsMTx4 improved cell viability, promoted the ability of cell motility and migration, and inhibited the degradation of BBB integrity-related proteins by inhibiting NLRP3 inflammasome activation. In addition, NLRP3 agonist abolished the beneficial effects of GsMTx4. Collectively, our results demonstrate that piezo1 might be involved in CCH-induced cognitive impairment and BBB damage, which may be at least partially mediated through regulation of NLRP3 inflammasome.

Regulatory mechanisms underlying yeast chemical stress response and development of robust strains for bioproduction.

Yeast is widely studied in producing biofuels and biochemicals using renewable biomass. Among various yeasts, Saccharomyces cerevisiae has been particularly recognized as an important yeast cell factory. However, economic bioproduction using S. cerevisiae is challenged by harsh environments during fermentation, among which inhibitory chemicals in the culture media or toxic products are common experiences. Understanding the stress-responsive mechanisms is conducive to developing robust yeast strains. Here, we review recent progress in mechanisms underlying yeast stress response, including regulation of cell wall integrity, membrane transport, antioxidative system, and gene transcription. We highlight epigenetic regulation of stress response and summarize manipulation of yeast stress tolerance for improved bioproduction. Prospects in the application of machine learning to improve production efficiency are also discussed.