Structural basis and synergism of ATP and Na+ activation in bacterial K+ uptake system KtrAB.

The K+ uptake system KtrAB is essential for bacterial survival in low K+ environments. The activity of KtrAB is regulated by nucleotides and Na+. Previous studies proposed a putative gating mechanism of KtrB regulated by KtrA upon binding to ATP or ADP. However, how Na+ activates KtrAB and the Na+ binding site remain unknown. Here we present the cryo-EM structures of ATP- and ADP-bound KtrAB from Bacillus subtilis (BsKtrAB) both solved at 2.8 Å. A cryo-EM density at the intra-dimer interface of ATP-KtrA was identified as Na+, as supported by X-ray crystallography and ICP-MS. Thermostability assays and functional studies demonstrated that Na+ binding stabilizes the ATP-bound BsKtrAB complex and enhances its K+ flux activity. Comparing ATP- and ADP-BsKtrAB structures suggests that BsKtrB Arg417 and Phe91 serve as a channel gate. The synergism of ATP and Na+ in activating BsKtrAB is likely applicable to Na+-activated K+ channels in central nervous system.

Recalcitrant components accumulation in dissolved organic matter decreases microbial metabolic quotient of red soil under long-term manuring.

Microbial metabolism is closely related to soil carbon dioxide emissions, which in turn is related to environmental issues such as global warming. Dissolved organic matter (DOM) affects many fundamental biogeochemical processes such as microbial metabolism involved in soil carbon cycle, not only directly by its availability, but also indirectly by its chemodiversity. However, the association between the DOM chemodiversity and bioavailability remains unclear. To address this knowledge gap, soils from two agro-ecological experimental sites subjected to various long-term fertilizations in subtropical area was collected. The chemodiversity of DOM was detected by multi-spectroscopic techniques including ultraviolet-visible spectrophotometry, Fourier transform infrared spectroscopy and excitation emission matrices fluorescence spectroscopy. Results showed that long-term manure amendments significantly decreased microbial metabolic quotient (qCO2) by up to 57%. We also observed that long-term manure amendments significantly increased recalcitrant components of DOM (indicated by the aromaticity, humification index, the ratio of aromatic carbon to aliphatic carbon, and the relative abundances of humic-like components) and decreased labile components of DOM. Negatively correlation between the qCO2 and the proportion of recalcitrant components of DOM supported that accumulation in recalcitrant components of DOM increased microbial carbon utilization efficiency. Random forest models also showed the highest contribution of the relative abundances of humic-like components and the aromaticity of DOM in affecting qCO2. Both of the redundancy analysis and structural equation modeling further indicated the decisive role of soil pH in influencing the DOM chemodiversity. Soil pH explained 56.7% of the variation in the chemodiversity of DOM. The accumulation of recalcitrant components in DOM with increasing soil pH might be attributed to the accelerated microbial consumption of bioavailability components and/or to the negative impact on the solubility of bioavailability components. Overall, this research highlights the significance of long-term manure amendments in regulating qCO2 by altering the chemodiversity of soil DOM.

HELQ deficiency impairs the induction of primordial germ cell-like cells.

Helicase POLQ-like (HELQ) is a DNA helicase essential for the maintenance of genome stability. A recent study identified two HELQ missense mutations in some cases of infertile men. However, the functions of HELQ in the process of germline specification are not well known and whether its function is conserved between mouse and human remains unclear. Here, we revealed that Helq knockout (Helq-/-) could significantly reduce the efficiency of mouse primordial germ cell-like cell (PGCLC) induction. In addition, Helq-/- embryonic bodies exhibited a severe apoptotic phenotype on day 6 of mouse PGCLC induction. p53 inhibitor treatment could partially rescue the generation of mouse PGCLCs from Helq mutant mouse embryonic stem cells. Finally, the genetic ablation of HELQ could also significantly impede the induction of human PGCLCs. Collectively, our study sheds light on the involvement of HELQ in the induction of both mouse and human PGCLCs, providing new insights into the mechanisms underlying germline differentiation and the genetic studies of human fertility.

Physical activity and the risk of chronic obstructive pulmonary disease: A longitudinal follow-up study in Taiwan.

BACKGROUND: This study aimed to investigate whether physical activity (PA) is associated with a lower risk of subsequently developing chronic obstructive pulmonary disease (COPD). METHODS: We conducted this population-based longitudinal follow-up study in a community in Taiwan. This study recruited 61,446 subjects who had participated in the Keelung Community-based Integrated Screening Program (KCIS) between 2005 and 2012. During their participation in KCIS, they were provided with structured questionnaires to collect their baseline characteristics, including weekly PA time. After excluding subjects diagnosed with COPD before they joined KCIS and/or who provided incomplete lifestyle data, 59,457 subjects remained, and were classified into three groups based on their weekly PA time: i.e., as NPA (no regular PA), LPA (low PA, <90 min/week) and HPA (high PA, ≥90 min/week). The primary outcome was a new diagnosis of COPD, followed up until the end of 2015 or their death. Cox proportional-hazard regression was used to assess the impact of PA on the risk of COPD. RESULTS: The risk of COPD was more than 20% lower in the LPA and HPA groups than in the NPA group. Specifically, the adjusted hazard ratio for the risk of COPD was 0.72 in the LPA group (95% CI, 0.61-0.85, p < 0.001) and 0.79 in the HPA group (95% CI, 0.69-0.90, p < 0.001). CONCLUSIONS: Our research uncovered an inverse relationship between PA and COPD. The findings suggest that PA might be useful as a strategy for the primary prevention of COPD.

Effect of Intraperitoneal Instillation of Dexmedetomidine With Local Anesthetics in Laparoscopic Cholecystectomy: A Systematic Review and Meta-analysis of Randomized Trials.

OBJECTIVE: Dexmedetomidine (DEX) can strengthen the analgesic effects of local anesthetics (LAs) when used as an adjuvant through intrathecal, perineural, and intraperitoneal routes. Many studies have used intraperitoneal instillation of DEX with LAs in laparoscopic cholecystectomy (LC) to relieve postoperative pain. We performed a systematic review and meta-analysis to synthesize evidence of the efficacy and safety of intraperitoneal instillation of DEX as an adjuvant of LAs in patients undergoing LC. METHODS: A comprehensive literature search of the MEDLINE, PubMed, EMBASE, and Cochrane Library databases was performed to identify randomized controlled trials in which patients received intraperitoneal instillation of DEX combined with LAs during LC. A meta-analysis and sensitivity analysis of the results were conducted. We also performed a subgroup analysis to investigate the source of heterogeneity. The Egger test was used to check for publication bias. RESULTS: Eleven randomized controlled trials involving 890 patients were analyzed. We found that the addition of DEX to LAs significantly decreased pain scores at six postoperative time points (0.5, 1, 2, 4, 12, and 24 h) and significantly prolonged the time to the first analgesic request by patients. In addition, 24-hour postoperative analgesic consumption was decreased in the experimental group, and no significant difference in the incidence of nausea and vomiting was observed. CONCLUSION: Our findings indicate that intraperitoneal instillation of DEX with LAs can reduce postoperative pain and prolong the time to first request analgesia after LC.

Design and characterization of edible chitooligosaccharide/fish skin gelatin nanofiber-based hydrogel with antibacterial and antioxidant characteristics.

Antibacterial and active packaging materials have gained significant research attention in response to the growing interest in food packaging. In this investigation, we developed hydrogel packaging materials with antibacterial and antioxidant properties by incorporating chitooligosaccharide (COS) and fish skin gelatin (FSG) nanofiber membranes, which readily absorbed water and exhibited swelling characteristics. The nanofiber membranes were fabricated by electrospinning technology, embedding COS within FSG, and subsequently crosslinked through the Maillard reaction facilitated by the addition of glucose. The behavior of conductivity, viscosity, and surface tension in the spinning solutions was analyzed to understand their variation patterns. Scanning electron microscopy (SEM) results revealed that the crosslinked COS/FSG nanofiber membranes possessed a uniform yet disordered fiber structure, with the diameter of the nanofibers increasing as the COS content increased. Remarkably, when the COS content reached 25 %, the COS/FSG nanofiber membranes (CF-C-25) exhibited a suitable fiber diameter of 437.16 ± 63.20 nm. Furthermore, the thermal crosslinking process involving glucose supplementation enhanced the hydrophobicity of CF-C-25. Upon hydration, the CF-H-25 hydrogel displayed a distinctive porous structure, exhibiting a remarkable swelling rate of 954 %. Notably, the inclusion of COS significantly augmented the antibacterial and antioxidant properties of the hydrogel-based nanofiber membranes. CF-H-25 demonstrated an impressive growth inhibition of 90.56 ± 5.91 % against E. coli, coupled with excellent antioxidant capabilities. In continuation, we performed a comprehensive analysis of the total colony count, pH, TVB-N, and TBA of crucian carp. The CF-H-25 hydrogel proved highly effective in extending the shelf life of crucian carp by 2-4 days, suggesting its potential application as an edible membrane for aquatic product packaging.

Long-term liming mitigates the positive responses of soil carbon mineralization to warming and labile carbon input.

Liming, as a common amelioration practice worldwide, has the potential to alleviate soil acidification and ensure crop production. However, the impacts of long-term liming on the temperature sensitivity (Q10) of soil organic carbon (SOC) mineralization and its response to labile C input remain unclear. To fill the knowledge gap, soil samples were collected from a long-term (∼10 years) field trial with unlimed and limed (CaO) plots. These soil samples were incubated at 15 °C and 25 °C for 42 days, amended without and with 13C-labeled glucose. Results showed that compared to the unlimed soil (3.6-8.6 mg C g-1 SOC), liming increased SOC mineralization (6.1-11.2 mg C g-1 SOC). However, liming significantly mitigated the positive response of SOC mineralization to warming, resulting in a lower Q10. Long-term liming increased bacterial richness and Shannon diversity as well as their response to warming which were associated with the decreased Q10. Furthermore, the decreased Q10 due to liming was attributed to the decreased response of bacterial oligotrophs/copiotrophs ratio, ß-glucosidase and xylosidase activities to warming. Labile C addition had a strong impact on Q10 in the unlimed soil, but only a marginal influence in the limed soil. Overall, our research highlights that acidification amelioration by long-term liming has the potential to alleviate the positive response of SOC mineralization to warming and labile C input, thereby facilitating SOC stability in agroecosystems, especially for acidic soils in subtropical regions.

An approach to complex transboundary water management in Central Asia: Evolutionary cooperation in transboundary basins under the water-energy-food-ecosystem nexus.

Water-related issues in transboundary basins are generally complicated by the challenges of climate change, the historical evolution of the basin characteristics, and the different interests of the riparian countries. Therefore, dealing with water-sharing and water cooperation problems among basin countries needs to be based on multi-factor system analysis in the context of regional water, energy, food (land) resources, and ecosystems. In the present study, the Aral Sea basin in Central Asia, where transboundary water problems are extremely prominent and complex, was selected as the research area. Firstly, the characteristics of the water-energy-food-ecosystem nexus of the Aral Sea basin are analyzed. Then, based on the game theory, a multi-objective game model is constructed, and the multi-objective evolutionary game process and evolutionary stable strategies (ESSs) of both the upstream and downstream countries are explored. Finally, the evolutionary stable strategy under the intervention of the basin commission is simulated. The results show that there are obvious reciprocal feedbacks among water, land, energy, and ecosystem in the Aral Sea basin, and the uneven distribution of natural resources, fragile ecosystems, and conflicting demands of multiple actors lead to the unstable evolution of the nexus. Driven by the maximization of upstream and downstream countries' respective interests, the optimal stabilization strategy of the system cannot be realized. Whereas, the introduction of the basin commission intervention and its restraint mechanism is conducive to promoting cooperation and maximizing the overall benefits of the basin. The incentives and penalties of the basin commission have significant effects on whether the system can reach Pareto optimality, and higher incentive coefficient and penalty coefficient help the system converge to the ideal state more quickly. The evolution of the water-energy-food-ecosystem nexus based on the perspective of the whole basin can provide theoretical support for dealing with the transboundary water conflicts, and the cooperation strategy aiming at maximizing the overall benefits of the basin can provide decision-making basis for promoting transboundary water cooperation and synergistic development of the water-energy-food-ecosystem nexus.

A global dataset of biochar application effects on crop yield, soil properties, and greenhouse gas emissions.

Biochar application is widely studied to mitigate the threats of soil degradation to food security and climate change. However, there are big variations in the effects of biochar application on crops, soils, and the atmosphere during crop production. This study provides a global dataset of biochar application effects on crop yield, soil properties, and greenhouse emissions. The dataset is extracted and integrated from 367 peer-reviewed studies with 891 independent field, laboratory, and incubation experiments across 37 countries. This dataset includes 21 variables before and after biochar application (including soil properties, crop yield, greenhouse gas emissions, etc.) of 2438 items, focusing on two main biochar application types: biochar application alone and combined with fertilizers. Background information on climate conditions, initial soil properties, management practices, and characteristics of biochar sources and production is also contained in the dataset. This dataset facilitates a comprehensive understanding of the impact of biochar application, supports the utilization of agricultural wastes for biochar production, and assists researchers in refining experimental protocols for further studies.

Cardiac toxicity of brentuximab vedotin: a real-word disproportionality analysis of the FDA Adverse Event Reporting System (FAERS) database.

Brentuximab vedotin (BV) has obtained approval for the therapeutic management of classical Hodgkin lymphoma as well as systemic anaplastic large cell lymphoma. Given the inherent constraints of conventional clinical trials, the correlation between BV and cardiac adverse events (AEs) remains enigmatic. The objective of this investigation is to comprehensively assess cardiac AEs attributed to BV by employing advanced data mining techniques, utilizing the FDA Adverse Event Reporting System (FAERS). The indices for the assessment of disproportionality encompass the reporting odds ratio (ROR), the proportional reporting ratio, the information component, and the empirical Bayesian geometric mean. Employing these sophisticated metrics, we gauged the extent of disproportionate occurrences. The dataset was sourced from the FAERS from the first quarter of 2012 to first quarter of 2023, facilitating a comprehensive analysis of the potential correlation between BV and cardiac AEs. This scrutiny encompassed a comparative analysis of both cardiac and non-cardiac AEs. A total of 495 cases of BV's cardiac AEs were discerned, with the identification of 31 preferred terms (PTs). Among these, 8 PTs emerged as conspicuous signals of cardiac AEs, notably encompassing ventricular hypokinesia (ROR 7.59), tachyarrhythmia (ROR 7.06), sinus tachycardia (ROR 6.18), cardiopulmonary failure (ROR 4.44), pericardial effusion (ROR 4.32), acute coronary syndrome (ROR 4.02), cardiomyopathy (ROR 3.30), and tachycardia (ROR 2.76). The manifestation of severe outcomes demonstrates a discernible correlation with the cardiac AEs (P < 0.001). Our investigation furnishes invaluable insights for healthcare practitioners to proactively mitigate the incidence of BV-associated cardiac AEs.

Lactobacillus plantarum supernatant inhibits growth of Riemerella anatipestifer and mediates intestinal antimicrobial defense in Muscovy ducks.

Riemerella anatipestifer (RA) is an important pathogen of waterfowl, with multiple serotypes and a lack of cross-protection between each serotype, which leads to the continued widespread in the world and causing significant economic losses to the duck industry. Thus, prevention and inhibition of RA infection are of great concern. Previous research has established that Lactobacillus plantarum supernatant (LPS) can prevents the pathogenic bacteria infection. However, LPS whether inhibits RA and underlying mechanisms have not yet been clarified. In this study, we investigated the direct and indirect effects of LPS-ZG7 against RA infection in Muscovy ducks. The results demonstrated that LPS-ZG7 prevented RA growth in the presence of pH-neutralized, and the inhibition was relatively stable and unaffected by heat, acid-base and ultraviolet light (UV). Following flow cytometry data found that LPS-ZG7 increased RA membrane permeability and leakage of intracellular molecules. And scanning electron microscopy revealed LPS-ZG7 damaged the RA membrane integrity and leading to RA death. Furthermore, quantitative real time polymerase chain reaction (qPCR) analysis represented that LPS-ZG7 upregulated mucosal tight junction proteins occludin, claudin-1, and Zo-1 in Muscovy ducks, and increasing mucosal transport channels SGLT-1, PepT1, AQP2, AQP3, and AQP10 in duodenum, jejunum, and colon, then decreased the intestinal permeability and intestinal barrier disruption which were caused from RA. From the data, it is apparent that LPS-ZG7 enhanced intestinal mucosal integrity by rising villus height, villus height-to-crypt depth ratio and lower crypt depth. LPS-ZG7 significantly decreased intestinal epithelia cells apoptosis caused by RA invasion, and enhanced intestinal permeability and contribute to barrier dysfunction, ultimately improving intestinal health of host, indirectly leading to reduce diarrhea rate and mortality caused by RA. Overall, this study strengthens the idea that LPS-ZG7 directly inhibited the RA growth by increased RA membrane permeability and damaged the RA membrane integrity, and then indirectly enhanced intestinal mucosal integrity, improved intestinal health of host and mediated intestinal antimicrobial defense.

MdMYB66 Is Associated with Anthocyanin Biosynthesis via the Activation of the MdF3H Promoter in the Fruit Skin of an Apple Bud Mutant.

Skin color is an important trait that is mainly determined by the content and composition of anthocyanins in apples. In this study, a new bud mutant (RM) from 'Oregon Spur II' (OS) of Red Delicious apple was obtained to reveal the mechanism underlying red color formation. Results showed that the total anthocyanin content in RM was significantly higher than that in OS with the development of fruit. Through widely-targeted metabolomics, we found that cyanidin-3-O-galactoside was significantly accumulated in the fruit skin of RM. Transcriptome analysis revealed that the structural gene MdF3H and MdMYB66 transcription factor were significantly up-regulated in the mutant. Overexpression of MdMYB66 in apple fruit and apple callus significantly promoted anthocyanin accumulation and significantly increased the expression level of MdMYB66 and structural genes related to anthocyanin synthesis. Y1H and LUC analysis verified that MdMYB66 could specifically bind to the promoter of MdF3H. The results of the double luciferase activity test showed that MdMYB66 activated MdF3H 3.8 times, which led to increased anthocyanin contents. This might explain the phenotype of red color in RM at the early stage. Taken together, these results suggested that MdMYB66 was involved in regulating the anthocyanin metabolic pathways through precise regulation of gene expression. The functional characterization of MdMYB66 provides insight into the biosynthesis and regulation of anthocyanins.

Recognition of small faults in coal fields based on multi-scale seismic curvature attributes fusion.

In order to meet the needs of intelligent development of coal mines in China for transparency of geological conditions, identifying small faults with a drop of about 3 m has become one of the important geological tasks in structural interpretation. However, the accuracy of conventional 3D seismic exploration data interpretation methods for detecting small faults is still low. On the basis of introducing the basic principles of S-transform time-frequency analysis, principal component analysis, and RGB fusion, this paper proposes a method for identifying small faults in coal fields using multi-scale seismic curvature attribute fusion. The method uses S-transform to perform time frequency analysis to obtain seismic data volumes with multiple frequencies and seismic data volumes at different frequencies correspond to different scales of underground geological information portrayal. Perform spectral analysis on seismic data, determine parameters such as the dominant frequency and frequency bandwidth of seismic signals, and extract the maximum positive curvature attributes of seismic data volumes at different frequencies. Then the principal component analysis (PCA) method is used to analyze the seismic attributes of different frequency seismic data, the GRB fusion method is used to fuse the first three principal components. The application results of actual seismic data show that the results of multi-scale seismic curvature attribute fusion have obvious advantages in identifying small faults, and can improve the accuracy and interpretation accuracy of small faults in seismic data.

Heat shock protein DNAJA2 regulates transcription-coupled repair by triggering CSB degradation via chaperone-mediated autophagy.

Transcription-coupled nucleotide excision repair (TC-NER) is an important genome maintenance system that preferentially removes DNA lesions on the transcribed strand of actively transcribed genes, including non-coding genes. TC-NER involves lesion recognition by the initiation complex consisting of RNA polymerase II (Pol II) and Cockayne syndrome group B (CSB), followed by NER-catalyzed lesion removal. However, the efficient lesion removal requires the initiation complex to yield the right of way to the excision machinery, and how this occurs in a timely manner is unknown. Here we show that heat shock protein DNAJA2 facilitates the HSC70 chaperone-mediated autophagy (CMA) to degrade CSB during TC-NER. DNAJA2 interacts with and enables HSC70 to recognize sumoylated CSB. This triggers the removal of both CSB and Pol II from the lesion site in a manner dependent on lysosome receptor LAMP2A. Defects in DNAJA2, HSC70 or LAMP2A abolish CSB degradation and block TC-NER. Our findings discover DNAJA2-mediated CMA as a critical regulator of TC-NER, implicating the DNAJA2-HSC70-CMA axis factors in genome maintenance.

Phlorizin Mitigates Dextran Sulfate Sodium-Induced Colitis in Mice by Modulating Gut Microbiota and Inhibiting Ferroptosis.

Phlorizin (PHZ) is the main active component of apple peel and presents a potential application value. In the past few years, some reports have suggested that PHZ may have antioxidant and anti-inflammatory effects. Herein, we have attempted to assess the protective effects of PHZ on dextran sodium sulfate (DSS)-induced colitis in mice and to determine the underlying molecular mechanisms. Our results suggested that early intervention with PHZ (20, 40, and 80 mg/kg) significantly reduced the severity of DSS-induced colitis in mice, as presented by a longer colon, improved tight junction protein, decreased disease activity index, and attenuated inflammatory factors. Additionally, early intervention with + (20, 40, and 80 mg/kg) significantly inhibited ferroptosis by decreasing the surrogate ferroptosis marker levels (MDA and Iron Content). Additionally, PHZ (80 mg/kg) increased the diversity of intestinal flora in colitic mice by elevating the levels of beneficial bacteria (Lactobacillaceae and Muribaculaceae) and reducing the levels of harmful bacteria (Lachnospiraceae). This indirectly led to an increase in the amount of short-chain fatty acids. A fecal microbial transplantation (FMT) test was conducted to show that PHZ (80 mg/kg) ameliorated ulcerative colitis (UC) by regulating gut dysbiosis. In conclusion, early intervention with PHZ decreased DSS-induced colitis in mice by preserving their intestinal barrier and regulating their intestinal flora.

Characterization of Molecular Chaperone GroEL as a Potential Virulence Factor in Cronobacter sakazakii.

The molecular chaperone GroEL of C. sakazakii, a highly conserved protein encoded by the gene grol, has the basic function of responding to heat shock, thus enhancing the bacterium's adaptation to dry and high-temperature environments, which poses a threat to food safety and human health. Our previous study demonstrated that GroEL was found in the bacterial membrane fraction and caused a strong immune response in C. sakazakii. In this study, we tried to elucidate the subcellular location and virulent effects of GroEL. In live C. sakazakii cells, GroEL existed in both the soluble and insoluble fractions. To study the secretory mechanism of GroEL protein, a non-reduced Western immunoblot was used to analyze the form of the protein, and the result showed that the exported GroEL protein was mainly in monomeric form. The exported GroEL could also be located on bacterial surface. To further research the virulent effect of C. sakazakii GroEL, an indirect immunofluorescence assay was used to detect the adhesion of recombinant GroEL protein to HCT-8 cells. The results indicated that the recombinant GroEL protein could adhere to HCT-8 cells in a short period of time. The recombinant GroEL protein could activate the NF-κB signaling pathway to release more pro-inflammatory cytokines (TNF-α, IL-6 and IL-8), downregulating the expression of tight-junction proteins (claudin-1, occluding, ZO-1 and ZO-2), which collectively resulted in dose-dependent virulent effects on host cells. Inhibition of the grol gene expression resulted in a significant decrease in bacterial adhesion to and invasion of HCT-8 cells. Moreover, the deficient GroEL also caused slow growth, decreased biofilm formation, defective motility and abnormal filamentation of the bacteria. In brief, C. sakazakii GroEL was an important virulence factor. This protein was not only crucial for the physiological activity of C. sakazakii but could also be secreted to enhance the bacterium's adhesion and invasion capabilities.

Single-cell multi-omics sequencing of human spermatogenesis reveals a DNA demethylation event associated with male meiotic recombination.

Human spermatogenesis is a highly ordered process; however, the roles of DNA methylation and chromatin accessibility in this process remain largely unknown. Here by simultaneously investigating the chromatin accessibility, DNA methylome and transcriptome landscapes using the modified single-cell chromatin overall omic-scale landscape sequencing approach, we revealed that the transcriptional changes throughout human spermatogenesis were correlated with chromatin accessibility changes. In particular, we identified a set of transcription factors and cis elements with potential functions. A round of DNA demethylation was uncovered upon meiosis initiation in human spermatogenesis, which was associated with male meiotic recombination and conserved between human and mouse. Aberrant DNA hypermethylation could be detected in leptotene spermatocytes of certain nonobstructive azoospermia patients. Functionally, the intervention of DNA demethylation affected male meiotic recombination and fertility. Our work provides multi-omics landscapes of human spermatogenesis at single-cell resolution and offers insights into the association between DNA demethylation and male meiotic recombination.

DNAJA2 deficiency activates cGAS-STING pathway via the induction of aberrant mitosis and chromosome instability.

Molecular chaperone HSP70s are attractive targets for cancer therapy, but their substrate broadness and functional non-specificity have limited their role in therapeutical success. Functioning as HSP70's cochaperones, HSP40s determine the client specificity of HSP70s, and could be better targets for cancer therapy. Here we show that tumors defective in HSP40 member DNAJA2 are benefitted from immune-checkpoint blockade (ICB) therapy. Mechanistically, DNAJA2 maintains centrosome homeostasis by timely degrading key centriolar satellite proteins PCM1 and CEP290 via HSC70 chaperone-mediated autophagy (CMA). Tumor cells depleted of DNAJA2 or CMA factor LAMP2A exhibit elevated levels of centriolar satellite proteins, which causes aberrant mitosis characterized by abnormal spindles, chromosome missegregation and micronuclei formation. This activates the cGAS-STING pathway to enhance ICB therapy response in tumors derived from DNAJA2-deficient cells. Our study reveals a role for DNAJA2 to regulate mitotic division and chromosome stability and suggests DNAJA2 as a potential target to enhance cancer immunotherapy, thereby providing strategies to advance HSPs-based cancer therapy.

MOTS-c: A potential anti-pulmonary fibrosis factor derived by mitochondria.

Pulmonary fibrosis (PF) is a serious lung disease characterized by diffuse alveolitis and disruption of alveolar structure, with a poor prognosis and unclear etiopathogenesis. While ageing, oxidative stress, metabolic disorders, and mitochondrial dysfunction have been proposed as potential contributors to the development of PF, effective treatments for this condition remain elusive. However, Mitochondrial open reading frame of the 12S rRNA-c (MOTS-c), a peptide encoded by the mitochondrial genome, has shown promising effects on glucose and lipid metabolism, cellular and mitochondrial homeostasis, as well as the reduction of systemic inflammatory responses, and is being investigated as a potential exercise mimetic. Additionally, dynamic expression changes of MOTS-c have been closely linked to ageing and ageing-related diseases, indicating its potential as an exercise mimetic. Therefore, the review aims to comprehensively analyze the available literature on the potential role of MOTS-c in improving PF development and to identify specific therapeutic targets for future treatment strategies.

αCGRP deficiency aggravates pulmonary fibrosis by activating the PPARγ signaling pathway.

In order to explore whether αCGRP (Calca) deficiency aggravates pulmonary fibrosis (PF). Clinical data from patients with PF (n = 52) were retrospectively analyzed. Lung tissue from a bleomycin (BLM)-induced rat model was compared with that of Calca-knockout (KO) and wild type (WT) using immunohistochemistry, RNA-seq, and UPLC-MS/MS metabolomic analyses. The results showed that decreased αCGRP expression and activation of the type 2 immune response were detected in patients with PF. In BLM-induced and Calca-KO rats, αCGRP deficiency potentiated apoptosis of AECs and induced M2 macrophages. RNA-seq identified enrichment of pathways involved in nuclear translocation and immune system disorders in Calca-KO rats compared to WT. Mass spectrometry of lung tissue from Calca-KO rats showed abnormal lipid metabolism, including increased levels of LTB4, PDX, 1-HETE. PPAR pathway signaling was significantly induced in both transcriptomic and metabolomic datasets in Calca-KO rats, and immunofluorescence analysis confirmed that the nuclear translocation of PPARγ in BLM-treated and Calca-KO rats was synchronized with STAT6 localization in the cytoplasmic and nuclear fractions. In conclusion, αCGRP is protective against PF, and αCGRP deficiency promotes M2 polarization of macrophages, probably by activating the PPARγ pathway, which leads to activation of the type 2 immune response and accelerates PF development.