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Abstract Background Diabetic nephropathy (DN) is a common complication of diabetes mellitus, and Prolyl 4-Hydroxylase Subunit Beta (P4HB) expression is increased in high glucose (HG)-induced renal tubular epithelial cells (TECs). But it’s role in HG-induced TECs remains to be elucidated. Methods The HK-2 cells were induced using HG and transfected with SiRNA-P4HB. DCFH-DA staining was utilized for the detection of cellular levels of ROS. WB and immunofluorescence were utilized to detect the expression of P4HB, epithelial-mesenchymal transition (EMT), fibrosis, and TGFβ/SMAD3-related proteins in HK-2 cells. Online databases were utilized for predicting the interaction target of P4HB, and immunoprecipitation (IP) experiments were employed to validate the binding of P4HB with the target. SiRNA and overexpression vectors of target gene were used to verify the mechanism of action of P4HB. Results HG induced an increase in the expression of P4HB and TGFβ, p-SMAD3, and ROS in HK-2 cells. Furthermore, HG downregulated the expression of E-cadherin and upregulated the expression of N-cadherin, Vimentin, α-SMA, Fibronectin, Collagen IV, SNAIL, and SLUG in HK-2 cells. Interfering with P4HB significantly reversed the expression of these proteins. Database predictions and IP experiments showed that P4HB interacts with PRMT1, and the expression of PRMT1 was increased in HG-induced HK-2 cells. Interfering with PRMT1 inhibited the changes in expression of EMT and fibrosis related proteins induced by HG. However, overexpression of PRMT1 weakened the regulatory effect of P4HB interference on the EMT, fibrosis, and TGFβ/SMAD3-related proteins in HK-2 cells. Conclusion P4HB regulated the TGFβ/SMAD3 signaling pathway through PRMT1 and thus participates in HG-induced EMT and fibrosis in HK-2 cells.

Abstract Non-muscle myosin heavy chain IIA (MYH9), a member of the non-muscle myosin II (NM II) family, is widely expressed in cells. The interaction of MYH9 with actin in the cytoplasm can hydrolyze ATP, completing the conversion of chemical energy to mechanical motion. MYH9 participates in various cellular processes, such as cell adhesion, migration, movement, and even signal transduction. Mutations in MYH9 are often associated with autosomal dominant platelet disorders and kidney diseases. Over the past decade, tumor-related research has gradually revealed a close relationship between MYH9 and the occurrence and development of tumors. This article provides a review of the research progress on the role of MYH9 in cancer regulation. We also discussed the anti-cancer effects of MYH9 under special circumstances, as well as its regulation of T cell function. In addition, given the importance of MYH9 as a key hub in oncogenic signal transduction, we summarize the current therapeutic strategies targeting MYH9 as well as the ongoing challenges.

Background Whether angiotensin receptor-neprilysin inhibitor (ARNI) can reduce the incidence of cardiovascular events and improve peritoneal function in peritoneal dialysis (PD) patients remains unclear. Thus, this study aims to clarify the role of ARNI in PD patients.Methods This was a multicenter retrospective study. A total of 102 patients were enrolled for analysis. Patients who continuously used ARNI for 12 months were assigned to the ARNI group (n = 55), while those who never used ARNI to the control group (n = 47). Clinical indicators and cardiovascular risk factors were analyzed, along with in vitro experiments on neoangiogenesis to investigate the underlying molecular mechanisms of peritoneal protection by ARNI.Results Systolic blood pressure (p = 0.001), diastolic blood pressure (p = 0.001), and left ventricular ejection fraction (p = 0.008) were statistically improved after 12 months of ARNI therapy, whereas these metrics did not change in control patients. The risk factors for the occurrence of cardiac events in PD patients included the use of ARNI [hazard ratio (HR) 0.053; 95% confidence interval (CI), 0.006–0.492] and NT-proBNP level (HR 2.317; 95% CI, 1.179–4.554). Additionally, there was a decrease in 4-hour ratio of creatinine concentration in dialysate to plasma (4h Scr D/P) in the ARNI group (p = 0.020). The in vitro experiments showed that LCZ696, a combination of sacubitril and valsartan, inhibited neoangiogenesis via the VEGFR2/ERK1/2 and Notch1 pathways.Conclusions ARNI may play a protective role in reducing the incidence of cardiovascular events and decreasing solute transport in PD patients.

AbstractObjectives The objective of this study was to investigate the glycolytic activity of adenomyosis, which is characterized by malignant biological behaviors including abnormal cell proliferation, migration, invasion, cell regulation, and epithelial-mesenchymal transition.Methods From January 2021 to August 2022, a total of 15 patients who underwent total hysterectomy for adenomyosis and 14 patients who had non-endometrial diseases, specifically with cervical squamous intraepithelial neoplasia and uterine myoma, were included in this study. Myometrium with ectopic endometrium from patients with adenomyosis while normal myometrium from patients in the control group were collected. All samples were confirmed by a histopathological examination. The samples were analyzed by liquid chromatography-mass spectrometry (LC-MS), real-time quantitative PCR, NAD+/NADH assay kit as well as the glucose and lactate assay kits.Results Endometrial stroma and glands could be observed within the myometrium of patients in the adenomyosis group. We found that the mRNA expressions of HK1, PFKFB3, glyceraldehyde-3-phospate dehydrogenase (GAPDH), PKM2, and PDHA as well as the protein expressions of PFKFB3 were elevated in ectopic endometrial tissues of the adenomyosis group as compared to normal myometrium of the control group. The level of fructose 1,6-diphosphate was increased while NAD + and NAD+/NADH ratio were decreased compared with the control group. Besides, increased glucose consumption and lactate production were observed in myometrium with ectopic endometrium.Conclusions We concluded that altered glycolytic phenotype of the myometrium with ectopic endometrium in women with adenomyosis may contribute the development of adenomyosis.

Abstract To enhance the anesthetic efficacy and reduce toxic side effects, a strategy is proposed involving the utilization of general anesthetics of Propofol (Pro) and Etomidate (Eto) to synergistic inhibition GABA receptors simultaneously. Four‐in‐one molecular aggregates were prepared to implement this strategy, which comprised of Pro and Eto with the bridging molecule monoglyceride monooleate (GMO) and surfactant F127 through intermolecular forces. The blood‐brain barrier (BBB) targeted lactoferrin (LF) is affixed to their surface, obtaining the final molecular aggregates. By employing lactoferrin enrich aggregates to the BBB, followed by ultrasound combine microbubbles to open the BBB, a remarkable 4.5‐fold enhancement in brain drug delivery was achieved. The molecular aggregates group maintained stable parameters of heart rate, diastolic blood pressure, and systolic blood pressure. A notable increase of more than twice therapeutic index (TI) value was observed, implying their higher anesthesia efficiency and reduced toxicity. Electroencephalogram (EEG) experiments demonstrate a significant elevation in the proportion of δ waves from 28% to 80% for aggregates, accompanied by a nearly fivefold reduction in the proportion of θ waves, meaning a significant improvement in synergistic anesthesia effectiveness (interaction index 0.289) with lower drug dosage. Furthermore, mouse immunofluorescence brain slice experiments suggest Pro and Eto enter the GABA receptor simultaneously, resulting in synergistic inhibition of GABA receptors.

The rising demand for increased integration and higher power outputs poses a hidden risk to the long-term reliable operation of third-generation semiconductors. Thus, the power cycling test (PCT) is widely regarded as the utmost critical test for assessing the packaging reliability of power devices. In this work, low-thermal-resistance packaging design structures of SiC devices are introduced, encompassing planar packaging with dual heat dissipation, press-pack packaging, three-dimensional (3D) packaging, and hybrid packaging. PCT methods and their control strategies are summarized and discussed. Direct-current PCT is the focus of this review. The failure mechanisms of SiC devices under PCT are pointed out. The electrical and temperature-sensitive parameters adopted to monitor the aging of SiC devices are organized. The existing international standards for PCT are evaluated. Due to the lack of authoritative statements for SiC devices, it is difficult to achieve comparison research results without consistent preconditions. Furthermore, the lifetimes of the various packaging designs of the tested SiC devices under PCTs are statistically analyzed. Additionally, problems related to parameter monitoring and test equipment are also summarized. This review explores the broader landscape by delving into the current challenges and main trends in PCTs for SiC devices.

Abstract Tyrosine kinase inhibitors have been the standard treatment for patients with Philadelphia chromosome-positive (Ph+) leukemia. However, a series of issues, including drug resistance, relapse and intolerance, are still an unmet medical need. Here, we report the targeted siRNA-based lipid nanoparticles in Ph+ leukemic cell lines for gene therapy of Ph+ leukemia, which specifically targets a recently identified NEDD8 E3 ligase RAPSYN in Ph+ leukemic cells to disrupt the neddylation of oncogenic BCR-ABL. To achieve the specificity for Ph+ leukemia therapy, a single-chain fragment variable region (scFv) of anti-CD79B monoclonal antibody was covalently conjugated on the surface of OA2-siRAPSYN lipid nanoparticles to generate the targeted lipid nanoparticles (scFv-OA2-siRAPSYN). Through effectively silencing RAPSYN gene in leukemic cell lines by the nanoparticles, BCR-ABL was remarkably degraded accompanied by the inhibition of proliferation and the promotion of apoptosis. The specific targeting, therapeutic effects and systemic safety were further evaluated and demonstrated in cell line-derived mouse models. The present study has not only addressed the clinical need of Ph+ leukemia, but also enabled gene therapy against a less druggable target. Graphical Abstract

BackgroundPeriventricular nodular heterotopia (PVNH) is a neuronal migration disorder caused by the inability of neurons to move to the cortex. Patients with PVNH often experience epilepsy due to ectopic neuronal discharges. Most cases of PVNH are associated with variations in filamin A (FLNA), which encodes an actin-binding protein. However, the underlying pathological mechanisms remain unclear.MethodsNext-generation sequencing was performed to detect variants in the patient with PVNH, and the findings were confirmed using Sanger sequencing. Iterative threading assembly refinement was used to predict the structures of the variant proteins, and the search tool for the retrieval of interacting genes/proteins database was used to determine the interactions between FLNA and motility-related proteins. An induced pluripotent stem cell (iPSC) line was generated as a disease model by reprogramming human peripheral blood mononuclear cells. The FLNA expression in iPSCs was assessed using western blot and quantitative real-time polymerase chain reaction (qRT-PCR). Immunofluorescence analysis was performed to determine the arrangement of F-actin.ResultsA novel FLNA frameshift variant (NM_001456.3: c.1466delG, p. G489Afs*9) was identified in a patient with PVNH and epilepsy. Bioinformatic analysis indicated that this variation was likely to impair FLNA function. Western blot and qRT-PCR analysis of iPSCs derived from the patient’s peripheral blood mononuclear cells revealed the absence of FLNA protein and mRNA. Immunofluorescence analysis suggested an irregular arrangement and disorganization of F-actin compared to that observed in healthy donors.ConclusionOur findings indicate that the frameshift variant of FLNA (NM_001456.3: c.1466delG, p. G489Afs*9) impairs the arrangement and organization of F-actin, potentially influencing cell migration and causing PVNH.

BackgroundKidney injuries often carry a grim prognosis, marked by fibrosis development, renal function loss, and macrophage involvement. Despite extensive research on macrophage polarization and its effects on other cells, like fibroblasts, limited attention has been paid to the influence of non-immune cells on macrophages. This study aims to address this gap by shedding light on the intricate dynamics and diversity of macrophages during renal injury and repair.MethodsDuring the initial research phase, the complexity of intercellular communication in the context of kidney injury was revealed using a publicly available single-cell RNA sequencing library of the unilateral ureteral obstruction (UUO) model. Subsequently, we confirmed our findings using an independent dataset from a renal ischemia-reperfusion injury (IRI) model. We treated two different types of endothelial cells with TGF-β and co-cultured their supernatants with macrophages, establishing an endothelial cell and macrophage co-culture system. We also established a UUO and an IRI mouse model. Western blot analysis, flow cytometry, immunohistochemistry and immunofluorescence staining were used to validate our results at multiple levels.ResultsOur analysis revealed significant changes in the heterogeneity of macrophage subsets during both injury processes. Amyloid β precursor protein (APP)-CD74 axis mediated endothelial-macrophage intercellular communication plays a dominant role. In the in vitro co-culture system, TGF-β triggers endothelial APP expression, which subsequently enhances CD74 expression in macrophages. Flow cytometry corroborated these findings. Additionally, APP and CD74 expression were significantly increased in the UUO and IRI mouse models. Immunofluorescence techniques demonstrated the co-localization of F4/80 and CD74 in vivo.ConclusionOur study unravels a compelling molecular mechanism, elucidating how endothelium-mediated regulation shapes macrophage function during renal repair. The identified APP-CD74 signaling axis emerges as a promising target for optimizing renal recovery post-injury and preventing the progression of chronic kidney disease.

The myosin heavy chain 9 (MYH9) gene, located on human chromosome 22, encodes non-muscle myosin heavy chain IIA (NM IIA). This protein is essential to various cellular events, such as generating intracellular chemomechanical force and facilitating the movement of the actin cytoskeleton. Mutations associated with thrombocytopenia in autosomal dominant diseases first highlighted the significance of the MYH9 gene. In recent years, numerous studies have demonstrated the pivotal roles of MYH9 in various cancers. However, its effects on cancer are intricate and not fully comprehended. Furthermore, the elevated expression of MYH9 in certain malignancies suggests its potential as a target for tumor therapy. Nonetheless, there is a paucity of literature summarizing MYH9’s role in tumors and the therapeutic strategies centered on it, necessitating a systematic analysis. This paper comprehensively reviews and analyzes the pertinent literature in this domain, elucidating the fundamental structural characteristics, biological functions, and the nexus between MYH9 and tumors. The mechanisms through which MYH9 contributes to tumor development and its multifaceted roles in the tumorigenic process are also explored. Additionally, we discuss the relationship between MYH9-related diseases (MYH9-RD) and tumors and also summarize tumor therapeutic approaches targeting MYH9. The potential clinical applications of studying the MYH9 gene include improving early diagnosis, clinical staging, and prognosis of tumors. This paper is anticipated to provide novel insights for tumor therapy.

The human gut microbiome (GM) impacts various physiological processes and can lead to pathological conditions and even carcinogenesis if homeostasis is disrupted. Recent studies have indicated a connection between the GM and prostatic disease. However, the underlying mechanisms are still unclear. This review aims to provide a summary of the existing information regarding the connection between the GM and various prostatic conditions such as chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS), benign prostatic hyperplasia (BPH), and prostate cancer (PCa). Furthermore, the review aims to identify possible pathogenic mechanisms and suggest potential ways of targeting GM to prevent and treat prostatic disease. Due to the complexity of the mechanism between GM and prostatic diseases, additional research is required to comprehend the association between the two. This will lead to more effective treatment options for prostatic disease.

BackgroundDespite the potential demonstrated by targeted plasma metabolite modulators in halting the progression of chronic kidney disease (CKD), a lingering uncertainty persists concerning the causal relationship between distinct plasma metabolites and the onset and progression of CKD.MethodsA genome-wide association study was conducted on 1,091 metabolites and 309 metabolite ratios derived from a cohort of 8,299 unrelated individuals of European descent. Employing a bidirectional two-sample Mendelian randomization (MR) analysis in conjunction with colocalization analysis, we systematically investigated the associations between these metabolites and three phenotypes: CKD, creatinine-estimated glomerular filtration rate (creatinine-eGFR), and urine albumin creatinine ratio (UACR). In the MR analysis, the primary analytical approach employed was inverse variance weighting (IVW), and sensitivity analysis was executed utilizing the MR-Egger method and MR-pleiotropy residual sum and outlier (MR-PRESSO). Heterogeneity was carefully evaluated through Cochrane’s Q test. To ensure the robustness of our MR results, the leave-one-out method was implemented, and the strength of causal relationships was subjected to scrutiny via Bonferroni correction.ResultsOur thorough MR analysis involving 1,400 plasma metabolites and three clinical phenotypes yielded a discerning identification of 21 plasma metabolites significantly associated with diverse outcomes. Specifically, in the forward MR analysis, 6 plasma metabolites were determined to be causally associated with CKD, 16 with creatinine-eGFR, and 7 with UACR. Substantiated by robust evidence from colocalization analysis, 6 plasma metabolites shared causal variants with CKD, 16 with creatinine-eGFR, and 7 with UACR. In the reverse analysis, a diminished creatinine-eGFR was linked to elevated levels of nine plasma metabolites. Notably, no discernible associations were observed between other plasma metabolites and CKD, creatinine-eGFR, and UACR. Importantly, our analysis detected no evidence of horizontal pleiotropy.ConclusionThis study elucidates specific plasma metabolites causally associated with CKD and renal functions, providing potential targets for intervention. These findings contribute to an enriched understanding of the genetic underpinnings of CKD and renal functions, paving the way for precision medicine applications and therapeutic strategies aimed at impeding disease progression.

Abstract The disruptor of telomeric silencing 1-like (DOT1L), a specific histone methyltransferase that catalyzed methylation of histone H3 on lysine 79, was associated with the pathogenesis of many diseases, but its role in peritoneal fibrosis remained unexplored. Here, we examined the role of DOT1L in the expression and activation of protein tyrosine kinases and development of peritoneal fibrosis. We found that a significant rise of DOT1L expression in the fibrotic peritoneum tissues from long-term PD patients and mice. Inhibition of DOT1L significantly attenuated the profibrotic phenotypic differentiation of mesothelial cells and macrophages, and alleviated peritoneal fibrosis. Mechanistically, RNA sequencing and proteomic analysis indicated that DOT1L was mainly involved in the processes of protein tyrosine kinase binding and extracellular matrix structural constituent in the peritoneum. Chromatin immunoprecipitation (ChIP) showed that intranuclear DOT1L guided H3K79me2 to upregulate EGFR in mesothelial cells and JAK3 in macrophages. Immunoprecipitation and immunofluorescence showed that extranuclear DOT1L could interact with EGFR and JAK3, and maintain the activated signaling pathways. In summary, DOT1L promoted the expression and activation of tyrosine kinases (EGFR in mesothelial cells and JAK3 in macrophages), promoting cells differentiate into profibrotic phenotype and thus peritoneal fibrosis. We provide the novel mechanism of dialysis-related peritoneal fibrosis (PF) and the new targets for clinical drug development. DOT1L inhibitor had the PF therapeutic potential.

Abstract Background We aimed to determine whether and how the combination of acetazolamide and remote ischemic preconditioning (RIPC) reduced the incidence and severity of acute mountain sickness (AMS). Methods This is a prospective, randomized, open-label, blinded endpoint (PROBE) study involving 250 healthy volunteers. Participants were randomized (1:1:1:1:1) to following five groups: Ripc (RIPC twice daily, 6 days), Rapid-Ripc (RIPC four times daily, 3 days), Acetazolamide (twice daily, 2 days), Combined (Acetazolamide plus Rapid-Ripc), and Control group. After interventions, participants entered a normobaric hypoxic chamber (equivalent to 4000 m) and stayed for 6 h. The primary outcomes included the incidence and severity of AMS, and SpO2 after hypoxic exposure. Secondary outcomes included systolic and diastolic blood pressure, and heart rate after hypoxic exposure. The mechanisms of the combined regime were investigated through exploratory outcomes, including analysis of venous blood gas, complete blood count, human cytokine antibody array, ELISA validation for PDGF-AB, and detection of PDGF gene polymorphisms. Results The combination of acetazolamide and RIPC exhibited powerful efficacy in preventing AMS, reducing the incidence of AMS from 26.0 to 6.0% (Combined vs Control: RR 0.23, 95% CI 0.07–0.70, P = 0.006), without significantly increasing the incidence of adverse reactions. Combined group also showed the lowest AMS score (0.92 ± 1.10). Mechanistically, acetazolamide induced a mild metabolic acidosis (pH 7.30 ~ 7.31; HCO3 − 18.1 ~ 20.8 mmol/L) and improved SpO2 (89 ~ 91%) following hypoxic exposure. Additionally, thirty differentially expressed proteins (DEPs) related to immune-inflammatory process were identified after hypoxia, among which PDGF-AB was involved. Further validation of PDGF-AB in all individuals showed that both acetazolamide and RIPC downregulated PDGF-AB before hypoxic exposure, suggesting a possible protective mechanism. Furthermore, genetic analyses demonstrated that individuals carrying the PDGFA rs2070958 C allele, rs9690350 G allele, or rs1800814 G allele did not display a decrease in PDGF-AB levels after interventions, and were associated with a higher risk of AMS. Conclusions The combination of acetazolamide and RIPC exerts a powerful anti-hypoxic effect and represents an innovative and promising strategy for rapid ascent to high altitudes. Acetazolamide improves oxygen saturation. RIPC further aids acetazolamide, which synergistically regulates PDGF-AB, potentially involved in the pathogenesis of AMS. Trial registration ClinicalTrials.gov NCT05023941.

Abstract Abnormal activation of telomerase occurs in most cancer types, which facilitates escaping from cell senescence. As the key component of telomerase, telomerase reverse transcriptase (TERT) is regulated by various regulation pathways. TERT gene changing in its promoter and phosphorylation respectively leads to TERT ectopic expression at the transcription and protein levels. The co-interacting factors play an important role in the regulation of TERT in different cancer types. In this review, we focus on the regulators of TERT and these downstream functions in cancer regulation. Determining the specific regulatory mechanism will help to facilitate the development of a cancer treatment strategy that targets telomerase and cancer cell senescence. As the most important catalytic subunit component of telomerase, TERT is rapidly regulated by transcriptional factors and PTM-related activation. These changes directly influence TERT-related telomere maintenance by regulating telomerase activity in telomerase-positive cancer cells, telomerase assembly with telomere-binding proteins, and recruiting telomerase to the telomere. Besides, there are also non-canonical functions that are influenced by TERT, including the basic biological functions of cancer cells, such as proliferation, apoptosis, cell cycle regulation, initiating cell formation, EMT, and cell invasion. Other downstream effects are the results of the influence of transcriptional factors by TERT. Currently, some small molecular inhibitors of TERT and TERT vaccine are under research as a clinical therapeutic target. Purposeful work is in progress.

Abstract Background Discoidin, CUB, and LCCL domain-containing type I (DCBLD1) is identified as an oncogene involved in multiple regulation of tumor progression, but specific mechanisms remain unclear in cervical cancer. Lactate-mediated lactylation modulates protein function. Whether DCBLD1 can be modified by lactylation and the function of DCBLD1 lactylation are unknown. Therefore, this study aims to investigate the lactylation of DCBLD1 and identify its specific lactylation sites. Herein, we elucidated the mechanism by which lactylation modification stabilizes the DCBLD1 protein. Furthermore, we investigated DCBLD1 overexpression activating pentose phosphate pathway (PPP) to promote the progression of cervical cancer. Methods DCBLD1 expression was examined in human cervical cancer cells and adjacent non-tumorous tissues using quantitative reverse transcription-polymerase chain reaction, western blotting, and immunohistochemistry. In vitro and in vivo studies were conducted to investigate the impact of DCBLD1 on the progression of cervical cancer. Untargeted liquid chromatography-tandem mass spectrometry (LC–MS/MS) metabolomics studies were used to characterize DCBLD1-induced metabolite alterations. Western blot, immunofuorescence and transmission electron microscopy were performed to detect DCBLD1 degradation of G6PD by activating autophagy. Chromatin immunoprecipitation, dual luciferase reporter assay for detecting the mechanism by which lactate increases DCBLD1 transcription. LC–MS/MS was employed to verify specific modification sites within the DCBLD1 protein. Results We found that lactate increased DCBLD1 expression, activating the PPP to facilitate the proliferation and metastasis of cervical cancer cells. DCBLD1 primarily stimulated PPP by upregulating glucose-6-phosphate dehydrogenase (G6PD) expression and enzyme activity. The mechanism involved the increased enrichment of HIF-1α in the DCBLD1 promoter region, enhancing the DCBLD1 mRNA expression. Additionally, lactate-induced DCBLD1 lactylation stabilized DCBLD1 expression. We identified DCBLD1 as a lactylation substrate, with a predominant lactylation site at K172. DCBLD1 overexpression inhibited G6PD autophagic degradation, activating PPP to promote cervical cancer progression. In vivo, 6-An mediated inhibition of G6PD enzyme activity, inhibiting tumor proliferation. Conclusions Our findings revealed a novel post-translational modification type of DCBDL1, emphasizing the significance of lactylation-driven DCBDL1-mediated PPP in promoting the progression of cervical cancer. Graphical Abstract Schematic illustration of DCBLD1-induced G6PD-mediated reprogramming of PPP metabolism in promoting cervical cancer progression.

Maintaining the structural integrity of genomic chromosomal DNA is an essential role of cellular life and requires two important biological mechanisms: the DNA damage response (DDR) mechanism and telomere protection mechanism at chromosome ends. Because abnormalities in telomeres and cellular DDR regulation are strongly associated with human aging and cancer, there is a reciprocal regulation of telomeres and cellular DDR. Moreover, several drug treatments for DDR are currently available. This paper reviews the progress in research on the interaction between telomeres and cellular DNA damage repair pathways. The research on the crosstalk between telomere damage and DDR is important for improving the efficacy of tumor treatment. However, further studies are required to confirm this hypothesis.

ObjectivesThe relationship between cathepsins and prostate cancer (PCa) has been reported. However, there is a lack of research on cathepsins and benign prostate diseases (BPDs). This study investigated the potential genetic link between cathepsins and BPDs through the utilization of Mendelian randomization (MR) analysis to determine if a causal relationship exists.MethodsPublicly accessible summary statistics on BPDs were obtained from FinnGen Biobank. The data comprised 149,363 individuals, with 30,066 cases and 119,297 controls for BPH, and 123,057 individuals, with 3,760 cases and 119,297 controls for prostatitis. The IEU OpenGWAS provided the Genome-wide association data on ten cathepsins. To evaluate the causal relationship between BPDs and cathepsins, five distinct MR analyses were employed, with the primary method being the inverse variance weighted (IVW) approach. Additionally, sensitivity analyses were conducted to examine the horizontal pleiotropy and heterogeneity of the findings.ResultsThe examination of IVW MR findings showed that cathepsin O had a beneficial effect on BPH (IVW OR=0.94, 95% CI 0.89–0.98, P=0.0055), while cathepsin X posed a threat to prostatitis (IVW OR=1.08, 95% CI 1.00–1.16, P=0.047). Through reverse MR analysis, it was revealed that prostatitis had an adverse impact on cathepsin V (IVW OR=0.89, 95% CI 0.80–0.99, P=0.035), while no favorable association was observed between BPH and cathepsins. The results obtained from MR-Egger, weighted median, simple mode, and weighted mode methods were consistent with the findings of the IVW approach. Based on sensitivity analyses, heterogeneity, and horizontal pleiotropy are unlikely to distort the results.ConclusionThis study offers the initial evidence of a genetic causal link between cathepsins and BPDs. Our findings revealed that cathepsin O was beneficial in preventing BPH, whereas cathepsin X posed a potential threat to prostatitis. Additionally, prostatitis negatively affected cathepsin V level. These three cathepsins could be targets of diagnosis and treatment for BPDs, which need further research.

High-risk human papillomaviruses (HPVs) are the causative agents of cervical cancer. Here, we report that HPV16 E6E7 promotes cervical cancer cell proliferation by activating the pentose phosphate pathway (PPP). We found that HPV16 E6 activates the PPP primarily by increasing glucose-6-phosphate dehydrogenase (G6PD) enzyme activity. Mechanistically, HPV16 E6 promoted G6PD dimer formation by inhibiting its lactylation. Importantly, we suggest that G6PD K45 was lactylated during G6PD-mediated antioxidant stress. In primary human keratinocytes and an HPV-negative cervical cancer C33A cells line ectopically expressing HPV16 E6, the transduction of G6PD K45A (unable to be lactylated) increased GSH and NADPH levels and, correspondingly, decreasing ROS levels. Conversely, the re-expression of G6PD K45T (mimicking constitutive lactylation) in HPV16-positive SiHa cells line inhibited cell proliferation. In vivo, the inhibition of G6PD enzyme activity with 6-aminonicotinamide (6-An) or the re-expression of G6PD K45T inhibited tumor proliferation. In conclusion, we have revealed a novel mechanism of HPV oncoprotein-mediated malignant transformation. These findings might provide effective strategies for treating cervical and HPV-associated cancers.

Abstract The spread of many infectious diseases relies on aerosol transmission to the respiratory tract. Here we design an intranasal mask comprising a positively-charged thermosensitive hydrogel and cell-derived micro-sized vesicles with a specific viral receptor. We show that the positively charged hydrogel intercepts negatively charged viral aerosols, while the viral receptor on vesicles mediates the entrapment of viruses for inactivation. We demonstrate that when displaying matched viral receptors, the intranasal masks protect the nasal cavity and lung of mice from either severe acute respiratory syndrome coronavirus 2 or influenza A virus. With computerized tomography images of human nasal cavity, we further conduct computational fluid dynamics simulation and three-dimensional printing of an anatomically accurate human nasal cavity, which is connected to human lung organoids to generate a human respiratory tract model. Both simulative and experimental results support the suitability of intranasal masks in humans, as the likelihood of viral respiratory infections induced by different variant strains is dramatically reduced.

Abstract Background Chronic interstitial fibrosis is the primary barrier against the long-term survival of transplanted kidneys. Extending the lifespan of allografts is vital for ensuring the long-term health of patients undergoing kidney transplants. However, few targets and their clinical applications have been identified. Moreover, whether dyslipidemia facilitates fibrosis in renal allograft remains unclear. Methods Blood samples were collected from patients who underwent kidney transplantation. Correlation analyses were conducted between the Banff score and body mass index, and serum levels of triacylglycerol, total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol. A rat model of renal transplantation was treated with the lipid-lowering drug, fenofibrate, and kidney fibrosis levels were determined by histochemical staining. Targeted metabolomic detection was conducted in blood samples from patients who underwent kidney transplantation and were divided into fibrotic and non-fibrotic groups. Rats undergoing renal transplantation were fed either an n-3 or n-6 polyunsaturated fatty acid (PUFA)-enriched diet. Immunohistochemical and Masson’s trichrome staining were used to determine the degree of fibrosis. Results Hyperlipidemia was associated with fibrosis development. Treatment with fenofibrate contributed to improve fibrosis in a rat model of renal transplantation. Moreover, n-3 PUFAs from fibrotic group showed significant downregulation compared to patients without fibrotic renal allografts, and n-3 PUFAs-enriched diet contributed to delayed fibrosis in a rat model of renal transplantation. Conclusions This study suggests that hyperlipidemia facilitates fibrosis of renal allografts. Importantly, a new therapeutic approach was provided that may delay chronic interstitial fibrosis in transplanted kidneys by augmenting the n-3 PUFA content in the diet.

The village of Wengding, ancestral home of the Wa ethnic group, considered as China’s last primitive tribe, suffered near-complete extinction due to a fire incident in 2021. Historical records indicate that stilt-style buildings, also in Wengding, are highly susceptible to fire. Nevertheless, this has not hindered the long-term existence of these distinctive architectural forms. This study analyses the reasons for the sustained existence of the traditional building forms in Wengding, from the perspective of resilience. The findings indicate that the requirements of the traditional nomadic civilization for rapid construction of dwellings, the communal consciousness toward disaster resistance, and the implementation of spatially oriented fire protection measures collectively account for the swift recovery and reconstruction observed in Wengding village after the disaster. These aspects are tangible manifestations of the capacity of the village for resilience. Overall, resilience is essential for the sustainability of such traditional villages in the long term.

Chronic interstitial fibrosis presents a significant challenge to the long-term survival of transplanted kidneys. Our research has shown that reduced expression of acyl-coenzyme A oxidase 1 (ACOX1), which is the rate-limiting enzyme in the peroxisomal fatty acid β-oxidation pathway, contributes to the development of fibrosis in renal allografts. ACOX1 deficiency leads to lipid accumulation and excessive oxidation of polyunsaturated fatty acids (PUFAs), which mediate epithelial–mesenchymal transition (EMT) and extracellular matrix (ECM) reorganization respectively, thus causing fibrosis in renal allografts. Furthermore, activation of Toll-like receptor 4 (TLR4)-nuclear factor kappa-B (NF-κB) signaling induced ACOX1 downregulation in a DNA methyltransferase 1 (DNMT1)-dependent manner. Overconsumption of PUFA resulted in endoplasmic reticulum (ER) stress, which played a vital role in facilitating ECM reorganization. Supplementation with PUFAs contributed to delayed fibrosis in a rat model of renal transplantation. The study provides a novel therapeutic approach that can delay chronic interstitial fibrosis in renal allografts by targeting the disorder of lipid metabolism.

The widespread presence of iron and sulfur compounds such as pyrite in marine waterlogged archeological wood (WAW) can cause irreversible damage to the safety of its preservation. This issue has been a longstanding concern for cultural heritage conservation communities. In this study, we examined the distribution and phase composition of Fe and sulfur compounds in wood samples obtained from the Nanhai I shipwreck using ESEM-EDS, micro-Raman spectroscopy, and an X-ray diffractometer. The removal of iron from WAW samples of the Nanhai I shipwreck using Acidithiobacillus ferrooxidans (A. ferrooxidans) was evaluated using conductivity and ICP-AES analysis. The results showed that A. ferrooxidans effectively improved the removal of iron from WAW. The degradation of fresh healthy wood during treatment was also analyzed using infrared spectroscopy, and the results showed that the treatment had little effect on the samples over a short period. This study demonstrates, for the first time, the feasibility of iron extraction from marine WAW by A.ferrooxidans. This was also the first attempt in China to apply biological oxidation to the removal of iron from marine archeological materials.

Background: Mesalazine, a preparation of 5-aminosalicylic acid, is a medication widely used in clinical practice as a first-line therapy in the treatment of mild and moderate inflammatory bowel disease. However, the long-term safety of mesalazine in large sample population was unknown. The current study was to assess mesalazine -related adverse events of real-world through data mining of the US Food and Drug Administration Adverse Event Reporting System (FAERS).Methods: Disproportionality analyses, including the reporting odds ratio (ROR), the proportional reporting ratio the Bayesian confidence propagation neural network and the multi-item gamma Poisson shrinker (MGPS) algorithms were employed to quantify the signals of mesalazine -associated AEs.Results: Out of 14,149,980 reports collected from the FDA Adverse Event Reporting System database, 24,284 reports of mesalazine -associated AEs were identified. A total of 170 significant disproportionality preferred terms conforming to the four algorithms simultaneously were retained. The most common AEs included colitis ulcerative, diarrhoea, condition aggravated, crohn’s disease, fatigue, abdominal pain, nausea, haematochezia, which were corresponding to those reported in the specification and clinical trials. Unexpected significant AEs as dizziness, drug ineffective, drug hypersensitivity, infection, off label use, weight decreased, decreased appetite, arthralgia, rash might also occur. The median onset time of mesalazine -related AEs was 1,127 days (interquartile range [IQR] 1,127–1,674 days), and most of the cases occurred 2 years later (n = 610, 70.93%) and within the first 1 month (n = 89, 10.35%) after mesalazine initiation.Conclusion: Results of our study were consistent with clinical observations. We also found potential new and unexpected AEs signals for mesalazine, suggesting prospective clinical studies were needed to confirm these results and illustrate their relationship. Our results could provide valuable evidence for further safety studies of mesalazine.

AbstractBackground The treatment of refractory nephrotic syndrome (RNS) is full of challenges and the role of rituximab (RTX) is not well-established, thus this study aims to demonstrate the role of RTX in RNS.Methods This was a multicenter retrospective study of all adult patients receiving RTX for RNS. Patients enrolled were divided into two groups according to pathological pattern: 20 patients as a group of podocytopathy (including minimal change disease [MCD] and focal and segmental glomerulosclerosis [FSGS]), and 26 patients as membranous nephropathy (MN) group. The remission rate, relapse rate, adverse effects, and predictors of remission were analyzed.Results A total of 75 patients received RTX for RNS and 48 were available for analysis after exclusion criteria. No significant difference in the remission rate at 6 or 12 months was observed between the MCD/FSGS and MN cases (p > 0.05). The median duration of the first complete remission (CR) was 1 month in the podocytopathy group and 12.5 months in the MN group. Three relapses were associated with infection as the ultimate outcome, and 6 out of 48 remained refractory representing a response rate of 87.5% in RNS. Clinical predictors of cumulative CR were estimated glomerular filtration rate (eGFR)

Introduction: Mathematical model can be used to model complex biological processes, and have shown potential in describing apoptosis in chondrocytes.Method: In order to investigate the regulatory mechanisms of TNF signaling pathway in regulating chondrocyte apoptosis, a fractional-order differential equation model is proposed to describe the dynamic behavior and mutual interaction of apoptosis-related genes under the activation of TNF signaling pathway. Compared with the traditional molecular biology techniques, the proposed mathematical modeling has advantages to providing a more comprehensive understanding of the regulatory mechanisms of TNF signaling pathway in chondrocyte apoptosis.Result: In this paper, differentially expressed genes induced by IL-1β in human chondrocyte apoptosis are screened using high-throughput sequencing. It is found that they were significantly enriched in the TNF signaling pathway. Therefore, a mathematical model of the TNF signaling pathway is built. Using real-time PCR experiments, mRNA data is measured and used to identify the model parameters, as well as the correlation coefficient. Finally, the sensitivity of the model parameters is discussed by using numerical simulation methods, which can be used to predict the effects of different interventions and explore the optimal intervention strategies for regulating chondrocyte apoptosis.Discussion: Therefore, fractional-order differential equation modeling plays an important role in understanding the regulatory mechanisms of TNF signaling pathway in chondrocyte apoptosis and its potential clinical applications.

Dissolved oxygen (DO) plays a significant role in maintaining the health of aquatic ecosystems. In this study, we propose a model that incorporates multiple machine learning methods for predicting DO. Firstly, the maximum information coefficient (MIC) was utilized to identify the key drivers of DO. Afterward, the particle swarm optimization (PSO) algorithm was used to enhance the traditional support vector regression (SVR) model, optimizing the penalty factor (c) and the width of the Gaussian kernel function (g). This resulted in the development of a MIC-PSO-SVR-based DO prediction model. As a case study, we analyzed three points (G1, G2, and Z1) located in the mainstem and tributaries of the Shuikou Reservoir in Fujian, China. The original dataset, encompassing various time scales and sample sizes, underwent reclassification. Key factors influencing DO were determined by calculating the MIC values between DO and each monitoring factor. The main findings of this study are as follows: (1) By assessing the correlation between candidate factors and DO, the MIC effectively eliminated irrelevant variables with low correlation, thereby reducing the dataset size. Furthermore, it was observed that the fluctuations in MIC values for each variable stabilized when the sample size exceeded 4000. (2) The model’s performance exhibited improvement with the reduced dataset. For instance, the mean absolute error (MAE) and root mean square error (RMSE) of the hybrid MIC-PSO-SVR model decreased by approximately 66% and 49%, respectively, whereas the R2 and Nash-Sutcliffe efficiency (NSE) are as high as 0.98 and 0.95, showing superior performance compared to the unreduced PSO-SVR model. (3) More importantly, the model successfully predicted sudden hypoxia events in the Shuikou reservoir area from October 11 to November 8, 2021. Additionally, the MIC-PSO-SVR model accurately captured DO changes in the point G2 in front of the Shuikou dam during a hypoxic event in the Shuikou reservoir. The prediction errors during hypoxia were as low as 0.23 mg·L-1 and 0.31 mg·L-1 for 1 h and 24 h, respectively.

Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors originating from chromaffin cells, holding significant clinical importance due to their capacity for excessive catecholamine secretion and associated cardiovascular complications. Roughly 80% of cases are associated with genetic mutations. Based on the functionality of these mutated genes, PPGLs can be categorized into distinct molecular clusters: the pseudohypoxia signaling cluster (Cluster-1), the kinase signaling cluster (Cluster-2), and the WNT signaling cluster (Cluster-3). A pivotal factor in the pathogenesis of PPGLs is hypoxia-inducible factor-2α (HIF2α), which becomes upregulated even under normoxic conditions, activating downstream transcriptional processes associated with pseudohypoxia. This adaptation provides tumor cells with a growth advantage and enhances their ability to thrive in adverse microenvironments. Moreover, pseudohypoxia disrupts immune cell communication, leading to the development of an immunosuppressive tumor microenvironment. Within Cluster-1a, metabolic perturbations are particularly pronounced. Mutations in enzymes associated with the tricarboxylic acid (TCA) cycle, such as succinate dehydrogenase (SDHx), fumarate hydratase (FH), isocitrate dehydrogenase (IDH), and malate dehydrogenase type 2 (MDH2), result in the accumulation of critical oncogenic metabolic intermediates. Notable among these intermediates are succinate, fumarate, and 2-hydroxyglutarate (2-HG), which promote activation of the HIFs signaling pathway through various mechanisms, thus inducing pseudohypoxia and facilitating tumorigenesis. SDHx mutations are prevalent in PPGLs, disrupting mitochondrial function and causing succinate accumulation, which competitively inhibits α-ketoglutarate-dependent dioxygenases. Consequently, this leads to global hypermethylation, epigenetic changes, and activation of HIFs. In FH-deficient cells, fumarate accumulation leads to protein succination, impacting cell function. FH mutations also trigger metabolic reprogramming towards glycolysis and lactate synthesis. IDH1/2 mutations generate D-2HG, inhibiting α-ketoglutarate-dependent dioxygenases and stabilizing HIFs. Similarly, MDH2 mutations are associated with HIF stability and pseudohypoxic response. Understanding the intricate relationship between metabolic enzyme mutations in the TCA cycle and pseudohypoxic signaling is crucial for unraveling the pathogenesis of PPGLs and developing targeted therapies. This knowledge enhances our comprehension of the pivotal role of cellular metabolism in PPGLs and holds implications for potential therapeutic advancements.

In the last 10 years, the Minjiang River, which is the longest river in the Fujian Province in Southeast China, has been facing a downward trend of dissolved oxygen (DO) and a frequent occurrence of hypoxia. In this study, the development of the continuous and short-term presence of low DO was investigated by using the water age concept and average DO consumption concept based on a three-dimensional Environmental Fluid Dynamics Code in the Minjiang River. The results revealed that the spatial distribution of DO was affected by temperature, runoff, pollution emission, tidal advection, and hypoxic water discharge from the reservoir bottom. The continuous low DO in the water of the North Channel occurred frequently when the enough pollutants were aerobically decomposed faster than the rate of oxygen reaeration during the high temperature and low river discharge period. In addition, the water age and reaeration time decreased with a rapid increase in the water flow from the Shuikou dam when the reservoir capacity was released via drainage. The results of this study provide scientific insights on the mechanism involved in the occurrence of hypoxia and suggest countermeasures for addressing hypoxic problems in estuaries. HIGHLIGHTS Water age concept and average dissolved oxygen (DO) consumption concept were used to investigate the low DO by an Environmental Fluid Dynamics Code (EFDC) model.; The spatial distribution of DO was affected by temperature, runoff, pollution emission, tidal advection, and hypoxic water discharge from the reservoir bottom.; The continuous low DO occurred frequently during the high temperature and low river discharge period.;

The excellent property that the intensity of autofocusing beams in the focal plane increases exponentially, makes them especially beneficial for biomedical treatment. We experimentally generate tunable (2+1)-dimensional circular parabolic umbilic beams (CPUBs) for the first time based on the high-dimensional diffraction catastrophe integral, which is determined by the potential function. Such CPUBs have circular and symmetrical intensity distributions in space through radial symmetry transformation. Due to the flexibility of high dimensionality, these light beams have rich light field structures and self-focusing property. Where, the maximum intensity suddenly increases by orders of magnitude in the focal plane. Unlike the classical circular Airy beams, CPUBs exhibit multiple self-focusing points along the optical axis and a needle-like structure during propagation, which can be affected by manipulating the control parameters. The rich properties provide a new perspective for exploring the novel physical mechanisms and phenomena in autofocusing beams. The experimental results verify the correctness of the numerical simulations. CPUBs greatly enrich the autofocusing beam family and will be advantageous for medical treatments, optical micromanipulation, and microscopic imaging.

Senescence is an inevitable biological process. Disturbances in glucose and lipid metabolism are essential features of cellular senescence. Given the important roles of these types of metabolism, we review the evidence for how key metabolic enzymes influence senescence and how senescence-related secretory phenotypes, autophagy, apoptosis, insulin signaling pathways, and environmental factors modulate glucose and lipid homeostasis. We also discuss the metabolic alterations in abnormal senescence diseases and anti-cancer therapies that target senescence through metabolic interventions. Our work offers insights for developing pharmacological strategies to combat senescence and cancer.

Introduction: Clear cell renal cell carcinoma (ccRCC) is associated with unfavorable clinical outcomes. To identify viable therapeutic targets, a comprehensive understanding of intratumoral heterogeneity is crucial. In this study, we conducted bioinformatic analysis to scrutinize single-cell RNA sequencing data of ccRCC tumor and para-tumor samples, aiming to elucidate the intratumoral heterogeneity in the ccRCC tumor microenvironment (TME).Methods: A total of 51,780 single cells from seven ccRCC tumors and five para-tumor samples were identified and grouped into 11 cell lineages using bioinformatic analysis. These lineages included tumor cells, myeloid cells, T-cells, fibroblasts, and endothelial cells, indicating a high degree of heterogeneity in the TME. Copy number variation (CNV) analysis was performed to compare CNV frequencies between tumor and normal cells. The myeloid cell population was further re-clustered into three major subgroups: monocytes, macrophages, and dendritic cells. Differential expression analysis, gene ontology, and gene set enrichment analysis were employed to assess inter-cluster and intra-cluster functional heterogeneity within the ccRCC TME.Results: Our findings revealed that immune cells in the TME predominantly adopted an inflammatory suppression state, promoting tumor cell growth and immune evasion. Additionally, tumor cells exhibited higher CNV frequencies compared to normal cells. The myeloid cell subgroups demonstrated distinct functional properties, with monocytes, macrophages, and dendritic cells displaying diverse roles in the TME. Certain immune cells exhibited pro-tumor and immunosuppressive effects, while others demonstrated antitumor and immunostimulatory properties.Conclusion: This study contributes to the understanding of intratumoral heterogeneity in the ccRCC TME and provides potential therapeutic targets for ccRCC treatment. The findings emphasize the importance of considering the diverse functional roles of immune cells in the TME for effective therapeutic interventions.

In the advanced microelectronic packaging, Cu/Sn joints require high-quality diffusion barriers to inhibit Cu–Sn intermetallic compounds (IMCs) growth and improve the interface brittleness. Cobalt-Phosphorous (Co–P) alloy coatings are ideal candidates due to their good wettability, promising diffusion resistance and low interfacial brittleness. In this work, the microstructural evolution of IMCs between crystalline/amorphous Co–P coatings and lead-free solders during the solid-state diffusion were systemically investigated. The microstructure, phase distribution, and grain characteristics of coatings and IMCs were carefully characterized by SEM, EPMA, EBSD, and TEM. It was found that the consumption rate of crystalline Co–P, 21.2 nm/h, was significantly slower than that of amorphous Co–P, 96.4 nm/h, and exhibited an excellent diffusion resistance, which was attributed to the nanocrystalline structure and the P-rich layer which performed the diffusion barriers for Sn and Cu atoms. Compared with Ni, amorphous Co–P coatings could better improve the interfacial brittleness with soft and ductile Co–Sn compounds (hardness of 3.0 GPa) growing with the rapid diffusion of Co, and the toughened Co–Sn–P attributing to the diffusion of Sn. Kinetic analysis showed that the growth rate-controlling process of Co–Sn IMCs was jointly controlled by interfacial reaction and volume diffusion, and the effect of the interfacial reaction is more pronounced in the amorphous system, which leads to coarse Co–Sn grains that are beneficial to the softness and ductility of IMCs. Crystalline and amorphous Co–P coatings can be applied to the surface treatment for die pads and print-circuit-board pads according to their own characteristics, respectively.

Background: The key focal adhesion protein β1 integrin plays an essential role in early skeletal development. However, roles of β1 integrin expression in osteocytes during the regulation of bone homeostasis and mechanotransduction are incompletely understood. Materials and methods: To study the in vivo function of osteocyte β1 integrin in bone, we utilized the 10-kb Dmp1 (Dentin matrix acidic phosphoprotein 1)-Cre to generate mice with β1 integrin deletion in this cell type. Micro-computerized tomography, bone histomorphometry and immunohistochemistry were performed to determine the effects of osteocyte β1 integrin loss on bone mass accrual and biomechanical properties. In vivo tibial loading model was applied to study the possible involvement of osteocyte β1 integrin in bone mechanotransduction. Results: Loss of β1 integrin expression in osteocytes resulted in a severe low bone mass and impaired biomechanical properties in load-bearing long bones and spines, but not in non-weight-bearing calvariae, in mice. The loss of β1 integrin led to enlarged size of lacunar-canalicular system, abnormal cell morphology, and disorientated nuclei in osteocytes. Furthermore, β1 integrin loss caused shortening and disorientated collagen I fibers in long bones. Osteocyte β1 integrin loss did not impact the osteoclast activities, but significantly reduced the osteoblast bone formation rate and, in the meantime, enhanced the adipogenic differentiation of the bone marrow stromal cells in the bone microenvironment. In addition, tibial loading failed to accelerate the anabolic bone formation and improve collagen I fiber integrity in mutant mice. Conclusions: Our studies demonstrate an essential role of osteocyte β1 integrin in regulating bone homeostasis and mechanotransduction.The transnational potential of this article: This study reveals the regulatory roles of osteocyte β1 integrin in vivo for the maintenance of bone mass accrual, biomechanical properties, extracellular matrix integrity as well as bone mechanobiology, which defines β1 integrin a potential therapeutic target for skeletal diseases, such as osteoporosis.

Abstract Background Cophylogeny reconciliation is a powerful method for analyzing host-parasite (or host-symbiont) co-evolution. It models co-evolution as an optimization problem where the set of all optimal solutions may represent different biological scenarios which thus need to be analyzed separately. Despite the significant research done in the area, few approaches have addressed the problem of helping the biologist deal with the often huge space of optimal solutions. Results In this paper, we propose a new approach to tackle this problem. We introduce three different criteria under which two solutions may be considered biologically equivalent, and then we propose polynomial-delay algorithms that enumerate only one representative per equivalence class (without listing all the solutions). Conclusions Our results are of both theoretical and practical importance. Indeed, as shown by the experiments, we are able to significantly reduce the space of optimal solutions while still maintaining important biological information about the whole space.

Lipid metabolism reprogramming is an important hallmark of tumor progression. Cancer cells require high levels of lipid synthesis and uptake not only to support their continued replication, invasion, metastasis, and survival but also to participate in the formation of biological membranes and signaling molecules. Sterol regulatory element binding proteins (SREBPs) are core transcription factors that control lipid metabolism and the expression of important genes for lipid synthesis and uptake. A growing number of studies have shown that SREBPs are significantly upregulated in human cancers and serve as intermediaries providing a mechanistic link between lipid metabolism reprogramming and malignancy. Different subcellular localizations, including endoplasmic reticulum, Golgi, and nucleus, play an indispensable role in regulating the cleavage maturation and activity of SREBPs. In this review, we focus on the relationship between aberrant regulation of SREBPs activity in three organelles and tumor progression. Because blocking the regulation of lipid synthesis by SREBPs has gradually become an important part of tumor therapy, this review also summarizes and analyzes several current mainstream strategies.

Colon adenocarcinoma is the most common type of colorectal cancer. The prognosis of advanced colorectal cancer patients who received treatment is still very poor. Therefore, identifying new biomarkers for prognosis prediction has important significance for improving treatment strategies. However, the power of biomarker analyses was limited by the used sample size of individual database. In this study, we combined Genotype-Tissue Expression (GTEx) and The Cancer Genome Atlas (TCGA) databases to expand the number of healthy tissue samples. We screened differentially expressed genes between the GTEx healthy samples and TCGA tumor samples. Subsequently, we applied least absolute shrinkage and selection operator (LASSO) regression and multivariate Cox analysis to identify nine prognosis-related immune genes: ANGPTL4, IDO1, NOX1, CXCL3, LTB4R, IL1RL2, CD72, NOS2, and NUDT6. We computed the risk scores of samples based on the expression levels of these genes and divided patients into high- and low-risk groups according to this risk score. Survival analysis results showed a significant difference in survival rate between the two risk groups. The high-risk group had a significantly lower overall survival rate and poorer prognosis. We found the receiver operating characteristic based on the risk score was showed to accurately predict patients’ prognosis. These prognosis-related immune genes may be potential biomarkers for colorectal cancer diagnosis and treatment. Our open-source code is freely available from GitHub at https://github.com/gutmicrobes/Prognosis-model.git.

Abstract Studies have shown that there is a certain correlation between air pollution and various human diseases, especially lung diseases, so it is very meaningful to monitor the concentration of pollutants in the air. Compared with the national air quality monitoring station (national control point), the micro air quality detector has the advantage that it can monitor the concentration of pollutants in real time and grid, but its measurement accuracy needs to be improved. This paper proposes a model combining the least absolute selection and shrinkage operator (LASSO) regression and nonlinear autoregressive models with exogenous inputs (NARX) to calibrate the data measured by the micro air quality detector. Before establishing the LASSO-NARX model, correlation analysis is used to test whether the correlation between the concentration of air pollutants and its influencing factors is significant, and to find out the main factors that affect the concentration of pollutants. Due to the multicollinearity between various influencing factors, LASSO regression is used to further screen the influencing factors and give the quantitative relationship between the pollutant concentration and various influencing factors. In order to improve the prediction accuracy of pollutant concentration, the predicted value of each pollutant concentration in the LASSO regression model and the measurement data of the micro air quality detector are used as input variables, and the LASSO-NARX model is constructed using the NARX neural network. Several indicators such as goodness of fit, root mean square error, mean absolute error and relative mean absolute percent error are used to compare various air quality models. The results show that the prediction results of the LASSO-NARX model are not only better than the LASSO model alone and the NARX model alone, but also better than the commonly used multilayer perceptron and radial basis function neural network. Using this model to calibrate the measurement data of the micro air quality detector can increase the accuracy by 61.3–91.7%.

Crystalline and amorphous cobalt-phosphorus (Co-P) coatings have their own advantages in interfacial diffusion resistance and mechanical ductility of solder joints, respectively, but it cannot be better at both. In this work, the hybrid crystalline-amorphous Co-P coating (Co-9.1 at.% P) was fabricated and applied on the Cu/Sn interface by controlling the crystallinity through compositional design. Combining the advantages of crystalline and amorphous Co-P, strategies for solder joints with high shear strength, ductile intermetallic compounds (IMCs) and slow interface consumption was proposed. The evolution, microstructure, phase, and mechanical properties of the Co-Sn, Co-Sn-P and P-rich layers in solid-state diffusion were systematically characterized and tested by means of SEM, EPMA, EBSD, TEM, nanoindentation, and shear test. It was found that the hybrid Co-P coating achieved a low consumption rate, 14.2 nm/h, attributing to the partially crystalline structure and the Co-Sn-P exfoliation behavior. In addition, solder joints containing large-thickness ductile Co-Sn IMCs, 3.2–3.6 GPa of hardness, was established. The shear strength after aging reached 75.4 MPa relying on the large thickness of Co-Sn IMCs. Severe mechanical loads would be able to be withstand by virtue of the plastic deformation of ductile IMCs. Hybrid crystalline-amorphous Co-P would be a promising interface material in microelectronic packaging.

Glucose-6-phosphate dehydrogenase (G6PD) is the only rate-limiting enzyme in the pentose phosphate pathway (PPP). Rapidly proliferating cells require metabolites from PPP to synthesize ribonucleotides and maintain intracellular redox homeostasis. G6PD expression can be abnormally elevated in a variety of cancers. In addition, G6PD may act as a regulator of viral replication and vascular smooth muscle function. Therefore, G6PD-mediated activation of PPP may promote tumor and non-neoplastic disease progression. Recently, studies have identified post-translational modifications (PTMs) as an important mechanism for regulating G6PD function. Here, we provide a comprehensive review of various PTMs (e.g., phosphorylation, acetylation, glycosylation, ubiquitination, and glutarylation), which are identified in the regulation of G6PD structure, expression and enzymatic activity. In addition, we review signaling pathways that regulate G6PD and evaluate the role of oncogenic signals that lead to the reprogramming of PPP in tumor and non-neoplastic diseases as well as summarize the inhibitors that target G6PD.

PurposeThe purpose of the study was to access the impact of phase 1 cardiac rehabilitation (CR) on cardiac function and hemodynamic changes in patients with coronary heart disease (CHD) and acute heart failure (AHF).Materials and methodsA total of 98 patients with CHD and AHF were recruited and randomized into two groups. Control group received standard pharmacotherapy and CR group received standard pharmacotherapy combined phase 1 CR. NT-proBNP and hemodynamic parameters measured by impedance cardiography (ICG) were estimated at baseline and at the end of treatment period.ResultsPhase 1 CR combined routine medical treatment could lower NT-proBNP levels. The percentage of high-risk patients was significantly decreased in CR group, although the post-treatment NT-proBNP level between control group and CR group showed no significant differences. Similarly, most hemodynamic parameters improved in the CR group, but not in the control group, suggesting that phase 1 CR in combination with the standard pharmacotherapy improved hemodynamic characteristics by elevating cardiac output, ameliorating preload, improving systolic and diastolic function, and relieving afterload, although the post-treatment hemodynamic parameters showed no statistically significant differences between the control group and the CR group.ConclusionPhase 1 CR combined routine medication can improve cardiac function and hemodynamic characteristics in patients with CHD and AHF. Thus, recommendation of phase 1 CR to stable patients is necessary.

AbstractThe shape of tailing particles is essential factors of their macroscopic mechanical properties. Scholars have studied the effects of controllable factors, such as loading method, confining pressure, and strain rate, on the strength of tailing sand. However, research on the tailing particle structure and shape through laboratory tests has proved to be difficult due to the uncertain and discrete tailing particle distribution. Thus, the macro-mesoscopic response of heteromorphic tailing particles is rarely investigated. In this paper, the macro-mesoscopic response of heteromorphic tailing particles is studied using multisphere approximation, and numerical simulation of triaxial tests on the particles is conducted. Nonlinear evolution patterns of porosity, internal friction angle, and cohesion of heteromorphic tailing particles with the variation of angularity were investigated using the flexible boundary program developed in this study, which revealed the intrinsic relationship between the mesostructure evolution mechanism and the macroscopic engineering characteristics of heteromorphic tailing particles. The research results showed that (1) changes in angularity led to tailing particle rearrangements and, in turn, porosity changes. With increased angularity and confining pressure, particle sphericity decreased, and the deviatoric and peak stress increased accordingly. In the meantime, the softening was more significant as the peak stress was exceeded, while the cohesive force generally increased. (2) With fixed particle shape and angularity, the internal friction angle decreased slightly as the effective confining pressure increased. (3) In the shearing process, the simulated contact force chain evolution of tailing particles with different shapes was similar. The disordered contact force chains gradually undergo directional connection, i.e., the increased confining pressure reduced the number of free tailing particles and increased the number of stressed particles. (4) The triaxial stress-strain and peak stress in rigid boundary simulations under different confining pressures were slightly lower than those in the flexible boundary simulations. However, the difference was insignificant, indicating the good feasibility and reasonability of rigid boundary simulations for the macroscopic mechanical behaviors in triaxial tests. The research results could offer more direct insights into the macro-mesoscopic response and mechanical mechanisms of nonspherical particles and provide references for the simulation of tailings at the microscopic levels.

Abstract Background Experimental autoimmune encephalomyelitis (EAE) is a model for inflammatory demyelinating diseases of the central nervous system (CNS), a group of autoimmune diseases characterized by inflammatory infiltration, demyelination, and axonal damage. miR-20a is dysregulated in patients with CNS inflammatory demyelinating diseases; however, the function of miR-20a remains unclear. In this study, we intended to explore the role of miR-20a in EAE. Methods The expression of miR-20a was detected by quantitative real-time PCR (qRT-PCR) in EAE mice and patients with MOG antibody-associated demyelinating diseases. CD4+ T cells of EAE mice were sorted, stimulated, and polarized with miR-20a knockdown. Activation and differentiation of CD4+ T cells were analyzed by flow cytometry. The expression of target gene Map3k9 was detected by qRT-PCR and western blot experiments. The binding of miR-20a to the 3’ UTR of Map3k9 was tested by luciferase assays. The feasibility of miR-20a as a therapeutic target to alleviate the severity of EAE was explored by intravenous administration of miR-20a antagomirs to EAE mice. Results miR-20a was upregulated in splenocytes and lymph node cells, CD4+ T cells, and spinal cords of EAE mice. Moreover, miR-20a knockdown did not influence the activation of antigen-specific CD4+ T cells but promoted their differentiation into Treg cells. Map3k9 was predicted to be a target gene of miR-20a. The expressions of Map3k9 and miR-20a were negatively correlated, and miR-20a knockdown increased the expression of Map3k9. In addition, miR-20a binded to the 3’ UTR of Map3k9, and simultaneous knockdown of miR-20a and Map3k9 counteracted the enhanced differentiation of Tregs observed when miR-20a was knocked down alone. Furthermore, injection of miR-20a antagomirs to EAE mice reduced the severity of the disease and increased the proportion of Treg cells in peripheral immune organs. Conclusions miR-20a suppresses the differentiation of antigen-specific CD4+ T cells into Tregs in EAE by decreasing the expression of Map3k9. miR-20a antagomirs alleviate EAE, suggesting a new therapy for EAE and CNS inflammatory demyelinating diseases.

The Mott transition is a celebrated example of a metal-insulator transition driven by electron correlations. Here, using magnetoresistance measurements, the authors demonstrate the presence of a spin-driven metal-insulator transition, where the insulating gap only opens below the Neel temperature.