Oteseconazole versus fluconazole for the treatment of severe vulvovaginal candidiasis: a multicenter, randomized, double-blinded, phase 3 trial.

Vulvovaginal candidiasis (VVC) is a common condition among women. Fluconazole remains the dominant treatment option for VVC. Oteseconazole is a highly selective inhibitor of fungal CYP51. This randomized, double-blinded, phase 3 trial was conducted to evaluate the efficacy and safety of oteseconazole compared with fluconazole in treating severe VVC. Female subjects presenting with vulvovaginal signs and symptoms score of ≥7 and positive Candida infection determined by potassium hydroxide test or Gram staining were randomly assigned to receive oteseconazole (600 mg on D1 and 450 mg on D2) or fluconazole (150 mg on D1 and D4) in a 1:1 ratio. The primary endpoint was the proportion of subjects achieving therapeutic cure [defined as achieving both clinical cure (absence of signs and symptoms of VVC) and mycological cure (negative culture of Candida species)] at D28. A total of 322 subjects were randomized and 321 subjects were treated. At D28, a statistically significantly higher proportion of subjects achieved therapeutic cure in the oteseconazole group than in the fluconazole group (66.88% vs 45.91%; P = 0.0002). Oteseconazole treatment resulted in an increased proportion of subjects achieving mycological cure (82.50% vs 59.12%; P < 0.0001) and clinical cure (71.25% vs 55.97%; P = 0.0046) compared with fluconazole. The incidence of treatment-emergent adverse events was similar between the two groups. No subjects discontinued study treatment or withdrew study due to adverse events. Oteseconazole showed statistically significant and clinically meaningful superiority over fluconazole for the treatment of severe VVC and was generally tolerated.

Tailoring Broadband Nonlinear Optical Characteristics and Ultrafast Photocarrier Dynamics of Bi2O2S Nanosheets by Defect Engineering.

Low-dimensional bismuth oxychalcogenides have shown promising potential in optoelectronics due to their high stability, photoresponse, and carrier mobility. However, the relevant studies on deep understanding for Bi2O2S is quite limited. Here, comprehensive experimental and computational investigations are conducted in the regulated band structure, nonlinear optical (NLO) characteristics, and carrier dynamics of Bi2O2S nanosheets via defect engineering, taking O vacancy (OV) and substitutional Se doping as examples. As the OV continuously increased to ≈35%, the optical bandgaps progressively narrow from ≈1.21 to ≈0.81 eV and NLO wavelengths are extended to near-infrared regions with enhanced saturable absorption. Simultaneously, the relaxation processes are effectively accelerated from tens of picoseconds to several picoseconds, as the generated defect energy levels can serve as both additional absorption cross-sections and fast relaxation channels supported by theoretical calculations. Furthermore, substitutional Se doping in Bi2O2S nanosheets also modulate their optical properties with the similar trends. As a proof-of-concept, passively mode-locked pulsed lasers in the ≈1.0 µm based on the defect-rich samples (≈35% OV and ≈50% Se-doping) exhibit excellent performance. This work deepens the insight of defect functions on optical properties of Bi2O2S nanosheets and provides new avenues for designing advanced photonic devices based on low-dimensional bismuth oxychalcogenides.

Efficacy and safety of oral ibrexafungerp in Chinese patients with vulvovaginal candidiasis: a phase III, randomized, double-blind study.

PURPOSE: To evaluate the efficacy and safety of oral ibrexafungerp (HS-10366) versus placebo in Chinese patients with vulvovaginal candidiasis (VVC). METHODS: A double-blind, placebo-controlled, randomized, multicenter phase III study was conducted in symptomatic VVC patients. Patients received (2:1) twice-daily oral ibrexafungerp 300 mg or matching placebo for 1 day. The primary endpoint was clinical cure (vulvovaginal signs and symptoms [VSS] score = 0) at test-of-cure (TOC) on day 11 ± 3. The secondary endpoints included mycological eradication, overall response, and clinical improvement (VSS score ≤ 1) at TOC, and vulvovaginal symptom resolution at follow-up on day 25 ± 4. RESULTS: In total, 360 patients were included in the modified intention-to-treat set (defined as positive Candida cultured and receiving at least one study drug; 239 for ibrexafungerp, 121 for placebo). Compared with placebo, patients receiving ibrexafungerp had a significantly higher proportion of clinical cure (51.0% vs. 25.6%), mycological eradication (55.6% vs. 18.2%), overall response (33.9%, vs. 8.3%) at TOC and complete symptom resolution (74.5% vs. 39.7%, all P < 0.001) at follow-up. Subgroup analysis of clinical cure indicated that patients with C. albicans could benefit from ibrexafungerp over placebo. A similar benefit trend was also observed in those with non-albicans Candida by post-hoc analysis. Further analyses revealed similar efficacy of ibrexafungerp between patients with fluconazole non-susceptible C. albicans and fluconazole susceptible C. albicans regarding clinical cure and mycological eradication. Ibrexafungerp was generally well tolerated. Adverse events were primarily gastrointestinal and were mainly mild in severity. CONCLUSIONS: As a first-in-class antifungal agent, ibrexafungerp demonstrated promising efficacy and favorable safety for VVC treatment in Chinese patients. CHINADRUGTRIALS.ORG. CN REGISTRY NUMBER: CTR20220918.

Evaluation of the diagnostic utility on 1.5T and 3.0T 1H magnetic resonance spectroscopy for temporal lobe epilepsy.

BACKGROUND: 1H magnetic resonance spectroscopy (1H-MRS) can be used to study neurological disorders because it can be utilized to examine the concentrations of related metabolites. However, the diagnostic utility of different field strengths for temporal lobe epilepsy (TLE) remains unclear. The purpose of this study is to make quantitative comparisons of metabolites of TLE at 1.5T and 3.0T and evaluate their efficacy. METHODS: Our retrospective collections included the single-voxel 1H-MRS of 23 TLE patients and 17 healthy control volunteers (HCs) with a 1.5T scanner, as well as 29 TLE patients and 17 HCs with a 3.0T scanner. Particularly, HCs were involved both the scans with 1.5T and 3.0T scanners, respectively. The metabolites, including the N-acetylaspartate (NAA), creatine (Cr), and choline (Cho), were measured in the left or right temporal pole of brain. To analyze the ratio of brain metabolites, including NAA/Cr, NAA/Cho, NAA/(Cho + Cr) and Cho/Cr, four controlled experiments were designed to evaluate the diagnostic utility of TLE on 1.5T and 3.0T MRS, included: (1) 1.5T TLE group vs. 1.5T HCs by the Mann-Whitney U Test, (2) 3.0T TLE group vs. 3.0T HCs by the Mann-Whitney U Test, (3) the power analysis for the 1.5T and 3.0T scanner, and (4) 3.0T HCs vs. 1.5T HCs by Paired T-Test. RESULTS: Three metabolite ratios (NAA/Cr, NAA/Cho, and NAA/(Cho + Cr) showed the same statistical difference (p < 0.05) in distinguishing the TLE from HCs in the bilateral temporal poles when using 1.5T or 3.0T scanners. Similarly, the power analysis demonstrated that four metabolite ratios (NAA/Cr, NAA/Cho, NAA/(Cho + Cr), Cho/Cr) had similar distinction abilities between 1.5T and 3.0T scanner, denoting both 1.5T and 3.0T scanners were provided with similar sensitivities and reproducibilities for metabolites detection. Moreover, the metabolite ratios of the same healthy volunteers were not statistically different between 1.5T and 3.0T scanners, except for NAA/Cho (p < 0.05). CONCLUSIONS: 1.5T and 3.0T scanners may have comparable diagnostic potential when 1H-MRS was used to diagnose patients with TLE.

Bone morphogenetic protein 6-mediated crosstalk between endothelial cells and hepatocytes recapitulates the iron-sensing pathway in vitro.

Liver sinusoidal endothelial cell-derived bone morphogenetic protein 6 (BMP6) and the BMP6-small mothers against decapentaplegic homolog (SMAD) signaling pathway are essential for the expression of hepcidin, the secretion of which is considered the systemic master switch of iron homeostasis. However, there are continued controversies related to the strong and direct suppressive effect of iron on hepatocellular hepcidin in vitro in contrast to in vivo conditions. Here, we directly studied the crosstalk between endothelial cells (ECs) and hepatocytes using in vitro coculture models that mimic hepcidin signaling in vivo. Huh7 cells were directly cocultured with ECs, and EC conditioned media (CM) were also used to culture Huh7 cells and primary mouse hepatocytes. To explore the reactions of ECs to surrounding iron, they were grown in the presence of ferric ammonium citrate and heme, two iron-containing molecules. We found that both direct coculture with ECs and EC-CM significantly increased hepcidin expression in Huh7 cells. The upstream SMAD pathway, including phosphorylated SMAD1/5/8, SMAD1, and inhibitor of DNA binding 1, was induced by EC-CM, promoting hepcidin expression. Efficient blockage of this EC-mediated hepcidin upregulation by an inhibitor of the BMP6 receptor ALK receptor tyrosine kinase 2/3 or BMP6 siRNA identified BMP6 as a major hepcidin regulator in this coculture system, which highly fits the model of hepcidin regulation by iron in vivo. In addition, EC-derived BMP6 and hepcidin were highly sensitive to levels of not only ferric iron but also heme as low as 500 nM. We here establish a hepatocyte-endothelial coculture system to fully recapitulate iron regulation by hepcidin using EC-derived BMP6.

Low selenium intake is associated with postpartum weight retention in Chinese women and impaired physical development of their offspring.

The aim of this study was to investigate the association between daily Se intake and postpartum weight retention (PPWR) among Chinese lactating women, and the impact of their Se nutritional status on infants' physical development. Se contents in breast milk and plasma collected from 264 lactating Chinese women at the 42nd day postpartum were analysed with inductively coupled plasma MS. Daily Se intake was calculated based on plasma Se concentration. The dietary data of 24-h records on three consecutive days were collected. Infant growth status was evaluated with WHO standards by Z-scores. Linear regression analyses and multinomial logistic regression were conducted to examine the impact of Se disequilibrium (including other factors) on PPWR and growth of infants, respectively. The results indicated that: (1) the daily Se intake of the subjects was negatively associated with their PPWR (B = -0·002, 95 % CI - 0·003, 0·000, P = 0·039); (2) both insufficient Se daily intake (B = -0·001, OR 0·999, 95 % CI 0·998, 1·000, P = 0·014) and low level of Se in milk (B = -0·025, OR 0·975, 95 % CI 0·951, 0·999, P = 0·021) had potential associations with their infants' wasting, and low level of Se in milk (B = -0·159, OR 0·853, 95 % CI 0·743, 0·980, P = 0·024) had a significant association with their infants' overweight. In conclusion, the insufficient Se nutritional status of lactating Chinese women was first found as one possible influencing factor of their PPWR as well as low physical development of their offspring.

[Association of fetal cardiac structural abnormalities and chromosomal aneuploidies and copy number variations].

OBJECTIVE: To investigate the association of fetal cardiac structural abnormalities with chromosomal aneuploidies and copy number variations (CNVs) in amniocytes. METHODS: 328 pregnant women were subjected to fetal ultrasonography and chromosomal microarray analysis (CMA). Based on the fetal heart structure, the subjects were divided into normal (n=273) and abnormal groups (n=55). The detection rates of chromosomal aneuploidies and CNVs were compared between the two groups. Spearman method was used to assess the association between the results and fetal cardiac structural abnormalities. RESULTS: The detection rates for chromosomal aneuploidies and CNVs in the abnormal group were significantly higher than that in the normal group (P< 0.05), and the incidence of fetal cardiac structural abnormalities was strongly associated with chromosomal aneuploidies and CNVs (P< 0.05). CONCLUSION: Fetal chromosomal aneuploidies and CNVs are strongly associated with cardiac structural abnormalities.

Identification of differentially expressed genes by single-cell transcriptional profiling of umbilical cord and synovial fluid mesenchymal stem cells.

The purpose of this study was to measure the heterogeneity in human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) and human synovial fluid-derived mesenchymal stem cells (hSF-MSCs) by single-cell RNA-sequencing (scRNA-seq). Using Chromium™ technology, scRNA-seq was performed on hUC-MSCs and hSF-MSCs from samples that passed our quality control checks. In order to identify subgroups and activated pathways, several bioinformatics tools were used to analyse the transcriptomic profiles, including clustering, principle components analysis (PCA), t-Distributed Stochastic Neighbor Embedding (t-SNE), gene set enrichment analysis, as well as Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. scRNA-seq was performed on the two sample sets. In total, there were 104 761 163 reads for the hUC-MSCs and 6 577 715 for the hSF-MSCs, with >60% mapping rate. Based on PCA and t-SNE analyses, we identified 11 subsets within hUC-MSCs and seven subsets within hSF-MSCs. Gene set enrichment analysis determined that there were 533, 57, 32, 44, 10, 319, 731, 1037, 90, 25 and 230 differentially expressed genes (DEGs) in the 11 subsets of hUC-MSCs and 204, 577, 30, 577, 16, 57 and 35 DEGs in the seven subsets of hSF-MSCs. scRNA-seq was not only able to identify subpopulations of hUC-MSCs and hSF-MSCs within the sample sets, but also provided a digital transcript count of hUC-MSCs and hSF-MSCs within a single patient. scRNA-seq analysis may elucidate some of the biological characteristics of MSCs and allow for a better understanding of the multi-directional differentiation, immunomodulatory properties and tissue repair capabilities of MSCs.

Prevalence and Clinical Significance of Portal Vein Thrombosis in Patients With Cirrhosis and Acute Decompensation.

BACKGROUND & AIMS: Portal vein thrombosis (PVT) is a common and serious complication in patients with cirrhosis. However, little is known about PVT in patients with cirrhosis and acute decompensation (AD). We investigated the prevalence and clinical significance of PVT in nonmalignant patients with cirrhosis and AD. METHODS: We performed a retrospective study of 2 cohorts of patients with acute exacerbation of chronic liver disease who participated in the Chinese AcuTe on CHronic LIver FailurE study, established by the Chinese Chronic Liver Failure Consortium, from January 2015 through December 2016 (n = 2600 patients) and July 2018 through January 2019 (n = 1370 patients). We analyzed data on the prevalence, clinical manifestations, and risk factors of PVT from 2826 patients with cirrhosis, with and without AD. RESULTS: The prevalence of PVT in patients with cirrhosis and AD was 9.36%, which was significantly higher than in patients with cirrhosis without AD (5.24%) (P = .04). Among patients with cirrhosis and AD, 63.37% developed PVT recently (the first detected PVT with no indication of chronic PVT). Compared with patients without PVT, a significantly higher proportion of patients with PVT had variceal bleeding (47.33% vs 19.63%; P < .001) and patients with PVT had a significantly higher median serum level of D-dimer (2.07 vs 1.25; P < .001). Splenectomy and endoscopic sclerotherapy were independent risk factors for PVT in patients with cirrhosis and AD. The 1-year mortality rate did not differ significantly between patients with vs without PVT. CONCLUSIONS: In an analysis of data from 2826 patients with cirrhosis, a significantly higher proportion of those with AD had PVT than those without AD. PVT was associated with increased variceal bleeding, which would increase the risk for AD. Strategies are needed to prevent PVT in patients with cirrhosis, through regular screening, to reduce portal hypertension. ClinicalTrials.gov no: NCT02457637 and NCT03641872.

The impact of HBV flare on the outcome of HBV-related decompensated cirrhosis patients with bacterial infection.

BACKGROUND: Hepatitis B virus (HBV) flare can occur in HBV patients either naïve or have interruption to treatment. Bacterial infection (BI) is a common complication of cirrhosis with potential severe outcomes. We aimed to assess the impact of HBV flare on the outcome of patients with HBV-related decompensated cirrhosis and BI. METHODS: This was a retrospective study from 2 tertiary academic hospitals in Shanghai, China of HBV patients admitted with or developed BI during admission. The characteristics of BI, prevalence of HBV flare, its impact on organ failure, acute-on-chronic liver failure (ACLF) and 90-day survival were evaluated. RESULTS: A total of 360 hospitalized patients (median age: 50 years, male: 79%, BI: at admission: 58.6%; during admission: 41.4%) were included. All patients including those with HBV flare (21%) received antiviral therapy after admission. Patients with HBV flare and BI had significantly higher percentage of liver (93.3% vs 48.8%), coagulation (64.0% vs 39.6%), cerebral (40.0% vs 21.8%) (all P < 0.01), and kidney failure (38.7% vs 26.3%, P < 0.05) compared to BI alone, associated with a higher risk of developing ACLF with a subdistribution hazard ratio (sHR) of 2.23 (95% confidence interval [CI]: 1.68-2.96). Multivariate analysis showed that ACLF development was the strongest risk factor for 90-day mortality (sHR, 95%CI: 7.36, 4.12-13.16). CONCLUSIONS: In HBV-related decompensated cirrhosis patients admitted with BI, HBV flare increased the risk of additional organ failures and ACLF, raising the risk of 90-day mortality by seven-fold. Optimization of HBV treatment in these patients should minimize the risk of HBV flare with improved outcomes.

Breast milk selenocystine as a biomarker for selenium intake in lactating women at differential geographical deficiency risk in China.

BACKGROUND AND OBJECTIVES: A reliable biomarker for optimal selenium (Se) intake in lactating women is not currently available. METHODS AND STUDY DESIGN: Daily dietary Se intake in lactating women was calculated from a 24-hour meal record survey for over 3 days. Se levels in plasma and breast milk were measured through inductively coupled plasma mass spectrometry. Plasma selenoprotein P 1 levels and glutathione peroxidase 3 activity were measured using an enzyme-linked immunosorbent assay. Ultra-performance liquid chromatography-tandem mass spectrometry was used to analyze proteinaceous Se species in enzymatically digested breast milk. RESULTS: Dietary Se intakes of lactating women from Liangshan, Beijing, and Enshi were 41.6±21.2 ng/d, 51.1±22.6 ng/d, and 615±178 ng/d, respectively (p<0.05). The Se levels in the blood and breast milk were significantly associated with the dietary Se intake (p<0.05). The proteinaceous Se species in breast milk were SeMet and SeCys2. The levels of SeMet in the lactating women from Liangshan, Beijing, and Enshi were 3.31±2.44 ng Se/mL, 7.34±3.70 ng Se/mL, and 8.99±9.64 ng Se/mL, while that of SeCys2 were 13.7±12.0 ng Se/mL, 35.6±20.9 ng Se/mL, and 57.4±13.2 ng Se/mL, respectively. Notably, the concentration of SeCys2, the metabolite of unstable SeCys, reached a saturation platform, whereas no similar phenomenon were found for the total Se SeMet from Secontaining proteins. CONCLUSIONS: SeCys2 in breast milk is a potential biomarker for determining the optimal Se intake in lactating women.

Metal hypersensitivity in patient with posterior lumbar spine fusion: a case report and its literature review.

BACKGROUND: Metal hypersensitivity, mostly documented in prosthesis implantation, is a rare complication after arthroplasty. Such cases become rarer and more difficult to diagnose when it comes to lumbar surgery. CASE PRESENTATION: We present the case of a 52-year-old female patient with reoccured low back pain and sciatica after posterior lumbar decompression and fusion (PLDF) for her lumbar disc herniation. The initial clinical and radiological examinations showed no pathologies. Further imaging and histopathological studies in later period revealed an aseptic loosening of the hardware and an aseptic inflammatory response which was diagnosed to be metal hypersensitivity. To our knowledge, few allergic cases in the matter of spinal fusion were reported so far. CONCLUSIONS: Metal hypersensitivity after spinal fusion should be considered in patients with representation of postoperative back pain. And elaborate history taking would conduce a lot to it's diagnose.

Posterior short segment pedicle screw fixation and TLIF for the treatment of unstable thoracolumbar/lumbar fracture.

BACKGROUND: Currently, Posterior Short Segment Pedicle Screw Fixation is a popular procedure for treating unstable thoracolumbar/lumbar burst fracture. But progressive kyphosis and a high rate of hardware failure because of lack of the anterior column support remains a concern. The efficacy of different methods remains debatable and each technique has its advantages and disadvantages. METHODS: A consecutive series of 20 patients with isolated thoracolumbar/lumbar burst fractures were treated by posterior short segment pedicle screw fixation and transforaminal thoracolumbar/lumbar interbody fusion (TLIF) between January 2005 and December 2007. All patients were followed up for a minimum of 2 years. Demographic data, neurologic status, anterior vertebral body heights, segmental Cobb angle and treatment-related complications were evaluated. RESULTS: The mean operative time was 167 minutes (range, 150-220). Blood loss was 450 ~ 1200 ml, an average of 820 ml. All patients recovered with solid fusion of the intervertebral bone graft, without main complications like misplacement of the pedicle screw, nerve or vessel lesion or hard ware failure. The post-operative radiographs demonstrated a good fracture reduction and it was well maintained until the bone graft fusion. Neurological recovery of one to three Frankel grade was seen in 14 patients with partial neurological deficit, three grades of improvement was seen in one patient, two grades of improvement was observed in 6 patients and one grade of improvement was found in 6 patients. All the 6 patients with no paraplegia on admission remained neurological intact, and in one patient with Frankel D on admission no improvement was observed. CONCLUSION: Posterior short-segment pedicle fixation in conjunction with TLIF seems to be a feasible option in the management of selected thoracolumbar/lumbar burst fractures, thereby addressing all the three columns through a single approach with less trauma and good results.

Frontiers in sarcopenia: Advancements in diagnostics, molecular mechanisms, and therapeutic strategies.

The onset of sarcopenia is intimately linked with aging, posing significant implications not only for individual patient quality of life but also for the broader societal healthcare framework. Early and accurate identification of sarcopenia and a comprehensive understanding of its mechanistic underpinnings and therapeutic targets paramount to addressing this condition effectively. This review endeavors to present a cohesive overview of recent advancements in sarcopenia research and diagnosis. We initially delve into the contemporary diagnostic criteria, specifically referencing the European Working Group on Sarcopenia in Older People (EWGSOP) 2 and Asian Working Group on Sarcopenia (AWGS) 2019 benchmarks. Additionally, we elucidate comprehensive assessment techniques for muscle strength, quantity, and physical performance, highlighting tools such as grip strength, chair stand test, dual-energy X-ray Absorptiometry (DEXA), bioelectrical impedance analysis (BIA), gait speed, and short physical performance battery (SPPB), while also discussing their inherent advantages and limitations. Such diagnostic advancements pave the way for early identification and unequivocal diagnosis of sarcopenia. Proceeding further, we provide a deep-dive into sarcopenia's pathogenesis, offering a thorough examination of associated signaling pathways like the Myostatin, AMP-activated protein kinase (AMPK), insulin/IGF-1 Signaling (IIS), and the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathways. Each pathway's role in sarcopenia mediation is detailed, underscoring potential therapeutic target avenues. From a mechanistic perspective, the review also underscores the pivotal role of mitochondrial dysfunction in sarcopenia, emphasizing elements such as mitochondrial oxidative overload, mitochondrial biogenesis, and mitophagy, and highlighting their therapeutic significance. At last, we capture recent strides made in sarcopenia treatment, ranging from nutritional and exercise interventions to potential pharmacological and supplementation strategies. In sum, this review meticulously synthesizes the latest scientific developments in sarcopenia, aiming to enhance diagnostic precision in clinical practice and provide comprehensive insights into refined mechanistic targets and innovative therapeutic interventions, ultimately contributing to optimized patient care and advancements in the field.

The potential value of the Purinergic pathway in the prognostic assessment and clinical application of kidney renal clear cell carcinoma.

The Purinergic pathway is involved in a variety of important physiological processes in living organisms, and previous studies have shown that aberrant expression of the Purinergic pathway may contribute to the development of a variety of cancers, including kidney renal clear cell carcinoma (KIRC). The aim of this study was to delve into the Purinergic pathway in KIRC and to investigate its potential significance in prognostic assessment and clinical treatment. 33 genes associated with the Purinergic pathway were selected for pan-cancer analysis. Cluster analysis, targeted drug sensitivity analysis and immune cell infiltration analysis were applied to explore the mechanism of Purinergic pathway in KIRC. Using the machine learning process, we found that combining the Lasso+survivalSVM algorithm worked well for predicting survival accuracy in KIRC. We used LASSO regression to pinpoint nine Purinergic genes closely linked to KIRC, using them to create a survival model for KIRC. ROC survival curve was analyzed, and this survival model could effectively predict the survival rate of KIRC patients in the next 5, 7 and 10 years. Further univariate and multivariate Cox regression analyses revealed that age, grading, staging, and risk scores of KIRC patients were significantly associated with their prognostic survival and were identified as independent risk factors for prognosis. The nomogram tool developed through this study can help physicians accurately assess patient prognosis and provide guidance for developing treatment plans. The results of this study may bring new ideas for optimizing the prognostic assessment and therapeutic approaches for KIRC patients.

Evaluating the Role of Neddylation Modifications in Kidney Renal Clear Cell Carcinoma: An Integrated Approach Using Bioinformatics, MLN4924 Dosing Experiments, and RNA Sequencing.

BACKGROUND: Neddylation, a post-translational modification process, plays a crucial role in various human neoplasms. However, its connection with kidney renal clear cell carcinoma (KIRC) remains under-researched. METHODS: We validated the Gene Set Cancer Analysis Lite (GSCALite) platform against The Cancer Genome Atlas (TCGA) database, analyzing 33 cancer types and their link with 17 neddylation-related genes. This included examining copy number variations (CNVs), single nucleotide variations (SNVs), mRNA expression, cellular pathway involvement, and methylation. Using Gene Set Variation Analysis (GSVA), we categorized these genes into three clusters and examined their impact on KIRC patient prognosis, drug responses, immune infiltration, and oncogenic pathways. Afterward, our objective is to identify genes that exhibit overexpression in KIRC and are associated with an adverse prognosis. After pinpointing the specific target gene, we used the specific inhibitor MLN4924 to inhibit the neddylation pathway to conduct RNA sequencing and related in vitro experiments to verify and study the specificity and potential mechanisms related to the target. This approach is geared towards enhancing our understanding of the prognostic importance of neddylation modification in KIRC. RESULTS: We identified significant CNV, SNV, and methylation events in neddylation-related genes across various cancers, with notably higher expression levels observed in KIRC. Cluster analysis revealed a potential trade-off in the interactions among neddylation-related genes, where both high and low levels of gene expression are linked to adverse prognoses. This association is particularly pronounced concerning lymph node involvement, T stage classification, and Fustat score. Simultaneously, our research discovered that PSMB10 exhibits overexpression in KIRC when compared to normal tissues, negatively impacting patient prognosis. Through RNA sequencing and in vitro assays, we confirmed that the inhibition of neddylation modification could play a role in the regulation of various signaling pathways, thereby influencing the prognosis of KIRC. Moreover, our results underscore PSMB10 as a viable target for therapeutic intervention in KIRC, opening up novel pathways for the development of targeted treatment strategies. CONCLUSION: This study underscores the regulatory function and potential mechanism of neddylation modification on the phenotype of KIRC, identifying PSMB10 as a key regulatory target with a significant role in influencing the prognosis of KIRC.

The SAMHD1-MX2 axis restricts HIV-1 infection at postviral DNA synthesis.

HIV-1 replication is tightly regulated in host cells, and various restriction factors have important roles in inhibiting viral replication. SAMHD1, a well-known restriction factor, suppresses HIV-1 replication by hydrolyzing intracellular dNTPs, thereby limiting the synthesis of viral cDNA in quiescent cells. In this study, we revealed an additional and distinct mechanism of SAMHD1 inhibition during the postviral cDNA synthesis stage. Using immunoprecipitation and mass spectrometry analysis, we demonstrated the interaction between SAMHD1 and MX2/MxB, an interferon-induced antiviral factor that inhibits HIV-1 cDNA nuclear import. The disruption of endogenous MX2 expression significantly weakened the ability of SAMHD1 to inhibit HIV-1. The crucial region within SAMHD1 that binds to MX2 has been identified. Notably, we found that SAMHD1 can act as a sensor that recognizes and binds to the incoming HIV-1 core, subsequently delivering it to the molecular trap formed by MX2, thereby blocking the nuclear entry of the HIV-1 core structure. SAMHD1 mutants unable to recognize the HIV-1 core showed a substantial decrease in antiviral activity. Certain mutations in HIV-1 capsids confer resistance to MX2 inhibition while maintaining susceptibility to suppression by the SAMHD1-MX2 axis. Overall, our study identifies an intriguing antiviral pattern wherein two distinct restriction factors, SAMHD1 and MX2, collaborate to establish an alternative mechanism deviating from their actions. These findings provide valuable insight into the complex immune defense networks against exogenous viral infections and have implications for the development of targeted anti-HIV therapeutics. IMPORTANCE: In contrast to most restriction factors that directly bind to viral components to exert their antiviral effects, SAMHD1, the only known deoxynucleotide triphosphate (dNTP) hydrolase in eukaryotes, indirectly inhibits viral replication in quiescent cells by reducing the pool of dNTP substrates available for viral cDNA synthesis. Our study provides a novel perspective on the antiviral functions of SAMHD1. In addition to its role in dNTP hydrolysis, SAMHD1 cooperates with MX2 to inhibit HIV-1 nuclear import. In this process, SAMHD1 acts as a sensor for incoming HIV-1 cores, detecting and binding to them, before subsequently delivering the complex to the molecular trap formed by MX2, thereby immobilizing the virus. This study not only reveals a new antiviral pathway for SAMHD1 but also identifies a unique collaboration and interaction between two distinct restriction factors, establishing a novel line of defense against HIV-1 infection, which challenges the traditional view of restriction factors acting independently. Overall, our findings further indicate the intricate complexity of the host immune defense network and provide potential targets for promoting host antiviral immune defense.

The diversity and risk of potential pathogenic bacteria on the surface of glaciers in the southeastern Tibetan Plateau.

Glaciers, which constitute the world's largest global freshwater reservoir, are also natural microbial repositories. The frequent pandemic in recent years underscored the potential biosafety risks associated with the release of microorganisms from the accelerated melting of glaciers due to global warming. However, the characteristics of pathogenic microorganisms in glaciers are not well understood. The glacier surface is the primary area where glacier melting occurs that is often the main subject of research on the dynamics of pathogenic microbial communities in efforts to assess glacier biosafety risks and devise preventive measures. In this study, high-throughput sequencing and quantitative polymerase chain reaction methods were employed in analyses of the composition and quantities of potential pathogenic bacteria on the surfaces of glaciers in the southeastern Tibetan Plateau. The study identified 441 potential pathogenic species ranging from 215 to 4.39 × 1011 copies/g, with notable seasonal and environmental variations being found in the composition and quantity of potential pathogens. The highest level of diversity was observed in April and snow, while the highest quantities were observed in October and cryoconite. Host analysis revealed that >70 % of the species were pathogens affecting animals, with the highest proportion of zoonotic pathogens being observed in April. Analysis of aerosols and glacial meltwater dispersion suggested that these microbes originated from West Asia, primarily affecting the central and southern regions of China. Null model analysis indicated that the assembly of potential pathogenic microbial communities on glacier surfaces was largely governed by deterministic processes. In conclusion, potential pathogenic bacteria on glacier surfaces mainly originated from the snow and exhibited significant temporal and spatial variation patterns. These findings can be used to enhance researchers' ability to predict potential biosafety risks associated with pathogenic bacteria in glaciers and to prevent their negative impact on populations and ecological systems.

South and Southeast Asia controls black carbon characteristics of Meili Snow Mountains in southeast Tibetan Plateau.

South and Southeast Asia (SSA) emitted black carbon (BC) exerts potential effects on glacier and snow melting and regional climate change in the Tibetan Plateau. In this study, online BC measurements were conducted for 1 year at a remote village located at the terminus of the Mingyong Glacier below the Meili Snow Mountains. The Weather Research and Forecasting model coupled with Chemistry (WRF-Chem) was used to investigate the contribution and potential effect of SSA-emitted BC. In addition, variations in the light absorption characteristics of BC and brown carbon (BrC) were examined. The results indicated that the annual mean concentration of BC was 415 ± 372 ngm-3, with the highest concentration observed in April (monthly mean: 930 ± 484 ngm-3). BC exhibited a similar diurnal variation throughout the year, with two peaks observed in the morning (from 8:00 to 9:00 AM) and in the afternoon (from 4:00 to 5:00 PM), with even lower values at nighttime. At a short wavelength of 370 nm, the absorption coefficient (babs) reached its maximum value, and the majority of babs values were < 20 Mm-1, indicating that the atmosphere was not overloaded with BC. At the same wavelength, BrC substantially contributed to babs, with an annual mean of 25.2 % ± 12.8 %. SSA was the largest contributor of BC (annual mean: 51.1 %) in the study area, particularly in spring (65.6 %). However, its contributions reached 20.2 % in summer, indicating non-negligible emissions from activities in other regions. In the atmosphere, the SSA BC-induced radiative forcing (RF) over the study region was positive. While at the near surface, the RF exhibited a significant seasonal variation, with the larger RF values occurring in winter and spring. Overall, our findings highlight the importance of controlling BC emissions from SSA to protect the Tibetan Plateau against pollution-related glacier and snow cover melting.

Biomass burning records of the Shulehe Glacier No. 4 from Northeastern Tibetan Plateau.

Biomass burning play a key role in the global carbon cycle by altering the atmospheric composition, and affect regional and global climate. Despite its importance, a very few high-resolution records are available worldwide, especially for recent climate change. This study analyzes levoglucosan, a specific tracer of biomass burning emissions, in a 38-year ice core retrieved from the Shulehe Glacier No. 4, northeastern Tibetan Plateau. The levoglucosan concentration in the Shulehe Glacier No. 4 ice core ranged from 0.1 to 55 ng mL-1, with an average concentration of 8 ± 8 ng mL-1. The concentrations showed a decreasing trend from 2002 to 2018. Meanwhile, regional wildfire activities in Central Asian also exhibited a declining trend during the same period, suggesting the potential correspondence between levoglucosan concentration of the Shulehe Glacier No. 4 ice core and the fire activity of Central Asia. Furthermore, a positive correlation also exists between the levoglucosan concentration of the Shulehe Glacier No. 4 ice core and the wildfire counts in Central Asia from 2002 to 2018. While backward air mass trajectory analysis and fire spots data showed a higher distribution of fire counts in South Asia compared to Central Asia, but the dominance of westerly circulation in the northern TP throughout the year. Therefore, the levoglucosan in the Shulehe Glacier No. 4 provides clear evidence of Central Asian wildfire influence on Tibetan Plateau glaciers through westerlies. This highlights a great importance of ice core data for wildfire history reconstruction in the Tibetan Plateau Glacier regions.