Logic-Based Strategy for Spatiotemporal Release of Dual Extracellular Vesicles in Osteoarthritis Treatment.

To effectively treat osteoarthritis (OA), the existing inflammation must be reduced before the cartilage damage can be repaired; this cannot be achieved with a single type of extracellular vesicles (EVs). Here, a hydrogel complex with logic-gates function is proposed that can spatiotemporally controlled release two types of EVs: interleukin 10 (IL-10)+ EVs to promote M2 polarization of macrophage, and SRY-box transcription factor 9 (SOX9)+ EVs to increase cartilage matrix synthesis. Following dose-of-action screening, the dual EVs are loaded into a matrix metalloporoteinase 13 (MMP13)-sensitive self-assembled peptide hydrogel (KM13E) and polyethylene glycol diacrylate/gelatin methacryloyl-hydrogel microspheres (PGE), respectively. These materials are mixed to form a "microspheres-in-gel" KM13E@PGE system. In vitro, KM13E@PGE abruptly released IL-10+ EVs after 3 days and slowly released SOX9+ EVs for more than 30 days. In vivo, KM13E@PGE increased the CD206+ M2 macrophage proportion in the synovial tissue and decreased the tumor necrosis factor-α and IL-1ß levels. The aggrecan and SOX9 expressions in the cartilage tissues are significantly elevated following inflammation subsidence. This performance is not achieved using anti-inflammatory or cartilage repair therapy alone. The present study provides an injectable, integrated delivery system with spatiotemporal control release of dual EVs, and may inspire logic-gates strategies for OA treatment.

Short-Term Exposure to PM2.5 Chemical Components and Depression Outpatient Visits: A Case-Crossover Analysis in Three Chinese Cities.

BACKGROUND: The association between specific chemical components of PM2.5 and depression remains largely unknown. METHODS: We conducted a time-stratified case-crossover analysis with a distributed lag nonlinear model (DLNM) to evaluate the relationship of PM2.5 and its chemical components, including black carbon (BC), organic matter (OM), sulfate (SO42-), nitrate (NO3-), and ammonium (NH4+), with the depression incidence. Daily depression outpatients were enrolled from Huizhou, Shenzhen, and Zhaoqing. RESULTS: Among 247,281 outpatients, we found the strongest cumulative effects of PM2.5 and its chemical components with the odd ratios (ORs) of 1.607 (95% CI: 1.321, 1.956) and 1.417 (95% CI: 1.245, 1.612) at the 50th percentile of PM2.5 and OM at lag 21, respectively. Furthermore, the ORs with SO42- and NH4+ at the 75th percentile on the same lag day were 1.418 (95% CI: 1.247, 1.613) and 1.025 (95% CI: 1.009, 1.140). Relatively stronger associations were observed among females and the elderly. CONCLUSIONS: Our study suggests that PM2.5 and its chemical components might be important risk factors for depression. Reducing PM2.5 emissions, with a particular focus on the major sources of SO42- and OM, might potentially alleviate the burden of depression in South China.

Exploring myometrial microenvironment changes at the single-cell level from nonpregnant to term pregnant states.

The microenvironment and cell populations within the myometrium play crucial roles in maintaining uterine structural integrity and protecting the fetus during pregnancy. However, the specific changes occurring at the single-cell level in the human myometrium between nonpregnant (NP) and term pregnant (TP) states remain unexplored. In this study, we used single-cell RNA sequencing (scRNA-Seq) and spatial transcriptomics (ST) to construct a transcriptomic atlas of individual cells in the myometrium of NP and TP women. Integrated analysis of scRNA-Seq and ST data revealed spatially distinct transcriptional characteristics and examined cell-to-cell communication patterns based on ligand-receptor interactions. We identified and categorized 87,845 high-quality individual cells into 12 populations from scRNA-Seq data of 12 human myometrium tissues. Our findings demonstrated alterations in the proportions of five subpopulations of smooth muscle cells in TP. Moreover, an increase in monocytic cells, particularly M2 macrophages, was observed in TP myometrium samples, suggesting their involvement in the anti-inflammatory response. This study provides unprecedented single-cell resolution of the NP and TP myometrium, offering new insights into myometrial remodeling during pregnancy.NEW & NOTEWORTHY Using single-cell RNA sequencing and spatial transcriptomics, the myometrium was examined at the single-cell level during pregnancy. We identified spatially distinct cell populations and observed alterations in smooth muscle cells and increased M2 macrophages in term pregnant women. These findings offer unprecedented insights into myometrial remodeling and the anti-inflammatory response during pregnancy. The study advances our understanding of pregnancy-related myometrial changes.

sFlt-1/PIGF ratio positive associated with non-dipper type change in ambulatory blood pressure monitoring(ABPM) for preeclampsia development.

In order to explore relationship of ambulatory blood pressure monitoring (ABPM) and soluble fms-like tyrosine kinase-1/placental growth factor (sFlt-1/PlGF) in suspected preeclampsia(PE), suspected PE participants in 28 + 0 to 33 + 6 weeks underwent ABPM and sFlt-1/PlGF from July 2020 to July 2022 were included(N = 476) in study. ABPM parameters were compared between sFlt-1/PlGF ≥38 and <38 groups. Correlation analysis was performed between ABPM and sFlt-1/PlGF, and logistic regression was used to explore prediction value for PE in 2 weeks. One hundred eighteen cases developed PE in 2 weeks with 114 from sFlt-1/PlGF ≥38 group. Daytime and nighttime BP were all increased,with increased non-dipper (58.4% vs. 30.3%), riser (22.1% vs. 13.1%) and and decreased Dipper (15.4% vs. 45.9%) type of ABPM in sFlt-1/PlGF ≥38 groups (P < 0.05).The riser group had the highest sFlt-1 and lowest PlGF. sFlt-1/PlGF and sFlt-1 were all positively correlated with systolic (SBP) & diastolic blood pressure(DBP)(P < 0.01), in which correlation coefficients of daytime and nighttime BP with sFlt-1 were ß = 150.05 & 157.67 for SBP, ß = 234 and 199.01 for DBP, respectively. However, PlGF was only negatively associated with nighttime SBP and DBP(P < 0.05), with no correlation with daytime BP (P > 0.05).Combining sFlt-1/PlGF and ABPM model, showed sFlt-1/PlGF (aOR = 2.01 (1.69-2.36)), Nighttime DBP (aOR = 1.14 (1.02-1.28)) contributed to preeclampsia prediction, and had improved predictive value compared to ABPM or sFlt-1/PlGF models alone(P < 0.05). sFlt-1/PlGF ratio was positively correlated with BP parameters, whereas PIGF was only negatively correlated with nocturnal BP and increased non-dipper type change in ABPM, which had a synergistic effect with sFlt-1/PlGF on PE prediction.

Natural and anthropogenic controls on environmental change during the Holocene based on a multi-proxy record obtained from subalpine peatland in southern China.

The interactions between past climate, human activity and environmental change in subtropical mountainous areas are poorly understood due to the lack of reliable records in South China. In this study, the evolution of the East Asian summer monsoon (EASM) during the Holocene, and the interactions between regional human activity and environmental change, were studied using multi-proxy records from a subalpine peat core recovered from South China. The chronology of this peat core has been well-constrained by 10 AMS 14C dates of peat stems. A series of proxy indicators, including carbon isotopes (δ13C), loss on ignition (LOI), magnetic susceptibility (MS), the chemical index of alteration (CIA), and geochemical elements from the Shiwangutian (SWGT) peatland were used to reconstruct the palaeohydrological changes during the Holocene. Regional moisture levels showed a generally arid-wet-arid pattern, and three phases of climatic change were detected as follows. 1) Between 11,600 and 9000 cal yr BP, the EASM was weak and a relatively dry climate developed. 2) Between 9000 and 4000 cal yr BP, the prevalence of humid climatic conditions was associated with a strong summer monsoon. 3) After 4000 cal yr BP, the climate shifted to relatively dry conditions. Further comparisons and analysis suggested that solar insolation, migration of the Intertropical Convergence Zone (ITCZ), and El Niño-Southern Oscillation (ENSO) activity played an important role in determining the variations in Holocene EASM intensity. In addition, the increase in both MS and heavy metal concentrations over the last 1000 years is consistent with an increase in the population of Hunan Province. Therefore, it can be inferred that population growth and the associated expansion of cropland and mining led to an increase in soil erosion and metal tool use. These findings suggest that the impact of human activity generally outweighed the natural climatic controls on the environment and landscape in the mountainous region of southern China over the last 1000 years.

Therapeutic strategies against BK polyomavirus infection in kidney transplant recipients: Systematic review and meta-analysis.

BACKGROUND: The selection of antiviral therapy for BK polyomavirus (BKPyV) infection has been extensively debated. Our study aimed to assess the efficacy and safety of various treatments for BKPyV infection. METHODS: We searched PubMed, EMBASE, and Web of Science databases for relevant studies regarding drug treatments for BKPyV viremia/DNAemia published between January 1, 1970 and September 30, 2022. Two independent authors screened the published studies, extracted pertinent data, and evaluated their methodological quality. A meta-analysis was performed using the RevMan software version 4.2.2. RESULTS: A total of 33 published studies involving 986 patients were included in the meta-analysis. Overall, therapeutic interventions comprised immunosuppression reduction alone or in combination with leflunomide, intravenous immunoglobulin (IVIG), cidofovir, or mTOR inhibitor (mTORi) therapy. The meta-analysis revealed that the efficacy of immunosuppression reduction alone for serum BKPyV clearance was 68% (95% confidence interval [CI]: 0.58-0.77; I2 = 78%). Moreover, the efficacy of immunosuppression reduction in combination with leflunomide, cidofovir, IVIG, or mTORi therapy for serum BKPyV clearance was 61% (95% CI: 0.47-0.74; I2 = 83%), 71% (95% CI: 0.63-0.78; I2 = 0), 87% (95% CI: 0.82-0.93; I2 = 45%), and 80% (95% CI: 0.59-1.00; I2 = 58%), respectively. Compared to immunosuppression reduction alone, immunosuppression reduction combined with IVIG therapy offered a statistically significant benefit in serum BKPyV clearance (P < 0.01) with minimal adverse reactions, whereas other adjunctive drug treatments did not demonstrate considerable effects. CONCLUSIONS: Reducing immunosuppression remains the primary approach for treating BKPyV infection. Although the combination treatment with IVIG proved to be most effective, other agents might offer varied antiviral advantages of high heterogeneity, which should be substantiated in future long-term randomized controlled trials.

Corrigendum: Dynamic risk prediction of BK polyomavirus reactivation after renal transplantation.

[This corrects the article DOI: 10.3389/fimmu.2022.971531.].

Anthropogenic influences on the sources and distribution of organic carbon, black carbon, and heavy metals in Daya Bay's surface sediments.

The total organic carbon (TOC), total nitrogen (TN), black carbon (BC), δ13CTOC, δ15N, δ13CBC, grain size, and heavy metals of surface sediments collected from Daya Bay were determined to investigate the spatial distributions of these parameters and to evaluate the influences of human activities. Marine organic matter was found to constitute approximately 84.41 ± 7.70 % of these sediments on average. The western and northern regions of Daya Bay exhibited relatively fine grain sizes, weak hydrodynamic conditions, and high sedimentation rates, which favored the burial and preservation of organic matter. The high concentration of organic matter could be attributed to the influence of petroleum and aquaculture industries. Fossil fuels were the main source of BC. The enrichment factor (EF) and geo-accumulation index (Igeo) were used to evaluate the sources and pollution levels of heavy metals. The results revealed that the source and distribution of heavy metals were strongly influenced by human activities, resulting in moderate pollution levels across most regions of Daya Bay. A strong correlation was observed between the Igeo values of heavy metals and BC, TOC, TN, and mean particle grain size (Mz). This suggests that the ability of sediments in Daya Bay to enrich and adsorb heavy metals depends on the sediment grain size, the content and type of organic matter. Importantly, sediments in the inner bay of Daya Bay exhibited a greater capacity to impede the migration of heavy metals compared to those in the outer bay.

Fatal BK polyomavirus-associated pneumonia: report of two cases with literature review.

BACKGROUND: In immunocompromised populations, such as patients with AIDS and recipients of solid organ and hematopoietic stem cell transplants, BK polyomavirus (BKPyV) can reactivate and cause several diseases, which can lead to death in their severe forms. Unlike hemorrhagic cystitis and BKPyV-associated nephropathy, BKPyV-associated pneumonia is rare, with only seven known cases worldwide. However, the disease can rapidly progress with extremely high mortality. CASE PRESENTATION: Herein, we report two cases of BKPyV-associated pneumonia following hematopoietic stem cell transplantation. Both patients had consistent infectious pneumonia and graft-versus-host disease after stem cell transplantation. The diagnosis of BKPyV-associated pneumonia was confirmed by metagenomic next-generation sequencing and polymerase chain reaction after the sudden worsening of the pulmonary infection signs and symptoms concomitant with renal dysfunction and systemic immune weakening. Both patients eventually died of systemic multi-organ failure caused by severe pneumonia. CONCLUSIONS: Currently, BKPyV reactivation cannot be effectively prevented. Immunocompromised patients must actively manage their primary lung infections, pay close attention to pulmonary signs and imaging changes. Especially during and after steroid pulse therapy or immunosuppressive therapy for graft versus host diseases, BKPyV load in blood/urine needs to be regularly measured, and the immunosuppressive intensity should be adjusted properly after the BKPyV reactivation diagnosis. Clinical trials of new antiviral drugs and therapies for BKPyV are urgently needed.

Microbiota of long-term indwelling hemodialysis catheters during renal transplantation perioperative period: a cross-sectional metagenomic microbial community analysis.

Background: Catheter-related infection (CRI) is a major complication in patients undergoing hemodialysis. The lack of high-throughput research on catheter-related microbiota makes it difficult to predict the occurrence of CRI. Thus, this study aimed to delineate the microbial structure and diversity landscape of hemodialysis catheter tips among patients during the perioperative period of kidney transplantation (KTx) and provide insights into predicting the occurrence of CRI.Methods: Forty patients at the Department of Transplantation undergoing hemodialysis catheter removal were prospectively included. Samples, including catheter tip, catheter outlet skin swab, catheter blood, peripheral blood, oropharynx swab, and midstream urine, from the separate pre- and post-KTx groups were collected and analyzed using metagenomic next-generation sequencing (mNGS). All the catheter tips and blood samples were cultured conventionally.Results: The positive detection rates for bacteria using mNGS and traditional culture were 97.09% (200/206) and 2.65% (3/113), respectively. Low antibiotic-sensitivity biofilms with colonized bacteria were detected at the catheter tip. In asymptomatic patients, no statistically significant difference was observed in the catheter tip microbial composition and diversity between the pre- and post-KTx group. The catheter tip microbial composition and diversity were associated with fasting blood glucose levels. Microorganisms at the catheter tip most likely originated from catheter outlet skin and peripheral blood.Conclusions: The long-term colonization microbiota at the catheter tip is in a relatively stable state and is not readily influenced by KTx. It does not act as the source of infection in all CRIs, but could reflect hematogenous infection to some extent.

Clinical features of Talaromyces marneffei infection in HIV-positive and HIV-negative individuals: A retrospective study in southern China.

Talaromyces marneffei (TSM) is a temperature-dependent dimorphic fungus endemic to Southeast Asia and southern China. As the number of people at risk of TSM infection continues to increase, the clinical manifestations are becoming increasingly complex, posing challenges for clinical management. In this study, we analyzed the medical records of 99 patients (71 human immunodeficiency virus [HIV]-positive and 28 HIV-negative) diagnosed with TSM infection from January 1, 2017, to December 31, 2022, in southern China and compared the clinical manifestations in HIV-positive and HIV-negative patients. Most patients (83/99, 84%) were male. The incidence of skin and soft tissue involvement (48% vs. 21%, P = .016); disseminated infection with blood circulation, hematopoietic, lymphatic, alimentary, or central nervous system involvement (69% vs. 36%, P = .002); and gastrointestinal bleeding (33% vs. 9%, P = .023) was higher in the HIV-positive group than the HIV-negative group. The HIV-positive group also had significantly higher alanine aminotransferase (ALT) levels (31 [26-42] vs. 14 [11-16] U/l, P < .001) and ALT/aspartate transaminase ratio (1.9 [1.5-2.2] vs. 1.3 [1.1-1.6], P = .006) than the HIV-negative group. The time to diagnosis (5.5 ± 1.1 vs. 5.1 ± 1.4 days, P = .103), antifungal regimen (P = .278), case fatality rate (20% vs. 21%, P = .849), and relapse/reinfection rate (11% vs. 19%, P = .576) did not differ significantly between the HIV-positive and HIV-negative groups. Poor antiretroviral therapy adherence (OR = 26.19, 95%CI 3.26-210.70, P = .002), advanced age (OR = 1.13, 95%CI 1.03-1.23, P = .010), and Epstein-Barr virus co-infection (OR = 37.13, 95%CI 3.03-455.64, P = .005) were independent risk factors for all-cause mortality from TSM infection in HIV-positive patients. Overall, the predominant infection sites, clinical manifestations, and complications of TSM infection differed by HIV status. However, with prompt diagnosis and appropriate treatment, HIV-positive patients with TSM infection can have similar outcomes to HIV-negative patients.

There are certain differences in the clinical features, sites of infection, and associated complications of Talaromyces marneffei infection between individuals with and without human immunodeficiency virus. It is necessary to accurately identify individuals at high risk to enable prompt diagnosis and standardized treatment.

Dynamic viral integration patterns actively participate in the progression of BK polyomavirus-associated diseases after renal transplantation.

The classical lytic infection theory along with large T antigen-mediated oncogenesis cannot explain the BK polyomavirus (BKPyV)-associated tumor secondary to BKPyV-associated nephropathy (BKVAN), viremia/DNAemia, and viruria after renal transplantation. This study performed virome capture sequencing and pathological examination on regularly collected urine sediment and peripheral blood samples, and BKVAN and tumor biopsy tissues of 20 patients with BKPyV-associated diseases of different stages. In the early noncancerous stages, well-amplified integration sites were visualized by in situ polymerase chain reaction, simultaneously with BKPyV inclusion bodies and capsid protein expression. The integration intensity, the proportion of microhomology-mediated end-joining integration, and host PARP-1 and POLQ gene expression levels increased with disease progression. Furthermore, multiomics analysis was performed on BKPyV-associated urothelial carcinoma tissues, identifying tandem-like structures of BKPyV integration using long-read genome sequencing. The carcinogenicity of BKPyV integration was proven to disturb host gene expression and increase viral oncoprotein expression. Fallible DNA double-strand break repair pathways were significantly activated in the parenchyma of BKPyV-associated tumors. Olaparib showed an antitumor activity dose-response effect in the tumor organoids without BRCA1/2 genes mutation. In conclusion, the dynamic viral integration patterns actively participate in the progression of BKPyV-associated diseases and thus could be a potential target for disease monitoring and intervention.

Integrating single-cell RNA sequencing with spatial transcriptomics reveals an immune landscape of human myometrium during labour.

BACKGROUND: The transition of the myometrium from a quiescent to a contractile state during labour is known to involve inflammation, which is characterized by the infiltration of immune cells and the secretion of cytokines. However, the specific cellular mechanisms underlying inflammation in the myometrium during human parturition are not yet fully understood. METHODS: Through the analysis of transcriptomics, proteomics, and cytokine arrays, the inflammation in the human myometrium during labour was revealed. By performing single-cell RNA sequencing (scRNA-seq) and spatiotemporal transcriptomic (ST) analyses on human myometrium in term in labour (TIL) and term in non-labour (TNL), we established a comprehensive landscape of immune cells, their transcriptional characteristics, distribution, function and intercellular communications during labour. Histological staining, flow cytometry, and western blotting were applied to validate some results from scRNA-seq and ST. RESULTS: Our analysis identified immune cell types, including monocytes, neutrophils, T cells, natural killer (NK) cells and B cells, present in the myometrium. TIL myometrium had a higher proportion of monocytes and neutrophils than TNL myometrium. Furthermore, the scRNA-seq analysis showed an increase in M1 macrophages in TIL myometrium. CXCL8 expression was mainly observed in neutrophils and increased in TIL myometrium. CCL3 and CCL4 were principally expressed in M2 macrophages and neutrophils-6, and decreased during labour; XCL1 and XCL2 were specifically expressed in NK cells, and decreased during labour. Analysis of cytokine receptor expression revealed an increase in IL1R2, which primarily expressed in neutrophils. Finally, we visualized the spatial proximity of representative cytokines, contraction-associated genes, and corresponding receptors in ST to demonstrate their location within the myometrium. CONCLUSIONS: Our analysis comprehensively revealed changes in immune cells, cytokines, and cytokine receptors during labour. It provided a valuable resource to detect and characterize inflammatory changes, yielding insights into the immune mechanisms underlying labour.

Inversion of Molecular Chirality Associated with Ferroelectric Switching in a High-Temperature Two-Dimensional Perovskite Ferroelectric.

Controlling molecular chirality by external stimuli is of great significance in both fundamental research and technological applications. Herein, we report a high-temperature (384 K) molecular ferroelectric of a Cu(II) complex whose spontaneous polarization can be switched associated with flipping of molecular chirality. In this two-dimensional perovskite structure, the inorganic layer is separated by (NH3(CH2)2SS(CH2)2NH3)2+ organic cations skewed in a chiral conformation (P- or M-helicity in an individual crystal). As the stereodynamic disulfide bridge determines the molecular dipole moment along the polar axis, the chiral organic cation can be converted to its enantiomer as a consequence of an electric field-induced shift of the S-S moiety relative to its screw axis during the ferroelectric switching. The variation of the molecular chirality is examined with single-crystal X-ray diffraction and circular dichroism spectra. The simultaneous switching of molecular chirality and spontaneous polarization in this perovskite ferroelectric may lead to novel chiral electronic phenomena.

XBP1 modulates endoplasmic reticulum and mitochondria crosstalk via regulating NLRP3 in renal ischemia/reperfusion injury.

The functional status of mitochondria and the endoplasmic reticulum are central to renal ischemia/reperfusion injury (IRI). X-box binding protein 1 (XBP1) is an important transcription factor in endoplasmic reticulum stress. NLR family pyrin domain containing-3 (NLRP3) inflammatory bodies are closely related to renal IRI. In vivo and in vitro, we examined the molecular mechanisms and functions of XBP1-NLRP3 signaling in renal IRI, which influences ER-mitochondrial crosstalk. In this study, mice were subjected to 45 min of unilateral renal warm ischemia, the other kidney resected, and reperfusion was performed for 24 h in vivo. In vitro, murine renal tubular epithelial cells (TCMK-1) were exposed to hypoxia for 24 h and reoxygenation for 2 h. Tissue or cell damage was evaluated by measuring blood urea nitrogen and creatinine levels, histological staining, flow cytometry, terminal deoxynucleotidyl transferase-mediated nick-end labeling, diethylene glycol staining, and transmission electron microscopy (TEM). Western blotting, immunofluorescence staining, and ELISA were used to analyze protein expression. Whether XBP1 regulates the NLRP3 promoter was evaluated using a luciferase reporter assay. Kidney damage was reduced with decreasing blood urea nitrogen, creatinine, interleukin-1ß, and interleukin-18 levels. XBP1 deficiency reduced tissue damage and cell apoptosis, protecting the mitochondria. Disruption of XBP1 was associated with reduced NLRP3 and cleaved caspase-1 levels and markedly improved survival. In vitro in TCMK-1 cells, XBP1 interference inhibited caspase-1-dependent mitochondrial damage and reduced the production of mitochondrial reactive oxygen species. The luciferase assay showed that spliced XBP1 isoforms enhanced the activity of the NLRP3 promoter. These findings reveal that XBP1 downregulation suppresses the expression of NLRP3, a potential regulator of endoplasmic reticulum mitochondrial crosstalk in nephritic injury and a potential therapeutic target in XBP1-mediated aseptic nephritis.

LSTMED: An uneven dynamic process monitoring method based on LSTM and Autoencoder neural network.

Due to the complicated production mechanism in multivariate industrial processes, different dynamic features of variables raise challenges to traditional data-driven process monitoring methods which assume the process data is static or dynamically consistent. To tackle this issue, this paper proposes a novel process monitoring method based on the long short-term memory (LSTM) and Autoencoder neural network (called LSTMED) for multivariate process monitoring with uneven dynamic features. First, the LSTM units are arranged in the encoder-decoder form to construct an end-to-end model. Then, the constructed model is trained in an unsupervised manner to capture long-term time dependency within variables and dominant representation of high dimensional process data. Afterward, the kernel density estimation (KDE) method is performed to determine the control limit only based on the reconstruction error from historical normal data. Finally, effective online monitoring for uneven dynamic process can be achieved. The performance and advantage of the process monitoring method proposed are explained through typical cases, including the numerical simulation and Tennessee Eastman (TE) benchmark process, and comparative experimental analysis with state-of-the-art methods.

Herpes Simplex Type 1 UL43 Multiple Membrane-Spanning Protein Increases Energy Metabolism in Host Cells through Interacting with ARL2.

Non-essential proteins for viral replication affect host cell metabolism, while the function of the UL43 protein of herpes simplex virus 1 (HSV-1) is not clear. Herein, we performed a comprehensive microarray analysis of HUVEC cells infected with HSV-1 and its UL43-deficient mutant and found significant variation in genes associated with cellular energy metabolic pathways. The localization of UL43 protein in host cells and how it affects cellular energy metabolism pathways were further investigated. Internalization analysis showed that the UL43 protein could be endocytosis-mediated by YPLF motif (aa144-147) and localized to mitochondria. At the same time, more ATP was produced by coupling with mitochondrial small G protein ARF-like 2 (ARL2) GTPase, which triggered the phosphorylation of ANT1 (SLC25A4) to affect the opening degree of mitochondrial permeability transition pore (mPTP), and significantly promoted the aerobic oxidation and oxidative phosphorylation of glucose. Our study shows that UL43 mediates the improvement of host cell metabolism after HSV-1 infection. Additionally, UL43 protein could be a valuable ATP-stimulating factor for mammalian cells.

A novel risk factor of contrast associated acute kidney injury in patients after enhanced computed tomography: a retrospective study.

Background: Contrast associated acute kidney injury (CA-AKI) is a major cause of acute renal failure and the incidence of CA-AKI is still high in recent years. Risk stratification is traditionally based on glomerular filtration rate(GFR). Hence, the aim of this study was to explore the novel risk factors for CA-AKI after enhanced computed tomography (CT). Methods: A retrospective cohort study was conducted in 632 in-hospital patients undergoing enhanced CT. The patients were divided into CA-AKI and no-CA-AKI groups. For comparative analyses, we applied one-to-four cohorts of those two groups using propensity score-matching methods addressing the imbalances of age, gender, weight, and smoking. The baseline clinical and biochemical data were compared. Logistic regression analysis was employed to investigate the CA-AKI risk factors. The receiver operating characteristic (ROC) curve was adopted to test the value of RDW in predicting CA-AKI after enhanced CT. Results: 25 (3.96%) patients suffered from CA-AKI. Those subjects who developed CA-AKI had advanced age, severer renal functional injury, lower albumin, higher baseline RDW, neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR) than those without CA-AKI. It also exhibited more severe anemia including decreased hemoglobin and red blood cell count (all p < 0.05). The baseline RDW, albumin and PLR between the two groups were statistically significant different after PSM. Binary logistic regression analysis showed that baseline RDW, albumin and eGFR were correlated with CA-AKI after contrast-enhanced CT examination. The RDW exhibited moderated discrimination ability for predicting CA-AKI beyond eGFR, with an AUC of 0.803 (95% CI [0.702-0.90]) vs 0.765 (95% CI [0.70-0.83]). Conclusion: Increased baseline RDW and decreased eGFR are risk factors for CA-AKI after enhanced CT. RDW exhibited good predictive value and can be used as an early warning marker for patients suffering from CA-AKI after enhanced CT.

A single-center analysis of genotype-phenotype characteristics of Chinese patients with autosomal dominant polycystic kidney disease by targeted exome sequencing.

Background: Autosomal dominant polycystic kidney disease (ADPKD) is mainly caused by PKD1 and PKD2 mutations. However, only a few studies have investigated the genotype and phenotype characteristics of Asian patients with ADPKD. This study aimed to investigate the relationship between the natural course of ADPKD genotype and phenotype. Methods: Genetic studies of PKD1/2 genes of Chinese patients with ADPKD in a single center were performed using targeted exome sequencing and next-generation sequencing on peripheral blood DNA. Results: Among the 140 patients analyzed, 80.00% (n = 112) harbored PKD1 mutations, 11.43% (n = 16) harbored PKD2 mutations, and 8.57% (n = 12) harbored neither PKD1 nor PKD2 mutations. The average age at dialysis was 52.60 ± 11.36, 60.67 ± 5.64, and 52.11 ± 14.63 years, respectively. The renal survival rate of ADPKD patients with PKD1 mutations (77/112) was significantly lower than that of those with PKD2 mutations (9/16), leading to an earlier onset of end-stage renal disease (ESRD). Renal prognosis was poor for those with nonsense mutations, and they required earlier renal replacement therapy. Conclusions: The genotype and phenotype characteristics of ADPKD patients potentially vary across ethnic groups. Our findings supplement the genetic profiles of Chinese ADPKD patients, could serve as a guide for therapy monitoring and prognosis assessment of ADPKD, and may improve the clinical diagnosis.