Structural insights into KSHV-GPCR constitutive activation and CXCL1 chemokine recognition.

Kaposi's sarcoma-associated herpesvirus (KSHV) encodes a viral G protein-coupled receptor, KSHV-GPCR, that contributes to KSHV immune evasion and pathogenesis of Kaposi's sarcoma. KSHV-GPCR shares a high similarity with CXC chemokine receptors CXCR2 and can be activated by selected chemokine ligands. Like other herpesvirus-encoded GPCRs, KSHV-GPCR is characterized by its constitutive activity by coupling to various G proteins. We investigated the structural basis of ligand-dependent and constitutive activation of KSHV-GPCR, obtaining high-resolution cryo-EM structures of KSHV-GPCR-Gi complexes with and without the bound CXCL1 chemokine. Analysis of the apo-KSHV-GPCR-Gi structure (2.81 Å) unraveled the involvement of extracellular loop 2 in constitutive activation of the receptor. In comparison, the CXCL1-bound KSHV-GPCR-Gi structure (3.01 Å) showed a two-site binding mode and provided detailed information of CXCL1 binding to a chemokine receptor. The dual activation mechanism employed by KSHV-GPCR represents an evolutionary adaptation for immune evasion and contributes to the pathogenesis of Kaposi's sarcoma. Together with results from functional assays that confirmed the structural models, these findings may help to develop therapeutic strategies for KSHV infection.

Combination CTLA4Ig and Anti-CD40 Ligand Treatment Modifies T and B Cell Metabolic Profiles and Promotes B Cell Receptor Remodeling in a Mouse Model of Systemic Lupus Erythematosus.

Systemic lupus erythematosus is a complex autoimmune disease with significant morbidity that demands further examination of tolerance-inducing treatments. Short-term treatment of lupus-prone NZB/WF1 mice with combination CTLA4Ig and anti-CD40 ligand, but not single treatment alone, suppresses disease for >6 mo via modulation of B and T cell function while maintaining immune responses to exogenous Ags. Three months after a 2-wk course of combination costimulatory blockade, we found a modest decrease in the number of activated T and B cells in both combination and single-treatment cohorts compared with untreated controls. However, only combination treatment mice showed a 50% decrease in spare respiratory capacity of splenic B and T cells. RNA sequencing and gene set enrichment analysis of germinal center (GC) B cells confirmed a reduction in the oxidative phosphorylation signature in the combination treatment cohort. This cohort also manifested increased expression of BCR-associated signaling molecules and increased phosphorylation of PLCγ in GC B cells after stimulation with anti-IgG and anti-CD40. GC B cells from combination treatment mice also displayed a signature involving remodeling of GPI-linked surface proteins. Accordingly, we found a decrease in cell surface expression of the inhibitory molecule CD24 on class-switched memory B cells from aged NZB/W mice that corrected in the combination treatment cohort. Because both a profound decrease in BCR signaling and remodeled immune cell metabolism enhance loss of tolerance in lupus-prone mice, our findings help to explain the restoration of tolerance observed after short-term combination costimulatory blockade.

LRG1 loss effectively restrains glomerular TGF-ß signaling to attenuate diabetic kidney disease.

Transforming growth factor (TGF)-ß signaling is a well-established pathogenic mediator of diabetic kidney disease (DKD). However, owing to its pleiotropic actions, its systemic blockade is not therapeutically optimal. The expression of TGF-ß signaling regulators can substantially influence TGF-ß's effects in a cell- or context-specific manner. Among these, leucine-rich α2-glycoprotein 1 (LRG1) is significantly increased in glomerular endothelial cells (GECs) in DKD. As LRG1 is a secreted molecule that can exert autocrine and paracrine effects, we examined the effects of LRG1 loss in kidney cells in diabetic OVE26 mice by single-cell transcriptomic analysis. Gene expression analysis confirmed a predominant expression of Lrg1 in GECs, which further increased in diabetic kidneys. Loss of Lrg1 led to the reversal of angiogenic and TGF-ß-induced gene expression in GECs, which were associated with DKD attenuation. Notably, Lrg1 loss also mitigated the increased TGF-ß-mediated gene expression in both podocytes and mesangial cells in diabetic mice, indicating that GEC-derived LRG1 potentiates TGF-ß signaling in glomerular cells in an autocrine and paracrine manner. Indeed, a significant reduction in phospho-Smad proteins was observed in the glomerular cells of OVE26 mice with LRG1 loss. These results indicate that specific antagonisms of LRG1 may be an effective approach to curb the hyperactive glomerular TGF-ß signaling to attenuate DKD.

Distinct Roles of Brd2 and Brd4 in Potentiating the Transcriptional Program for Th17 Cell Differentiation.

The BET proteins are major transcriptional regulators and have emerged as new drug targets, but their functional distinction has remained elusive. In this study, we report that the BET family members Brd2 and Brd4 exert distinct genomic functions at genes whose transcription they co-regulate during mouse T helper 17 (Th17) cell differentiation. Brd2 is associated with the chromatin insulator CTCF and the cohesin complex to support cis-regulatory enhancer assembly for gene transcriptional activation. In this context, Brd2 binds the transcription factor Stat3 in an acetylation-sensitive manner and facilitates Stat3 recruitment to active enhancers occupied with transcription factors Irf4 and Batf. In parallel, Brd4 temporally controls RNA polymerase II (Pol II) processivity during transcription elongation through cyclin T1 and Cdk9 recruitment and Pol II Ser2 phosphorylation. Collectively, our study uncovers both separate and interdependent Brd2 and Brd4 functions in potentiating the genetic program required for Th17 cell development and adaptive immunity.

Four additional natural 7-deazaguanine derivatives in phages and how to make them.

Bacteriophages and bacteria are engaged in a constant arms race, continually evolving new molecular tools to survive one another. To protect their genomic DNA from restriction enzymes, the most common bacterial defence systems, double-stranded DNA phages have evolved complex modifications that affect all four bases. This study focuses on modifications at position 7 of guanines. Eight derivatives of 7-deazaguanines were identified, including four previously unknown ones: 2'-deoxy-7-(methylamino)methyl-7-deazaguanine (mdPreQ1), 2'-deoxy-7-(formylamino)methyl-7-deazaguanine (fdPreQ1), 2'-deoxy-7-deazaguanine (dDG) and 2'-deoxy-7-carboxy-7-deazaguanine (dCDG). These modifications are inserted in DNA by a guanine transglycosylase named DpdA. Three subfamilies of DpdA had been previously characterized: bDpdA, DpdA1, and DpdA2. Two additional subfamilies were identified in this work: DpdA3, which allows for complete replacement of the guanines, and DpdA4, which is specific to archaeal viruses. Transglycosylases have now been identified in all phages and viruses carrying 7-deazaguanine modifications, indicating that the insertion of these modifications is a post-replication event. Three enzymes were predicted to be involved in the biosynthesis of these newly identified DNA modifications: 7-carboxy-7-deazaguanine decarboxylase (DpdL), dPreQ1 formyltransferase (DpdN) and dPreQ1 methyltransferase (DpdM), which was experimentally validated and harbors a unique fold not previously observed for nucleic acid methylases.

Podocyte-derived soluble RARRES1 drives kidney disease progression through direct podocyte and proximal tubular injury.

Retinoic acid receptor responder protein-1 (RARRES1) is a podocyte-enriched transmembrane protein whose increased expression correlates with human glomerular disease progression. RARRES1 promotes podocytopenia and glomerulosclerosis via p53-mediated podocyte apoptosis. Importantly, the cytopathic actions of RARRES1 are entirely dependent on its proteolytic cleavage into a soluble protein (sRARRES1) and subsequent podocyte uptake by endocytosis, as a cleavage mutant RARRES1 exerted no effects in vitro or in vivo. As RARRES1 expression is upregulated in human glomerular diseases, here we investigated the functional consequence of podocyte-specific overexpression of RARRES1 in mice in the experimental focal segmental glomerulosclerosis and diabetic kidney disease. We also examined the effects of long-term RARRES1 overexpression on slowly developing aging-induced kidney injury. As anticipated, the induction of podocyte overexpression of RARRES1 (Pod-RARRES1WT) significantly worsened glomerular injuries and worsened kidney function in all three models, while overexpression of RARRES1 cleavage mutant (Pod-RARRES1MT) did not. Remarkably, direct uptake of sRARRES1 was also seen in proximal tubules of injured Pod-RARRES1WT mice and associated with exacerbated tubular injuries, vacuolation, and lipid accumulation. Single-cell RNA sequence analysis of mouse kidneys demonstrated RARRES1 led to a marked deregulation of lipid metabolism in proximal tubule subsets. We further identified matrix metalloproteinase 23 (MMP23) as a highly podocyte-specific metalloproteinase and responsible for RARRES1 cleavage in disease settings, as adeno-associated virus 9-mediated knockdown of MMP23 abrogated sRARRES1 uptake in tubular cells in vivo. Thus, our study delineates a previously unrecognized mechanism by which a podocyte-derived protein directly facilitates podocyte and tubular injury in glomerular diseases and suggests that podocyte-specific functions of RARRES1 and MMP23 may be targeted to ameliorate glomerular disease progression in vivo.

A large-scale retrospective study enabled deep-learning based pathological assessment of frozen procurement kidney biopsies to predict graft loss and guide organ utilization.

Lesion scores on procurement donor biopsies are commonly used to guide organ utilization for deceased-donor kidneys. However, frozen sections present challenges for histological scoring, leading to inter- and intra-observer variability and inappropriate discard. Therefore, we constructed deep-learning based models to recognize kidney tissue compartments in hematoxylin & eosin-stained sections from procurement needle biopsies performed nationwide in years 2011-2020. To do this, we extracted whole-slide abnormality features from 2431 kidneys and correlated with pathologists' scores and transplant outcomes. A Kidney Donor Quality Score (KDQS) was derived and used in combination with recipient demographic and peri-transplant characteristics to predict graft loss or assist organ utilization. The performance on wedge biopsies was additionally evaluated. Our model identified 96% and 91% of normal/sclerotic glomeruli respectively; 94% of arteries/arterial intimal fibrosis; 90% of tubules. Whole-slide features of Sclerotic Glomeruli (GS)%, Arterial Intimal Fibrosis (AIF)%, and Interstitial Space Abnormality (ISA)% demonstrated strong correlations with corresponding pathologists' scores of all 2431 kidneys, but had superior associations with post-transplant estimated glomerular filtration rates in 2033 and graft loss in 1560 kidneys. The combination of KDQS and other factors predicted one- and four-year graft loss in a discovery set of 520 kidneys and a validation set of 1040 kidneys. By using the composite KDQS of 398 discarded kidneys due to "biopsy findings", we suggest that if transplanted, 110 discarded kidneys could have had similar survival to that of other transplanted kidneys. Thus, our composite KDQS and survival prediction models may facilitate risk stratification and organ utilization while potentially reducing unnecessary organ discard.

High-dimensional mass cytometry identified circulating natural killer T-cell subsets associated with protection from cytomegalovirus infection in kidney transplant recipients.

Cytomegalovirus (CMV) infection is associated with poor kidney transplant outcomes. While innate and adaptive immune cells have been implicated in its prevention, an in-depth characterization of the in vivo kinetics of multiple cell subsets and their role in protecting against CMV infection has not been achieved. Here, we performed high-dimensional immune phenotyping by mass cytometry, and functional assays, on 112 serially collected samples from CMV seropositive kidney transplant recipients. Advanced unsupervised deep learning analysis was used to assess immune cell populations that significantly correlated with prevention against CMV infection and anti-viral immune function. Prior to infection, kidney transplant recipients who developed CMV infection showed significantly lower CMV-specific cell-mediated immune (CMI) frequencies than those that did not. A broad diversity of circulating cell subsets within innate and adaptive immune compartments were associated with CMV infection or protective CMV-specific CMI. While percentages of CMV (tetramer-stained)-specific T cells associated with high CMI responses and clinical protection, circulating CD3+CD8midCD56+ NK-T cells overall strongly associated with low CMI and subsequent infection. However, three NK-T cell subsets sharing the CD11b surface marker associated with CMV protection and correlated with strong anti-viral CMI frequencies in vitro. These data were validated in two external independent cohorts of kidney transplant recipients. Thus, we newly describe the kinetics of a novel NK-T cell subset that may have a protective role in post-transplantation CMV infection. Our findings pave the way to more mechanistic studies aimed at understanding the function of these cells in protection against CMV infection.

Prostaglandin E2 promotes Th17 differentiation induces corneal epithelial cell apoptosis and participates in the progression of dry eye.

This study is mainly based on T helper type 17 (Th17) cells analysis of the mechanism of prostaglandin E2 (PGE2) promoting the progression of dry eye (DE). Scopolamine and dry environment were used to induce mice DE model. Celecoxib was used to inhibit PGE2. Corneal epithelial cells and CD4+ T cells were used to construct a co-culture system. The osmotic pressure was increased by adding NaCl to simulate DE in vitro. AH6809 and E7046 were used to pre-culture to inhibit EP2/4 in T cells to verify the effect of exogenous PGE2 on Th17 cell differentiation and corneal epithelial cell apoptosis. The function of Th17 cells was analyzed by detecting RORγt and interleukin-17 (IL-17). PGE2 was instilled on the ocular surface to induce DE symptoms of mice. AH6809 and E7046 were used to inhibit EP2/4. The corneal epithelial cell apoptosis was observed by TUNEL. The proportion of Th17 cells in corneal tissue and draining lymph nodes (DLNs) was detected by flow cytometry. In DE mice, the concentration of PGE2 and IL-17 increased in tears, and the proportion of Th17 increased, while inhibition of PGE2 alleviated the symptoms of DE and inhibited Th17 differentiation. Hypertonic environment induces corneal epithelial cells to secrete PGE2. PGE2 promoted the expression of EP2/4 and the differentiation of Th17 cells in vitro. The hypertonic environment promoted PGE2 level and the apoptosis of corneal epithelial cells in the co-culture system. PGE2 alone did not cause corneal epithelial cell apoptosis, while PGE2 promoted apoptosis by promoting Th17. Blocking EP2/4 reduced the induction of Th17 differentiation by PGE2 and the promoted corneal epithelial cell apoptosis. Animal experiments showed that exogenous PGE2 induced DE symptoms. Blocking EP2/4 not only inhibited the proportion of Th17, but also alleviated the apoptosis of corneal epithelial cells caused by PGE2. PGE2 induces aggravation of inflammation by promoting the level of Th17 in the ocular surface, and causes corneal epithelial cell apoptosis, thereby participating in the progression of DE.

Thalassotalea psychrophila sp. nov., Thalassotalea nanhaiensis sp. nov. and Thalassotalea fonticola sp. nov., three psychrophilic bacteria isolated from deep-sea sediment.

Three psychrophilic bacteria, designated as strains SQ149T, SQ345T, and S1-1T, were isolated from deep-sea sediment from the South China Sea. All three strains were the most closely related to Thalassotalea atypica RZG4-3-1T based on the 16S rRNA gene sequence analysis (similarity ranged from 96.45 to 96.67 %). Phylogenetic analysis based on the 16S rRNA gene and core-genome sequences showed that three strains formed a cluster within the genus Thalassotalea. The average amino acid identity, average nucleotide identity, and digital DNA-DNA hybridization values among the three strains and closest Thalassotalea species were far below the cut-off value recommended for delineating species, indicating they each represented a novel species. All three strains were Gram-stain-negative, rod-shaped, and contained summed feature 3 (C16 : 1 ω7c and/or C16 : 1 ω6c) as the predominant fatty acid, Q-8 as the major respiratory quinone, and phosphatidylethanolamine and phosphatidylglycerol as predominant polar lipids. Based on the genomic, phylogenetic, and phenotypic characterizations, each strain is considered to represent a novel species within the genus Thalassotalea, for which the names Thalassotalea psychrophila sp. nov. (type strain SQ149T=MCCC 1K04231T=JCM 33807T), Thalassotalea nanhaiensis sp. nov. (type strain SQ345T=MCCC 1K04232T=JCM 33808T), and Thalassotalea fonticola sp. nov. (type strain S1-1T=MCCC 1K06879T=JCM 34824T) are proposed.

Apoptotic vesicles (apoVs) derived from fibroblast-converted hepatocyte-like cells effectively ameliorate liver fibrosis.

Liver fibrosis is a serious global health issue for which effective treatment remains elusive. Chemical-induced hepatocyte-like cells (ciHeps) have emerged as an appealing source for cell transplantation therapy, although they present several challenges such as the risk of lung thromboembolism or hemorrhage. Apoptotic vesicles (apoVs), small membrane vesicles generated during the apoptosis process, have gained attention for their role in regulating various physiological and pathological processes. In this study, we generated ciHep-derived apoVs (ciHep-apoVs) and investigated their therapeutic potential in alleviating liver fibrosis. Our findings revealed that ciHep-apoVs induced the transformation of macrophages into an anti-inflammatory phenotype, effectively suppressed the activity of activated hepatic stellate cells (aHSCs), and enhanced the survival of hepatocytes. When intravenously administered to mice with liver fibrosis, ciHep-apoVs were primarily engulfed by macrophages and myofibroblasts, leading to a reduction in liver inflammation and fibrosis. Proteomic and miRNA analyses showed that ciHep-apoVs were enriched in various functional molecules that modulate crucial cellular processes, including metabolism, signaling transduction, and ECM-receptor interactions. ciHep-apoVs effectively suppressed aHSCs activity through the synergistic inhibition of glycolysis, the PI3K/AKT/mTOR pathway, and epithelial-to-mesenchymal transition (EMT) cascades. These findings highlight the potential of ciHep-apoVs as multifunctional nanotherapeutics for liver fibrosis and provide insights into the treatment of other liver diseases and fibrosis in other organs.

Parkinson's disease with anxiety: clinical characteristics and their correlation with oxidative stress, inflammation, and pathological proteins.

OBJECTIVE: This study was performed to explore the differences in the clinical characteristics and oxidative stress indicators, inflammatory factors, and pathological proteins in serum between Parkinson's disease (PD) with anxiety (PD-A) and with no anxiety (PD-NA) patients, and further correlations among clinical characteristics and above variables were analyzed in PD-A and PD-NA groups. METHODS: A total of 121 patients with PD were enrolled in this study and assessed by the Hamilton Anxiety Scale (14 items) (HAMA-14). These patients were divided into PD-A and PD-NA groups according to a cut-off point of 7 of HAMA-14. Demographic variables were collected, and clinical symptoms were assessed by multiple rating scales. The levels of free radicals, inflammatory factors, and pathological proteins in serum were measured by chemical colorimetric method and enzyme-linked immunosorbent assay (ELISA). The differences of above variables were compared between PD-A and PD-NA groups, and the correlations of clinical symptoms with the abovevariables were analyzed in PD-A and PD-NA groups. RESULTS: The frequency of PD-A was 62.81%. PD-A group exhibited significantly impaired motor dysfunction and multiple non-motor symptoms, including fatigue, sleep behavior disorder, restless leg syndrome and autonomic dysfunction, and dramatically compromised activities of daily living compard with PD-NA group. PD-A group displayed prominently increasedlevels of hydroxyl radical (·OH) and tumor necrosis factor (TNF)-α, and a decreased nitric oxide (NO) level in serum compared with PD-NA group (P<0.001, P = 0.001, P= 0.027, respectively). ·OH, NO, and TNF-α were identified as the risk factors of PD-A (OR = 1.005, P = 0.036; OR = 0.956, P = 0.017; OR = 1.039, P = 0.033, respectively). In PD patients, HAMA-14 score was significantly and positively correlated with the levels of ·OH and TNF-α in serum (P<0.001, P = 0.002, respectively). In PD-A group, ·OH level was significantly and negatively correlated with Aß1-42 level, while TNF-α level was significantly and positively correlated with P-tau (S396) level in serum. CONCLUSIONS: The frequency of PD-A is high. PD-A patients present more severe motor dysfunction and multiple non-motor symptoms, and poorer activities of daily living. The increased levels of ·OH and TNF-α levels and the decreased NO level in serum are all associated with more severe anxiety in PD patients.Findings from this study may provide in-depth insights into the clinical characteristics, underlying mechanisms of PD-A, and potential correlations among anxiety, oxidative stress, inflammation, and cognitive decline in PD patients.

Antimicrobial peptide cecropin B functions in pathogen resistance of Mythimna separata.

Mythimna separata (Lepidoptera: Noctuidae) is an omnivorous pest that poses a great threat to food security. Insect antimicrobial peptides (AMPs) are small peptides that are important effector molecules of innate immunity. Here, we investigated the role of the AMP cecropin B in the growth, development, and immunity of M. separata. The gene encoding M. separata cecropin B (MscecropinB) was cloned. The expression of MscecropinB was determined in different developmental stages and tissues of M. separata. It was highest in the prepupal stage, followed by the pupal stage. Among larval stages, the highest expression was observed in the fourth instar. Tissue expression analysis of fourth instar larvae showed that MscecropinB was highly expressed in the fat body and haemolymph. An increase in population density led to upregulation of MscecropinB expression. MscecropinB expression was also upregulated by the infection of third and fourth instar M. separata with Beauveria bassiana or Bacillus thuringiensis (Bt). RNA interference (RNAi) targeting MscecropinB inhibited the emergence rate and fecundity of M. separata, and resulted in an increased sensitivity to B. bassiana and Bt. The mortality of M. separata larvae was significantly higher in pathogen plus RNAi-treated M. separata than in controls treated with pathogens only. Our findings indicate that MscecropinB functions in the eclosion and fecundity of M. separata and plays an important role in resistance to infection by B. bassiana and Bt.

Reversed-engineered human alveolar lung-on-a-chip model.

Here, we present a physiologically relevant model of the human pulmonary alveoli. This alveolar lung-on-a-chip platform is composed of a three-dimensional porous hydrogel made of gelatin methacryloyl with an inverse opal structure, bonded to a compartmentalized polydimethylsiloxane chip. The inverse opal hydrogel structure features well-defined, interconnected pores with high similarity to human alveolar sacs. By populating the sacs with primary human alveolar epithelial cells, functional epithelial monolayers are readily formed. Cyclic strain is integrated into the device to allow biomimetic breathing events of the alveolar lung, which, in addition, makes it possible to investigate pathological effects such as those incurred by cigarette smoking and severe acute respiratory syndrome coronavirus 2 pseudoviral infection. Our study demonstrates a unique method for reconstitution of the functional human pulmonary alveoli in vitro, which is anticipated to pave the way for investigating relevant physiological and pathological events in the human distal lung.

Spatial and temporal assessment of China's skiing climate resources.

This study introduces an improved Ski Climate Index (SCI) designed to assess skiing suitability in China by applying fuzzy logic. Using daily meteorological data from 733 weather stations for the periods 1961-1990 and 1991-2020, the study identifies significant changes in SCI distribution over time. Additionally, a coupled analysis is performed, integrating the SCI results with the distribution and spatial vitality of 389 ski resorts in China. This analysis provides a comprehensive understanding of the interplay between actual ski resources and the ongoing evolution of the skiing industry in China and three significant results:1) The snow module has a major impact on SCI distribution, while other non-snow natural elements, such as sunshine duration, wind speed, and thermal comfort, influence the overall SCI assessment less; 2) High SCI values are concentrated in Northwestern and Northeastern China, with increased ski climate resources being observed in Shaanxi-Gansu-Ningxia, Southwest Tibet, and Sichuan due to climate change and noticeable declines in the Southern regions of Northeast China.; 3) In terms of the distribution and vitality of ski resorts, the SCI also partially reflects the development of ski resorts. This skiing suitability model uses climate resources to offer valuable insights for key decision-making in resort development and operation, thereby supporting advancement of the ice-snow economy.

Super Hydrous Solvated Structure of Chaotropic Ca2+ Contributes Superior Anti-Freezing Aqueous Electrolytes and Stabilizes the Zn anode.

The further development of aqueous zinc (Zn)-ion batteries (AZIBs) is constrained by the high freezing points and the instability on Zn anodes. Current improvement strategies mainly focus on regulating hydrogen bond (HB) donors (H) of solvent water to disrupt HBs, while neglecting the environment of HB-acceptors (O). Herein, we propose a mechanism of chaotropic cation-regulated HB-acceptor via a "super hydrous solvated" structure. Chaotropic Ca2+ can form a solvated structure via competitively binding O atoms in H2O, effectively breaking the HBs among H2O molecules, thereby reducing the glass transition temperature of hybrid 1 mol L-1 (M) ZnCl2+4 M CaCl2 electrolyte (-113.2 °C). Meanwhile, the high hydratability of Ca2+ contributes to the water-poor solvated structure of Zn2+, suppressing side reactions and uneven Zn deposition. Benefiting from the anti-freezing electrolyte and high reversible Zn anode, the Zn||Pyrene-4,5,9,10-tetraone (PTO) batteries deliver an ultrahigh capacity of 183.9 mAh g-1 at 1.0 A g-1 over 1600-time stable cycling at -60 °C. This work presents a cheap and efficient aqueous electrolyte to simultaneously improve low-temperature performances and Zn stability, broadening the design concepts for antifreeze electrolytes.

"Anions-in-Colloid" Hydrated Deep Eutectic Electrolyte for High Reversible Zinc Metal Anodes.

Zn metal as a promising anode for aqueous batteries suffers from severe zinc dendrites, anion-related side reactions, hydrogen evolution reaction (HER) and narrow electrochemical stable window (ESW). Herein, an "anions-in-colloid" hydrated deep eutectic electrolyte consisting of Zn(ClO4)2 ⋅ 6H2O, ß-cyclodextrin (ß-CD), and H2O with mass ratio of 7 : 4.5 : 3 (ACDE-3) is designed to improve the stability of zinc anode. The ACDE-3 reconfigures the hydrogen-bond (HB) network and regulates the solvation shell. More importantly, the hydroxyl-rich ß-cyclodextrins (ß-CDs) in ACDE-3 self-assemble into micelles, in which the steric effect between adjacent ß-CDs in micelles restricts the movement of anions. This unique "anions-in-colloid" structure enables the eutectic system with a high Zn2+ transference number (tZn 2+) of 0.84. Thus, ACDE-3 inhibits the formation of dendrite, prevents the anion-involved side reactions, suppresses the HER, and enlarges the ESW to 2.32 V. The Zn//Zn symmetric cell delivers a long lifespan of 900 hours at 0.5 mA cm-2, and the Zn//Cu half cells have a high average columbic efficiency (ACE) of 97.9 % at 0.5 mA cm-2 from cycle 15 to 200 with a uniform and compact zinc deposition. When matched with a poly(1,5-naphthalenediamine) (poly(1, 5-NAPD)) cathode, the full battery with a low negative/positive capacity (N/P) ratio of 2 can still cycle steadily for 200 cycles at a current density of 1.0 A g-1. Additionally, this electrolyte has been proven to be operative over a wide temperature range from -40 °C to 40 °C.

Tubular-specific expression of HIV protein Vpr leads to severe tubulointerstitial damage accompanied by progressive fibrosis and cystic development.

Chronic kidney disease (CKD) is a common cause of morbidity in human immunodeficiency virus (HIV)-positive individuals. HIV infection leads to a wide spectrum of kidney cell damage, including tubular epithelial cell (TEC) injury. Among the HIV-1 proteins, the pathologic effects of viral protein R (Vpr) are well established and include DNA damage response, cell cycle arrest, and cell death. Several in vitro studies have unraveled the molecular pathways driving the cytopathic effects of Vpr in tubular epithelial cells. However, the in vivo effects of Vpr on tubular injury and CKD pathogenesis have not been thoroughly investigated. Here, we use a novel inducible tubular epithelial cell-specific Vpr transgenic mouse model to show that Vpr expression leads to progressive tubulointerstitial damage, interstitial inflammation and fibrosis, and tubular cyst development. Importantly, Vpr-expressing tubular epithelial cells displayed significant hypertrophy, aberrant cell division, and atrophy; all reminiscent of tubular injuries observed in human HIV-associated nephropathy (HIVAN). Single-cell RNA sequencing analysis revealed the Vpr-mediated transcriptomic responses in specific tubular subsets and highlighted the potential multifaceted role of p53 in the regulation of cell metabolism, proliferation, and death pathways in Vpr-expressing tubular epithelial cells. Thus, our study demonstrates that HIV Vpr expression in tubular cells is sufficient to induce HIVAN-like tubulointerstitial damage and fibrosis, independent of glomerulosclerosis and proteinuria. Additionally, as this new mouse model develops progressive CKD with diffuse fibrosis and kidney failure, it can serve as a useful tool to examine the mechanisms of kidney disease progression and fibrosis in vivo.

Assessing the relationship between monoallelic PRKN mutations and Parkinson's risk.

Biallelic Parkin (PRKN) mutations cause autosomal recessive Parkinson's disease (PD); however, the role of monoallelic PRKN mutations as a risk factor for PD remains unclear. We investigated the role of single heterozygous PRKN mutations in three large independent case-control cohorts totalling 10 858 PD cases and 8328 controls. Overall, after exclusion of biallelic carriers, single PRKN mutations were more common in PD than controls conferring a >1.5-fold increase in the risk of PD [P-value (P) = 0.035], with meta-analysis (19 574 PD cases and 468 488 controls) confirming increased risk [Odds ratio (OR) = 1.65, P = 3.69E-07]. Carriers were shown to have significantly younger ages at the onset compared with non-carriers (NeuroX: 56.4 vs. 61.4 years; exome: 38.5 vs. 43.1 years). Stratifying by mutation type, we provide preliminary evidence for a more pathogenic risk profile for single PRKN copy number variant (CNV) carriers compared with single nucleotide variant carriers. Studies that did not assess biallelic PRKN mutations or consist of predominantly early-onset cases may be biasing these estimates, and removal of these resulted in a loss of association (OR = 1.23, P = 0.614; n = 4). Importantly, when we looked for additional CNVs in 30% of PD cases with apparent monoallellic PRKN mutations, we found that 44% had biallelic mutations, suggesting that previous estimates may be influenced by cryptic biallelic mutation status. While this study supports the association of single PRKN mutations with PD, it highlights confounding effects; therefore, caution is needed when interpreting current risk estimates. Together, we demonstrate that comprehensive assessment of biallelic mutation status is essential when elucidating PD risk associated with monoallelic PRKN mutations.