Inhibition of HDAC6 with CAY10603 alleviates acute and chronic kidney injury by suppressing the ATF6 branch of UPR.

BACKGROUND: Histone deacetylase 6 (HDAC6) inhibitor CAY10603 has been identified as a potential therapeutic agent for the treatment of diabetic kidney disease (DKD). The objective of this study was to investigate the therapeutic effects of CAY10603 in mice with acute kidney injury (AKI) and chronic kidney diseases (CKD). METHODS: Renal immunohistology was performed to assess the expression levels of HDAC6 in both human and mouse kidney samples. C57BL/6J mice were intraperitoneal injected with lipopolysaccharide (LPS) to induce AKI; CD-1 mice were fed with adenine diet to induce adenine-nephropathy as CKD model. Serum creatinine, blood urea nitrogen and uric acid were measured to reflect renal function; renal histology was applied to assess kidney damage. Western blot and immunohistology were used to analyze the unfolded protein response (UPR) level. RESULTS: HDAC6 was significantly upregulated in renal tubular epithelial cells (RTECs) of both AKI and CKD patients as well as mice. In the murine models of AKI induced by LPS and adenine-induced nephropathy, CAY10603 exhibited notable protective effects, including improvement in biochemical indices and pathological changes. In vivo and in vitro studies revealed that CAY10603 effectively suppressed the activation of activating transcription factor 6 (ATF6) branch of UPR triggered by thapsigargin (Tg), a commonly employed endoplasmic reticulum (ER) stressor. Consistent with these findings, CAY10603 also displayed substantial inhibition of ATF6 activation in RTECs from both murine models of LPS-induced AKI and adenine-induced nephropathy. CONCLUSIONS: Collectively, these results suggest that CAY10603 holds promise as a potential therapeutic agent for both acute and chronic kidney injury.

Urban network noise control based on road grade optimization considering comprehensive traffic environment benefit.

A double-decision optimization model based on the road grade optimization strategy and considered comprehensive traffic environment benefit is proposed to control the traffic noise. The upper-level model maximizes the comprehensive traffic environment benefit, including network noise emission and traffic efficiency. Adjusting the emphasis on noise optimization benefits and traffic efficiency in road network planning through setting weights. The lower-level resolves the question of network traffic flow assignment using a stochastic user-equilibrium model. The increase of traffic environment demand, network noise emissions decrease and travel time rises. In the case, with a low environmental requirement (weighting with 1.1), the sound pressure emission of the network decreases by 9.23% with only a 4.01% increase in travel time. Under the high environmental requirement (weighting with 0.2), the sound pressure decreases by 26.8%, but the travel time rises by as high as 30.9%. The network is optimized towards road grade degradation and is the first to optimize the arterial roads. In addition, it is found that the influence of speed on traffic noise is greater than that of traffic volume through case validation. This method proposing traffic noise optimization strategies at the road network planning level provides technical support for the proactive governance of traffic noise pollution and the improvement of traffic sound environment quality.

Ultrafast and Ultralarge Lithium-Ion Storage Enabled by Fluorine-Nitrogen Co-Implanted Carbon Tubes.

As a holy grail in electrochemistry, both high-power and high-energy electrochemical energy storage system (EES) has always been a pursued dream. To simultaneously achieve the "both-high" EES, a rational design of structure and composition for storage materials with characteristics of battery-type and capacitor-type storage is crucial. Herein, fluorine-nitrogen co-implanted carbon tubes (FNCT) have been designed, in which plentiful active sites and expanded interlayer space have been created benefiting from the heteroatom engineering and the fluorine-nitrogen synergistic effect, thus the above two-type storage mechanism can get an optimal balance in the FNCT. The implanted fluorine heteroatoms can not only amplify interlayer spacing, but also induce the transformation of nitrogen configuration from pyrrole nitrogen to pyridine nitrogen, further promoting the activity of the carbon matrix. The extraordinary electrochemical performance as results can be witnessed for FNCT, which exhibit fast lithium-ion storage capability with a high energy density of 119.4 Wh kg-1 at an ultrahigh power density of 107.5 kW kg-1 .

Computational infrared and Raman spectra by hybrid QM/MM techniques: a study on molecular and catalytic material systems.

Vibrational spectroscopy is one of the most well-established and important techniques for characterizing chemical systems. To aid the interpretation of experimental infrared and Raman spectra, we report on recent theoretical developments in the ChemShell computational chemistry environment for modelling vibrational signatures. The hybrid quantum mechanical and molecular mechanical approach is employed, using density functional theory for the electronic structure calculations and classical forcefields for the environment. Computational vibrational intensities at chemical active sites are reported using electrostatic and fully polarizable embedding environments to achieve more realistic vibrational signatures for materials and molecular systems, including solvated molecules, proteins, zeolites and metal oxide surfaces, providing useful insight into the effect of the chemical environment on the signatures obtained from experiment. This work has been enabled by the efficient task-farming parallelism implemented in ChemShell for high-performance computing platforms.  This article is part of a discussion meeting issue 'Supercomputing simulations of advanced materials'.

Multiscale QM/MM modelling of catalytic systems with ChemShell.

Hybrid quantum mechanical/molecular mechanical (QM/MM) methods are a powerful computational tool for the investigation of all forms of catalysis, as they allow for an accurate description of reactions occurring at catalytic sites in the context of a complicated electrostatic environment. The scriptable computational chemistry environment ChemShell is a leading software package for QM/MM calculations, providing a flexible, high performance framework for modelling both biomolecular and materials catalysis. We present an overview of recent applications of ChemShell to problems in catalysis and review new functionality introduced into the redeveloped Python-based version of ChemShell to support catalytic modelling. These include a fully guided workflow for biomolecular QM/MM modelling, starting from an experimental structure, a periodic QM/MM embedding scheme to support modelling of metallic materials, and a comprehensive set of tutorials for biomolecular and materials modelling.

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Objective: To investigate the role of histone deacetylase 6 (HDAC6) in podocyte injury in diabetic kidney disease (DKD) in mice. Methods: 1) The 8-week-old male CD-1 mice were selected to construct the model of DKD with streptozocin (STZ). After the model was established, the mice were intraperitoneally injected with HDAC6 inhibitor CAY10603 (5mg/kg/daily) or same volume vehicle as control. The mice were divided into four groups, control (CTL)+vehicle (Veh) (n=5), CLT+CAY10603 (n=3), STZ+Veh (n=9), and STZ+CAY10603 (n=7). Mice in STZ+Veh and STZ+CAY10603 groups developed DKD, while mice in the CTL+Veh and CTL+CAY10603 groups were served as normal controls. The therapeutic effect was evaluated through urine albumin-to-creatinine ratio (uACR) and renal pathology after the 2-week treatment with CAY10603. 2) Human podocytes were cultured in vitro and were divided into four groups as follows: CTL, transforming growth factor-ß (TGFß), TGFß+CAY10603 (250 nmol/L), and TGFß+CAY10603 (500 nmol/L) groups. The control group did not receive any treatment, the last three groups were given 36-h TGFß treatment at 5 ng/µL, with or without CAY10603 as indicated for an additional 12 h. Western blot was performed to determine the inhibitory effect of CAY10603 on NLRP3 inflammasome. 3) HDAC6 knockout (KO) mice were generated and used to create STZ-induced model of DKD. The mice were divided into four groups: C57BL/6J wild type (WT) (n=6), HDAC6 KO (n=6), WT+STZ (n=10), and HDAC6 KO+STZ (n=9). Samples were collected 16 weeks after successful modeling and changes in uACR and renal pathology were evaluated accordingly. Results: After 2 weeks of treatment, mice in the STZ+CAY10603 group exhibited reduction in uACR (P<0.05) and inhibition of glomerular mesangium expansion (P<0.05) compared with those of the mice in the STZ+Veh group. There was no statistically significant difference in the indicators between the CTL+Veh group and the CTL+CAY10603 group. In vitro cultured podocytes, compared with the control group, NLRP3 inflammasome activation was seen in the TGFß group. CAY10603 treatment significantly inhibited the activation of NLRP3 in the dosage-dependent manner (P<0.05). Compared with those of the WT group, the WT+STZ group showed increased uACR (P<0.05), obvious glomerulosclerosis and loss of podocytes numbers. Compared with those of the WT+STZ group, the HDAC6 KO+STZ group showed effectively reduction of uACR (P<0.05) and improvement in the renal pathological changes in mice. There was no significant difference in these aspects between the WT and HDAC6 KO groups. Conclusion: Inhibition of HDAC6 alleviates proteinuria and podocyte injury in the mouse model of DKD by suppressing the activation of NLRP3 inflammasome.

Application of Familial Y-STR Haplotype Mismatch Tolerance in Genealogy Inference.

OBJECTIVES: To provide a guideline for genealogy inference and family lineage investigation through a study of the mismatch tolerance distribution of Y-STR loci in Chinese Han male lineage. METHODS: Three Han lineages with clear genetic relationships were selected. YFiler Platinum PCR amplification Kit was used to obtain the typing data of 35 Y-STR loci in male samples. The variation of Y-STR haplotypes in generation inheritance and the mismatch tolerance at 1-7 kinship levels were statistically analyzed. RESULTS: Mutations in Y-STR were family-specific with different mutation loci and numbers of mutation in different lineages. Among all the mutations, 66.03% were observed on rapidly and fast mutating loci. At 1-7 kinship levels, the number of mismatch tolerance ranged from 0 to 5 on all 35 Y-STR loci, with a maximum step size of 6. On medium and slow mutant loci, the number of mismatch tolerance ranged from 0 to 2, with a maximum step size of 3; on rapidly and fast mutant loci, the number of mismatch tolerance ranged from 0 to 3, with a maximum step size of 6. CONCLUSIONS: Combined use of SNP genealogy inference and Y-STR lineage investigation, both 0 and multiple mismatch tolerance need to be considered. Family lineage with 0-3 mismatch tolerance on all 35 Y-STR loci and 0-1 mismatch tolerance on medium and slow loci can be prioritized for screening. When the number of mismatch tolerance is eligible, family lineages with long steps should be carefully excluded. Meanwhile, adding fast mutant loci should also be handled with caution.

An Endogenous Prompting Mechanism for Sulfur Conversions Via Coupling with Polysulfides in Li-S Batteries.

The sluggish kinetics process and shuttling of soluble intermediates present in complex conversion between sulfur and lithium sulfide severely limit the practical application of lithium-sulfur batteries. Herein, by introducing a designated functional organic molecule to couple with polysulfide intermediators, an endogenous prompting mechanism of sulfur conversions has thus been created leading to an alternative sulfur-electrode process, in another words, to build a fast "internal cycle" of promotors that can promote the slow "external cycle" of sulfur conversions. The coupling-intermediators between the functional organic molecule and polysulfides, organophosphorus polysulfides, to be the "promotors" for sulfur conversions, are not only insoluble in the electrolyte but also with higher redox-activity. So the sulfur-electrode process kinetics is greatly improved and the shuttle effect is eliminated simultaneously by this strategy. Meanwhile, with the endogenous prompting mechanism, the morphology of the final discharge product can be modified into a uniform covering film, which is more conducive to its decomposition when charging. Benefiting from the effective mediation of reaction kinetics and control of intermediates solubility, the lithium-sulfur batteries can act out excellent rate performance and cycling stability.

Protein phosphatase 2Acα modulates fatty acid oxidation and glycolysis to determine tubular cell fate and kidney injury.

Energy metabolism is crucial in maintaining cellular homeostasis and adapting to stimuli for tubular cells. However, the underlying mechanisms remain largely unknown. Here, we report that PP2Acα was upregulated in damaged tubular cells from patients and animal models with acute or chronic kidney injury. Using in vitro and in vivo model, we demonstrated that PP2Acα induction in damaged tubular cells suppresses fatty acid oxidation and promotes glycolysis, leading to cell death and fibrosis. Mechanistically, we revealed that PP2Acα dephosphorylates ACC through interaction with B56δ, leading to the regulation of fatty acid oxidation. Furthermore, PP2Acα also dephosphorylates p-Glut1 (Thr478) and suppresses Trim21-mediated Glut1 ubiquitination and degradation, leading to the promotion of glucose intake and glycolysis. Thus, this study adds new insight into the tubular cell metabolic alterations in kidney diseases. PP2Acα may be a promising therapeutic target for kidney injury.

An Active-Oxygen-Scavenging Oriented Cathode-Electrolyte-Interphase for Long-Life Lithium-Rich Cathode Materials.

Lithium-rich layered oxides with high energy density are promising cathode materials, thus having attracted a large number of researchers. However, the materials cannot be commercialized for application so far. The crucial problem is the releasing of lattice oxygen at high voltage and resulting consequence, such as decomposition of electrolyte, irreversible phase transition of crystal structure, capacity degradation, and voltage decay. Therefore, capturing active-oxygen and further constructing a cathode-electrolyte-interface (CEI) protective layer via the scavenging effects should be a fundamental step to solve these issues. Herein, ß-carotene with antioxidant properties is used as a scavenging molecule to achieve this goal. The control of active oxygen species effectively alleviates the decomposition of carbonate electrolyte under high voltage. The introduction of ß-carotene additives can also be adjusted in situ to generate a customized CEI film, which is a double-layer structure with external organic components and internal inorganic components. Moreover, the ß-carotene-containing electrolyte system exhibits better thermal stability. Benefited from these, Lithium-rich cathode of ß-carotene-containing electrolyte shows outstanding long-life cycle stability, with 93.4% capacity retention rate after 200 cycles at 1 C; this electrochemical stability is superior to other electrolyte additive systems reported at present.

Regulating Lithium Plating/Stripping Behavior by a Composite Polymer Electrolyte Endowed with Designated Ion Channels.

The urgent demand for high energy and safety storage devices is pushing the development of lithium metal batteries. However, unstable solid electrolyte interface (SEI) formation and uncontrollable lithium dendrite growth are still huge challenges for the practical use of lithium metal batteries. Herein, a composite polymer electrolyte (CPE) endowed with designated ion channels is fabricated by constructing nanoscale Uio66-NH2 layer, which has uniformly distributed pore structure to regulate reversible Li plating/stripping in lithium metal batteries. The regular channels within the Uio66-NH2 layer work as an ion sieve to restrict larger TFSI- anions inside its channels and extract Li+ across selectively, which result in a high Li-ion transference number ( t Li + ${t_{{\rm{L}}{{\rm{i}}^{\bm{ + }}}}}$ ) of 0.6. Moreover, CPE provides high ion conductivity (0.245 mS cm-1 at room temperature) and expanded oxidation window (5.1 V) and forms a stable SEI layer. As a result, the assembled lithium metal batteries with CPE exhibit outstanding cyclic stability and capacity retention. The Li/CPE/Li symmetric cell continues plating/stripping over 500 h without short-circuiting. The Li/CPE/LFP cell delivers a reversible capacity of 149.3 mAh g-1 with a capacity retention of 99% after 100 cycles.

Prognostic ability of lung immune prognostic index in limited-stage small cell lung cancer.

BACKGROUND: Lung immune prognostic index (LIPI) is a prognostic marker of extensive-stage small cell lung cancer (ES-SCLC) patients received immunotherapy or chemotherapy. However, its ability in limited-stage SCLC (LS-SCLC) should be evaluated extensively. METHODS: We retrospectively enrolled 497 patients diagnosed as LS-SCLC between 2015 and 2018, and clinical data included pretreatment lactate dehydrogenase (LDH), white blood cell count, and absolute neutrophil count levels were collected. According to the LIPI scores, the patients were stratified into low-risk (0 points) and high-risk (1-2 points). The correlations between LIPI and overall survival (OS) or progression-free survival (PFS) were analyzed by the Cox regression. Additionally, the propensity score matching (PSM) and inverse probability of treatment weight (IPTW) methods were used to reduce the selection and confounding bias. A nomogram was constructed using on multivariable Cox model. RESULTS: Two hundred fifty and 247 patients were in the LIPI high-risk group and low-risk group, and their median OS was 14.67 months (95% CI: 12.30-16.85) and 20.53 months (95% CI: 17.67-23.39), respectively. In the statistical analysis, High-risk LIPI was significantly against worse OS (HR = 1.377, 95%CI:1.114-1.702) and poor PFS (HR = 1.338, 95%CI:1.1-1.626), and the result was similar after matching and compensating with the PSM or IPTW method. A novel nomogram based on LIPI has a decent level of predictive power. CONCLUSION: LIPI stratification was a significant factor against OS or PFS of LS-SCLC patients.

Zebrafish GSDMEb Cleavage-Gated Pyroptosis Drives Septic Acute Kidney Injury In Vivo.

The bacteria LPS is one of the leading endotoxins responsible for sepsis; its sensing pathway-induced pyroptosis plays an important role in innate immunity. However, excessive pyroptosis might cause immunological diseases, even multiple organ failure and death by undefined mechanisms. Given that the development of acute kidney injury (AKI) in patients with sepsis causes significant morbidity and mortality, the mechanism of pyroptosis in regulating septic AKI remains unknown. In this study, we establish a zebrafish crispant in vivo analysis model and reveal that both caspy2 and gasdermin Eb (GSDMEb) contribute to lethal LPS-induced septic shock. Meanwhile, the in vitro analysis reveals that caspy2 activation can specifically cleave GSDMEb to release its N terminus to mediate pyroptosis, which functions as GSDMD in mammals. Interestingly, we establish an in vivo propidium iodide-staining method and reveal that the caspy2-GSDMEb signaling cascade is essential for enhancing renal tubular damage during lethal LPS-induced septic shock, whereas administration of the zebrafish-specific GSDMEb-derived peptide inhibitor Ac-FEID-CMK can attenuate mortality and septic AKI in vivo. Moreover, we confirm that either caspase-11 or GSDMD deficiency decreases both inflammatory cytokines and kidney dysfunction enzyme release and prolongs survival in a murine model of septic shock. Taken together, these findings demonstrate an evolutionary executor for pyroptosis in zebrafish and reveal that the pyroptosis of renal tubular cells is a major cause of septic AKI, and also provide an ideal in vivo screening model for potential antisepsis therapeutic strategies.

Prognostic Significance of Clinicopathological Factors Influencing Overall Survival and Event-Free Survival of Patients with Cervical Cancer: A Systematic Review and Meta-Analysis.

BACKGROUND Cervical cancer (CC) is the most frequent type of cancer among women and its poor prognosis is a main concern, while the prognostic factors for CC have still remained controversial. We conducted this systematic review and meta-analysis to identify the prognostic significance of clinicopathological factors, influencing overall survival (OS), and event-free survival (EFS) of CC patients. MATERIAL AND METHODS The electronic databases of PubMed, EmBase, and the Cochrane library were systematically searched for identification of eligible studies published until June 2021. The pooled hazard ratio (HR) with 95% confidence interval (CI) were calculated using the random-effects model. Sensitivity and subgroup analyses and assessment of publication bias were also conducted. RESULTS We selected 140 studies that involved 47 965 patients for the meta-analysis. The results revealed that age, cell type, depth of tumor invasion, the International Federation of Gynecology and Obstetrics stage, hemoglobin level, histological grade, leukocytosis, lymph node involvement, lymph-vascular space invasion, neutrophil-to-lymphocyte ratio, parametrial invasion, platelet-to-lymphocyte ratio, resection margin, squamous cell carcinoma antigen level, thrombocytosis, tumor grade, tumor size, and tumor volume were clinicopathological factors influencing OS and EFS of CC patients (P<0.05). CONCLUSIONS This study comprehensively identified the prognostic significance of clinicopathological factors, influencing OS, and EFS of CC patients. However, further large-scale prospective studies should be conducted to verify our findings and develop more accurate prognostic models for CC.

Local tuning of radiomics-based model for predicting pathological response to neoadjuvant chemoradiotherapy in locally advanced rectal cancer.

PURPOSE: This study aims to further enhance a validated radiomics-based model for predicting pathologic complete response (pCR) after chemo­radiotherapy in locally advanced rectal cancer (LARC) for use in clinical practice. METHODS: A generalized linear model (GLM) to predict pCR in LARC patients previously trained in Europe and validated with an external inter-continental cohort (59 patients), was first examined with further 88 intercontinental patient datasets to assess its reproducibility; then new radiomics and clinical features, and validation methods were investigated to build a new model for enhancing the pCR prediction for patients admitted to our department. The patients were divided into training group (75%) and validation group (25%) according to their demographic. The least absolute shrinkage and selection operator (LASSO) logistic regression was used to reduce the dimensionality of the extracted features of the training group and select the optimal ones; the performance of the reference GLM and enhanced models was compared through the area under curve (AUC) of the receiver operating characteristics. RESULTS: The value of AUC of the reference model was 0.831 (95% CI, 0.701-0.961), and 0.828 (95% CI, 0.700-0.956) in the original and new validation cohorts, respectively, showing a reproducibility in the applicability of the GLM model. Eight features were found to be significant with LASSO and used to establish an enhanced model. The AUC of the enhanced model of 0.926 (95% CI, 0.859-0.993) for training, and 0.926 (95% CI, 0.767-1.00) for the validation group shows better performance than the reference model. CONCLUSIONS: The GLM model shows good reproducibility in predicting pCR in LARC; the enhanced model has the potential to improve prediction accuracy and may be a candidate in clinical practice.

Genotypic diversity and antifungal susceptibility of Scedosporium species from clinical settings in China.

BACKGROUND: Scedosporium species have drawn significant interest as inhabitants of polluted soil and water and as cause of high mortality in near-drowning patients. So far, most cases have been reported from Europe and Australia, while knowledge on their prevalence and genotypic diversity from Asia is scant. OBJECTIVES: To increase the knowledge of the genetic diversity and in vitro antifungal susceptibility of Scedosporium species involved in human infections from China. METHODS: Here, we applied the ISHAM-MLST consensus scheme for molecular typing of Scedosporium species and revealed both high species diversity and high genotypic diversity among 45 Chinese clinical Scedosporium isolates. RESULTS: Among the five species, Scedosporium boydii (n = 22) was the most common, followed by S. apiospermum (n = 18), S. aurantiacum (n = 4) and S. dehoogii (n = 1). S. aurantiacum was reported for the first time from clinical samples in China. The predominant sequence types (STs) were ST17 in S. apiospermum, ST4 in S. boydii and ST92 in S. aurantiacum, including four novel STs (ST40, ST41, ST42 and ST43) in S. apiospermum. Based on the CLSI-M38 A2 criterion, voriconazole was the only antifungal compound with low MIC values (MIC90 ≤ 1 µg/ml) for all Scedosporium isolates in our study. CONCLUSIONS: The genetic diversity of clinical isolates of Scedosporium species from China is extremely high, with S. boydii being predominant and S. aurantiacum being firstly reported here. VOR was the only antifungal compound with low MIC values for all Scedosporium isolates in our study, which should be recommended as the firstline antifungal treatment against scedosporiosis in China.

Super-Enhancer-Associated Transcription Factors Maintain Transcriptional Regulation in Mature Podocytes.

BACKGROUND: Transcriptional programs control cell fate, and identifying their components is critical for understanding diseases caused by cell lesion, such as podocytopathy. Although many transcription factors (TFs) are necessary for cell-state maintenance in glomeruli, their roles in transcriptional regulation are not well understood. METHODS: The distribution of H3K27ac histones in human glomerulus cells was analyzed to identify superenhancer-associated TFs, and ChIP-seq and transcriptomics were performed to elucidate the regulatory roles of the TFs. Transgenic animal models of disease were further investigated to confirm the roles of specific TFs in podocyte maintenance. RESULTS: Superenhancer distribution revealed a group of potential TFs in core regulatory circuits in human glomerulus cells, including FOXC1/2, WT1, and LMX1B. Integration of transcriptome and cistrome data of FOXC1/2 in mice resolved transcriptional regulation in podocyte maintenance. FOXC1/2 regulated differentiation-associated transcription in mature podocytes. In both humans and animal models, mature podocyte injury was accompanied by deregulation of FOXC1/2 expression, and FOXC1/2 overexpression could protect podocytes in zebrafish. CONCLUSIONS: FOXC1/2 maintain podocyte differentiation through transcriptional stabilization. The genome-wide chromatin resources support further investigation of TFs' regulatory roles in glomeruli transcription programs.

Chromatin architecture reveals cell type-specific target genes for kidney disease risk variants.

BACKGROUND: Cell type-specific transcriptional programming results from the combinatorial interplay between the repertoire of active regulatory elements. Disease-associated variants disrupt such programming, leading to altered expression of downstream regulated genes and the onset of pathological states. However, due to the non-linear regulatory properties of non-coding elements such as enhancers, which can activate transcription at long distances and in a non-directional way, the identification of causal variants and their target genes remains challenging. Here, we provide a multi-omics analysis to identify regulatory elements associated with functional kidney disease variants, and downstream regulated genes. RESULTS: In order to understand the genetic risk of kidney diseases, we generated a comprehensive dataset of the chromatin landscape of human kidney tubule cells, including transcription-centered 3D chromatin organization, histone modifications distribution and transcriptome with HiChIP, ChIP-seq and RNA-seq. We identified genome-wide functional elements and thousands of interactions between the distal elements and target genes. The results revealed that risk variants for renal tumor and chronic kidney disease were enriched in kidney tubule cells. We further pinpointed the target genes for the variants and validated two target genes by CRISPR/Cas9 genome editing techniques in zebrafish, demonstrating that SLC34A1 and MTX1 were indispensable genes to maintain kidney function. CONCLUSIONS: Our results provide a valuable multi-omics resource on the chromatin landscape of human kidney tubule cells and establish a bioinformatic pipeline in dissecting functions of kidney disease-associated variants based on cell type-specific epigenome.

High-Performance Lithium-Oxygen Batteries Using a Urea-Based Electrolyte with Kinetically Favorable One-Electron Li2 O2 Oxidation Pathways.

Glymes are the most widely used electrolyte solvents in lithium-oxygen batteries (LOBs) due to their relatively high stability. However, their associated LOBs have long been plagued by large charge overpotential, which is closely related to the sluggish two-electron Li2 O2 oxidation mechanism. Here, we report a new electrolyte solvent-1,1,3,3-tetramethylurea (TMU) for LOBs with high performance and an alternative mechanism, where a kinetically favorable one-electron Li2 O2 oxidation pathway can happen in the urea electrolyte system, thus leading to a much lower charge overpotential (≈0.51 V) compared to the tetraglyme-based LOBs (≈1.27 V). Besides, TMU also exhibits good stability since it does not contain any α-hydrogen atoms that are vulnerable to be attacked by superoxide species, thus suppressing the hydrogen abstraction side reactions. Consequently, the TMU-based LOBs can stably work for more than 135 cycles, which is four times that of the tetraglyme-based LOBs (≈28 cycles).

A Highly Reversible Lithium Metal Anode by Constructing Lithiophilic Bi-Nanosheets.

As a favorable candidate for the next-generation anode materials, metallic lithium is faced with two crucial problems: uncontrollable lithium plating/stripping process and huge volume expansion during cycling. Herein, a 3D lithiophilic skeleton modified with nanoscale Bi sheets (Ni@Bi Foam, i.e., NBF) through one-step facile substitution reaction is constructed. Benefiting from the nanoscale modification, smooth and dense lithiophilic Li3 Bi layer is in situ formed, which improves the uniform deposition of Li subsequently. Meanwhile, the 3D structure inhibits the growth of Li dendrites effectively by reducing local areal current density. Consequently, the NBF exhibits outstanding cycling stability with a high average Coulombic efficiency of 98.46% at 1 mA cm-2 with 1 mAh cm-2 (>500 cycles). Symmetrical cell with NBF exhibits a high reversibility at 1 mA cm-2 with 1 mAh cm-2 (>2000 h). Moreover, superior long-term cycling and rate performance of NBF@Li anode are also acquired when assembled with high areal loading of LiFePO4 (10.1 mg cm-2 ) cathode (Negative/Positive ratio: 2.91). Even in anode-free metal lithium batteries, NBF has higher capacity during cycling compared with NF. To conclude, NBF shows excellent electrochemical performance and provides an idea of facile preparation method which can be extend to other metal batteries.