Notoginsenoside R1 attenuates ischemic heart failure by modulating MDM2/ß arrestin2-mediated ß2-adrenergic receptor ubiquitination.

ß2 adrenergic receptor (ß2AR) is a G-protein-coupled receptor involved in cardiac protection. In chronic heart failure (CHF), persistent sympathetic nervous system activation occurs, resulting in prolonged ß2AR activation and subsequent receptor desensitization and downregulation. Notoginsenoside R1 (NGR1) has the functions of enhancing myocardial energy metabolism and mitigating myocardial fibrosis. The mechanisms of NGR1 against ischemic heart failure are unclear. A left anterior descending (LAD) artery ligation procedure was performed on C57BL/6 J mice for four weeks. From the 4th week onwards, they were treated with various doses (3, 10, 30 mg/kg/day) of NGR1. Subsequently, the impacts of NGR1 on ischemic heart failure were evaluated by assessing cardiac function, morphological changes in cardiac tissue, and the expression of atrial natriuretic peptide (ANP) and beta-myosin heavy chain (ß-MHC). H9c2 cells were protected by NGR1 when exposed to OGD/R conditions. H9c2 cells were likewise protected from OGD/R damage by NGR1. Furthermore, NGR1 increased ß2AR levels and decreased ß2AR ubiquitination. Mechanistic studies revealed that NGR1 enhanced MDM2 protein stability and increased the expression of MDM2 and ß-arrestin2 while inhibiting their interaction. Additionally, under conditions produced by OGD/R, the protective benefits of NGR1 on H9c2 cells were attenuated upon administration of the MDM2 inhibitor SP141. According to these findings, NGR1 impedes the interplay between ß-arrestin2 and MDM2, thereby preventing the ubiquitination and degradation of ß2AR to improve CHF.

Astrocytes modulate brain phosphate homeostasis via polarized distribution of phosphate uptake transporter PiT2 and exporter XPR1.

Aberrant inorganic phosphate (Pi) homeostasis causes brain calcification and aggravates neurodegeneration, but the underlying mechanism remains unclear. Here, we found that primary familial brain calcification (PFBC)-associated Pi transporter genes Pit2 and Xpr1 were highly expressed in astrocytes, with importer PiT2 distributed over the entire astrocyte processes and exporter XPR1 localized to astrocyte end-feet on blood vessels. This polarized PiT2 and XPR1 distribution endowed astrocyte with Pi transport capacity competent for brain Pi homeostasis, which was disrupted in mice with astrocyte-specific knockout (KO) of either Pit2 or Xpr1. Moreover, we found that Pi uptake by PiT2, and its facilitation by PFBC-associated galactosidase MYORG, were required for the high Pi transport capacity of astrocytes. Finally, brain calcification was suppressed by astrocyte-specific PiT2 re-expression in Pit2-KO mice. Thus, astrocyte-mediated Pi transport is pivotal for brain Pi homeostasis, and elevating astrocytic Pi transporter function represents a potential therapeutic strategy for reducing brain calcification.

KLHL21 suppresses gastric tumourigenesis via maintaining STAT3 signalling equilibrium in stomach homoeostasis.

OBJECTIVE: Precancerous metaplasia transition to dysplasia poses a risk for subsequent intestinal-type gastric adenocarcinoma. However, the molecular basis underlying the transformation from metaplastic to cancerous cells remains poorly understood. DESIGN: An integrated analysis of genes associated with metaplasia, dysplasia was conducted, verified and characterised in the gastric tissues of patients by single-cell RNA sequencing and immunostaining. Multiple mouse models, including homozygous conditional knockout Klhl21-floxed mice, were generated to investigate the role of Klhl21 deletion in stemness, DNA damage and tumour formation. Mass-spectrometry-based proteomics and ribosome sequencing were used to elucidate the underlying molecular mechanisms. RESULTS: Kelch-like protein 21 (KLHL21) expression progressively decreased in metaplasia, dysplasia and cancer. Genetic deletion of Klhl21 enhances the rapid proliferation of Mist1+ cells and their descendant cells. Klhl21 loss during metaplasia facilitates the recruitment of damaged cells into the cell cycle via STAT3 signalling. Increased STAT3 activity was confirmed in cancer cells lacking KLHL21, boosting self-renewal and tumourigenicity. Mechanistically, the loss of KLHL21 promotes PIK3CB mRNA translation by stabilising the PABPC1-eIF4G complex, subsequently causing STAT3 activation. Pharmacological STAT3 inhibition by TTI-101 elicited anticancer effects, effectively impeding the transition from metaplasia to dysplasia. In patients with gastric cancer, low levels of KLHL21 had a shorter survival rate and a worse response to adjuvant chemotherapy. CONCLUSIONS: Our findings highlighted that KLHL21 loss triggers STAT3 reactivation through PABPC1-mediated PIK3CB translational activation, and targeting STAT3 can reverse preneoplastic metaplasia in KLHL21-deficient stomachs.

Effect of the degree of follicular diameter ≥18mm differentiation on the day of hCG administration to the outcome of controlled ovarian hyperstimulation (COH).

Objective: To explore the impact of the level of differentiation in a minimum of two follicles with a diameter of ≥18 mm on the outcome of controlled ovarian hyperstimulation on the day of human chorionic gonadotropin (hCG) administration. Methods: Single-center data from January 2018 to December 2021 was retrospectively analyzed for 1,199 patients with fresh embryo transfer for assisted reproduction. The absolute value of the standard deviation of the follicle size of at least 2 follicles ≥18 mm in diameter in both ovaries on the day of hCG was taken as the degree of differentiation of the dominant follicle after ovulation induction, based on the standard deviation response to the degree of dispersion of the data. The degree of follicular differentiation was divided into 3 groups according to the size of the value, and the general clinical conditions, laboratory indexes, and clinical outcomes of the patients in the 3 groups were compared. Results: Among the three groups, the body mass index (BMI) of the ≤1s group was lower than that of the other two groups (P< 0.05), while the follicle-stimulating hormone (FSH) and Anti-Mullerian hormone (AMH) were higher (P< 0.05), and the implantation rate and clinical pregnancy rate were significantly higher than those of the other two groups (P< 0.01). After multifactorial logistic regression to correct for confounding factors, with the ≤1s group as the reference, the implantation rate, hCG-positive rate, clinical pregnancy rate and live birth rate of embryo transfer in the ≥2S group were significantly lower (P< 0.01). The results of curve fitting analysis showed that the live birth rate decreased gradually with the increase of the absolute standard deviation (P=0.0079). Conclusion: Differences in follicle diameters ≥18 mm on the day of hCG injection did not have an impact on embryo quality, but had an impact on pregnancy outcomes. The less the variation in follicle size, the more homogeneous the follicle development and the higher the likelihood of live births.

Terahertz flexible multiplexing chip enabled by synthetic topological phase transitions.

Flexible multiplexing chips that permit reconfigurable multidimensional channel utilization are indispensable for revolutionary 6G terahertz communications, but the insufficient manipulation capability of terahertz waves prevents their practical implementation. Herein, we propose the first experimental demonstration of a flexible multiplexing chip for terahertz communication by revealing the unique mechanism of topological phase (TP) transition and perseveration in a heterogeneously coupled bilayer valley Hall topological photonic system. The synthetic and individual TPs operated in the coupled and decoupled states enable controllable on-chip modular TP transitions and subchannel switching. Two time-frequency interleaved subchannels support 10- and 12-Gbit/s QAM-16 high-speed data streams along corresponding paths over carriers of 120 and 130 GHz with 2.5- and 3-GHz bandwidths, respectively. This work unlocks interlayer heterogeneous TPs for inspiring ingenious on-chip terahertz-wave regulation, allowing functionality-reconfigurable, compactly integrated and CMOS-compatible chips.

Vinyl-bearing sp2 carbon-conjugated covalent organic framework composites for enhanced electrochemical performance in hydrogen evolution reaction and lithium-sulfur batteries.

Vinyl-bearing triazine-functionalized covalent organic frameworks (COFs) have emerged as promising materials for electrocatalysis and energy storage. Guided by density functional theory calculations, a vinyl-enriched COF (VCOF-1) featuring a donor-acceptor structure was synthesized based on the Knoevenagel reaction. Moreover, the VCOF-1@Ru without pyrolysis was obtained through chemical coordination interactions between VCOF-1 and RuCl3, exhibiting enhanced electrocatalytic performance in the hydrogen evolution reaction when exposed to 0.5 M H2SO4. The results demonstrated that the protonation of VCOF-1@Ru enhanced the electrical conductivity and accelerated the generation of H2 on the catalytically active site Ru. Additionally, VCOF-1@CNT with a tubular structure was prepared by uniformly wrapping VCOF-1 onto carbon nanotubes (CNTs) and using it as a cathode for lithium-sulfur batteries by chemically and physically encapsulating S. The enhanced performance of VCOF-1@CNT was attributed to the effective suppression of lithium polysulfide migration. This suppression was achieved through several mechanisms, including the inverse vulcanization of vinyl on VCOF-1@CNT, the enhancement of material conductivity, and the interaction between N in the materials and Li ions. This study demonstrated a strategy for enhancing material performance by precisely modulating the COF structure at the molecular level.

Highly Conductive and Stable Composite Polymer Electrolyte with Boron Nitride Nanotubes for All-Solid-State Lithium Metal Batteries.

All-solid-state lithium metal batteries (ASSLMBs) have emerged as the most promising next-generation energy storage devices. However, the unsatisfactory ionic conductivity of solid electrolytes at room temperature has impeded the advancement of solid-state batteries. In this work, a multifunctional composite solid electrolyte (CSE) is developed by incorporating boron nitride nanotubes (BNNTs) into polyvinylidene fluoride-hexafluoropropylene (PVDF-HFP). BNNTs, with a high aspect ratio, trigger the dissociation of Li salts, thus generating a greater population of mobile Li+, and establishing long-distance Li+ transport pathways. PVDF-HFP/BNNT exhibits a high ionic conductivity of 8.0 × 10-4 S cm-1 at room temperature and a Li+ transference number of 0.60. Moreover, a Li//Li symmetric cell based on PVDF-HFP/BNNT demonstrates robust cyclic performance for 3400 h at a current density of 0.2 mA cm-2. The ASSLMB formed from the assembly of PVDF-HFP/BNNT with LiFePO4 and Li exhibits a capacity retention of 93.2% after 850 cycles at 0.5C and 25 °C. The high-voltage all-solid-state LiCoO2/Li cell based on PVDF-HFP/BNNT also exhibits excellent cyclic performance, maintaining a capacity retention of 96.4% after 400 cycles at 1C and 25 °C. Furthermore, the introduction of BNNTs is shown to enhance the thermal conductivity and flame retardancy of the CSE.

LncRNA GABPB1-AS1 is a potential target for the diagnosis of prostate cancer.

BACKGROUND: Prostate cancer is an adverse tumor that occurs in the male reproductive system. The symptoms of patients in the early stage are not obvious and are generally difficult to detect. AIM: The aim of this study was to determine the regulation of lncRNA GABPB1-AS1 (GABPB1-AS1) on prostate cancer progression and explore the diagnostic potential of GABPB1-AS1. METHODS: The contents of serum GABPB1-AS1 and miR-330-3p were examined by RT-qPCR assay. The functions of silencing GABPB1-AS1 and miR-330-3p inhibitor in prostate cancer cells were determined using transfection assay, CCK-8 assay and Transwell assay. The target of GABPB1-AS1 was predicted and verified at the molecular level by bioinformatics and luciferase reporter gene assay. The function of GABPB1-AS1 in prostate cancer diagnosis was evaluated via ROC method. RESULTS: GABPB1-AS1 was upregulated in prostate cancer serum, which was associated with patients' Gleason score and TNM stage. Mechanistically, GABPB1-AS1 directly targeted miR-330-3p, and there was a negative correlation between them. Reduced levels of GABPB1-AS1 in cells after knockdown of GABPB1-AS1 resulted in decreased prostate cancer cell growth and activity, and these inhibitory effects were repaired by miR-330-3p inhibitor. CONCLUSION: The present study confirmed that GABPB1-AS1 was overexpressed in prostate cancer, and its sponge miR-330-3p may be an effective target for timely diagnosis of prostate cancer.

NRF3 suppresses the metastasis of triple-negative breast cancer cells by inhibiting ERK activation in a ROS-dependent manner.

PURPOSE: Our previous study demonstrated that NRF3 (NFE2L3, Nuclear Factor-erythroid 2-related factor 3) could suppress cell metastasis and proliferation in breast cancer. In this study, we investigated the mechanisms underlying its function in breast cancer. METHODS: In the present study, NRF3 expression and its clinical characteristics in breast cancer were analyzed using public datasets and clinical specimens. After breast cancer cells were overexpressed NRF3, FACS was used to detect the intracellular ROS levels. The migration and invasion activities of NRF3-ectopic expressed breast cancer cells were determined by transwell assay. To validate the role of ROS/ERK axis in the inhibitory effect of NRF3 in cell metastasis, ROS scavenger NAC was also included. RESULTS: We found that NRF3 mRNA was highly expressed, while NRF3 protein was extremely lowly expressed in breast cancer tissues compared with their normal counterparts, and low level NRF3 was associated with poorer prognosis in patients with triple negative breast cancer (TNBC). More interestingly, overexpression of NRF3 protein significantly increased cellular ROS production and dramatically decreased p-ERK level and cell migration in TNBC cells. Mechanistically, NRF3 protein was found to be mutually regulated by valosin-containing protein (VCP). Strikingly, VCP-knockdown dramatically increased NRF3 protein expression, but NRF3-knockin also decreased VCP expression in return. Moreover, antioxidant NAC treatment effectively increased the level of p-ERK and VCP expression, as well as cell migration and invasion abilities of TNBC cells. CONCLUSION: NRF3, a tumor suppressor downregulated by VCP, could attenuate cell metastasis in TNBC cells by increasing cellular ROS accumulation and subsequently inhibiting the ERK phosphorylation.

Identification of the conductivity type of single-walled carbon nanotubes via dual-modulation dielectric force microscopy.

The conductivity type is one of the most fundamental transport properties of semiconductors, which is usually identified by fabricating the field-effect transistor, the Hall-effect device, etc. However, it is challenging to obtain an Ohmic contact if the sample is down to nanometer-scale because of the small size and intrinsic heterogeneity. Noncontact dielectric force microscopy (DFM) can identify the conductivity type of the sample by applying a DC gate voltage to the tip, which is effective in tuning the accumulation or depletion of charge carriers. Here, we further developed a dual-modulation DFM, which simplified the conductivity type identification from multiple scan times under different DC gate voltages to a single scan under an AC gate voltage. Taking single-walled carbon nanotubes as testing samples, the semiconducting-type sample exhibits a more significant charge carrier accumulation/depletion under each half-period of the AC gate voltage than the metallic-type sample due to the stronger rectification effect. The charge carrier accumulation or depletion of the p-type sample is opposite to that of the n-type sample at the same half-period of the AC gate voltage because of the reversed charge carrier type.

Increased ONECUT2 induced by Helicobacter pylori promotes gastric cancer cell stemness via an AKT-related pathway.

Helicobacter pylori (HP) infection initiates and promotes gastric carcinogenesis. ONECUT2 shows promise for tumor diagnosis, prognosis, and treatment. This study explored ONECUT2's role and the specific mechanism underlying HP infection-associated gastric carcinogenesis to suggest a basis for targeting ONECUT2 as a therapeutic strategy for gastric cancer (GC). Multidimensional data supported an association between ONECUT2, HP infection, and GC pathogenesis. HP infection upregulated ONECUT2 transcriptional activity via NFκB. In vitro and in vivo experiments demonstrated that ONECUT2 increased the stemness of GC cells. ONECUT2 was also shown to inhibit PPP2R4 transcription, resulting in reduced PP2A activity, which in turn increased AKT/ß-catenin phosphorylation. AKT/ß-catenin phosphorylation facilitates ß-catenin translocation to the nucleus, initiating transcription of downstream stemness-associated genes in GC cells. HP infection upregulated the reduction of AKT and ß-catenin phosphorylation triggered by ONECUT2 downregulation via ONECUT2 induction. Clinical survival analysis indicated that high ONECUT2 expression may indicate poor prognosis in GC. This study highlights a critical role played by ONECUT2 in promoting HP infection-associated GC by enhancing cell stemness through the PPP2R4/AKT/ß-catenin signaling pathway. These findings suggest promising therapeutic strategies and potential targets for GC treatment.

Progressive encephalomyelitis with rigidity and myoclonus: a pediatric case report and literature review.

BACKGROUND: Progressive encephalomyelitis with rigidity and myoclonus (PERM) is a rare and life-threatening autoimmune disease of the central nervous system. So far, only ten cases of PERM have been reported in children worldwide, including the one in this study. CASE PRESENTATION: We report a case of an 11-year-old boy with PERM with an initial presentation of abdominal pain, skin itching, dysuria, urinary retention, truncal and limb rigidity, spasms of the trunk and limbs during sleep, deep and peripheral sensory disturbances, and dysphagia. A tissue-based assay using peripheral blood was positive, demonstrated by fluorescent staining of mouse cerebellar sections. He showed gradual and persistent clinical improvement after immunotherapy with intravenous immunoglobulin, steroids, plasmapheresis and rituximab. CONCLUSIONS: We summarized the diagnosis and treatment of a patient with PERM and performed a literature review of pediatric PERM to raise awareness among pediatric neurologists. A better comprehension of this disease is required to improve its early diagnosis, treatment, and prognosis.

SETDB1 regulates short interspersed nuclear elements and chromatin loop organization in mouse neural precursor cells.

BACKGROUND: Transposable elements play a critical role in maintaining genome architecture during neurodevelopment. Short Interspersed Nuclear Elements (SINEs), a major subtype of transposable elements, are known to harbor binding sites for the CCCTC-binding factor (CTCF) and pivotal in orchestrating chromatin organization. However, the regulatory mechanisms controlling the activity of SINEs in the developing brain remains elusive. RESULTS: In our study, we conduct a comprehensive genome-wide epigenetic analysis in mouse neural precursor cells using ATAC-seq, ChIP-seq, whole genome bisulfite sequencing, in situ Hi-C, and RNA-seq. Our findings reveal that the SET domain bifurcated histone lysine methyltransferase 1 (SETDB1)-mediated H3K9me3, in conjunction with DNA methylation, restricts chromatin accessibility on a selective subset of SINEs in neural precursor cells. Mechanistically, loss of Setdb1 increases CTCF access to these SINE elements and contributes to chromatin loop reorganization. Moreover, de novo loop formation contributes to differential gene expression, including the dysregulation of genes enriched in mitotic pathways. This leads to the disruptions of cell proliferation in the embryonic brain after genetic ablation of Setdb1 both in vitro and in vivo. CONCLUSIONS: In summary, our study sheds light on the epigenetic regulation of SINEs in mouse neural precursor cells, suggesting their role in maintaining chromatin organization and cell proliferation during neurodevelopment.

Integrated analysis of genes shared between type 2 diabetes mellitus and osteoporosis.

Background: The relationship between type 2 diabetes mellitus (T2DM) and osteoporosis (OP) has been widely recognized in recent years, but the mechanism of interaction remains unknown. The aim of this study was to investigate the genetic features and signaling pathways that are shared between T2DM and OP. Methods: We analyzed the GSE76894 and GSE76895 datasets for T2DM and GSE56815 and GSE7429 for OP from the Gene Expression Omnibus (GEO) database to identify shared genes in T2DM and OP, and we constructed coexpression networks based on weighted gene coexpression network analysis (WGCNA). Shared genes were then further analyzed for functional pathway enrichment. We selected the best common biomarkers using the least absolute shrinkage and selection operator (LASSO) algorithm and validated the common biomarkers, followed by RT-PCR, immunofluorescence, Western blotting, and enzyme-linked immunosorbent assay (ELISA) to validate the expression of these hub genes in T2DM and OP mouse models and patients. Results: We found 8,506 and 2,030 DEGs in T2DM and OP, respectively. Four modules were identified as significant for T2DM and OP using WGCNA. A total of 19 genes overlapped with the strongest positive and negative modules of T2DM and OP. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed these genes may be involved in pantothenate and CoA biosynthesis and the glycosaminoglycan biosynthesis-chondroitin sulfate/dermatan sulfate and renin-angiotensin system signaling pathway. The LASSO algorithm calculates the six optimal common biomarkers. RT-PCR results show that LTB, TPBG, and VNN1 were upregulated in T2DM and OP. Immunofluorescence and Western blot show that VNN1 is upregulated in the pancreas and bones of T2DM model mice and osteoporosis model mice. Similarly, the level of VNN1 in the sera of patients with T2DM, OP, and T2DM and OP was higher than that in the healthy group. Conclusion: Based on the WGCNA and LASSO algorithms, we identified genes and pathways that were shared between T2DM and OP. Both pantothenate and CoA biosynthesis and the glycosaminoglycan biosynthesis-chondroitin sulfate/dermatan sulfate and renin-angiotensin systems may be associated with the pathogenesis of T2DM and OP. Moreover, VNN1 may be a potential diagnostic marker for patients with T2DM complicated by OP. This study provides a new perspective for the systematic study of possible mechanisms of combined OP and T2DM.

A crystal capping layer for formation of black-phase FAPbI3 perovskite in humid air.

Black-phase formamidinium lead iodide (α-FAPbI3) perovskites are the desired phase for photovoltaic applications, but water can trigger formation of photoinactive impurity phases such as δ-FAPbI3. We show that the classic solvent system for perovskite fabrication exacerbates this reproducibility challenge. The conventional coordinative solvent dimethyl sulfoxide (DMSO) promoted δ-FAPbI3 formation under high relative humidity (RH) conditions because of its hygroscopic nature. We introduced chlorine-containing organic molecules to form a capping layer that blocked moisture penetration while preserving DMSO-based complexes to regulate crystal growth. We report power conversion efficiencies of >24.5% for perovskite solar cells fabricated across an RH range of 20 to 60%, and 23.4% at 80% RH. The unencapsulated device retained 96% of its initial performance in air (with 40 to 60% RH) after 500-hour maximum power point operation.

A Soldering Flux Tackles Complex Defects Chemistry in Sn-Pb Perovskite Solar Cells.

Developing tin-lead (Sn-Pb) narrow-bandgap perovskites is crucial for the deployment of all-perovskite tandem solar cells, which can help to exceed the limits of single-junction photovoltaics. However, the Sn-Pb perovskite suffers from a large number of bulk traps and interfacial nonradiative recombination centers, with unsatisfactory open-circuit voltage and the consequent device efficiency. Herein, for the first time, it is shown that abietic acid (AA), a commonly used flux for metal soldering, effectively tackles complex defects chemistry in Sn-Pb perovskites. The conjugated double bond within AA molecule plays a key role for self-elimination of Sn4+-Pb0 defects pair, via a redox process. In addition, C═O group is able to coordinate with Sn2+, leading to the improved antioxidative stability of Sn-Pb perovskites. Consequently, a ten-times longer carrier lifetime is observed, and the defects-associated dual-peak emission feature at low temperature is significantly inhibited. The resultant device achieves a power conversion efficiency improvement from 22.28% (Ref) to 23.42% with respectable stability under operational and illumination situations.

Association of retinal microvascular curve tortuosity and multiple sclerosis: A cross-section analysis from the UK Biobank.

BACKGROUND: There is growing evidence supporting that vascular abnormalities contribute to multiple sclerosis (MS), and retinal microvasculature functions as a visible window to observe vessels. We hypothesized that retinal vascular curve tortuosity is associated with MS, which this study aims to address. METHODS: Participants from the UK Biobank with complete clinical records and gradable fundus photos were included in the study. Arteriolar and venular curve tortuosity and vessel area density are quantified automatically using a deep learning system. Individuals with MS were matched to healthy controls using propensity score matching (PSM). Conditional logistic regression was used to investigate the association between retinal vascular characteristics and MS. We also used a receiver operating characteristic (ROC) curve to assess the diagnostic performance of MS. RESULTS: Venular curve tortuosity (VCT) was found to be significantly associated with MS. And patients with multiple sclerosis were probable to have lower VCT than the non-MS group (OR = 0.22 [95 % CI, 0.05 to 0.92], P < 0.05). CONCLUSIONS: Our study reveals a significant association between vessel curve tortuosity and MS. The lower curve tortuosity of the retinal venular network may indicate a higher risk of incident multiple sclerosis.

Full-length GSDME mediates pyroptosis independent from cleavage.

Gasdermin (GSDM) family proteins, known as the executors of pyroptosis, undergo protease-mediated cleavage before inducing pyroptosis. We here discovered a form of pyroptosis mediated by full-length (FL) GSDME without proteolytic cleavage. Intense ultraviolet-C irradiation-triggered DNA damage activates nuclear PARP1, leading to extensive formation of poly(ADP-ribose) (PAR) polymers. These PAR polymers are released to the cytoplasm, where they activate PARP5 to facilitate GSDME PARylation, resulting in a conformational change in GSDME that relieves autoinhibition. Moreover, ultraviolet-C irradiation promotes cytochrome c-catalysed cardiolipin peroxidation to elevate lipid reactive oxygen species, which is then sensed by PARylated GSDME, leading to oxidative oligomerization and plasma membrane targeting of FL-GSDME for perforation, eventually inducing pyroptosis. Reagents that concurrently stimulate PARylation and oxidation of FL-GSDME, synergistically promoting pyroptotic cell death. Overall, the present findings elucidate an unreported mechanism underlying the cleavage-independent function of GSDME in executing cell death, further enriching the paradigms and understanding of FL-GSDME-mediated pyroptosis.

Clinical characteristics of membranous nephropathy after allogeneic hematopoietic stem cell transplantation: A real-world multicenter study.

Membranous nephropathy (MN) is a rare complication that can occur after allogeneic hematopoietic stem cell transplantation (allo-HSCT). MN patients may develop nephrotic syndrome or even kidney failure, which greatly affects their quality of life and prognosis. However, current knowledge regarding MN after allo-HSCT is limited. Thus, a multicenter nested case‒control study was conducted. Patients who had been diagnosed with MN after allo-HSCT were retrospectively identified at 8 HSCT centers. A total of 51 patients with MN after allo-HSCT were included. The median age of MN patients after allo-HSCT was 38 years, and the median duration from HSCT to MN was 18 months. The use of HLA-matched donors (P = 0.0102) and peripheral blood as the graft source (P = 0.0060) were identified as independent predisposing risk factors for the onset of MN after allo-HSCT. Compared to those in the control group, the incidence of extensive chronic graft-versus-host disease was greater in the MN patients (P = 0.0002). A total of 31 patients developed nephrotic syndrome. Patients receiving combination treatments of corticosteroids and immunosuppressants appeared to have better outcomes. In conclusion, MN is a rare but occasionally severe complication following HSCT and may require active treatment.

Enhanced editing efficiency in Arabidopsis with a LbCas12a variant harboring D156R and E795L mutations.

Cas12a (Cpf1), a Class 2 Type V CRISPR/Cas nuclease, has several unique attributes for genome editing and may provide a valuable alternative to Cas9. However, a low editing efficiency due to temperature sensitivity and insufficient cleavage activity of the Cas12a nuclease are major obstacles to its broad application. In this report, we generated two variants, ttAsCas12 Ultra and ttLbCas12a Ultra harboring three (E174R, M537R, and F870L) or two (D156R and E795L) mutations, respectively, by combining the mutations from the temperature-tolerant variants ttAsCas12a (E174R) and ttLbCas12a (D156R), and those from the highly active variants AsCas12a Ultra (M537R and F870L) and LbCas12a Ultra (E795L). We compared editing efficiencies of the five resulting Cas12a variants (LbCas12a, ttLbCas12a, ttLbCas12a Ultra, AsCas12a Ultra, and ttAsCas12 Ultra) at six target sites of four genes in Arabidopsis (Arabidopsis thaliana). The variant ttLbCas12a Ultra, harboring the D156R and E795L mutations, exhibited the highest editing efficiency of all variants tested in Arabidopsis and can be used to generate homozygous or biallelic mutants in a single generation in Arabidopsis plants grown at 22 °C. In addition, optimization of ttLbCas12a Ultra, by varying nuclear localization signal sequences and codon usage, further greatly improved editing efficiency. Collectively, our results indicate that ttLbCas12a Ultra is a valuable alternative to Cas9 for editing genes or promoters in Arabidopsis. Supplementary Information: The online version contains supplementary material available at 10.1007/s42994-024-00144-w.