Endoplasmic reticulum protein ALTERED MERISTEM PROGRAM 1 negatively regulates senescence in Arabidopsis.

Plant senescence is a highly regulated developmental program crucial for nutrient reallocation and stress adaptation in response to developmental and environmental cues. Stress-induced and age-dependent natural senescence share both overlapping and distinct molecular responses and regulatory schemes. Previously, we have utilized a carbon-deprivation (C-deprivation) senescence assay using Arabidopsis (Arabidopsis thaliana) seedlings to investigate senescence regulation. Here we conducted a comprehensive time-resolved transcriptomic analysis of Arabidopsis wild type seedlings subjected to C-deprivation treatment at multiple time points, unveiling substantial temporal changes and distinct gene expression patterns. Moreover, we identified ALTERED MERISTEM PROGRAM 1 (AMP1), encoding an endoplasmic reticulum protein, as a potential regulator of senescence based on its expression profile. By characterizing loss-of-function alleles and overexpression lines of AMP1, we confirmed its role as a negative regulator of plant senescence. Genetic analyses further revealed a synergistic interaction between AMP1 and the autophagy pathway in regulating senescence. Additionally, we discovered a functional association between AMP1 and the endosome-localized ABNORMAL SHOOT3 (ABS3)-mediated senescence pathway and positioned key senescence-promoting transcription factors downstream of AMP1. Overall, our findings shed light on the molecular intricacies of transcriptome reprogramming during C-deprivation-induced senescence and the functional interplay among endomembrane compartments in controlling plant senescence.

Single-cell sequencing reveals distinct immune cell features in cutaneous lesions of pemphigus vulgaris and bullous pemphigoid.

Bullous pemphigoid (BP) and pemphigus vulgaris (PV) are two common subtypes of autoimmune bullous disease (AIBD). The key role of circulating autoreactive immune cells contributing to skin damage of AIBD has been widely recognized. Nevertheless, the immune characteristics in cutaneous lesions remain unclear. Here, we performed single-cell RNA sequencing (scRNA-seq) and single-cell VDJ sequencing (scRNA-seq) to generate transcriptional profiles for cells and T/B cell clonetype in skin lesions of BP and PV. We found that the proportions of NK&T, macrophages/ dendritic cells, B cells, and mast cells increased in BP and PV lesions. Then, BP and PV cells constituted over 75% of all myeloid cell subtypes, CD4+ T cell subtypes and CD8+ T cell subtypes. Strikingly, CD8+ Trm was identified to be expanded in PV, and located in the intermediate state of the pseudotime trajectory from CD8+ Tm to CD8+ Tem. Interestingly, CD8+ Tem and CD4+ Treg highly expressed exhaustion-related genes, especially in BP lesions. Moreover, the enhanced cell communication between stromal cells and immune cells like B cells and macrophages/ dendritic cells was also identified in BP and PV lesions. Finally, clone expansion was observed in T cells of BP and PV compared with HC, while CD8+ Trm represented the highest ratio of hyperexpanded TCR clones among all T cell subtypes. Our study generally depicts a large and comprehensive single-cell landscape of cutaneous lesions and highlights immune cell features in BP and PV. This offers potential research targets for further investigation.

Metabolism-Regulating Nanozyme System for Advanced Nanocatalytic Cancer Therapy.

Nanocatalytic therapy, an emerging approach in cancer treatment, utilizes nanomaterials to initiate enzyme-mimetic catalytic reactions within tumors, inducing tumor-suppressive effects. However, the targeted and selective catalysis within tumor cells is challenging yet critical for minimizing the adverse effects. The distinctive reliance of tumor cells on glycolysis generates abundant lactate, influencing the tumor's pH, which can be manipulated to selectively activate nanozymatic catalysis. Herein, small interfering ribonucleic acid (siRNA) targeting lactate transporter-mediated efflux is encapsulated within the iron-based metal-organic framework (FeMOF) and specifically delivered to tumor cells through cell membrane coating. This approach traps lactate within the cell, swiftly acidifying the tumor cytoplasm and creating an environment for boosting the catalysis of the FeMOF nanozyme. The nanozyme generates hydroxyl radical (·OH) in the reversed acidic environment, using endogenous hydrogen peroxide (H2O2) produced by mitochondria as a substrate. The induced cytoplasmic acidification disrupts calcium homeostasis, leading to mitochondrial calcium overload, resulting in mitochondrial dysfunction and subsequent tumor cell death. Additionally, the tumor microenvironment is also remodeled, inhibiting migration and invasion, thus preventing metastasis. This groundbreaking strategy combines metabolic regulation with nanozyme catalysis in a toxic drug-free approach for tumor treatment, holding promise for future clinical applications.

Passivating Grain Boundaries via Graphene Additive for Efficient Kesterite Solar Cells.

Grain boundaries (GBs)-triggered severe non-radiative recombination is recently recognized as the main culprits for carrier loss in polycrystalline kesterite photovoltaic devices. Accordingly, further optimization of kesterite-based thin film solar cells critically depends on passivating the grain interfaces of polycrystalline Cu2 ZnSn(S,Se)4 (CZTSSe) thin films. Herein, 2D material of graphene is first chosen as a passivator to improve the detrimental GBs. By adding graphene dispersion to the CZTSSe precursor solution, single-layer graphene is successfully introduced into the GBs of CZTSSe absorber. Due to the high carrier mobility and electrical conductivity of graphene, GBs in the CZTSSe films are transforming into electrically benign and do not act as high recombination sites for carrier. Consequently, benefitting from the significant passivation effect of GBs, the use of 0.05 wt% graphene additives increases the efficiency of CZTSSe solar cells from 10.40% to 12.90%, one of the highest for this type of cells. These results demonstrate a new route to further increase kesterite-based solar cell efficiency by additive engineering.

Association of phthalate exposure with reproductive outcomes among infertile couples undergoing in vitro fertilization: A systematic review.

Human fertility is impacted by changes in lifestyle and environmental deterioration. To increase human fertility, assisted reproductive technology (ART) has been extensively used around the globe. As early as 2009, the Endocrine Society released its first scientific statement on the potential adverse effects of environmental endocrine-disrupting chemicals (EDCs) on human health and disease development. Chemicals known as phthalates, frequently employed as plasticizers and additives, are common EDCs. Numerous studies have shown that phthalate metabolites in vivo exert estrogen-like or anti-androgenic effects in both humans and animals. They are associated with the progression of a range of diseases, most notably interference with the reproductive process, damage to the placenta, and the initiation of chronic diseases in adulthood. Phthalates are ingested by infertile couples in a variety of ways, including household products, diet, medical treatment, etc. Exposure to phthalates may exacerbate their infertility or poor ART outcomes, however, the available data on phthalate exposure and ART pregnancy outcomes are sparse and contradictory. Therefore, this review conducted a systematic evaluation of 16 papers related to phthalate exposure and ART pregnancy outcomes, to provide more aggregated results, and deepen our understanding of reproductive outcomes in infertile populations with phthalate exposure.

Human-multimodal deep learning collaboration in 'precise' diagnosis of lupus erythematosus subtypes and similar skin diseases.

BACKGROUND: Lupus erythematosus (LE) is a spectrum of autoimmune diseases. Due to the complexity of cutaneous LE (CLE), clinical skin image-based artificial intelligence is still experiencing difficulties in distinguishing subtypes of LE. OBJECTIVES: We aim to develop a multimodal deep learning system (MMDLS) for human-AI collaboration in diagnosis of LE subtypes. METHODS: This is a multi-centre study based on 25 institutions across China to assist in diagnosis of LE subtypes, other eight similar skin diseases and healthy subjects. In total, 446 cases with 800 clinical skin images, 3786 multicolor-immunohistochemistry (multi-IHC) images and clinical data were collected, and EfficientNet-B3 and ResNet-18 were utilized in this study. RESULTS: In the multi-classification task, the overall performance of MMDLS on 13 skin conditions is much higher than single or dual modals (Sen = 0.8288, Spe = 0.9852, Pre = 0.8518, AUC = 0.9844). Further, the MMDLS-based diagnostic-support help improves the accuracy of dermatologists from 66.88% ± 6.94% to 81.25% ± 4.23% (p = 0.0004). CONCLUSIONS: These results highlight the benefit of human-MMDLS collaborated framework in telemedicine by assisting dermatologists and rheumatologists in the differential diagnosis of LE subtypes and similar skin diseases.

Effects of high-normal fasting blood glucose on ART outcomes of frozen-thawed single blastocyst transfer in women with normal BMI.

PURPOSE: This retrospective cohort study aims to investigate whether high-normal fasting blood glucose (FBG) affects assisted reproductive technology (ART) outcomes undergoing single blastocyst frozen-thawed embryo transfer (FET) cycles in women with normal body mass index (BMI). METHODS: 944 women with normal BMI and FBG levels undergoing single blastocyst FET cycles were enrolled. Based on the median of FBG (4.97 mmol/L, 1 mmol/L = 18 mg/dL), the subjects were categorized into the low-normal group (3.90 ≤ FBG ≤ 4.97 mmol/L, n = 472) and the high-normal group (4.97 < FBG < 6.10 mmol/L, n = 472). Multivariable logistic regression and receiver operating characteristic (ROC) were used to analyze the relationship between high-normal FBG and ART outcomes. PRIMARY OUTCOME: live birth rate (LBR). RESULTS: LBR was significantly lower in the high-normal group than in the low-normal group (36.8% vs. 45.1%, p = 0.010), and the miscarriage rate was considerably higher than that in the low-normal group (23.9% vs. 16.5%, p = 0.041). High-normal FBG of female was an independent predictor of live birth (adjusted OR:0.747, 95% CI: 0.541-0.963, p = 0.027) and miscarriage (adjusted OR:1.610, 95% CI: 1.018-2.547, p = 0.042). ROC analyses showed that the cut-off values of FBG (endpoints: live birth and miscarriage) were 5.07 mmol/L, and 5.01 mmol/L, respectively. CONCLUSIONS: In women with normal BMI, high-normal FBG is an independent risk factor for lower LBR and higher miscarriage rate in single blastocyst FET cycles. Attention to preconception FBG monitoring in this particular population may allow early intervention to improve ART outcomes.

Monocyte to high-density lipoprotein ratio as a novel-potential biomarker for predicting prognosis of Bell's palsy.

OBJECTIVES: In several disorders, the monocyte to high-density lipoprotein ratio (MHR) has been considered a biomarker of systemic inflammation and oxidative stress. However, its role in Bell's palsy (BP) remains unclear. This study investigates the relationship between elevated MHR and poor recovery in BP patients. METHODS: The clinical data of 729 BP patients were analyzed retrospectively. The House-Brackmann Facial Nerve Grading System (H-B) was utilized to assess the severity of facial motor dysfunction during admission and the follow-up period after discharge. According to the 6 months follow-up data, H-B grades 1-2 were classified as recovered (n = 557), and H-B grades 3-6 as unrecovered (n = 172). The patients were split into MHR ≤ 0.26 (n = 361) and MHR > 0.26 (n = 368) groups based on the median MHR to further analyze the connection between different MHRs and prognosis. RESULTS: The level of MHR was substantially greater in the unrecovered group of BP patients than in the restored group (medians[interquartile range], 0.32[0.20, 0.49] vs 0.24[0.11, 0.39], P < 0.001). MHR was an independent risk factor for BP prognosis as indicated by the multivariate logistic regression analysis (OR = 4.467, 95% CI = 1.875-10.646, P = 0.001). The area under the curve (AUC) was 0.615 (95% CI = 0.566-0.664, P < 0.001). The initial H-B score did not differ significantly between MHR ≤ 0.26 (n = 361) and MHR > 0.26 (n = 368) groups. However, after 6 months of follow-up, the high-MHR group's H-B score was considerably greater than the low-MHR group's. CONCLUSIONS: MHR is expected to be an accessible and effective biomarker of BP. In BP patients, elevated MHR is related to an increased chance of poor recovery.

LncRNA SNHG3 discriminates rheumatoid arthritis from healthy individuals and regulates inflammatory response and oxidative stress via modulating miR-128-3p.

OBJECTIVES: This study evaluated the expression and significance of SNHG3 in Rheumatoid arthritis (RA) aiming to explore a biomarker and regulator for RA. METHODS: The expression of SNHG3 in serum and synovial tissue was compared between RA patients and healthy individuals using PCR. The RA animal models were induced by the porcine type II collagen with Wistar rats and validated by the foot volume and AI score. The human fibroblast-like synoviocytes (H-FLS) were treated with LPS to mimic the injury during RA onset and the cell growth was assessed by CCK8 assay. RESULTS: SNHG3 was significantly downregulated in the serum and synovial tissue of RA patients compared with healthy individuals. Downregulated SNHG3 could discriminate RA patients from healthy individuals with high sensitivity (0.875) and specificity (0.844). Porcine type II collagen induced increasing foot volume and AI scores of rats and SNHG3 was downregulated in RA rats. In LPS-induced H-FLS, SNHG3 negatively regulated miR-128-3p, and the alleviated effect of SNHG3 overexpression on cellular inflammation and oxidative stress was reversed by miR-128-3p upregulation. CONCLUSIONS: Serum SNHG3 was considered a potential diagnostic biomarker for RA from healthy individuals. SNHG3 regulated inflammatory response and oxidative stress via negatively modulating miR-128-3p.

A comprehensive lettuce variation map reveals the impact of structural variations in agronomic traits.

BACKGROUND: As an important vegetable crop, cultivated lettuce is grown worldwide and a great variety of agronomic traits have been preserved within germplasm collections. The mechanisms underlying these phenotypic variations remain to be elucidated in association with sequence variations. Compared with single nucleotide polymorphisms, structural variations (SVs) that have more impacts on gene functions remain largely uncharacterized in the lettuce genome. RESULTS: Here, we produced a comprehensive SV set for 333 wild and cultivated lettuce accessions. Comparison of SV frequencies showed that the SVs prevalent in L. sativa affected the genes enriched in carbohydrate derivative catabolic and secondary metabolic processes. Genome-wide association analysis of seven agronomic traits uncovered potentially causal SVs associated with seed coat color and leaf anthocyanin content. CONCLUSION: Our work characterized a great abundance of SVs in the lettuce genome, and provides a valuable genomic resource for future lettuce breeding.

Boosting Glioblastoma Therapy with Targeted Pyroptosis Induction.

Glioblastoma (GBM) is a highly aggressive cancer that currently lacks effective treatments. Pyroptosis has emerged as a promising therapeutic approach for cancer, but there is still a need for new pyroptosis boosters to target cancer cells. In this study, it is reported that Aloe-emodin (AE), a natural compound derived from plants, can inhibit GBM cells by inducing pyroptosis, making it a potential booster for pyroptosis-mediated GBM therapy. However, administering AE is challenging due to the blood-brain barrier (BBB) and its non-selectivity. To overcome this obstacle, AE@ZIF-8 NPs are developed, a biomineralized nanocarrier that releases AE in response to the tumor's acidic microenvironment (TAM). Further modification of the nanocarrier with transferrin (Tf) and polyethylene glycol-poly (lactic-co-glycolic acid) (PEG-PLGA) improves its penetration through the BBB and tumor targeting, respectively. The results show that AE-NPs (Tf-PEG-PLGA modified AE@ZIF-8 NPs) significantly increase the intracranial distribution and tumor tissue accumulation, enhancing GBM pyroptosis. Additionally, AE-NPs activate antitumor immunity and reduce AE-related toxicity. Overall, this study provides a new approach for GBM therapy and offers a nanocarrier that is capable of penetrating the BBB, targeting tumors, and attenuating toxicity.

Association of serum 25-hydroxyvitamin D levels with all-cause and cause-specific mortality among postmenopausal females: results from NHANES.

BACKGROUND: Vitamin D deficiency is common among the population, but its relationship with mortality of postmenopausal females is unclear. The aim of this study is to explore the association between serum 25-Hydroxyvitamin D (25(OH)D) and all-cause and cause-specific mortality among postmenopausal women in the United States. METHODS: 6812 participants of postmenopausal females from the National Health and Nutrition Examination Survey (2001-2018) were included in this study. The mortality status of the follow-up was ascertained by linkage to National Death Index (NDI) records through 31 December 2019. We used cox proportional hazards models to estimate the association of serum 25(OH)D concentrations and mortality of postmenopausal females. RESULTS: The mean level of serum 25(OH)D was 72.57 ± 29.93 nmol/L, and 65.34% had insufficient vitamin D. In postmenopausal females, low serum 25(OH)D concentrations were significantly associated with higher levels of glycohemoglobin, glucose, and lower levels of HDL. During follow-up, 1448 all-cause deaths occurred, including 393 cardiovascular disease (CVD)-related deaths and 263 cancer deaths. After multivariate adjustment, higher serum 25(OH)D levels were significantly related with lower all-cause and CVD mortality. In addition, serum 25(OH)D presented a L-shaped relationship with all-cause mortality, while appeared a U-shaped with CVD mortality, and the cut-off value is 73.89 nmol/L and 46.75 nmol/L respectively. CONCLUSIONS: Low serum 25(OH)D levels are associated with the higher risk of all-cause and CVD mortality in postmenopausal females. These findings provide new ideas and targets for the health management of postmenopausal women.

A single-cell map of peripheral alterations after FMT treatment in patients with systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is characterized by loss of self-tolerance and persistent self-aggression, sustained chronic inflammation, production of autoantibodies and multi-system damage, and is largely incurable to date. The gut microbiota and its metabolites, now recognized as crucial environmental triggers of local/systemic immune reactions, have been implicated in the development and progression of SLE. Fecal microbiota transplantation (FMT) is restoration of disturbed microbiota by transplanting foreign gut microbiota from healthy individuals into the gastrointestinal tract of diseased individuals. Our previous clinical trial suggests that FMT is a potentially safe and effective treatment for SLE. In order to elucidate the potential effect of FMT on peripheral immune cells of patients with SLE, we collected PBMCs (n = 30) of 13 SLE patients who participated in the clinical trial before and after the FMT-treatment, and performed single-cell RNA sequencing. The results first revealed that peripheral T lymphocytes of SLE patients decreased and NK cells increased after the FMT treatment. Then, sub-clustering analysis discovered that total CD4+ T cells highly expressed genes of IL7R, CD28, and CD8+ T cells highly expressed genes of GZMH and NKG7 after FMT treatment. Moreover, FMT treatment reduced the expression of interferon-related genes (IRGs) in CD4+ T, CD8+ T, DP, NK, and B cells of SLE patients. More importantly, interferon-related pathways were more enriched in cells of the FMT non-responder group, and further the interferon genes expression of lymphocytes and myeloid cells was negatively correlated with the efficiency of FMT treatment. Collectively, our data identified various immunophenotypic and associated gene set changes following FMT treatment, illustrating the heterogeneity of response to FMT treatment in SLE.

Effects of fecal microbiota transplant on DNA methylation in patients with systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a highly heterogeneous autoimmune disease characterized by multiple organ damage accompanied by the over-production of autoantibodies. Decreased intestinal flora diversity and disruption of homeostasis have been proven to be associated with pathogenesis of SLE. In previous study, a clinical trial was conducted to verify the safety and effectiveness of fecal microbiota transplantation (FMT) in the treatment of SLE. To explore the mechanism of FMT in the treatment of SLE, we included 14 SLE patients participating in clinical trials, including 8 in responders group (Rs) and 6 in non-responders group (NRs), and collected peripheral blood DNA and serum. We found that the serum of S-adenosylmethionine (SAM), methylation group donor, was upregulated after FMT, accompanied by an increase in genome-wide DNA methylation level in Rs. We further showed that the methylation levels in promoter regions of Interferon-γ (IFN-γ), induced Helicase C Domain Containing Protein 1 (IFIH1), endoplasmic reticulum membrane protein complex 8 (EMC8), and Tripartite motif-containing protein 58 (TRIM58) increased after FMT treatment. On the contrary, there was no significant change in the methylation of IFIH1 promoter region in the NRs after FMT, and the methylation level of IFIH1 in the Rs was significantly higher than that in the NRs at week 0. We included 850 K methylation chip sequencing, combining previous data of metagenomic sequencing, and metabolomic sequencing for multi-omics analysis to discuss the relationship between flora-metabolite-methylation in FMT. Finally, we found that hexanoic acid treatment can up-regulate the global methylation of peripheral blood mononuclear cells in SLE patients. Overall, our results delineate changes in methylation level after FMT treatment of SLE and reveal possible mechanisms of FMT treatment in terms of the recovery of abnormal hypomethylation.

Fecal microbiota transplantation in the treatment of systemic lupus erythematosus: What we learnt from the explorative clinical trial.

Systemic lupus erythematosus (SLE) is an autoimmune disease with the characterized presence of autoantibodies and resulting in multiple organ damage, which is incurable and can be lethal. The current treatments are limited and less progress has been made in drug discovery for the last few decades. Researches imply that gut dysbiosis exists in both patients and murine models with SLE, taking part in the pathogenesis of SLE through multiple mechanisms such as microbiota translocation and molecular mimicry. Intestinal interventions on the gut microbiome by fecal transplantations to reconstitute the gut-immunity homeostasis serve as a novel therapeutic option for SLE patients. Fecal microbiota transplantation (FMT), which is usually used in intestinal diseases, has been firstly demonstrated to be safe and efficient in recovering gut microbiota structure of SLE patients and reducing lupus activity in our recent clinical trial, which is the first trial testing FMT therapy in SLE treatment. In this paper, we reviewed the results of the single-arm clinical trial and made recommendations on FMT practice in SLE treatment including therapeutic indications, screening items and dosage regimen, trying to provide references for future study and clinical practice. We also came up with the unanswered questions that need to be solved by the ongoing randomized controlled trial as well as the future expectations for the intestinal intervention strategies of SLE patients.

Association between household fuel combustion and diabetes among middle-aged and older adults in China: A cohort study.

BACKGROUND: Few studies examined the associations of household fuel combustion with incident diabetes. The current study emphasizes the association of domestic fuel combustion with diabetes among middle- and older- Chinese. METHODS: The data was extracted from a national and prospective cohort, the China Health and Retirement Longitudinal Study (CHARLS), which enrolled adults ≥ 45 years. A total of 4610 and 5570 participants were involved in heating and cooking-related analyses. Multivariable logistic models were conducted to assess the association of domestic fuel combustion for heating and cooking with diabetes. Furthermore, we also examined whether it differed from switching fuel types. Subgroup and interaction analyses were performed based on covariates to examine the robustness and find potential effect modifiers. RESULTS: After about 5-year follow-up, 592 and 716 diabetes were diagnosed in heating and cooking-related analyses. Compared to cleaner fuel users, those who used solid fuel for heating [OR (95 % CI):1.32 (1.05-1.66)] maintained higher risks of incident diabetes. In addition, participants who were exposed to solid fuel for both heating and cooking [OR (95 % CI):1.55 (1.17-2.06)] might have further elevated diabetic risk. Those risks are likely to be attenuated if people switched cooking fuel from solid to cleaner [OR (95 % CI): 0.68 (0.53-0.89)]. CONCLUSIONS: Home solid fuel use for heating is associated with an increased risk of incident diabetes. If solid fuel was concurrently used for both cooking and heating, those risks might be further elevated. Interestingly, as compared to solid fuel users, the participants switching cooking fuel types from solid to cleaner presented reduced diabetic risk.

Defect of TIMP4 Is Associated with High Myopia and Participates in Rat Ocular Development in a Dose-Dependent Manner.

Thinning of the sclera happens in myopia eyes owing to extracellular matrix (ECM) remodeling, but the initiators of the ECM remodeling in myopia are mainly unknown. The matrix metalloproteinase (MMPs) and tissue inhibitors of matrix metalloproteinase (TIMPs) regulate the homeostasis of the ECM. However, genetic studies of the MMPs and TIMPs in the occurrence of myopia are poor and limited. This study systematically investigated the association between twenty-nine genes of the TIMPs and MMPs families and early-onset high myopia (eoHM) based on whole exome sequencing data. Two TIMP4 heterozygous loss-of-function (LoF) variants, c.528C>A in six patients and c.234_235insAA in one patient, were statistically enriched in 928 eoHM probands compared to that in 5469 non-high myopia control (p = 3.7 × 10-5) and that in the general population (p = 2.78 × 10-9). Consequently, the Timp4 gene editing rat was further evaluated to explore the possible role of Timp4 on ocular and myopia development. A series of ocular morphology abnormalities in a dose-dependent manner (Timp4-/- < Timp4+/- < Timp4+/+) were observed in a rat model, including the decline in the retinal thickness, the elongation in the axial length, more vulnerable to the form deprivation model, morphology changes in sclera collagen bundles, and the decrease in collagen contents of the sclera and retina. Electroretinogram revealed that the b-wave amplitudes of Timp4 defect rats were significantly reduced, consistent with the shorter length of the bipolar axons detected by HE and IF staining. Heterozygous LoF variants in the TIMP4 are associated with early onset high myopia, and the Timp4 defect disturbs ocular development by influencing the morphology and function of the ocular tissue.

Proteasome subunit α4s is essential for formation of spermatoproteasomes and histone degradation during meiotic DNA repair in spermatocytes.

Meiosis, which produces haploid progeny, is critical to ensuring both faithful genome transmission and genetic diversity. Proteasomes play critical roles at various stages of spermatogenesis, including meiosis, but the underlying mechanisms remain unclear. The atypical proteasomes, which contain the activator PA200, catalyze the acetylation-dependent degradation of the core histones in elongated spermatids and DNA repair in somatic cells. We show here that the testis-specific proteasome subunit α4s/PSMA8 is essential for male fertility by promoting proper formation of spermatoproteasomes, which harbor both PA200 and constitutive catalytic subunits. Immunostaining of a spermatocyte marker, SYCP3, indicated that meiosis was halted at the stage of spermatocytes in the α4s-deficient testes. α4s stimulated the in vitro degradation of the acetylated core histones, instead of nonacetylated histones, by the PA200-proteasome. Deletion of α4s blocked degradation of the core histones at DNA damage loci in spermatocytes, leading to meiotic arrest at metaphase I. Thus, α4s is required for histone degradation at meiotic DNA damage loci, proper progression of meiosis, and fertility in males by promoting proper formation of spermatoproteasomes. These results are important for understanding male infertility and might provide potential targets for male contraception or treatment of male infertility.

Single-cell transcriptome reveals immunopathological cell composition of skin lesions in subacute cutaneous lupus erythematosus.

Subacute cutaneous lupus erythematosus (SCLE) is a clinical subtype of cutaneous lupus erythematosus with psoriatic-like or annular papules with scaly erythemas, the pathological mechanism of which is poorly understood. To investigate the immune pathogenesis of SCLE, we performed single-cell RNA sequencing (scRNA-seq) of SCLE skin lesions and integrated the scRNA-seq data from skin tissues of healthy controls (HCs). Our results identified expanded fibroblasts and keratinocytes subtypes, abnormally activated lymphocyte and inflammatory M1 macrophages in SCLE. In SCLE, stromal cells, such as keratinocytes and fibroblasts, showed enhanced chemotactic functions for recruiting immune cells. Importantly, interferon-related genes were identified as key intermediate genes in the potential trajectory of fibroblasts, keratinocytes, and B cells from HCs to SCLE. Our investigation provides a comprehensive description of cell composition in SCLE and highlights several important clues for understanding the pathogenesis of SCLE.

The signaling pathway of levamisole-sensitive-acetylcholine receptors involved in short-term forgetting of Caenorhabditis elegans.

In contrast to the popular opinion that forgetting is only the opposite of learning and memory, active forgetting explains the intrinsic instability of a labile memory that lasts for hours and has its own signal transduction pathways. However, the detailed mechanisms underlying forgetting are still lacking, though the investigations available in this field offer the first insights into their regulation. To identify the alternative signaling pathways that control the process of forgetting, we used the short-term forgetting model of Caenorhabditis elegans and discovered the involvement of lev-10, a scaffolded transmembrane protein of L-AChR, by screening the candidate genes that potentially functioned in synaptic plasticity. The LEV-9/LEV-10/L-AChR functional complex was confirmed to participate in forgetting occurrence. Furthermore, EGL-9 functioned upstream of LEV-10 and negatively regulated the latter during forgetting. Meanwhile, EGL-9 was also the target of miR-51, and hence the mutation of miR-51 similarly affected the function of L-AChR and delayed the short-term forgetting. Our findings have identified an integrated signaling pathway responsible for active forgetting, which provides the new experimental evidence on the cholinergic forgetting signal.