A New Orthonairovirus Associated with Human Febrile Illness.

BACKGROUND: In June 2019, a patient presented with persistent fever and multiple organ dysfunction after a tick bite at a wetland park in Inner Mongolia. Next-generation sequencing in this patient revealed an infection with a previously unknown orthonairovirus, which we designated Wetland virus (WELV). METHODS: We conducted active hospital-based surveillance to determine the prevalence of WELV infection among febrile patients with a history of tick bites. Epidemiologic investigation was performed. The virus was isolated, and its infectivity and pathogenicity were investigated in animal models. RESULTS: WELV is a member of the orthonairovirus genus in the Nairoviridae family and is most closely related to the tickborne Hazara orthonairovirus genogroup. Acute WELV infection was identified in 17 patients from Inner Mongolia, Heilongjiang, Jilin, and Liaoning, China, by means of reverse-transcriptase-polymerase-chain-reaction assay. These patients presented with nonspecific symptoms, including fever, dizziness, headache, malaise, myalgia, arthritis, and back pain and less frequently with petechiae and localized lymphadenopathy. One patient had neurologic symptoms. Common laboratory findings were leukopenia, thrombocytopenia, and elevated d-dimer and lactate dehydrogenase levels. Serologic assessment of convalescent-stage samples obtained from 8 patients showed WELV-specific antibody titers that were 4 times as high as those in acute-phase samples. WELV RNA was detected in five tick species and in sheep, horses, pigs, and Transbaikal zokors (Myospalax psilurus) sampled in northeastern China. The virus that was isolated from the index patient and ticks showed cytopathic effects in human umbilical-vein endothelial cells. Intraperitoneal injection of the virus resulted in lethal infections in BALB/c, C57BL/6, and Kunming mice. The Haemaphysalis concinna tick is a possible vector that can transovarially transmit WELV. CONCLUSIONS: A newly discovered orthonairovirus was identified and shown to be associated with human febrile illnesses in northeastern China. (Funded by the National Natural Science Foundation of China and the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences.).

IFITM3 inhibits severe fever with thrombocytopenia syndrome virus entry and interacts with viral Gc protein.

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging tick-borne hemorrhagic fever disease with high fatality rate of 10%-20%. Vaccines or specific therapeutic measures remain lacking. Human interferon inducible transmembrane protein 3 (hIFITM3) is a broad-spectrum antiviral factor targeting viral entry. However, the antiviral activity of hIFITM3 against SFTS virus (SFTSV) and the functional mechanism of IFITM3 remains unclear. Here we demonstrate that endogenous IFITM3 provides protection against SFTSV infection and participates in the anti-SFTSV effect of type Ⅰ and Ⅲ interferons (IFNs). IFITM3 overexpression exhibits anti-SFTSV function by blocking Gn/Gc-mediated viral entry and fusion. Further studies showed that IFITM3 binds SFTSV Gc directly and its intramembrane domain (IMD) is responsible for this interaction and restriction of SFTSV entry. Mutation of two neighboring cysteines on IMD weakens IFITM3-Gc interaction and attenuates the antiviral activity of IFITM3, suggesting that IFITM3-Gc interaction may partly mediate the inhibition of SFTSV entry. Overall, our data demonstrate for the first time that hIFITM3 plays a critical role in the IFNs-mediated anti-SFTSV response, and uncover a novel mechanism of IFITM3 restriction of SFTSV infection, highlighting the potential of clinical intervention on SFTS disease.

Childhood Gender Nonconformity and Parental Maltreatment as Mediators of Sexual Orientation Disparities in Childhood Emotional and Behavioral Difficulties.

The mechanisms underlying sexual orientation differences in psychopathology originating in childhood remain understudied since sexual orientation does not directly manifest in childhood. This study tested whether childhood gender nonconformity and parental maltreatment before age 6 years 9 months partly explained sexual orientation disparities in the developmental trajectories of emotional and behavioral difficulties from age 6 years 9 months to 11 years 8 months. The Avon Longitudinal Study of Parents and Children was used (2182 boys and 2422 girls, Mage = 15.5, 90% White). After controlling for early life factors, non-heterosexual boys and girls displayed significantly greater emotional and behavioral difficulties than their heterosexual counterparts at all three ages. There was a sex difference in the mediating effects. For girls, sexual orientation disparities in childhood emotional and behavioral difficulties were partially explained by childhood gender nonconformity. For boys, sexual orientation disparities in childhood emotional and behavioral difficulties were partially explained by a path through greater childhood gender nonconformity, leading to increased risk of being the targets of parental maltreatment. Childhood gender nonconformity, parental maltreatment, and other early life factors only partially explain sexual orientation disparities in childhood emotional and behavioral difficulties. The mediating effects of childhood gender nonconformity and parental maltreatment on the association between sexual orientation and childhood emotional and behavioral difficulties differ between the sexes.

Clinical and molecular significance of homologous recombination deficiency positive non-small cell lung cancer in Chinese population: An integrated genomic and transcriptional analysis.

Objective: The clinical significance of homologous recombination deficiency (HRD) in breast cancer, ovarian cancer, and prostate cancer has been established, but the value of HRD in non-small cell lung cancer (NSCLC) has not been fully investigated. This study aimed to systematically analyze the HRD status of untreated NSCLC and its relationship with patient prognosis to further guide clinical care. Methods: A total of 355 treatment-naïve NSCLC patients were retrospectively enrolled. HRD status was assessed using the AmoyDx Genomic Scar Score (GSS), with a score of ≥50 considered HRD-positive. Genomic, transcriptomic, tumor microenvironmental characteristics and prognosis between HRD-positive and HRD-negative patients were analyzed. Results: Of the patients, 25.1% (89/355) were HRD-positive. Compared to HRD-negative patients, HRD-positive patients had more somatic pathogenic homologous recombination repair (HRR) mutations, higher tumor mutation burden (TMB) (P<0.001), and fewer driver gene mutations (P<0.001). Furthermore, HRD-positive NSCLC had more amplifications in PI3K pathway and cell cycle genes, MET and MYC in epidermal growth factor receptor (EGFR)/anaplastic lymphoma kinase (ALK) mutant NSCLC, and more PIK3CA and AURKA in EGFR/ALK wild-type NSCLC. HRD-positive NSCLC displayed higher tumor proliferation and immunosuppression activity. HRD-negative NSCLC showed activated signatures of major histocompatibility complex (MHC)-II, interferon (IFN)-γ and effector memory CD8+ T cells. HRD-positive patients had a worse prognosis and shorter progression-free survival (PFS) to targeted therapy (first- and third-generation EGFR-TKIs) (P=0.042). Additionally, HRD-positive, EGFR/ALK wild-type patients showed a numerically lower response to platinum-free immunotherapy regimens. Conclusions: Unique genomic and transcriptional characteristics were found in HRD-positive NSCLC. Poor prognosis and poor response to EGFR-TKIs and immunotherapy were observed in HRD-positive NSCLC. This study highlights potential actionable alterations in HRD-positive NSCLC, suggesting possible combinational therapeutic strategies for these patients.

NDUFV1 attenuates renal ischemia-reperfusion injury by improving mitochondrial homeostasis.

Impaired mitochondrial function and dysregulated energy metabolism have been shown to be involved in the pathological progression of kidney diseases such as acute kidney injury (AKI) and diabetic nephropathy. Hence, improving mitochondrial function is a promising strategy for treating renal dysfunction. NADH: ubiquinone oxidoreductase core subunit V1 (NDUFV1) is an important subunit of mitochondrial complex I. In the present study, we found that NDUFV1 was reduced in kidneys of renal ischemia/reperfusion (I/R) mice. Meanwhile, renal I/R induced kidney dysfunction as evidenced by increases in BUN and serum creatinine, severe injury of proximal renal tubules, oxidative stress, and cell apoptosis. All these detrimental outcomes were attenuated by increased expression of NDUFV1 in kidneys. Moreover, knockdown of Ndufv1 aggravated cell insults induced by H2 O2 in TCMK-1 cells, which further confirmed the renoprotective roles of NDUFV1. Mechanistically, NDUFV1 improved the integrity and function of mitochondria, leading to reduced oxidative stress and cell apoptosis. Overall, our data indicate that NDUFV1 has an ability to maintain mitochondrial homeostasis in AKI, suggesting therapies by targeting mitochondria are useful approaches for dealing with mitochondrial dysfunction associated renal diseases such as AKI.

Discrimination and Deaf Adolescents' Subjective Well-Being: The Role of Deaf Identity.

This study tested the influence of Deaf identity (cognitive identification and affective identification) on the association between perceived deaf discrimination and subjective well-being among Chinese adolescents who are deaf and hard-of-hearing (DHH), based on the rejection-identification model. Questionnaires on perceived deaf discrimination, subjective well-being, Deaf identity, and demographic information were completed by 246 DHH students (15-23 years old) from special residential schools in China. The results indicated that: (1) higher level of perceived deaf discrimination was significantly associated with lower level of subjective well-being (direct effect = -0.24, 95% confidence interval [CI] = [-0.37, -0.12], p < .001); (2) there was a significant indirect effect of perceived deaf discrimination on subjective well-being via cognitive identification (indirect effect = -0.07, 95% CI = [-0.12, -0.01], p < .05); and (3) positive affective identification due to increased cognitive identification with Deaf community may help counteract the negative impact of perceived deaf discrimination on subjective well-being (indirect effect = 0.06, 95% CI = [0.03, 0.10], p < .001). These findings further support the notion that the different components of group identification should be examined separately.

Total Synthesis and Anti-Tobacco Mosaic Virus Activity of the Furofuran Lignan (±)-Phrymarolin II and Its Analogues.

Phrymarolin II, a furofuran lignan isolated from Phryma leptostachya L., features a 3,7-dioxabicyclo[3.3.0]octane skeleton. Herein, we report an alternative total synthesis of (±)-phrymarolin II (2), which was performed in 9 steps from commercially available sesamol. The key steps of the synthesis included a zinc-mediated Barbier-type allylation and a copper-catalyzed anomeric O-arylation. Our total synthesis allowed the synthesis of analogues of (±)-phrymarolin II. Most derivatives displayed good to excellent in vivo activity against tobacco mosaic virus (TMV). (±)-Phrymarolin II (2) and compounds (±)-31d and (±)-31g exhibited similar or higher activity than commercial ningnanmycin, which indicated that phrymarolin lignans are a promising new class of plant virus inhibitors.

DNAzyme assisted recycling amplification method for ultrasensitive amperometric determination of lead(II) based on the use of a hairpin assembly on a composite prepared from nitrogen doped graphene, perylenetetracarboxylic anhydride, thionine and gold nanoparticles.

A Pb(II)-DNAzyme is used in an amperometric method for the determination of Pb(II). The method is based on two feedback processes. In the first, the Pb(II)-DNAzyme initiates a reaction in presence of Pb(II) in a micro-tube to release a linear DNA (S1). In the second, the S1 triggers the recycling amplification between two types of hairpin-shaped DNA templates (H1 and H2) which consist of a primer sequence and a Pb(II)-DNAzyme substrate sequence. The Pb(II)-DNAzyme has excellent cleavage specificity toward the substrate sequence in S1 that combined firstly with H1 and then is linked to H2. This process will connect H1 and H2. After hybridization with H1 and H2 to form two DNA complexes, S1 is released and initiates the next recycling process. This results in efficient amplification. A glassy carbon electrode (GCE) was immersed into solution of HAuCl4 to electrodeposit a layer of gold nanoparticles. This is followed by the assembly of the hairpin probe H1 on the GCE. In addition, a nanohybrid consisting of 3, 4, 9, 10-Perylenetetracarboxylic acid (PTCA) and nitrogen-doped graphene (NG) was loaded with electroactive thionine (Thi) and gold to form nanoparticles of type NG-PTCA-Thi-Au. This is responsible for generating the amperometric signal (best measured at around -0.30 V vs. SCE) and also acts as the reducing agent for synthesizing the NG-PTCA-Thi-Au nanohybrid. H2 is immobilized on NG-PTCA-Thi-Au to form a new tracer label. The concentration of Pb(II) in a solution can be quantified by determination of the amount of cleaved S1. The method has high sensitivity and selectivity for Pb(II). The detection limit is 0.42 pM (S/N = 3), and the detection range extends from 1 pM to 1000 nM. Graphical abstract Schematic representation of electrodes for the determination of the lead ions (Pb2+). The sensor is using Pb2+-DNAzyme assisted recycling amplification based on hairpin assembly on a composite prepared from nitrogen doped graphene, perylenetetracarboxylic anhydride, thionine and gold nanoparticles (NG-PTCA-Thi-Au). This versatile platform expands studies on the detection of heavy metal ions.

Prevalence of Childhood Sexual Abuse in China: A Meta-Analysis.

The objective of the current study was to explore the estimated prevalence of childhood sexual abuse in China. We conducted a meta-analysis that used the data from 36 articles. A total of 125 independent samples and 131,734 participants were included. The results revealed no significant difference in the prevalence of childhood sexual abuse between Chinese men (9.1%) and women (8.9%). The prevalence of childhood sexual abuse in studies from mainland areas was significantly higher than that from Hong Kong/Taiwan. The estimated prevalence of childhood sexual abuse in China also differed according to the definition of child sexual abuse, data collection method, year of data collection, and the mean age of participants at the time of assessment.

Cross-View Approximation on Grassmann Manifold for Multiview Clustering.

In existing multiview clustering research, the comprehensive learning from multiview graph and feature spaces simultaneously remains insufficient when achieving a consistent clustering structure. In addition, a postprocessing step is often required. In light of these considerations, a cross-view approximation on Grassman manifold (CAGM) model is proposed to address inconsistencies within multiview adjacency matrices, feature matrices, and cross-view combinations from the two sources. The model uses a ratio-formed objective function, enabling parameter-free bidirectional fusion. Furthermore, the CAGM model incorporates a paired encoding mechanism to generate low-dimensional and orthogonal cross-view embeddings. Through the approximation of two measurable subspaces on the Grassmann manifold, the direct acquisition of the indicator matrix is realized. Furthermore, an effective optimization algorithm corresponding to the CAGM model is derived. Comprehensive experiments on four real-world datasets are conducted to substantiate the effectiveness of our proposed method.

Parental Homework Involvement and Students' Achievement: A Three-Level Meta-Analysis.

BACKGROUND: Applying a three-level meta-analysis, the goal of our investigation was to examine the relationship between parental homework involvement and students' achievement, and to investigate whether certain study features could have resulted in the inconsistent results relating to this relationship from prior studies. METHOD: We identified a total of 28 studies (32 independent samples) with 252 effect sizes for a total of 378222 participants. RESULTS: Our meta-analysis revealed an overall weak negative relationship between parental homework involvement and students' achievement ( r = −0.064, p < 0.001). The overall relationship was moderated by the dimension of parental homework involvement. Specifically, students' achievement was positively related to autonomy support, but largely unrelated to content support, parental control, frequency, and mixed. Additionally, the overall relationship was moderated by achievement measure, grade level, and parent gender. CONCLUSIONS: Given that parental autonomy support was the only dimension that was positively related to students' achievement, it would be important to conduct qualitative research that provides longitudinal descriptions of parent-child interactions relating to homework tasks as children make their transition from elementary to middle and high school.

A case of fat-forming solitary fibrous tumor that is prone to be confused with liposarcoma.

Fat-forming solitary fibrous tumor is a rare and specific subtype of solitary fibrous tumor. In this case, a mass of 8.3 cm in diameter was found in a 59-year-old male patient's right retroperitoneum, as revealed by abdominal contrast-enhanced computed tomography (CT) images. The tumor exhibited a well-circumscribed nature and histological features characterized by a combination of hemangiopericytomatous vasculature and mature adipose tissue, comprising around 70% of the total tumor composition. Immunohistochemistry staining revealed diffuse positive expression of STAT6 and CD34 in the tumor cells. Based on these findings, the final diagnosis was determined to be a fat-forming solitary fibrous tumor located in the retroperitoneum. It is important to consider other potential differential diagnoses, including angiomyolipoma, dedifferentiated liposarcoma, spindle cell lipoma, and atypical lipomatous tumor/well-differentiated liposarcoma.

Engineering Escherichia coli for utilization of PET degraded ethylene glycol as sole feedstock.

From both economic and environmental perspectives, ethylene glycol, the principal constituent in the degradation of PET, emerges as an optimal feedstock for microbial cell factories. Traditional methods for constructing Escherichia coli chassis cells capable of utilizing ethylene glycol as a non-sugar feedstock typically involve overexpressing the genes fucO and aldA. However, these approaches have not succeeded in enabling the exclusive use of ethylene glycol as the sole source of carbon and energy for growth. Through ultraviolet radiation-induced mutagenesis and subsequent laboratory adaptive evolution, an EG02 strain emerged from E. coli MG1655 capable of utilizing ethylene glycol as its sole carbon and energy source, demonstrating an uptake rate of 8.1 ± 1.3 mmol/gDW h. Comparative transcriptome analysis guided reverse metabolic engineering, successfully enabling four wild-type E. coli strains to metabolize ethylene glycol exclusively. This was achieved through overexpression of the gcl, hyi, glxR, and glxK genes. Notably, the engineered E. coli chassis cells efficiently metabolized the 87 mM ethylene glycol found in PET enzymatic degradation products following 72 h of fermentation. This work presents a practical solution for recycling ethylene glycol from PET waste degradation products, demonstrating that simply adding M9 salts can effectively convert them into viable raw materials for E. coli cell factories. Our findings also emphasize the significant roles of genes associated with the glycolate and glyoxylate degradation I pathway in the metabolic utilization of ethylene glycol, an aspect frequently overlooked in previous research.

Quantitative monitoring ofloxacin in beef by TLC-SERS combined with machine learning analysis.

Ofloxacin is one kind of quinolone antibiotic drugs, the abuse of ofloxacin in livestock and aquaculture may bring bacterial resistance and healthy problem of people. The illegally feeding cattle with ofloxacin will help it keep health, but the sedimentation of ofloxacin could bring problem in food safety. The accurate, simple and instant monitoring ofloxacin from beef by portable sensor was of vital issue in food quality. A simple and reliable method was proposed for instant and quantitative detecting ofloxacin in beef, in which the thin-layer chromatography (TLC) -surface-enhanced Raman scattering (SERS) spectroscopy was in tandem with machine learning analysis base one principal component analysis-back propagation neural network (PCA-BPNN). The TLC plate was composed with diatomite, that was function as the stationary phase to separate ofloxacin from beef. The real beef juice was directly casted onto the diatomite plate for separating and detecting. The directly monitor ofloxacin from beef was achieved and the sensitivity down to 0.01 ppm. The PCA-BPNN was used as reliable model for quantitative predict the concentration of ofloxacin, that shown superior accuracy compared with the traditional model. The results verify that the diatomite plate TLC-SERS combined with machine-learning analysis is an effective, simple and accurate technique for detecting and quantifying antibiotic drug in meat stuff to improve the food safety.

Design, Synthesis, and Fungicidal Activities of Novel N-(Pyrazol-5-yl)benzamide Derivatives Containing a Diphenylamine Moiety.

To accelerate the development of novel fungicides, a variety of N-(pyrazol-5-yl)benzamide derivatives with a diphenylamine moiety were designed and synthesized using a pharmacophore recombination strategy based on the structure of pyrazol-5-yl-aminophenyl-benzamides. The bioassay results demonstrated that most of the target compounds had excellent in vitro antifungal activities against Sclerotinia sclerotiorum, Valsa mali, and Botrytis cinerea. In particular, compound 5IIIh exhibited remarkable activity against S. sclerotiorum (EC50 = 0.37 mg/L), which was similar to that of fluxapyroxad (EC50 = 0.27 mg/L). In addition, compound 5IIIc (EC50 = 1.32 mg/L) was observed to be more effective against V. mali than fluxapyroxad (EC50 = 12.8 mg/L) and comparable to trifloxystrobin (EC50 = 1.62 mg/L). Furthermore, compound 5IIIh demonstrated remarkable in vivo protective antifungal properties against S. sclerotiorum, with an inhibition rate of 96.8% at 100 mg/L, which was close to that of fluxapyroxad (99.6%). Compounds 5IIIc (66.7%) and 5IIIh (62.9%) exhibited good in vivo antifungal effects against V. mali at 100 mg/L, which were superior to that of fluxapyroxad (11.1%) but lower than that of trifloxystrobin (88.9%). The succinate dehydrogenase (SDH) enzymatic inhibition assay was conducted to confirm the mechanism of action. Molecular docking analysis further revealed that compound 5IIIh has significant hydrogen-bonding, π-π, and p-π conjugation interactions with ARG 43, SER 39, TRP 173, and TYR 58 in the binding site of SDH, and the binding mode was similar to that of the commercial fungicide fluxapyroxad. All of the results suggest that compound 5IIIh could be a potential SDH inhibitor, offering a valuable reference for future studies.

A new freshwater species of Pinnularia (Bacillariophyta) from Hunan Province, China.

This study describes a new species of Pinnularia, P.hupingensissp. nov., on the basis of light and scanning electron microscope images. Pinnulariahupingensissp. nov. is characterised by its linear valve outline, extremely divergent striae, and very large hexagonal central area occupying ca. 1/5-1/8 of the valve length. The primary and secondary sides of the valve and the internal proximal raphe fissures are discussed. The new species is compared to similar taxa of the genus Pinnularia.

Effect of Rosemary on Growth Performance, Meat Quality, Fatty Acid Content, Intestinal Flora, and Antioxidant Capacity of Broilers.

Rosemary (Rosmarinus officinalis L.) is a natural spice plant with an aromatic flavor and antioxidant properties that can help enhance the flavor and texture of food, as well as be used as an antioxidant source in pet feed. This study explored the effect of rosemary on the growth performance and antioxidant capacity of broiler chickens. In total, 144 healthy 1-day-old Arbor Acres broilers were randomly divided into four groups: The control group was fed a basic diet, while the positive control group was fed a basic diet supplemented with 30 mg/kg kitasamycin, and the treatment groups were fed a basic diet supplemental with 0.5% rosemary, or 2% rosemary. The average daily feed intake of broilers fed with 0.5% and 2% rosemary in 1-42 days was higher than that in the basal diet group (p < 0.05). The pH was lower in the rosemary groups than in the 30 mg/kg kitasamycin group as measured in the thigh muscle tissue (p < 0.05), and the monounsaturated fatty acid C17:1 heptadecanoic acid content of the 2% rosemary group was higher than that of the other groups (p < 0.05). With 0.5% rosemary supplementation, the activities of the serum and liver antioxidant enzymes catalase (CAT) activity and total antioxidant capacity (T-AOC) increased (p < 0.05); malondialdehyde content decreased (p < 0.05). The serum activities of CAT, total superoxide dismutase, and T-AOC increased with 2% rosemary supplementation (p < 0.05). The relative expression of liver antioxidant genes, the nuclear factor E2-related factor 2, glutathione catalase 1, and superoxide dismutase 1 increased (p < 0.05) with 0.5% rosemary supplementation. The addition of rosemary resulted in higher intestinal lactobacilli counts and lower E. coli counts. In summary, adding 0.5% or 2% rosemary to the diet improved the growth performance of Arbor Acres broilers and increased the number of intestinal probiotics, and supplementing with 0.5% rosemary yielded better results than adding 2% rosemary. This study provides valuable insights into the broader application of plant-derived antioxidants in promoting sustainable and health-focused animal farming practices.

Exploring the De Novo NMN Biosynthesis as an Alternative Pathway to Enhance NMN Production.

Nicotinamide mononucleotide (NMN) serves as a precursor for NAD+ synthesis and has been shown to have positive effects on the human body. Previous research has predominantly focused on the nicotinamide phosphoribosyltransferase-mediated route (NadV-mediated route) for NMN biosynthesis. In this study, we have explored the de novo NMN biosynthesis route as an alternative pathway to enhance NMN production. Initially, we systematically engineered Escherichia coli to enhance its capacity for NMN synthesis and accumulation, resulting in a remarkable over 100-fold increase in NMN yield. Subsequently, we progressively enhanced the de novo NMN biosynthesis route to further augment NMN production. We screened and identified the crucial role of MazG in catalyzing the enzymatic cleavage of NAD+ to NMN. And the de novo NMN biosynthesis route was optimized and integrated with the NadV-mediated NMN biosynthetic pathways, leading to an intracellular concentration of 844.10 ± 17.40 µM NMN. Furthermore, the introduction of two transporters enhanced the uptake of NAM and the excretion of NMN, resulting in NMN production of 1293.73 ± 61.38 µM. Finally, by engineering an E. coli strain with optimized PRPP synthetase, we achieved the highest NMN production, reaching 3067.98 ± 27.25 µM after 24 h of fermentation at the shake flask level. In addition to constructing an efficient E. coli cell factory for NMN production, our findings provide new insights into understanding the NAD+ salvage pathway and its role in energy metabolism within E. coli.

Enhancing Gpx1 palmitoylation to inhibit angiogenesis by targeting PPT1.

The significance of protein S-palmitoylation in angiogenesis has been largely overlooked, leaving various aspects unexplored. Recent identification of Gpx1 as a palmitoylated protein has generated interest in exploring its potential involvement in novel pathological mechanisms related to angiogenesis. In this study, we demonstrate that Gpx1 undergoes palmitoylation at cysteine-76 and -113, with PPT1 playing a crucial role in modulating the depalmitoylation of Gpx1. Furthermore, we find that PPT1-regulated depalmitoylation negatively impacts Gpx1 protein stability. Interestingly, inhibiting Gpx1 palmitoylation, either through expression of a non-palmitoylated Gpx1 mutant or by expressing PPT1, significantly enhances neovascular angiogenesis. Conversely, in PPT1-deficient mice, angiogenesis is notably attenuated compared to wild-type mice in an Oxygen-Induced Retinopathy (OIR) model, which mimics pathological angiogenesis. Physiologically, under hypoxic conditions, Gpx1 palmitoylation levels are drastically reduced, suggesting that increasing Gpx1 palmitoylation may have beneficial effects. Indeed, enhancing Gpx1 palmitoylation by inhibiting PPT1 with DC661 effectively suppresses retinal angiogenesis in the OIR disease model. Overall, our findings highlight the pivotal role of protein palmitoylation in angiogenesis and propose a novel mechanism whereby the PPT1-Gpx1 axis modulates angiogenesis, thereby providing a potential therapeutic strategy for targeting PPT1 to combat angiogenesis.

Late gestational exposure to fenvalerate impacts ovarian reserve in neonatal mice via YTHDF2-mediated P-body assembly.

Fenvalerate (FEN), a type II pyrethroid pesticide, finds extensive application in agriculture, graziery and public spaces for pest control, resulting in severe environmental pollution. As an environmental endocrine disruptor with estrogen-like activity, exposure to FEN exhibited adverse effects on ovarian functions. Additionally, the presence of the metabolite of FEN in women's urine shows a positive association with the risk of primary ovarian insufficiency (POI). In mammals, the primordial follicle pool established during the early life serves as a reservoir for storing all available oocytes throughout the female reproductive life. The initial size of the primordial follicle pool and the rate of its depletion affect the occurrence of POI. Nevertheless, there is very limited research about the impact of FEN exposure on primordial folliculogenesis. In this study, pregnant mice were orally administrated with 0.2, 2.0 and 20.0 mg/kg FEN from 16.5 to 18.5 days post-coitus (dpc). Ovaries exposed to FEN exhibited the presence of large germ-cell cysts that persist on 1 days post-parturition (1 dpp), followed by a significant reduction in the total number of oocytes in pups on 5 dpp. Moreover, the levels of m6A-RNA and its associated proteins METTL3 and YTHDF2 were significantly increased in the ovaries exposed to FEN. The increased YTHDF2 promoted the assembly of the cytoplasmic processing bodies (P-body) in the oocytes, accompanied with altered expression of transcripts. Additionally, when YTHDF2 was knocked-down in fetal ovary cultures, the primordial folliculogenesis disrupted by FEN exposure was effectively restored. Further, the female offspring exposed to FEN displayed ovarian dysfunctions reminiscent of POI in early adulthood, characterized by decreases in ovarian coefficient and female hormone levels. Therefore, the present study revealed that exposure to FEN during late pregnancy disrupted primordial folliculogenesis by YTHDF2-mediated P-body assembly, causing enduring adverse effects on female fertility.