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.

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.

Platelet membrane biomimetic nanoparticle-targeted delivery of TGF-ß1 siRNA attenuates renal inflammation and fibrosis.

The progression of renal fibrosis to end-stage renal disease (ESRD) is significantly influenced by transforming growth factor-beta (TGF-beta) signal pathway. This study aimed to develop nanoparticles (PMVs@PLGA complexes) with platelet membrane camouflage, which can transport interfering RNA to target and regulate the TGF-ß1 pathway in damaged renal tissues. The aim is to reduce the severity of acute kidney injury and to reduce fibrosis in chronic kidney disease. Hence, we formulated PMVs@TGF-ß1-siRNA NP complexes and employed them for both in vitro and in vivo therapy. From the experimental findings we know that the PMVs@siRNA NPs could effectively target the kidneys in unilateral ureteral obstruction (UUO) mice and ischemia/reperfusion injury (I/R) mice. In animal models of treatment, PMVs@siRNA NP complexes effectively decreased the expression of TGF-ß1 and mitigated inflammation and fibrosis in the kidneys by blocking the TGF-ß1/Smad3 pathway. Therefore, these PMVs@siRNA NP complexes can serve as a promising biological delivery system for treating kidney diseases.

Maternal exposure to beta-Cypermethrin disrupts placental development by dysfunction of trophoblast cells from oxidative stress.

As a broad-spectrum and efficient insecticide, beta-Cypermethrin (ß-CYP) poses a health risk to pregnancy. It matters the mechanisms of maternal exposure to ß-CYP for impacting reproductive health. The placenta, a transient organ pivotal for maternal-fetal communication during pregnancy, plays a crucial role in embryonic development. The effect of ß-CYP exposure on the placenta and its underlying molecular mechanisms remain obscure. The objective of this study was to investigate the effect of ß-CYP exposure on placental development and the function of trophoblast, as well as the underlying mechanisms through CD-1 mouse model (1, 10, 20 mg/kg.bw) and in vitro HTR-8/SVneo cell model (12.5, 25, 50, 100 µM). We found slower weight gain and reduced uterine wet weight in pregnant mice with maternal exposure to ß-CYP during pregnancy, as well as adverse pregnancy outcomes such as uterine bleeding and embryo resorption. The abnormal placental development in response to ß-CYP was noticed, including imbalanced placental structure and disrupted labyrinthine vascular development. Trophoblasts, pivotal in placental development and vascular remodeling, displayed abnormal differentiation under ß-CYP exposure. This aberration was characterized by thickened trophoblast layers in the labyrinthine zone, accompanied by mitochondrial and endoplasmic reticulum swelling within trophoblasts. Further researches on human chorionic trophoblast cell lines revealed that ß-CYP exposure induced apoptosis in HTR-8/SVneo cells. This induction resulted in a notable decrease in migration and invasion abilities, coupled with oxidative stress and the inhibition of the Notch signaling pathway. N-acetylcysteine (an antioxidant) partially restored the impaired Notch signaling pathway in HTR-8/SVneo cells, and mitigated cellular functional damage attributed to ß-CYP exposure. Collectively, exposure to ß-CYP induced oxidative stress and then led to inhibition of the Notch signaling pathway and dysfunction of trophoblast cells, ultimately resulted in abnormal placenta and pregnancy. These findings indicate Reactive Oxygen Species as potential intervention targets to mitigate ß-CYP toxicity. The comprehensive elucidation contributes to our understanding of ß-CYP biosafety and offers an experimental basis for preventing and managing its reproductive toxicity.

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.

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 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.

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.

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.

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.

Parental Homework Involvement and Students’ Achievement: A Three-Level Meta-Analysis / Implicación de los Padres en los Deberes y Rendimiento Académico: un Meta-Análisis de Tres Niveles

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.(AU)

Antecedentes: Mediante un meta-análisis de tres niveles, el objetivo de esta investigación fue examinar la relación entre la participación de los padres en los deberes escolares y el rendimiento académico de los estudiantes, así como estudiar el rol mediador en esta relación de ciertas variables que podrían haber estado relacionadas con algunos resultados inconsistentes en estudios primarios. Método: Se identificaron 28 estudios, con 252 tamaños del efecto, para un total de 378222 participantes. Resultados: Los resultados revelaron una débil relación negativa entre la implicación de los padres en los deberes y el rendimiento de los estudiantes (r = −0,064, p < 0,001). Esta relación fue moderada por el tipo de implicación parental. Específicamente, el rendimiento de los estudiantes se relacionó positivamente con el apoyo a la autonomía, pero no con el apoyo al contenido, el control de los padres, la frecuencia y la combinación de estas dimensiones. Además, dicha relación fue moderada por la medida de rendimiento, el curso de los estudiantes y el género de los padres. Conclusiones: Es necesaria más investigación cualitativa sobre lo que ocurre en torno a las interacciones entre padres e hijos a la hora de la realización de los deberes escolares.(AU)

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.

Discovery of Novel Pyrazol-5-yl-benzamide Derivatives Containing a Thiocyanato Group as Broad-Spectrum Fungicidal Candidates.

In an effort to promote the development of new fungicides, a series of 48 novel N-(1-methyl-4-thiocyanato-1H-pyrazol-5-yl)-benzamide derivatives A1-A36 and B1-B12 were designed and synthesized by incorporating a thiocyanato group into the pyrazole ring, and their fungicidal activities were evaluated against Sclerotinia sclerotiorum, Valsa mali, Botrytis cinerea, Rhizoctonia solani, and Phytophthora capsici. In the in vitro antifungal/antioomycete assay, many of the target compounds exhibited good broad-spectrum fungicidal activities. Among them, compound A36 displayed the best antifungal activity against V. mali with an EC50 value of 0.37 mg/L, which was significantly higher than that of the positive controls fluxapyroxad (13.3 mg/L) and dimethomorph (10.3 mg/L). Meanwhile, compound B6 exhibited the best antioomycete activity against P. capsici with an EC50 value of 0.41 mg/L, which was higher than that of azoxystrobin (29.2 mg/L) but lower than that of dimethomorph (0.13 mg/L). Notably, compound A27 displayed broad-spectrum inhibitory activities against V. mali, B. cinerea, R. solani, S. sclerotiorum, and P. capsici with respective EC50 values of 0.71, 1.44, 1.78, 0.87, and 1.61 mg/L. The in vivo experiments revealed that compounds A27 and B6 presented excellent protective and curative efficacies against P. capsici, similar to that of the positive control dimethomorph. Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) analyses showed that compound B6 could change the mycelial morphology and severely damage the ultrastructure of P. capsici. The results of the in vitro SDH enzymatic inhibition experiments indicated that compounds A27 and B6 could effectively inhibit the activity of P. capsici SDH (PcSDH). Furthermore, molecular docking analysis demonstrated significant hydrogen bonds and Pi-S bonding between the target compounds and the key amino acid residues of PcSDH, which could explain the probable mechanism of action. Collectively, these studies provide a valuable approach to expanding the fungicidal spectrum of pyrazol-5-yl-benzamide derivatives.

Cryo-EM structure of severe fever with thrombocytopenia syndrome virus.

The severe fever with thrombocytopenia syndrome virus (SFTSV) is a tick-borne human-infecting bunyavirus, which utilizes two envelope glycoproteins, Gn and Gc, to enter host cells. However, the structure and organization of these glycoproteins on virion surface are not yet known. Here we describe the structure of SFTSV determined by single particle reconstruction, which allows mechanistic insights into bunyavirus assembly at near-atomic resolution. The SFTSV Gn and Gc proteins exist as heterodimers and further assemble into pentameric and hexameric peplomers, shielding the Gc fusion loops by both intra- and inter-heterodimer interactions. Individual peplomers are associated mainly through the ectodomains, in which the highly conserved glycans on N914 of Gc play a crucial role. This elaborate assembly stabilizes Gc in the metastable prefusion conformation and creates some cryptic epitopes that are only accessible in the intermediate states during virus entry. These findings provide an important basis for developing vaccines and therapeutic drugs.

Comparing asexual with heterosexual, bisexual, and gay/lesbian individuals in common mental health problems: A multivariate meta-analysis.

We aimed to test whether asexual individuals were at increased risk of higher levels of depressive symptoms, self-harm attempts, and suicide attempts compared with heterosexual, bisexual, or gay/lesbian individuals using multivariate meta-analysis. Seventeen, five, and eight samples were included for depressive symptoms, self-harm attempts, and suicide attempts, respectively, reaching a total sample size of 125,675, 30,116, and 73,366, respectively. Asexual individuals reported higher levels of depressive symptoms than heterosexual individuals (Hedges' g = -0.44, 95%CI = [-0.61, -0.26]) but did not differ from heterosexual individuals in the risk of self-harm (odds ratio = 1.11, 95%CI = [0.88, 1.39]) and suicide attempts (odds ratio = 0.76, 95%CI = [0.56, 1.04]). Asexual individuals were at lower risk of self-harm and suicide attempts than bisexual and gay/lesbian individuals but did not differ from bisexual and gay/lesbian individuals in the levels of depressive symptoms. The greatest risk of higher levels of depressive symptoms was found in bisexual and asexual, followed by gay/lesbian individuals; the greatest risk of self-harm and suicide attempts was found in bisexual, followed by gay/lesbian individuals, and the lowest risk was found in asexual individuals. The magnitude of the disparities in the risk of poorer mental health among heterosexual, bisexual, gay/lesbian, and asexual individuals depended on the type of mental health outcomes.

Evaluating Flight Performance and Eye Movement Patterns Using Virtual Reality Flight Simulator.

Efficient and economical performance evaluation of pilots has become critical to the aviation industry. With the development of virtual reality (VR) and the combination of eye-tracking technology, solutions to meet these needs are becoming a reality. Previous studies have explored VR-based flight simulators, focusing mainly on technology validation and flight training. The current study developed a new VR flight simulator to evaluate pilots' flight performance based on eye movement and flight indicators in a 3D immersive scene. During the experiment, 46 participants were recruited: 23 professional pilots and 23 college students without flight experience. The experiment results showed significant differences in flight performance between participants with and without flight experience, the former being higher than the latter. In contrast, those with flight experience showed more structured and efficient eye-movement patterns. These results of the differentiation of flight performance demonstrate the validity of the current VR flight simulator as a flight performance assessment method. The different eye-movement patterns with flight experience provide the basis for future flight selection. However, this VR-based flight simulator has shortcomings like motion feedback compared to traditional flight simulators. This flight simulator platform is highly flexible except for the apparent low cost. It can meet the diverse needs of researchers (e.g., measuring situation awareness, VR sickness, and workload by adding relevant scales).

Maternal exposure to dibutyl phthalate regulates MSH6 crotonylation to impair homologous recombination in fetal oocytes.

Homologous recombination (HR) during early oogenesis repairs programmed double-strand breaks (DSBs) to ensure female fertility and offspring health. The exposure of fetal ovaries to endocrine disrupting chemicals (EDCs) can cause reproductive disorders in the adulthood. The EDC dibutyl phthalate (DBP) is widely distributed in flexible plastic products, leading to ubiquitous human exposure. Here, we report that maternal exposure to DBP caused gross aberrations in meiotic prophase I of fetal oocytes, including delayed progression, impaired DNA damage response, uncoupled localization of DMC1 and RAD51, and decreased HR. However, programmed DSBs were efficiently repaired. DBP exposure negatively regulated lysine crotonylation (Kcr) of MSH6. Similar meiotic defects were observed in fetal ovaries with targeted disruption of Msh6, and mutation of K544cr of MSH6 impaired its association with Ku70, thereby promoting non-homologous end joining (NHEJ) and inhibiting HR. Unlike mature F1 females, F2 female mice exhibited premature follicular activation, precocious puberty, and anxiety-like behaviors. Therefore, DBP can influence early meiotic events, and Kcr of MSH6 may regulate preferential induction of HR or NHEJ for DNA repair during meiosis.

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.

Nanotechnology-integrated ovarian cancer metastasis therapy: Insights from the metastatic mechanisms into administration routes and therapy strategies.

Ovarian cancer is a kind of malignant tumour which locates in the pelvic cavity without typical clinical symptoms in the early stages. Most patients are diagnosed in the late stage while about 60 % of them have suffered from the cancer cells spreading in the abdominal cavity. The high recurrence rate and mortality seriously damage the reproductive needs and health of women. Although recent advances in therapeutic regimes and other adjuvant therapies improved the overall survival of ovarian cancer, overcoming metastasis has still been a challenge and is necessary for achieving cure of ovarian cancer. To present potential targets and new strategies for curbing the occurrence of ovarian metastasis and the treatment of ovarian cancer after metastasis, the first section of this paper explained the metastatic mechanisms of ovarian cancer comprehensively. Nanomedicine, not limited to drug delivery, offers opportunities for metastatic ovarian cancer therapy. The second section of this paper emphasized the advantages of various administration routes of nanodrugs in metastatic ovarian cancer therapy. Furthermore, the third section of this paper focused on advances in nanotechnology-integrated strategies for targeting metastatic ovarian cancer based on the metastatic mechanisms of ovarian cancer. Finally, the challenges and prospects of nanotherapeutics for ovarian cancer metastasis therapy were evaluated. In general, the greatest emphasis on using nanotechnology-based strategies provides avenues for improving metastatic ovarian cancer outcomes in the future.