Aal-circRNA-407 regulates ovarian development of Aedes albopictus, a major arbovirus vector, via the miR-9a-5p/Foxl axis.

Aedes albopictus shows a rapid global expansion and dramatic vectorial capacity for various arboviruses, thus posing a severe threat to global health. Although many noncoding RNAs have been confirmed to play functional roles in various biological processes in Ae. albopictus, the roles of circRNA remain a mystery. In the present study, we first performed high-throughput circRNA sequencing in Ae. albopictus. Then, we identified a cysteine desulfurase (CsdA) superfamily gene-originated circRNA, named aal-circRNA-407, which was the third most abundant circRNA in adult females and displayed a fat body highly expressed manifestation and blood feeding-dependent onset. SiRNA-mediated knockdown of circRNA-407 resulted in a decrease in the number of developing follicles and a reduction in follicle size post blood meal. Furthermore, we demonstrated that circRNA-407 can act as a sponge of aal-miR-9a-5p to promote the expression of its target gene Foxl and eventually regulate ovarian development. Our study is the first to report a functional circRNA in mosquitoes, expanding our current understanding of important biological roles in mosquitoes and providing an alternative genetic strategy for mosquito control.

The AalNix3&4 isoform is required and sufficient to convert Aedes albopictus females into males.

Aedes albopictus is one of the most invasive insect species in the world and an effective vector for many important arboviruses. We reported previously that Ae. albopictus Nix (AalNix) is the male-determining factor of this species. However, whether AalNix alone is sufficient to initiate male development is unknown. Transgenic lines that express each of the three AalNix isoforms from the native promoter were obtained using piggyBac transformation. We verified the stable expression of AalNix isoforms in the transgenic lines and confirm that one isoform, AalNix3&4, is sufficient to convert females into fertile males (pseudo-males) that are indistinguishable from wild-type males. We also established a stable sex-converted female mosquito strain, AalNix3&4-♂4-pseudo-male. The pseudo-male mosquitoes can fly and mate normally with wild-type female, although their mating competitiveness is lower than wild-type. This work further clarifies the role of AalNix in the sex determination pathway and will facilitate the development of Ae. albopictus control strategies that rely on male-only releases such as SIT and sex-ratio distortion.

Postoperative seizure and memory outcome of temporal lobe epilepsy with hippocampal sclerosis: A systematic review.

We conducted a systematic review and meta-analysis to evaluate postoperative seizure and memory outcomes of temporal lobe epilepsy with different hippocampal sclerosis (HS) subtypes classified by International League Against Epilepsy (ILAE) Consensus Guidelines in 2013. Following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) and MOOSE (Meta-Analysis of Observational Studies in Epidemiology) guidelines, we searched PubMed, Embase, Web of Science, and Cochrane Library from January 1, 2013 to August 6, 2023. Observational studies reporting seizure and memory outcomes among different HS subtypes were included. We used the Newcastle-Ottawa scale to assess the risk of bias and the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach to grade the quality of evidence. Seizure freedom and improved outcome (Engel 1 or ILAE class 1-2) ≥1 year after surgery were defined as the primary and secondary seizure outcome. A random-effects meta-analysis by DerSimonian and Laird method was performed to obtain pooled risk ratio (RRs) with 95% confidence interval (CIs). The memory impairment was narratively reviewed because of various evaluation tools. Fifteen cohort studies with 2485 patients were eligible for the meta-analysis of seizure outcome. Six cohorts with detailed information on postoperative memory outcome were included. The pooled RRs of seizure freedom, with moderate to substantial heterogeneity, were .98 (95% CI = .84-1.15) between HS type 2 and type 1, 1.11 (95% CI = .82-1.52) between type 3 and type 1, and .80 (95% CI = .62-1.03) between the no-HS and HS groups. No significant difference of improved outcome was found between different subtypes (p > .05). The quality of evidence was deemed to be low to very low according to GRADE. The long-term seizure outcome (≥5 years after surgery) and memory impairment remained controversial.

L-serine combined with carboxymethyl chitosan guides amorphous calcium phosphate to remineralize enamel.

The aim of this study is to investigate a robust and stable calcium-phosphorus system to remineralize human early enamel caries lesions with nanocomplexes of carboxymethyl chitosan/L-serine/amorphous calcium phosphate (CMC-Ser-ACP) to develop an effective method for mimicking the amelogenin (AMEL) mineralization pattern through ACP assembly. A CMC-Ser-ACP nanocomplex solution was first synthesized by a chemical precipitation method, and then 1% sodium hypochlorite (NaClO) was added to induce ACP phase formation. The morphologies of the nanocomplexes were characterized by transmission electron microscopy (TEM), and zeta potential analysis and Fourier transform infrared spectroscopy (FTIR) were performed to detect surface charge and functional group changes. The subtle changes of the demineralized enamel models induced by the remineralization effect were observed by scanning electron microscopy (SEM) and X-ray diffraction (XRD). The CMC-Ser-ACP nanocomplex solution could be preserved without any precipitation for 45 days. After the application of NaClO and through the guidance of Ser, ACP nanoparticles transformed into relatively orderly arranged hydroxyapatite (HAP) crystals, generating an aprismatic enamel-like layer closely integrated with the demineralized enamel, which resulted in enhanced mechanical properties for the treatment of early enamel caries lesions. The CMC-Ser-ACP nanocomplex solution is a remineralization system with great solution stability, and when NaClO is added, it can rapidly regenerate an aprismatic enamel-like layer in situ on the demineralized enamel surface. This novel remineralization system has stable chemical properties and can greatly increase the therapeutic effects against early enamel caries.

Recombinant Human Clusterin Seals Damage to the Ocular Surface Barrier in a Mouse Model of Ophthalmic Preservative-Induced Epitheliopathy.

There is a significant unmet need for therapeutics to treat ocular surface barrier damage, also called epitheliopathy, due to dry eye and related diseases. We recently reported that the natural tear glycoprotein CLU (clusterin), a molecular chaperone and matrix metalloproteinase inhibitor, seals and heals epitheliopathy in mice subjected to desiccating stress in a model of aqueous-deficient/evaporative dry eye. Here we investigated CLU sealing using a second model with features of ophthalmic preservative-induced dry eye. The ocular surface was stressed by topical application of the ophthalmic preservative benzalkonium chloride (BAC). Then eyes were treated with CLU and sealing was evaluated immediately by quantification of clinical dye uptake. A commercial recombinant form of human CLU (rhCLU), as well as an rhCLU form produced in our laboratory, designed to be compatible with U.S. Food and Drug Administration guidelines on current Good Manufacturing Practices (cGMP), were as effective as natural plasma-derived human CLU (pCLU) in sealing the damaged ocular surface barrier. In contrast, two other proteins found in tears: TIMP1 and LCN1 (tear lipocalin), exhibited no sealing activity. The efficacy and selectivity of rhCLU for sealing of the damaged ocular surface epithelial barrier suggests that it could be of therapeutic value in treating BAC-induced epitheliopathy and related diseases.

[The neural basis underlying primary dysmenorrhea: evidence from neuroimaging and animal model studies].

Primary dysmenorrhea (PDM), cyclic menstrual pain in the absence of pelvic anomalies, is characterized by acute and chronic gynecological pain disorders in childbearing age women. PDM strongly affects the quality of life of patients and leads to economic losses. PDM generally do not receive radical treatment and often develop into other chronic pain disorders later in life. The clinical treatment status of PDM, the epidemiology of PDM and chronic pain comorbidities, and the abnormal physiological and psychological characteristics of patients with PDM suggest that PDM not only is related to the inflammation around the uterus, but also may be related to the abnormal pain processing and regulation function of patients' central system. Therefore, exploring the brain neural mechanism of PDM is indispensable and important to understand the pathological mechanism of PDM, and is also a hotspot of brain science research in recent years, which will bring new inspiration to explore the target of PDM intervention. Based on the progress of the neural mechanism of PDM, this paper systematically summarizes the evidence from neuroimaging and animal model studies.

Mixed lineage kinase 3 requires a functional CRIB domain for regulation of blood pressure, cardiac hypertrophy, and left ventricular function.

Mixed lineage kinase 3 (MLK3) modulates blood pressure and left ventricular function, but the mechanisms governing these effects remain unclear. In the current study, we therefore investigated the role of the MLK3 Cdc42/Rac interactive binding (CRIB) domain in cardiovascular physiology. We examined baseline and left ventricular pressure overload responses in a MLK3 CRIB mutant (MLK3C/C) mouse, which harbors point mutations in the CRIB domain to disrupt MLK3 activation by Cdc42. Male and female MLK3C/C mice displayed increased invasively measured blood pressure compared with wild-type (MLK3+/+) littermate controls. MLK3C/C mice of both sexes also developed left and right ventricular hypertrophy but normal baseline LV function by echocardiography and invasive hemodynamics. In LV tissue from MLK3C/C mice, map3k11 mRNA, which encodes MLK3, and MLK3 protein were reduced by 74 ± 6% and 73 ± 7%, respectively. After 1-wk LV pressure overload with 25-gauge transaortic constriction (TAC), male MLK3C/C mice developed no differences in LV hypertrophy but displayed reduction in the LV systolic indices ejection fraction and dP/dt normalized to instantaneous pressure. JNK activation was also reduced in LV tissue of MLK3C/C TAC mice. TAC induced MLK3 translocation from cytosolic fraction to membrane fraction in LV tissue from MLK3+/+ but not MLK3C/C mice. These findings identify a role of the MLK3 CRIB domain in MLK3 regulation of basal blood pressure and cardiac morphology, and in promoting the compensatory LV response to pressure overload.NEW & NOTEWORTHY Here, we identified that the presence of two discrete point mutations within the Cdc42/Rac interaction and binding domain of the protein MLK3 recapitulates the effects of whole body MLK3 deletion on blood pressure, cardiac hypertrophy, and left ventricular compensation after pressure overload. These findings implicate the CRIB domain, and thus MLK3 activation by this domain, as critical for maintenance of cardiovascular homeostasis.

Albumin alleviated esketamine-induced neuronal apoptosis of rat retina through downregulation of Zn2+-dependent matrix metalloproteinase 9 during the early development.

AIMS: Esketamine upregulates Zn2+-dependent matrix metalloproteinase 9 (MMP9) and increases the neuronal apoptosis in retinal ganglion cell layer during the early development. We aimed to test whether albumin can alleviate esketamine-induced apoptosis through downregulating Zn2+-dependent MMP9. METHODS: We investigate the role of Zn2+ in esketamine-induced neuronal apoptosis by immunofluorescence. MMP9 protein expression and enzyme activity were investigated by zymography in situ., western blot and immunofluorescence. Whole-mount retinas from P7 Sprague-Dawley rats were used. RESULTS: We demonstrated that esketamine exposure increased Zn2+ in the retinal GCL during the early development. Zn2+-dependent MMP9 expression and enzyme activity up-regulated, which eventually aggravated apoptosis. Albumin effectively down-regulated MMP9 expression and activity via binding of free zinc, ultimately protected neurons from apoptosis. Meanwhile albumin treatment promoted activated microglia into multi-nucleated macrophagocytes and decreased the inflammation. CONCLUSION: Albumin alleviates esketamine-induced neuronal apoptosis through decreasing Zn2+ accumulation in GCL and downregulating Zn2+-dependent MMP9.

The Prognosis of Radical Prostatectomy, External Beam Radiotherapy plus Brachytherapy, and External Beam Radiotherapy Alone for Patients above 70 Years with Very High-Risk Prostate Cancer: A Population-Matched Study.

OBJECTIVE: The aim of this study was to evaluate the survival outcomes of radical prostatectomy (RP), external beam radiotherapy plus brachytherapy (EBRT + BT), and EBRT alone among elderly men (aged 70 years and above) with very high-risk (VHR) prostate cancer (PCa). METHODS: We identified elderly men diagnosed with VHR PCa between 2004 and 2015 in the Surveillance, Epidemiology, and End Results database. The propensity score-matching method was adopted to balance the covariates and generate new cohorts. -Kaplan-Meier and Cox analyses were conducted to build up survival curves and evaluate the overall survival (OS) and PCa-specific survival (PCSS) outcomes. RESULTS: A total of 9,818 patients were identified. Of them, 5,839 were in the EBRT group, 725 in the EBRT + BT group, and 3,254 in the RP group. The survival curves of the overall cohort showed that RP was associated with the best OS, followed by EBRT + BT and EBRT (p < 0.001). As for the PCSS, RP shared similar outcomes with EBRT + BT (hazard ratio [HR]: 1.25 [0.93-1.69], p = 0.175). EBRT was associated with significantly worse PCSS than both RP (HR: 1.88, 95% confidence interval [95% CI] [1.64-2.15], p < 0.001) and EBRT + BT (HR: 1.48, 95% CI [1.19-1.85], p = 0.002). In the matched cohorts, RP presented better OS (HR: 1.41, 95% CI [1.07-1.86], p = 0.041) and similar PCSS with EBRT + BT (HR: 1.50, 95% CI [0.91-2.47], p = 0.12). RP was associated with significantly better OS and PCSS outcomes than EBRT alone (OS HR: 1.58, 95% CI [1.59-2.12], p < 0.001; PCSS HR: 2.08 [1.60-2.72], p < 0.001). EBRT + BT also had significantly better OS and PCSS outcomes than EBRT alone (OS HR: 1.33, 95% CI [1.11-1.60], p < 0.001; PCSS HR: 1.57 [1.13-2.19], p = 0.003). CONCLUSIONS: For patients above 70 years with VHR PCa, RP was associated with better OS and similar PCSS than EBRT + BT. Both RP and EBRT + BT have better OS and PCSS than EBRT alone.

The reciprocal associations between caregiver burden, and mental health in primary caregivers of cancer patients: A longitudinal study: Family functioning, caregiver burden, and mental health Wenjun Yu et al.

OBJECTIVE: The vital role played by primary caregivers in caring for cancer patients is well-recognized, but the caregiver burden and impact on family functioning to caregivers' mental health is poorly understood. This study examined the prospective and reciprocal relationships between family functioning, caregiver burden, and mental health. We aimed to determine whether inferior family functioning and heavy caregiver burden act as risk factors for mental health, as consequences of mental health, or both. METHODS: Participants were 187 primary caregivers of cancer patients. They completed questionnaires with standardized measures assessing family functioning, caregiver burden, and mental health. A quantitative longitudinal design and a cross-lag model were used to test the reciprocal relationships between variables at three time points with 6-month intervals during the first year of early-stage cancer diagnosis and treatment. RESULTS: Family functioning did not predict participants' future mental health, but their mental health state predicted future caregiver burden and family functioning. Caregiver burden also predicted participants' future mental health. There was a dynamic reciprocal relationship between caregiver burden and mental health over time. CONCLUSIONS: The findings of this study emphasize the adverse effects of caregiver burden and may contribute to shedding light on the distinct mechanisms that underlie the relationships between caregiver burden, family functioning, and mental health. Our findings indicate the necessity of developing interventions to reduce the burden of caregiving and to facilitate family functioning. They will provide direction for family-centered nursing to meet primary caregivers' mental health needs in the care of cancer patients.

Exenatide Twice Daily Plus Glargine Versus Aspart 70/30 Twice Daily in Patients With Type 2 Diabetes With Inadequate Glycemic Control on Premixed Human Insulin and Metformin.

OBJECTIVE: Many patients with type 2 diabetes treated with premixed insulin gradually have inadequate glycemic control and switch to a basal-bolus regimen, which raises some concerns for weight gain and increased hypoglycemic risk. Switching to combination use of glp-1 agonist and basal insulin may be an alternative option. METHODS: After a 12-week premixed human insulin 70/30 dosage optimization period, 200 patients with HbA1c of 7.0% to 10.0% were randomized into 24-week treatment groups with exenatide twice a day plus glargine or with aspart 70/30 twice a day. RESULTS: After 24 weeks, the patients receiving exenatide plus glargine (n = 90) had improved HbA1c control compared with those receiving aspart 70/30 (n = 90) (least squares mean change: ‒0.59 vs ‒0.13%; difference [95% CI]: ‒0.45 [‒0.74 to ‒0.17]) in the full analysis set population. Weight decreased 3.5 kg with exenatide and decreased 0.4 kg with aspart 70/30 (P < .001). The insulin dose was reduced 10.7 units/day (95% CI, ‒12.2 to ‒9.2 units; P < .001) with exenatide, and increased 9.7 units/day (95% CI, 8.2 to 11.2 units; P < .001) with aspart 70/30. The most common adverse events were gastrointestinal adverse effects in the exenatide group (nausea [21%], vomiting [16%], diarrhea [13%]). The incidence of hypoglycemia was similar in 2 groups (27% for exenatide and 38% for aspart 70/30; P = .1). CONCLUSION: In premixed human insulin‒treated patients with type 2 diabetes with inadequate glycemic control, switching to exenatide twice a day plus glargine was superior to aspart 70/30 twice a day for glycemic and weight control.

A novel mutation of MSX1 inherited from maternal mosaicism causes a severely affected child with nonsyndromic oligodontia.

Mutations of MSX1 have been associated with nonsyndromic hypodontia. To seek the causal gene mutation sites in a family with nonsyndromic oligodontia, whole-exome sequencing (WES) was performed to seek the causative locus of the family. The candidate mutation was further identified by Sanger sequencing afterward. Two mutations of MSX1 were found both in the proband and her mother. One novel heterozygous missense mutation (c.C667G, p.R223G) of MSX1 inherited from the asymptomatic mother with mosaic mutation was located in the highly conserved fragment of exon 2. The other was a synonymous mutation (c.C348T, p.G116G) in exon 1, which had been reported. The novel maternal heterozygous missense mutation (c.C667G, p.R223G) was likely to be the major reason for nonsyndromic oligodontia in the family. This is the first mosaic variant that has been recorded of the MSX1 gene. Our study expands the phenotype-genotype correlation associated with MSX1 variants. Our study also suggests that the determination of the mosaicism is essential for precise genetic counseling if a disease appears to arise de novo.

Structure Selectivity of Alkaline Periodate Oxidation on Lignocellulose for Facile Isolation of Cellulose Nanocrystals.

Reported here for the first time is the alkaline periodate oxidation of lignocelluloses for the selective isolation of cellulose nanocrystals (CNCs). With the high concentrations as a potassium salt at pH 10, periodate ions predominantly exist as dimeric orthoperiodate ions (H2 I2 O104- ). With reduced oxidizing activity in alkaline solutions, dimeric orthoperiodate ions preferentially oxidized non-ordered cellulose regions. The alkaline surroundings promoted the degradation of these oxidized cellulose chains by ß-alkoxy fragmentation and generated CNCs. The obtained CNCs were uniform in size and generally contained carboxy groups. Furthermore, the reaction solution could be reused after regeneration of the periodate with ozone gas. This method allows direct production of CNCs from diverse sources, in particular lignocellulosic raw materials including sawdust (European beech and Scots pine), flax, and kenaf, in addition to microcrystalline cellulose and pulp.

Single-cell RNA-seq reveals the metabolic status of immune cells response to immunotherapy in triple-negative breast cancer.

Immune checkpoint blockade (ICB) therapy offers promise in the treatment of triple-negative breast cancer (TNBC); however, its limited efficacy in certain TNBC patients poses a challenge. In this study, we elucidated the metabolic mechanism at 'sub-subtype' resolution underlying the non-response to ICB therapy in TNBC. Here, an analytic pipeline was developed to reveal the metabolic heterogeneity, which is correlated with the ICB outcomes, within each immune cell subtype. First, we identified metabolic 'sub-subtypes' within certain cell subtypes, predominantly T cell subsets, which are enriched in ICB non-responders and named as non-responder-enriched (NR-E) clusters. Notably, most of NR-E T metabolic cells exhibit globally higher metabolic activities compared to other cells within the same individual subtype. Further, we investigated the extra-cellular signals that trigger the metabolic status of NR-E T cells. In detail, the prediction of cell-to-cell communication indicated that NR-E T cells are regulated by plasmatic dendritic cells (pDCs) through TNFSF9, as well as by macrophages expressing SIGLEC9. In addition, we also validate the communication between TNFSF9+ pDCs and NR-E T cells utilizing deconvolution of spatial transcriptomics analysis. In summary, our research identified specific metabolic 'sub-subtypes' associated with ICB non-response and uncovered the mechanisms of their regulation in TNBC. And the proposed analytical pipeline can be used to examine metabolic heterogeneity within cell types that correlate with diverse phenotypes.

A low bleeding risk thrombolytic agent: citPA5.

AIMS: Alteplase is a cornerstone thrombolytic agent in clinical practice but presents a potential bleeding risk. Stroke patients need pre-screening to exclude haemorrhagic stroke before using alteplase. In this study, we develop a new thrombolytic agent citPA5, characterized by an enhanced safety profile and minimal bleeding tendency. METHODS AND RESULTS: A clot lysis agent, named citPA5, is developed based on rtPA with point mutations to completely suppress its proteolytic activity in the absence of fibrin. In the presence of fibrin, citPA5 exhibited significantly higher fibrinolytic activity (a 15.8-fold increase of kcat/Km). Furthermore, citPA5 showed resistance to endogenous fibrinolysis inhibitor, PAI-1, resulting in enhanced potency. In a series of safety evaluation experiments, including thrombelastography assay, mice tail bleeding assay, and a murine intracerebral haemorrhage (ICH) model, citPA5 did not cause systemic bleeding or worsen ICH compared with alteplase. This highlights the low risk of bleeding associated with citPA5. Finally, we found that citPA5 effectively improved cerebral blood flow and reduced infarct volume in a carotid embolism-induced stroke model. CONCLUSION: This clot lysis agent, citPA5, not only exhibits a low risk of bleeding but also demonstrates highly effective thrombolysis capabilities. As a result, citPA5 shows great potential for administration prior to the classification of stroke types, making it possible for use in ambulances at the onset of stroke when symptoms are identified. The findings presented in this study also suggest that this strategy could be applied to develop a new generation of fibrinolytic drugs that offer greater safety and specificity in targeting fibrin.

Metagenomic analysis reveals the virome profiles of Aedes albopictus in Guangzhou, China.

Introduction: Aedes albopictus is an aggressive invasive mosquito species widely distributed around the world, and it is also a known vector of arboviruses. Virus metagenomics and RNA interference (RNAi) are important in studying the biology and antiviral defense of Ae. albopictus. However, the virome and potential transmission of plant viruses by Ae. albopictus remain understudied. Methods: Mosquito samples of Ae. albopictus were collected from Guangzhou, China, and small RNA sequencing was performed. Raw data were filtered, and virus-associated contigs were generated using VirusDetect. The small RNA profiles were analyzed, and maximum-likelihood phylogenetic trees were constructed. Results: The small RNA sequencing of pooled Ae. albopictus revealed the presence of five known viruses, including Wenzhou sobemo-like virus 4, mosquito nodavirus, Aedes flavivirus, Hubei chryso-like virus 1, and Tobacco rattle virus RNA1. Additionally, 21 new viruses that had not been previously reported were identified. The mapping of reads and contig assembly provided insights into the viral diversity and genomic characteristics of these viruses. Field survey confirmed the detection of the identified viruses in Ae. albopictus collected from Guangzhou. Discussion: The comprehensive analysis of the virus metagenomics of Ae. albopictus in this study sheds light on the diversity and prevalence of viruses in mosquito populations. The presence of known and novel viruses highlights the need for continued surveillance and investigation into their potential impact on public health. The findings also emphasize the importance of understanding the virome and potential transmission of plant viruses by Ae. albopictus. Conclusion: This study provides valuable insights into the virome of Ae. albopictus and its potential role as a vector for both known and novel viruses. Further research is needed to expand the sample size, explore additional viruses, and investigate the implications for public health.

Progesterone alleviates esketamine-induced hypomyelination via PI3K/Akt signaling pathway in the developing rat brain.

The neurodevelopmental toxicity of anesthetics has been confirmed repeatedly, and esketamine is now widely used in pediatric surgeries. Oligodendrocyte precursor cells (OPCs) evolved into mature oligodendrocytes (OLs) and formed myeline sheath during the early brain development. In this study, we investigated whether esketamine exposure interrupted development of OPCs and induced hypomyelination in rats. Further we explored the roles of PI3K/Akt phosphorylation in OPCs development and myelination. Sprague Dawley rats with different ages (postnatal day (P) 1, 3, 7 and 12) were exposed to 40mg/kg esketamine. Progesterone treatment was given (16 mg/kg per day for 3 days) 24 h after esketamine exposure via the intraperitoneal route. Corpus callosum tissues were collected at P8 or P14 for western blot and immunofluorescence analyses. Esketamine exposure at P7 and P12 significantly reduced myelin basic protein (MBP) expression and CC1+ OLs number in corpus callosum. Esketamine exposure at P7 not only aggravated the mature OLs apoptosis, also decreased the OPCs proliferation and differentiation, which was related with dephosphorylation of PI3K/Akt. Progesterone was able to promote OPCs differentiation and ameliorate esketamine-induced hypomyelination by enhancing PI3K/Akt phosphorylation. Stage-dependent abnormality of OPCs/OLs after esketamine leads to the esketamine-induced hypomyelination. Esketamine interrupted OPCs evolution via PI3K/Akt signaling pathway, which can be ameliorated by progesterone.

Aberrant structural rich club organization in temporal lobe epilepsy with focal to bilateral tonic-clonic seizures.

OBJECTIVE: The purpose of this study was to assess the differences of topological characteristic and rich club organization between temporal lobe epilepsy (TLE) patients with focal seizure (FS) only and those with focal to bilateral tonic-clonic seizures (FBTCS). METHODS: We recruited 130 unilateral TLE patients, of which 57 patients with FS only and 73 patients with both FS and FBTCS, and 68 age- and gender-matched healthy controls (HC). Whole-brain networks were constructed based on diffusion weighted imaging data. Graph theory was applied to quantify the topological network metrics and rich club organization. Network-based statistic (NBS) analysis was administered to investigate the difference in edge-wise connectivity strength. The non-parametric permutation test was applied to evaluate the differences between groups. Benjamini-Hochberg FDR at the alpha of 5% was carried out for multiple comparations. RESULTS: In comparison with HC, both the FS and FBTCS group displayed a significant reduction in whole-brain connectivity strength and global efficiency. The FBTCS group showed lower connectivity strength both in the rich club and feeder connections compared to HC. The FS group had lower connectivity strength in the feeder and local connections compared to HC. NBS analysis revealed a wider range of decreased connectivity strength in the FBTCS group, involving 90% of the rich club regions, mainly affecting temporal-subcortical, frontal-parietal, and frontal-temporal lobe, the majority decreasing connections were between temporal lobe and stratum. While the decreased connectivity strength in the FS group were relatively local, involving 50% of rich club regions, mainly concentrated on the temporal-subcortical lobe. CONCLUSIONS: Network integration was reduced in TLE. TLE with FBTCS selectively disrupted the rich club regions, while TLE with FS only were more likely to affect the non-rich club regions, emphasizing the contribution of rich club organization to seizure generalization.

Mosquito densovirus significantly reduces the vector susceptibility to dengue virus serotype 2 in Aedes albopictus mosquitoes (Diptera: Culicidae).

BACKGROUND: Dengue virus (DENV) is a major public health threat, with Aedes albopictus being the confirmed vector responsible for dengue epidemics in Guangzhou, China. Mosquito densoviruses (MDVs) are pathogenic mosquito-specific viruses, and a novel MDV was previously isolated from Ae. albopictus in Guangzhou. This study aims to determine the prevalence of MDVs in wild Ae. albopictus populations and investigate their potential interactions with DENV and impact on vector susceptibility for DENV. METHODS: The prevalence of MDV in wild mosquitoes in China was investigated using open access sequencing data and PCR detection in Ae. albopictus in Guangzhou. The viral infection rate and titers in MDV-persistent C6/36 cells were evaluated at 12, 24, 48, 72, 96, and 120 h post infection (hpi) by indirect immunofluorescence assay (IFA) and real time quantitative PCR (RT-qPCR). The midgut infection rate (MIR), dissemination rate (DR), and salivary gland infection rate (SGIR) in various tissues of MDV-infected mosquitoes were detected and quantified at 0, 5, 10, and 15 days post infection (dpi) by RT-PCR and RT-qPCR. The chi-square test evaluated dengue virus serotype 2 (DENV-2) and Aedes aegypti densovirus (AaeDV) infection rates and related indices in mosquitoes, while Tukey's LSD and t-tests compared viral titers in C6/36 cells and tissues over time. RESULTS: The results revealed a relatively wide distribution of MDVs in Aedes, Culex, and Anopheles mosquitoes in China and an over 68% positive rate. In vitro, significant reductions in DENV-2 titers in supernatant at 120 hpi, and an apparent decrease in DENV-2-positive cells at 96 and 120 hpi were observed. In vivo, DENV-2 in the ovaries and salivary glands was first detected at 10 dpi in both monoinfected and superinfected Ae. albopictus females, while MDV superinfection with DENV-2 suppressed the salivary gland infection rate at 15 dpi. DENV-2 titer in the ovary and salivary glands of Ae. albopictus was reduced in superinfected mosquitoes at 15 dpi. CONCLUSIONS: MDVs is widespread in natural mosquito populations, and replication of DENV-2 is suppressed in MDV-infected Ae. albopictus, thus reducing vector susceptibility to DENV-2. Our study supports the hypothesis that MDVs may contribute to reducing transmission of DENV and provides an alternative strategy for mosquito-transmitted disease control.

A triple fusion tissue-type plasminogen activator (TriF-ΔtPA) enhanced thrombolysis in carotid embolism-induced stroke model.

Recombinant tissue-type plasminogen activator (rtPA, or Alteplase) is the first approved thrombolytic drug for acute ischemic stroke, but suffers from a short half-life and poor resistance to plasminogen activator inhibitor (PAI-1), limiting its clinical use. The development of novel thrombolytic agents with improved benefit/risk balance has always been of great significance. In this study, we identified a mutant of serine protease domain of tPA (named ΔtPAA146V) capable of escaping the inhibition by endogenous PAI-1 with 66-fold increased resistance compared to the wild type tPA. Based on this mutant, we generated a triple fusion ΔtPA (TriF-ΔtPA) containing albumin and fibrin binding peptide(FBP). The fusion with albumin effectively prolonged the plasma half-life of ΔtPA in mice to 144 min, which is much longer than ΔtPA and did not affect its thrombolytic activity. Furthermore, FBP rendered fibrin specificity of the fusion protein, giving a dissociation constant of âˆ¼ 25 ± 0.9 µM. In a novel murine carotid embolism-induced stroke (CES) model, i.v. administration of TriF-ΔtPA promoted vascular recanalization, reduced infarct volume, and mitigated neurobehavioral deficits more significantly compared to ΔtPA-HSA or Alteplase, showing little bleeding risk. Together, this long-acting PAI-1-resistant thrombolytic agent holds great potential for clinical applications.