Brain region-specific roles of brain-derived neurotrophic factor in social stress-induced depressive-like behavior.

Brain-derived neurotrophic factor is a key factor in stress adaptation and avoidance of a social stress behavioral response. Recent studies have shown that brain-derived neurotrophic factor expression in stressed mice is brain region-specific, particularly involving the corticolimbic system, including the ventral tegmental area, nucleus accumbens, prefrontal cortex, amygdala, and hippocampus. Determining how brain-derived neurotrophic factor participates in stress processing in different brain regions will deepen our understanding of social stress psychopathology. In this review, we discuss the expression and regulation of brain-derived neurotrophic factor in stress-sensitive brain regions closely related to the pathophysiology of depression. We focused on associated molecular pathways and neural circuits, with special attention to the brain-derived neurotrophic factor-tropomyosin receptor kinase B signaling pathway and the ventral tegmental area-nucleus accumbens dopamine circuit. We determined that stress-induced alterations in brain-derived neurotrophic factor levels are likely related to the nature, severity, and duration of stress, especially in the above-mentioned brain regions of the corticolimbic system. Therefore, BDNF might be a biological indicator regulating stress-related processes in various brain regions.

GnRH antagonist impairs the process of embryo implantation by inhibiting motility of endometrial stromal cells through reducing c-kit expression.

BACKGROUND: It has been recognized that the gonadotropin-releasing hormone antagonist (GnRH-ant) protocol has a detrimental effect on clinical outcomes compared to the GnRH agonist (GnRH-a) protocol during in vitro fertilization-fresh embryo transfer (IVF-ET) cycles. However, the related mechanisms were unclear. METHODS: A total of 18,561 patients, who underwent fresh IVF-ET cycles in the Center for Assisted Reproduction of Jiangxi Maternal and Child Health Hospital from January 2014 to September 2021, were retrospectively analyzed. The propensity score matching (PSM) technique was used to control for confounding factors between the GnRH-ant and GnRH-a groups. Human endometrial stromal cells (hESCs) were collected for primary culture and treated with relevant receptor antagonists and activators. RT-PCR, Western Blot, immunofluorescence staining, cell migration and adhesion assays, and animal experiments were employed to elucidate the molecular mechanism by which GnRH antagonist affects the migration and adhesion ability of hESCs. RESULTS: There was no statistical difference between the two groups in terms of baseline characteristics after matching basal status by propensity score matching. The result showed that the endometrial thickness (10.4 ± 2.35 vs. 11.03 ± 2.61 mm, p < .001) on trigger day was significantly lower in the GnRH-ant group. Compared with the GnRH-a protocol, the implantation rate (39.71% vs. 50.36%, p < .001), biochemical pregnancy rate (64.26% vs. 72.7%, p < .001), clinical pregnancy rate (56.39% vs. 65.24%, p < .001), live birth rate (45.25% vs. 56.1%, p < .001) in the GnRH-ant group were significantly decreased. Contrarily, the rate of early miscarriage in the GnRH-ant group (13.95% vs. 9.04%, p < .001) was higher than in the GnRH-a group. Furthermore, after treating with GnRH-ant, hESCs showed a reduced expression of HOXA10 and MMP-9 proteins, and a weakened migration ability. Subsequently, by establishing the co-culture system of hESCs and JAR trophoblast spheroids, we found that GnRH-ant inhibited the adhesion and invasion ability of trophoblast cells. Moreover, we also found a decreased expression and phosphorylation of c-kit receptor in decidualized hESCs after treating with GnRH-ant. Similar results as observed above were also confirmed when inhibiting the activation of c-kit receptor by imatinib. CONCLUSIONS: GnRH-ant could reduce the motility of hESCs by inhibiting the expression and activation of the C-kit receptor, which impaired the process of embryo implantation.

Pueraria Extract Ameliorates Alcoholic Liver Disease via the Liver-Gut-Brain Axis: Focus on Restoring the Intestinal Barrier and Inhibiting Alcohol Metabolism.

Alcoholic liver disease (ALD) is one of the causes of hepatocellular carcinoma, accompanied by intestinal leakage and microbial changes. Pueraria has protective effects on liver injury. The aim of this study was to investigate the mechanism of pueraria in the treatment of ALD. UPLC-Q/TOF-MS was used to analyze the composition of the pueraria extract (PUE). Acute and chronic ALD models were established to evaluate the antialcoholic and hepatoprotective effects of PUE. As a result, PUE treatment reduced the serum levels of ALT, AST, TC, and TG and inflammatory factors and alleviated liver inflammation and drunk state. PUE decreased the gene expression of ADH1 and the serum level of acetaldehyde (ACH) to inhibit the generation of ACH from ethanol metabolism, increased the gene level of ALDH2 to accelerate the decomposition of ACH, and thereby alleviated liver inflammation and intestinal barrier damage. Meanwhile, 16 S rDNA revealed that PUE altered the microbiota composition, reduced the amount of Proteobacteria and Desulfobacterota, and thus inhibited the generation of lipopolysaccharide and its downstream-like TLR4/MyD88/NF-κB pathway. PUE also increased the abundance of Bacteroides, Ruminococcus, and Prevotella and producted short-chain fatty acids to protect the intestinal wall. Treatment with fecal microbiota transplantation further confirmed that PUE gut microbiota dependently alleviated ALD. Therefore, PUE regulated gut microbiota and inhibited ethanol metabolism to alleviate ALD through the liver-gut-brain axis. It has good prospects in the future.

Dronedarone hydrochloride inhibits gastric cancer proliferation in vitro and in vivo by targeting SRC.

BACKGROUND: Gastric cancer (GC) is a significant global concern, ranking as the fifth most prevalent cancer. Unfortunately, the five-year survival rate is less than 30 %. Additionally, approximately 50 % of patients experience a recurrence or metastasis. As a result, finding new drugs to prevent relapse is of utmost importance. METHODS: The inhibitory effect of Dronedarone hydrochloride (DH) on gastric cancer cells was examined using proliferation assays and anchorage-dependent assays. The binding of DH with SRC was detected by molecular docking, pull-down assays, and cellular thermal shift assays (CETSA). DH's inhibition of Src kinase activity was confirmed through in vitro kinase assays. The SRC knockout cells, established using the CRISPR-Cas9 system, were used to verify Src's role in GC cell proliferation. Patient-derived xenograft (PDX) models were employed to elucidate that DH suppressed tumor growth in vivo. RESULTS: Our research discovered DH inhibited GC cell proliferation in vitro and in vivo. DH bound to the SRC protein to inhibit the SRC/AKT1 signaling pathway in gastric cancer. Additionally, we observed a decrease in the sensitivity of gastric cancer cells to DH upon down-regulation of SRC. Notably, we demonstrated DH's anti-tumor effects were similar to those of Dasatinib, a well-known SRC inhibitor, in GC patient-derived xenograft models. CONCLUSION: Our research has revealed that Dronedarone hydrochloride, an FDA-approved drug, is an SRC inhibitor that can suppress the growth of GC cells by blocking the SRC/AKT1 signaling pathway. It provides a scientific basis for use in the clinical treatment of GC.

High-resolution and programmable RNA-IN and RNA-OUT genetic circuit in living mammalian cells.

RNAs and their encoded proteins intricately regulate diverse cell types and states within the human body. Dysregulated RNA expressions or mutations can lead to various diseased cell states, including tumorigenesis. Detecting and manipulating these endogenous RNAs offers significant promise for restoring healthy cell states and targeting tumors both in research and clinical contexts. This study presents an RNA-IN and RNA-OUT genetic circuit capable dynamically sensing and manipulating any RNA target in a programmable manner. The RNA-IN module employes a programmable CRISPR-associated protease (CASP) complex for RNA detection, while the RNA-OUT module utilizes an engineered protease-responsive dCas9-VPR activator. Additionally, the CASP module can detect point mutations by harnessing an uncovered dual-nucleotide synergistic switching effect within the CASP complex, resulting in the amplification of point-mutation signals from initially undetectable levels (1.5-fold) to a remarkable 94-fold. We successfully showcase the circuit's ability to rewire endogenous RNA-IN signals to activate endogenous progesterone biosynthesis pathway, dynamically monitor adipogenic differentiation of mesenchymal stem cells (MSCs) and the epithelial-to-mesenchmal trans-differentiation, as well as selective killing of tumor cells. The programmable RNA-IN and RNA-OUT circuit exhibits tremendous potential for applications in gene therapy, biosensing and design of synthetic regulatory networks.

Silencing of maternally expressed RNAs in Dlk1-Dio3 domain causes fatal vascular injury in the fetal liver.

The mammalian imprinted Dlk1-Dio3 domain contains multiple lncRNAs, mRNAs, the largest miRNA cluster in the genome and four differentially methylated regions (DMRs), and deletion of maternally expressed RNA within this locus results in embryonic lethality, but the mechanism by which this occurs is not clear. Here, we optimized the model of maternally expressed RNAs transcription termination in the domain and found that the cause of embryonic death was apoptosis in the embryo, particularly in the liver. We generated a mouse model of maternally expressed RNAs silencing in the Dlk1-Dio3 domain by inserting a 3 × polyA termination sequence into the Gtl2 locus. By analyzing RNA-seq data of mouse embryos combined with histological analysis, we found that silencing of maternally expressed RNAs in the domain activated apoptosis, causing vascular rupture of the fetal liver, resulting in hemorrhage and injury. Mechanistically, termination of Gtl2 transcription results in the silencing of maternally expressed RNAs and activation of paternally expressed genes in the interval, and it is the gene itself rather than the IG-DMR and Gtl2-DMR that causes the aforementioned phenotypes. In conclusion, these findings illuminate a novel mechanism by which the silencing of maternally expressed RNAs within Dlk1-Dio3 domain leads to hepatic hemorrhage and embryonic death through the activation of apoptosis.

Enhanced endoplasmic reticulum stress signaling disrupts porcine sertoli cell function in response to Bisphenol A exposure.

Bisphenol A (BPA), a pervasive substance in our daily lives and livestock excreta, poses significant threats due to its infiltration into foods and water sources. BPA has adverse impacts on male reproductive function, particularly affecting the critical Sertoli (ST) cells that play a pivotal role in the process of spermatogonia differentiating into spermatozoa. In this study, we examined the prevalence of BPA within the pig industry and delved into the impact of BPA exposure on the motility of boar sperm, the function of pig ST cells, as well as the underlying molecular mechanisms involved. This study revealed spatial disparities in the global distribution of BPA and its analogue contamination, utilizing data compiled from 130 comprehensive studies. The average concentration of BPA found in pig feed ranges from 9.7 to 47.9 µg/kg, while in serum, it averages between 55.1 and 75.6 ng/L. The BPA concentration in feed exhibits a negative correlation with sperm viability and the percentage of progressive motile spermatozoa. Exposure to BPA reduced sperm motility in boar and ST cell activity at both 6 and 24 h. The transcriptome analysis revealed that, compared to untreated control cells, endoplasmic reticulum stress (ERS)-related genes were upregulated in ST cells exposed to BPA at 6 and 24 h. This activation of ERS in ST cells was mediated by receptor protein kinase RNA-like endoplasmic reticulum kinase (PERK), inositol-requiring protein-1α (IRE1α), and activating transcription factor 6 (ATF6). Additionally, BPA exposure triggered oxidative stress and a proinflammatory response mediated by the transcription factor NF-κB, accompanied by an increase in downstream proinflammatory cytokines. BPA exposure also led to apoptosis in ST cells and upregulated the expression levels of pro-apoptosis proteins. However, inhibiting ERS activity with 4-PBA attenuated the BPA-induced inflammatory response and apoptosis in ST cells. Our findings suggest that BPA induced apoptosis and inflammatory response in porcine ST cells through persistent activation of ERS, thereby compromising the normal function of these cells.

Factors associated with dysfunction of autogenous arteriovenous fistula in patients with secondary hyperparathyroidism after parathyroidectomy.

BACKGROUND: Secondary hyperparathyroidism (SHPT) is a prevalent chronic complication in patients undergoing hemodialysis. Parathyroidectomy (PTX) is crucial for reducing mortality and improving the prognosis in the treatment of refractory hyperparathyroidism. However, it is often associated with a number of postoperative complications such as postoperative hypotension, hyperkalemia, and hungry bone syndrome. A previous study demonstrated that low blood pressure influences the patency of autogenous arteriovenous fistulas (AVF). Few studies have examined AVF dysfunction following PTX. This study aimed to identify and describe the risk variables associated with AVF dysfunction after PTX. METHODS: Cases of AVF dysfunction after PTX between 2015 and 2021 were studied. Four controls were identified for each patient and were matched for sex and age. Biochemical parameters and blood pressure of the patients before and after PTX were recorded. Risk factors for AVF dysfunction after PTX were identified using conditional logistic regression analysis. RESULTS: Sixteen patients and 64 controls were included in this study. Baseline demographic and laboratory data were compared. Patients in the AVF dysfunction group had lower levels of postoperative calcium than the controls. After surgery, calcium levels decreased more in patients with AVF dysfunction than in the control group. The decrease in systolic blood pressure (ΔSBP) after PTX was greater in the AVF dysfunction group than that in the control group. For each 1 mmHg increment in ΔSBP, the risk of AVF dysfunction after surgery increased by 11.6% (OR = 1.116, 95% CI, 1.005-1.239, p = .040). The likelihood of developing AVF dysfunction after surgery was twelvefold higher in diabetic patients than in non-diabetic patients (OR = 12.506, 95% CI, 1.113-140.492, p = .041). Among patients with ΔSBP > 5.8 mmHg after PTX, the AVF failure rate was significantly greater in patients with diabetes than in those without diabetes. Patients with a history of AVF failure had a nine-fold higher risk of developing AVF dysfunction (OR = 9.143, 95% CI, 1.151-72.627, p = .036). Serum albumin, hemoglobin, ΔiPTH, and age were not independent predictors of AVF dysfunction. The cutoff value for SBP was 5.8 mmHg, as determined by the Youden index of the receiver operating characteristic curve. CONCLUSION: Decreased systolic blood pressure (ΔSBP) after PTX, diabetes, and AVF failure history were risk factors for AVF dysfunction following PTX in patients with SHPT. Diabetes patients with ΔSBP > 5.8 mmHg were more prone to AVF dysfunction after PTX.

ELAVL1 regulates glycolysis in nasopharyngeal carcinoma cells through the HMGB3/ß-catenin axis.

BACKGROUND: The role of ELAVL1 in the progression of various tumors has been demonstrated. Our research aims to investigate how ELAVL1 controls the glycolytic process in nasopharyngeal carcinoma cells through the HMGB3/ß-catenin pathway. METHODS: The expression of ELAVL1 was detected in clinical tumor samples and nasopharyngeal carcinoma cell lines. A subcutaneous tumor model was established in nude mice to investigate the role of ELAVL1 in tumor progression. The relationship between HMGB3 and ELAVL1 was validated by RNA pull down and RIP assays. TOPFlash/FOPFlash reporter assay was used to detect ß-catenin activity. Assay kits were utilized to measure glucose consumption, lactate production, and G6PD activity in nasopharyngeal carcinoma cells. Western blot was conducted to detect the expression of glycolysis-related proteins. The glycolytic capacity was analyzed through extracellular acidification rate (ECAR). RESULTS: In both clinical samples and nasopharyngeal carcinoma cell lines, the expression levels of ELAVL1 mRNA and protein were found to be upregulated. Knockdown of ELAVL1 significantly inhibited the in vivo proliferation of nasopharyngeal carcinoma and suppressed the glycolytic capacity of nasopharyngeal carcinoma cells. ELAVL1 interacts with HMGB3, leading to an increase in the stability of HMGB3 mRNA. Overexpression of HMGB3 elevated the reduced ß-catenin activity caused by sh-ELAVL1 and reversed the inhibitory effect of sh-ELAVL1 on cellular glycolytic capacity. Treatment with ß-catenin inhibitor (FH535) effectively suppressed the promotion of glycolytic capacity induced by HMGB3 overexpression. CONCLUSIONS: ELAVL1 promotes glycolysis in nasopharyngeal carcinoma cells by interacting with HMGB3 to stabilize HMGB3 mRNA, thereby activating ß-catenin pathway. Therefore, targeting the ELAVL1-HMGB3-ß-catenin axis has the potential to be a novel approach for treating nasopharyngeal carcinoma.

Metabolic engineering of Halomonas bluephagenesis for the production of ethylene glycol and glycolate from xylose.

Halophilic Halomonas bluephagenesis, a natural producer of poly-3-hydroxybutyrate (PHB), was metabolically engineered to synthesize ethylene glycol and glycolate from xylose. Xylose utilization was achieved by overexpressing either the xylonate pathway or the ribulose-1-phosphate pathway. The key genes encoding for xylonate dehydratase and 2-keto-3-deoxy-xylonate aldolase in the xylonate pathway were screened. With further overexpressing aldehyde reductase gene yjgB, ethylene glycol accumulation was improved to 0.91 g/L, accompanied with 1.48 g/L of PHB accumulation. The disruption of native glycolate oxidase was found to be essential for glycolate production, and the defective recombinant strain produced 0.80 g/L glycolate with 1.14 g/L PHB in shake flask cultures. These results indicated that H. bluephagenesis has the potential to produce diverse metabolic chemicals from xylose.

Modification of gut and airway microbiota on ozone-induced airway inflammation.

Ground-level ozone (O3) has been shown to induce airway inflammation, the underlying mechanisms remain unclear. The aim of this study was to determine whether gut and airway microbiota dysbiosis, and airway metabolic alterations were associated with O3-induced airway inflammation. Thirty-six 8-week-old male C57BL/6 N mice were divided into 2 groups: sterile water group and broad-spectrum antibiotics group (Abx). Each group was further divided into two subgroups, filtered air group (Air) and O3 group (O3), with 9 mice in each subgroup. Mice in the Air and O3 groups were exposed to filtered air or 1 ppm O3, 4 h/d for 5 consecutive days, respectively. Mice in Abx + Air and Abx + O3 groups were exposed to filtered air or O3, respectively, after drinking broad-spectrum Abx. 24 h after the final O3 exposure, mouse feces and bronchoalveolar lavage fluids (BALF) were collected and subjected to measurements of airway oxidative stress and inflammation biomarkers, 16S rRNA sequencing and metabolite profiling. Hematoxylin-eosin staining of lung tissues was applied to examine the pathological changes of lung tissue. The results showed that O3 exposure resulted in airway oxidative stress and inflammation, as well as gut and airway microbiota dysbiosis, and airway metabolism alteration. Abx pre-treatment markedly changed gut and airway microbiota and promoted O3-induced metabolic disorder and airway inflammation. Spearman correlation analyses indicated that inter-related gut and airway microbiota dysbiosis and airway metabolic disorder were associated with O3-induced airway inflammation. Together, inhaled O3 causes airway inflammation, which may implicate gut and airway microbiota dysbiosis and airway metabolic alterations.

Field-Free Superconducting Diode Effect and Magnetochiral Anisotropy in FeTe0.7Se0.3 Junctions with the Inherent Asymmetric Barrier.

Nonreciprocal electrical transport, characterized by an asymmetric relationship between the current and voltage, plays a crucial role in modern electronic industries. Recent studies have extended this phenomenon to superconductors, introducing the concept of the superconducting diode effect (SDE). The SDE is characterized by unequal critical supercurrents along opposite directions. Due to the requirement on broken inversion symmetry, the SDE is commonly accompanied by electrical magnetochiral anisotropy (eMCA) in the resistive state. Achieving a magnetic-field-free SDE with field tunability is pivotal for advancements in superconductor devices. Conventionally, field-free SDE has been achieved in Josephson junctions by intentionally intercalating an asymmetric barrier layer. Alternatively, internal magnetism was employed. Both approaches pose challenges in the selection of superconductors and fabrication processes, thereby impeding the development of SDE. Here, we present a field-free SDE in FeTe0.7Se0.3 (FTS) junction with eMCA, a phenomenon absent in FTS single nanosheets. The field-free property is associated with the presence of a gradient oxide layer on the upper surface of each FTS nanosheet, while eMCA is linked to spin splitting arising from the absence of inversion symmetry. Both SDE and eMCA respond to magnetic fields with distinct temperature dependencies. This work presents a versatile and straightforward strategy for advancing superconducting electronics.

GRHL2 regulates keratinocyte EMT-MET dynamics and scar formation during cutaneous wound healing.

After cutaneous wounds successfully heal, keratinocytes that underwent the epithelial-mesenchymal transition (EMT) regain their epithelial characteristics, while in scar tissue, epidermal cells persist in a mesenchymal state. However, the regulatory mechanisms governing this reversion are poorly understood, and the impact of persistent mesenchymal-like epidermal cells in scar tissue remains unclear. In the present study, we found that during wound healing, the regulatory factor GRHL2 is highly expressed in normal epidermal cells, downregulated in EMT epidermal cells, and upregulated again during the process of mesenchymal-epithelial transition (MET). We further demonstrated that interfering with GRHL2 expression in epidermal cells can effectively induce the EMT. Conversely, the overexpression of GRHL2 in EMT epidermal cells resulted in partial reversion of the EMT to an epithelial state. To investigate the effects of failed MET in epidermal cells on skin wound healing, we interfered with GRHL2 expression in epidermal cells surrounding the cutaneous wound. The results demonstrated that the persistence of epidermal cells in the mesenchymal state promoted fibrosis in scar tissue, manifested by increased thickness of scar tissue, deposition of collagen and fibronectin, as well as the activation of myofibroblasts. Furthermore, the miR-200s/Zeb1 axis was perturbed in GRHL2 knockdown keratinocytes, and transfection with miR-200s analogs promoted the reversion of EMT in epidermal cells, which indicates that they mediate the EMT process in keratinocytes. These results suggest that restoration of the epithelial state in epidermal cells following the EMT is essential to wound healing, providing potential therapeutic targets for preventing scar formation.

Autocatalytic DNA circuitries.

Autocatalysis, a self-sustained replication process where at least one of the products functions as a catalyst, plays a pivotal role in life's evolution, from genome duplication to the emergence of autocatalytic subnetworks in cell division and metabolism. Leveraging their programmability, controllability, and rich functionalities, DNA molecules have become a cornerstone for engineering autocatalytic circuits, driving diverse technological applications. In this tutorial review, we offer a comprehensive survey of recent advances in engineering autocatalytic DNA circuits and their practical implementations. We delve into the fundamental principles underlying the construction of these circuits, highlighting their reliance on DNAzyme biocatalysis, enzymatic catalysis, and dynamic hybridization assembly. The discussed autocatalytic DNA circuitry techniques have revolutionized ultrasensitive sensing of biologically significant molecules, encompassing genomic DNAs, RNAs, viruses, and proteins. Furthermore, the amplicons produced by these circuits serve as building blocks for higher-order DNA nanostructures, facilitating biomimetic behaviors such as high-performance intracellular bioimaging and precise algorithmic assembly. We summarize these applications and extensively address the current challenges, potential solutions, and future trajectories of autocatalytic DNA circuits. This review promises novel insights into the advancement and practical utilization of autocatalytic DNA circuits across bioanalysis, biomedicine, and biomimetics.

Mesoporous Silica Supported Hydrophilic Ionic Liquid Gel Microspheres for Solvent-Free Deep Oxidative Desulfurization.

Solvent-free oxidative desulfurization can avoid environmental pollution caused by organic solvents as well as prevent loss of fuel during the oil-water separation process. In this work, first, hydrophilic ionic liquid gel microspheres with [BMIM]BF4 and PHEMA as the dispersion medium and gel network, respectively, were successfully prepared by using mesoporous silica microspheres as a supporting skeleton capable of stabilizing the gel through an anchoring effect, and then the catalyst [BMIM]PW and oxidant H2O2 were incorporated into the gel microspheres to construct a liquid compartment microreactor for deep desulfurization. The prepared microreactor (SiO2@[BMIM]PW/ILG-microspheres) has excellent extraction-catalytic capacity and exhibited ∼100% desulfurization ratio for a model oil of n-heptane with 500 ppm of DBT at 60 °C for 3 h without solvents. Additionally, the prepared microreactor can absorb hydrophilic desulfurization products after the reaction and has advantages of reusability and simple recovery without polluting the fuel oil, which is beneficial for potential petroleum industrial application.

A novel inactivated oral rabies vaccine with the incorporation of U-OMP19 enhances the immunogenicity by reducing viral proteins degradation and activating dendritic cells in a mouse model.

Currently, dogs, especially stray dogs, and/or wild animals are the main sources of rabies transmission, and oral vaccination is the most practical way to control rabies in these animals. Safety and efficacy are two key criteria for developing oral vaccines. Concerning the efficacy of oral vaccines, degradation of immunogens by gastrointestinal fluid is a major challenge, resulting in suboptimal immune responses after vaccination. For safety reasons, inactivated vaccines are the most optimal choice. In the present study, a recombinant rabies virus (RABV) with un-lipidated outer membrane protein 19 (U-OMP19) of Brucella spp incorporated into RABV virions, designated as LBNSE-OMP19-G, was constructed and rescued. We found that U-OMP19 was incorporated into LBNSE-OMP19-G virion, which could protect RABV G protein from digestion by gastrointestinal fluids in vitro. Moreover, the immunogenicity of LBNSE-OMP19-G as an inactivated oral vaccine was evaluated, and the inactivated LBNSE-OMP19-G could activate more dendritic cells (DCs) and promote the generation of follicular helper T (TFH) cells, germinal center (GC) B cells, and plasma cells in immunized mice compared with those in mice immunized with parent virus LNBSE, which consequently induced a higher level of virus neutralizing antibody and provided better protection after a lethal challenge of rabies. These data indicate that LBNSE-OMP19-G, which has good safety and immunogenicity, could be a potential inactivated oral rabies vaccine candidate.

Dissecting neural correlates of theory of mind and executive functions in behavioral variant frontotemporal dementia.

Behavioral variant frontotemporal dementia (bvFTD) is characterized by profound and early deficits in social cognition (SC) and executive functions (EF). To date it remains unclear whether deficits of the respective cognitive domains are based on the degeneration of distinct brain regions. In 103 patients with a diagnosis of bvFTD (possible/probable/definite: N = 40/58/5) from the frontotemporal lobar degeneration (FTLD) consortium Germany cohort (age 62.5±9.4 years, gender 38 female/65 male) we applied multimodal structural imaging, i.e. voxel-based morphometry, cortical thickness (CTH) and networks of structural covariance via source based morphometry. We cross-sectionally investigated associations with performance in a modified Reading the Mind in the Eyes Test (RMET; reflective of theory of mind - ToM) and five different tests reflective of EF (i.e. Hamasch-Five-Point Test, semantic and phonemic Fluency, Trail Making Test, Stroop interference). Finally, we investigated the conjunction of RMET correlates with functional networks commonly associated with SC respectively ToM and EF as extracted meta-analytically within the Neurosynth database. RMET performance was mainly associated with gray matter volume (GMV) and CTH within temporal and insular cortical regions and less within the prefrontal cortex (PFC), whereas EF performance was mainly associated with prefrontal regions (GMV and CTH). Overlap of RMET and EF associations was primarily located within the insula, adjacent subcortical structures (i.e. putamen) and the dorsolateral PFC (dlPFC). These patterns were more pronounced after adjustment for the respective other cognitive domain. Corroborative results were obtained in analyses of structural covariance networks. Overlap of RMET with meta-analytically extracted functional networks commonly associated with SC, ToM and EF was again primarily located within the temporal and insular region and the dlPFC. In addition, on a meta-analytical level, strong associations were found for temporal cortical RMET correlates with SC and ToM in particular. These data indicate a temporo-frontal dissociation of bvFTD related disturbances of ToM and EF, with atrophy of the anterior temporal lobe being critically involved in ToM deficits. The consistent overlap within the insular cortex may be attributable to the multimodal and integrative role of this region in socioemotional and cognitive processing.

Body Mass Index and Postacute Sequelae of SARS-CoV-2 Infection in Children and Young Adults.

Importance: Obesity is associated with increased severity of COVID-19. Whether obesity is associated with an increased risk of post-acute sequelae of SARS-CoV-2 infection (PASC) among pediatric populations, independent of its association with acute infection severity, is unclear. Objective: To quantify the association of body mass index (BMI) status before SARS-CoV-2 infection with pediatric PASC risk, controlling for acute infection severity. Design, Setting, and Participants: This retrospective cohort study occurred at 26 US children's hospitals from March 2020 to May 2023 with a minimum follow-up of 179 days. Eligible participants included children and young adults aged 5 to 20 years with SARS-CoV-2 infection. Data analysis was conducted from October 2023 to January 2024. Exposures: BMI status assessed within 18 months before infection; the measure closest to the index date was selected. The BMI categories included healthy weight (≥5th to <85th percentile for those aged 5-19 years or ≥18.5 to <25 for those aged >19 years), overweight (≥85th to <95th percentile for those aged 5-19 years or ≥25 to <30 for for those aged >19 years), obesity (≥95th percentile to <120% of the 95th percentile for for those aged 5-19 years or ≥30 to <40 for those aged >19 years), and severe obesity (≥120% of the 95th percentile for those aged 5-19 years or ≥40 for those aged >19 years). Main Outcomes And Measures: To identify PASC, a diagnostic code specific for post-COVID-19 conditions was used and a second approach used clusters of symptoms and conditions that constitute the PASC phenotype. Relative risk (RR) for the association of BMI with PASC was quantified by Poisson regression models, adjusting for sociodemographic, acute COVID severity, and other clinical factors. Results: A total of 172 136 participants (mean [SD] age at BMI assessment 12.6 [4.4] years; mean [SD] age at cohort entry, 13.1 [4.4] years; 90 187 female [52.4%]) were included. Compared with participants with healthy weight, those with obesity had a 25.4% increased risk of PASC (RR, 1.25; 95% CI, 1.06-1.48) and those with severe obesity had a 42.1% increased risk of PASC (RR, 1.42; 95% CI, 1.25-1.61) when identified using the diagnostic code. Compared with those with healthy weight, there was an increased risk for any occurrences of PASC symptoms and conditions among those with obesity (RR, 1.11; 95% CI, 1.06-1.15) and severe obesity (RR, 1.17; 95% CI, 1.14-1.21), and the association held when assessing total incident occurrences among those with overweight (RR, 1.05; 95% CI, 1.00-1.11), obesity (RR, 1.13; 95% CI, 1.09-1.19), and severe obesity (RR, 1.18; 95% CI, 1.14-1.22). Conclusions And Relevance: In this cohort study, elevated BMI was associated with a significantly increased PASC risk in a dose-dependent manner, highlighting the need for targeted care to prevent chronic conditions in at-risk children and young adults.