Phased genome assemblies reveal haplotype-specific genetic load in the critically endangered Chinese Bahaba (Teleostei, Sciaenidae).

While haplotype-specific genetic load shapes the evolutionary trajectory of natural and captive populations, mixed-haplotype assembly and genotyping hindered its characterization in diploids. Herein, we produced two phased genome assemblies of the critically endangered fish Chinese Bahaba (Bahaba taipingensis, Sciaenidae, Teleostei) and resequenced 20 whole genomes to quantify population genetic load at a haplotype level. We identified frame-shifting variants as the most deleterious type, followed by mutations in the 5'-UTR, 3'-UTR and missense mutations at conserved amino acids. Phased haplotypes revealed gene deletions and high-impact deleterious variants. We estimated ~1.12% of genes missing or interrupted per haplotype, with a significant overlap of disrupted genes (30.35%) between haplotype sets. Relative proportions of deleterious variant categories differed significantly between haplotypes. Simulations suggested that purifying selection struggled to purge slightly deleterious genetic load in captive breeding compared to genotyping interventions, and that higher inter-haplotypic variance of genetic load predicted more efficient purging by artificial selection. Combining the knowledge of haplotype-resolved genetic load with predictive modelling will be immensely useful for understanding the evolution of deleterious variants and guiding conservation planning.

Establishment of a hydrodynamic delivery system in ducks.

Chronic hepatitis B virus (HBV) poses a significant global health challenge as it can lead to acute or chronic liver disease and hepatocellular carcinoma (HCC). To establish a safety experimental model, a homolog of HBV-duck HBV (DHBV) is often used for HBV research. Hydrodynamic-based gene delivery (HGD) is an efficient method to introduce exogenous genes into the liver, making it suitable for basic research. In this study, a duck HGD system was first constructed by injecting the reporter plasmid pLIVE-SEAP via the ankle vein. The highest expression of SEAP occurred when ducks were injected with 5 µg/mL plasmid pLIVE-SEAP in 10% bodyweight volume of physiological saline for 6 s. To verify the distribution and expression of exogenous genes in multiple tissues, the relative level of foreign gene DNA and ß-galactosidase staining of LacZ were evaluated, which showed the plasmids and their products were located mainly in the liver. Additionally, ß-galactosidase staining and fluorescence imaging indicated the delivered exogenous genes could be expressed in a short time. Further, the application of the duck HGD model on DHBV treatment was investigated by transferring representative anti-HBV genes IFNα and IFNγ into DHBV-infected ducks. Delivery of plasmids expressing IFNα and IFNγ inhibited DHBV infection and we established a novel efficient HGD method in ducks, which could be useful for drug screening of new genes, mRNAs and proteins for anti-HBV treatment.

Brain-wide changes in excitation-inhibition balance of major depressive disorder: a systematic review of topographic patterns of GABA- and glutamatergic alterations.

The excitation-inhibition (E/I) imbalance is an important molecular pathological feature of major depressive disorder (MDD) as altered GABA and glutamate levels have been found in multiple brain regions in patients. Healthy subjects show topographic organization of the E/I balance (EIB) across various brain regions. We here raise the question of whether such EIB topography is altered in MDD. Therefore, we systematically review the gene and protein expressions of inhibitory GABAergic and excitatory glutamatergic signaling-related molecules in postmortem MDD brain studies as proxies for EIB topography. Searches were conducted through PubMed and 45 research articles were finally included. We found: i) brain-wide GABA- and glutamatergic alterations; ii) attenuated GABAergic with enhanced glutamatergic signaling in the cortical-subcortical limbic system; iii) that GABAergic signaling is decreased in regions comprising the default mode network (DMN) while it is increased in lateral prefrontal cortex (LPFC). These together demonstrate abnormal GABA- and glutamatergic signaling-based EIB topographies in MDD. This enhances our pathophysiological understanding of MDD and carries important therapeutic implications for stimulation treatment.

Preparation of a Key Intermediate En Route to the Anti-HIV Drug Lenacapavir.

A very efficient four-step synthesis of the main fragment of Gilead's anti-HIV drug lenacapavir is described. The route showcases a 1,2-addition to an intermediate aldehyde using an organozinc halide derived from a commercially available difluorobenzyl Grignard reagent. This sets the stage for the oxidation of the resulting secondary alcohol to the desired ketone, which relies solely on catalytic amounts of TEMPO together with NaClO as the terminal oxidant, affording the targeted ketone in 67% overall yield.

Enhancing Chemical Reaction Monitoring with a Deep Learning Model for NMR Spectra Image Matching to Target Compounds.

In the synthetic laboratory, researchers typically rely on nuclear magnetic resonance (NMR) spectra to elucidate structures of synthesized products and confirm whether they match the desired target compounds. As chemical synthesis technology evolves toward intelligence and continuity, efficient computer-assisted structure elucidation (CASE) techniques are required to replace time-consuming manual analysis and provide the necessary speed. However, current CASE methods typically aim to derive precise chemical structures from spectroscopic data, yet they suffer from drawbacks such as low accuracy, high computational cost, and reliance on chemical libraries. In meticulously designed chemical synthesis reactions, researchers prioritize confirming the attainment of the target product based on NMR spectra, rather than focusing on identifying the specific product obtained. For this purpose, we innovatively developed a binary classification model, termed as MatCS, to directly predict the relationship between NMR spectra image (including 1H NMR and 13C NMR) and the molecular structure of the target compound. After evaluating various feature extraction methods, MatCS employs a combination of the Graph Attention Networks and Graph Convolutional Networks to learn the structural features of molecular graphs and the pretrained ResNet101 network with a Convolutional Block Attention Module to extract features from NMR spectra images. The results show that on a challenging Testsim data set, which poses difficulty in distinguishing spectra of similar molecular structures, MatCS achieves comprehensive evaluation metrics with an F1-score of 0.81 and an AUC value of 0.87. Simultaneously, it exhibited commendable performance on an external SDBS data set containing experimental NMR spectra, showcasing substantial potential for structural verification tasks in real automated chemical synthesis.

Effects of Aerobic Exercise on Executive and Memory Functions in Patients With Alzheimer's Disease: A Systematic Review.

BACKGROUND: Alzheimer's disease threatens the health of older adults, particularly by disrupting executive and memory functions, and many studies have shown that aerobic exercise prevents and improves the symptoms associated with the disease. OBJECTIVE: The objective was to systematically review the effects of aerobic exercise on executive and memory functions in patients with Alzheimer's disease and to determine the effect factors and mechanisms of the design of aerobic exercise intervention programs. METHOD: Relevant literature was searched in three databases (PubMed, Web of Science, and EBSCO) from January 1, 2014 to March 1, 2023, using a subject-word search method. Data on 10 items, including author and country, were extracted from the literature after screening. The quality of the literature was evaluated using the Physiotherapy Evidence Database scale, and a systematic review was performed. RESULTS: Twelve papers from seven countries were ultimately included, embodying 11 randomized controlled trials and one study with a repeated-measures design. The overall quality of the studies was good as 657 study participants, aged 45 years and older who had varying degrees of Alzheimer's disease and significant symptoms, were included. Aerobic exercise was found to have a significant positive impact on executive and memory functions in people with Alzheimer's disease. CONCLUSION: The effects of aerobic exercise on aspects of executive function were mainly characterized by improvements in inhibitory control, working memory, and cognitive flexibility, whereas the effects on aspects of memory function were mainly characterized by improvements in logical memory, situational memory, and short-term memory.

Tetrandrine synergizes with MAPK inhibitors in treating KRAS-mutant pancreatic ductal adenocarcinoma via collaboratively modulating the TRAIL-death receptor axis.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and lethal malignancies lacking effective therapies. KRAS mutations that occur in over 90% of PDAC are major oncogenic drivers of PDAC. The MAPK signaling pathway plays a central role in KRAS-driven oncogenic signaling. However, pharmacological inhibitors of the MAPK pathway are poorly responded in KRAS-mutant PDAC, raising a compelling need to understand the mechanism behind and to seek new therapeutic solutions. Herein, we perform a screen utilizing a library composed of 800 naturally-derived bioactive compounds to identify natural products that are able to sensitize KRAS-mutant PDAC cells to the MAPK inhibition. We discover that tetrandrine, a natural bisbenzylisoquinoline alkaloid, shows a synergistic effect with MAPK inhibitors in PDAC cells and xenograft models. Mechanistically, pharmacological inhibition of the MAPK pathway exhibits a double-edged impact on the TRAIL-death receptor axis, transcriptionally upregulating TRAIL yet downregulating its agonistic receptors DR4 and DR5, which may explain the limited therapeutic outcomes of MAPK inhibitors in KRAS-mutant PDAC. Of great interest, tetrandrine stabilizes DR4/DR5 protein via impairing ubiquitination-mediated protein degradation, thereby allowing a synergy with MAPK inhibition in inducing apoptosis in KRAS-mutant PDAC. Our findings identify a new combinatorial approach for treating KRAS-mutant PDAC and highlight the role of TRAIL-DR4/DR5 axis in dictating the therapeutic outcome in KRAS-mutant PDAC.

Advances of autoimmune rheumatic diseases related to malignant tumors.

BACKGROUND: Malignant neoplasms are a well-recognized global public health concern, with significant impacts on human health and quality of life. The interplay between tumors and autoimmune rheumatic diseases is complex, and the resulting tumor-associated rheumatic diseases represent a rare and intricate group of conditions that occur in the context of malignant tumors. In addition, various rheumatic diseases can arise as a consequence of oncology treatment. These diseases present with intricate clinical manifestations and pathological features, often rendering them challenging to diagnose and impacting patients' quality of life. Despite this, they have yet to be fully recognized. METHODS: This article presents a literature review of published original articles and review articles concerning paraneoplastic rheumatic syndromes and rheumatic diseases associated with cancer treatment. We conducted a comprehensive literature search in PubMed, Web of Science and Google Scholar databases, excluding duplicated and irrelevant studies. In cases of duplicated research, we selected articles with higher impact factors for the review. RESULTS: This review focuses on the clinical features, diagnosis, and treatment of paraneoplastic rheumatic diseases, as well as the pathogenesis of these diseases. Additionally, we summarize the autoimmune rheumatic diseases associated with cancer treatment. Ultimately, the goal of this review is to enhance recognition and improve the management of autoimmune rheumatic diseases related to tumors.

Physical activity interventions for cardiopulmonary fitness in obese children and adolescents: a systematic review and meta-analysis.

PURPOSE: This study [PROSPERO CRD42023416272] systematically analysed the effects of a physical activity intervention on cardiorespiratory fitness in obese children and adolescents and elucidated the factors that influenced those effects. METHODS: A systematic review of the literature on physical activity interventions for improving cardiopulmonary fitness in obese children and adolescents from January 1, 2011, to March 1, 2023, was conducted. The search was performed on the Web of Science and PubMed databases, and the selected literature was first screened and then assessed for quality. Finally, a systematic review was conducted. RESULTS: Out of the initially identified 1424 search records, 28 studies were eventually included in the systematic review. These studies encompassed a total of 2724 participants aged 5 to 18 years, with the publication dates of the literature primarily ranging from 2011 to 2023. Physical activity was found to effectively improve the following parameters in obese children and adolescents: weight [mean difference (MD), -2.03 (95% confidence interval, -2.59 to -1.47), p < 0.00001], maximal oxygen consumption [MD, -1.95 (95% CI, -1.06 to -2.84), p < 0.0001], heart rate [MD, -2.77 (95% CI, -4.88 to -0.67), p = 0.010], systolic blood pressure [MD, -8.11 (95% CI, -11.41 to -4.81), p < 0.00001], and diastolic blood pressure [MD, -4.18 (95% CI, -5.32 to -3.03), p < 0.00001]. High-intensity exercise was found to yield greater improvements than low- to moderate-intensity exercise in maximal oxygen consumption [MD, 1.43 (95% CI, 0.04 to 2.82), p = 0.04] and diastolic blood pressure [MD, -6.94 (95% CI, -10.61 to -3.26), p = 0.0002] in obese children and adolescents. CONCLUSION: Physical activity can effectively improve the body weight, maximal oxygen consumption, heart rate, systolic blood pressure, and diastolic blood pressure of obese children and adolescents. The type of physical activity directly influences the participation interest of obese children and adolescents, with moderate- to high-intensity physical activity showing the most significant impact on intervention outcomes. High-frequency, long-term interventions yield better results than short-term interventions.

Sexually dimorphic age-related molecular differences in the entorhinal cortex of cognitively intact elderly: Relation to early Alzheimer's changes.

INTRODUCTION: Women are more vulnerable to Alzheimer's disease (AD) than men. The entorhinal cortex (EC) is one of the earliest structures affected in AD. We identified in cognitively intact elderly different molecular changes in the EC in relation to age. METHODS: Changes in 12 characteristic molecules in relation to age were determined by quantitative immunohistochemistry or in situ hybridization in the EC. They were arbitrarily grouped into sex steroid-related molecules, markers of neuronal activity, neurotransmitter-related molecules, and cholinergic activity-related molecules. RESULTS: The changes in molecules indicated increasing local estrogenic and neuronal activity accompanied by a higher and faster hyperphosphorylated tau accumulation in women's EC in relation to age, versus a mainly stable local estrogenic/androgenic and neuronal activity in men's EC. DISCUSSION: EC employs a different neurobiological strategy in women and men to maintain cognitive function, which seems to be accompanied by an earlier start of AD in women. HIGHLIGHTS: Local estrogen system is activated with age only in women's entorhinal cortex (EC). EC neuronal activity increased with age only in elderly women with intact cognition. Men and women have different molecular strategies to retain cognition with aging. P-tau accumulation in the EC was higher and faster in cognitively intact elderly women.

Nitrogen repression of deoxynivalenol biosynthesis is mediated by Mep2 ammonium permease in Fusarium graminearum.

Fusarium graminearum is an important wheat pathogen and a producer of deoxynivalenol (DON). Biosynthesis of DON is suppressed by ammonium and induced by arginine and polyamines. To better understand ammonium repression of DON biosynthesis, in this study, we functionally characterized three ammonium permease (MEP) genes in F. graminearum. All the mep deletion mutants were normal in growth on V8 agar. Whereas deletion of MEP1 had no detectable phenotypes, the mep2 and mep3 mutants had defects in hyphal growth under ammonium limiting conditions and infection of wheat heads, with the latter having less severe defects. Deletion of MEP2 but not MEP3 affected nitrogen repression of DON biosynthesis and genes involved in nitrate metabolism. The mep2 mep3 double mutant had more severe defects in nitrogen repression than the mep2 mutant and was defective in ascospore releasing. Mutant alleles of MEP2 with truncated C-terminal cytoplasmic tail (CT) failed to complement the mep2 mutant. Expression of a dominant active allele of RAS2 partially rescued the defects of mep2 in nitrogen repression. Taken together, these results suggest that Mep2 acts as the major sensor of ammonium availability in F. graminearum and its CT region functions in nitrogen repression via RAS2 and downstream signalling pathways.

Overexpression of PDE4D in mouse liver is sufficient to trigger NAFLD and hypertension in a CD36-TGF-ß1 pathway: therapeutic role of roflumilast.

Emerging evidence has shown that nonalcoholic fatty liver disease (NAFLD) may be both a consequence and a cause of hypertension. Recent studies have demonstrated that phosphodiesterase 4 (PDE4)-cAMP signaling represents a pathway relevant to the pathophysiology of metabolic disorders. This study aims to investigate the impact and the underlying mechanism of PDE4 in the pathogenesis of NAFLD and its associated hypertension. Here we demonstrated that high-fat-diet (HFD) fed mice developed NAFLD and hypertension, with an associated increase in hepatic PDE4D expression, which can be prevented and even reversed by PDE4 inhibitor roflumilast. Furthermore, we demonstrated that hepatic overexpression of PDE4D drove significant hepatic steatosis and elevation of blood pressure. Mechanistically, PDE4D activated fatty acid translocase CD36 signaling which facilitates hepatic lipid deposition, resulting in TGF-ß1 production by hepatocytes and excessive TGF-ß1 signaling in vessels and consequent hypertension. Specific silencing of TGF-ß1 in hepatocytes by siRNA using poly (ß-amino ester) nanoparticles significantly normalized hepatic PDE4D overexpression-activated TGF-ß1 signaling in vessels and hypertension. Together, the conclusions indicated that PDE4D plays an important role in the pathogenesis of NAFLD and associated hypertension via activation of CD36-TGF-ß1 signaling in the liver. PDE4 inhibitor such as roflumilast, which is clinically approved for chronic obstructive pulmonary disease (COPD) treatment, has the potential to be used as a preventive or therapeutic drug against NAFLD and associated hypertension in the future.

ppm Pd-Containing Nanoparticles as Catalysts for Negishi Couplings in Water.

New technology is reported that enables Negishi couplings to be run under sustainable, far greener conditions. Thus, ppm Pd-containing nanoparticles (NPs) have been developed that catalyze couplings in recyclable water under very mild conditions. These heterogeneous reactions involve loadings of Pd of typically only 2500 ppm (0.25 mol %). Highly functionalized aromatic and heteroaromatic bromides readily participate, including examples taken from the Merck Informer Library indicative of the functional group tolerance associated with these couplings. Direct comparisons with existing literature routes are made. Very low residual levels of Pd in newly formed products are to be expected, as determined by ICP-MS. The reagent involved has been extensively characterized via DLS, TEM, cryo-TEM, and EDX measurements.

Water-Sculpting of a Heterogeneous Nanoparticle Precatalyst for Mizoroki-Heck Couplings under Aqueous Micellar Catalysis Conditions.

Powdery, spherical nanoparticles (NPs) containing ppm levels of palladium ligated by t-Bu3P, derived from FeCl3, upon simple exposure to water undergo a remarkable alteration in their morphology leading to nanorods that catalyze Mizoroki-Heck (MH) couplings. Such NP alteration is general, shown to occur with three unrelated phosphine ligand-containing NPs. Each catalyst has been studied using X-ray photoelectron spectroscopy (XPS), energy-dispersive X-ray spectroscopy (EDX), transmission electron microscopy (TEM), and cryogenic transmission electron microscopy (cryo-TEM) analyses. Couplings that rely specifically on NPs containing t-Bu3P-ligated Pd occur under aqueous micellar catalysis conditions between room temperature and 45 °C, and show broad substrate scope. Other key features associated with this new technology include low residual Pd in the product, recycling of the aqueous reaction medium, and an associated low E Factor. Synthesis of the precursor to galipinine, a member of the Hancock family of alkaloids, is suggestive of potential industrial applications.

Sex differences in the neuropathological hallmarks of Alzheimer's disease: focus on cognitively intact elderly individuals.

AIMS: Women are more vulnerable to Alzheimer's disease (AD) than men. We investigated (i) whether and at what age the AD hallmarks, that is, ß-amyloid (Aß) and hyperphosphorylated Tau (p-Tau) show sex differences; and (ii) whether such sex differences may occur in cognitively intact elderly individuals. METHODS: We first analysed the entire post-mortem brain collection of all non-demented 'controls' and AD donors from our Brain Bank (245 men and 403 women), for the presence of sex differences in AD hallmarks. Second, we quantitatively studied possible sex differences in Aß, Aß42 and p-Tau in the entorhinal cortex of well-matched female (n = 31) and male (n = 21) clinically cognitively intact elderly individuals. RESULTS: Women had significantly higher Braak stages for tangles and amyloid scores than men, after 80 years. In the cognitively intact elderly, women showed higher levels of p-Tau, but not Aß or Aß42, in the entorhinal cortex than men, and a significant interaction of sex with age was found only for p-Tau but not Aß or Aß42. CONCLUSIONS: Enhanced p-Tau in the entorhinal cortex may play a major role in the vulnerability to AD in women.

Bidirectional planar-displacement waveguide tracker for high-concentration photovoltaics.

A bidirectional planar-displacement waveguide tracker was devised to replace the traditional two-axis tracking system for high-concentration photovoltaics, with improved module thickness, optical field uniformity, and current matching. The concentrating magnification reaches 725 times, and the sun tracking angle is more than 170°, which is equivalent to 11.3 tracking hours per day. The module thickness is only 6.16 cm. This design enabled us to place the module flat on the ground, in which swing was not required. This will greatly improve the mechanical strength and the lifetime of the module and solve the development dilemma faced by III-V multijunction solar cells.

Comprehensive preimplantation genetic testing by massively parallel sequencing.

STUDY QUESTION: Can whole genome sequencing (WGS) offer a relatively cost-effective approach for embryonic genome-wide haplotyping and preimplantation genetic testing (PGT) for monogenic disorders (PGT-M), aneuploidy (PGT-A) and structural rearrangements (PGT-SR)? SUMMARY ANSWER: Reliable genome-wide haplotyping, PGT-M, PGT-A and PGT-SR could be performed by WGS with 10× depth of parental and 4× depth of embryonic sequencing data. WHAT IS KNOWN ALREADY: Reduced representation genome sequencing with a genome-wide next-generation sequencing haplarithmisis-based solution has been verified as a generic approach for automated haplotyping and comprehensive PGT. Several low-depth massively parallel sequencing (MPS)-based methods for haplotyping and comprehensive PGT have been developed. However, an additional family member, such as a sibling, or a proband, is required for PGT-M haplotyping using low-depth MPS methods. STUDY DESIGN, SIZE, DURATION: In this study, 10 families that had undergone traditional IVF-PGT and 53 embryos, including 13 embryos from two PGT-SR families and 40 embryos from eight PGT-M families, were included to evaluate a WGS-based method. There were 24 blastomeres and 29 blastocysts in total. All embryos were used for PGT-A. Karyomapping validated the WGS results. Clinical outcomes of the 10 families were evaluated. PARTICIPANTS/MATERIALS, SETTING, METHODS: A blastomere or a few trophectoderm cells from the blastocyst were biopsied, and multiple displacement amplification (MDA) was performed. MDA DNA and bulk DNA of family members were used for library construction. Libraries were sequenced, and data analysis, including haplotype inheritance deduction for PGT-M and PGT-SR and read-count analysis for PGT-A, was performed using an in-house pipeline. Haplotyping with a proband and parent-only haplotyping without additional family members were performed to assess the WGS methodology. Concordance analysis between the WGS results and traditional PGT methods was performed. MAIN RESULTS AND THE ROLE OF CHANCE: For the 40 PGT-M and 53 PGT-A embryos, 100% concordance between the WGS and single-nucleotide polymorphism (SNP)-array results was observed, regardless of whether additional family members or a proband was included for PGT-M haplotyping. For the 13 embryos from the two PGT-SR families, the embryonic balanced translocation was detected and 100% concordance between WGS and MicroSeq with PCR-seq was demonstrated. LIMITATIONS, REASONS FOR CAUTION: The number of samples in this study was limited. In some cases, the reference embryo for PGT-M or PGT-SR parent-only haplotyping was not available owing to failed direct genotyping. WIDER IMPLICATIONS OF THE FINDINGS: WGS-based PGT-A, PGT-M and PGT-SR offered a comprehensive PGT approach for haplotyping without the requirement for additional family members. It provided an improved complementary method to PGT methodologies, such as low-depth MPS- and SNP array-based methods. STUDY FUNDING/COMPETING INTEREST(S): This research was supported by the research grant from the National Key R&D Program of China (2018YFC0910201 and 2018YFC1004900), the Guangdong province science and technology project of China (2019B020226001), the Shenzhen Birth Defect Screening Project Lab (JZF No. [2016] 750) and the Shenzhen Municipal Government of China (JCYJ20170412152854656). This work was also supported by the National Natural Science Foundation of China (81771638, 81901495 and 81971344), the National Key R&D Program of China (2018YFC1004901 and 2016YFC0905103), the Shanghai Sailing Program (18YF1424800), the Shanghai Municipal Commission of Science and Technology Program (15411964000) and the Shanghai 'Rising Stars of Medical Talent' Youth Development Program Clinical Laboratory Practitioners Program (201972). The authors declare no competing interests. TRIAL REGISTRATION NUMBER: N/A.

Toll-like receptor-2 gene knockout results in neurobehavioral dysfunctions and multiple brain structural and functional abnormalities in mice.

OBJECTIVE: Toll-like receptor-2 (TLR2), a member of TLR family, plays an important role in the induction and regulation of immune/inflammation. TLR2 gene knockout (TLR2KO) mice have been widely used for animal models of neurological diseases. Since there is close relationship between immune system and neurobehavioral functions, it is important to clarify the exact role of TLR2 defect itself in neurobehavioral functions. The present study aimed to investigate the effect of TLR2KO on neurobehavioral functions in mice and the mechanisms underlying the observed changes. METHODS: Male TLR2KO and wild type (WT) mice aged 3, 7, and 12 months were used for neurobehavioral testing and detection of protein expression by Western blot. Brain magnetic resonance imaging (MRI), electrophysiological recording, and Evans blue (EB) assay were applied to evaluate regional cerebral blood flow (rCBF), synaptic function, and blood-brain barrier (BBB) integrity in 12-month-old TLR2KO and age-matched WT mice. RESULTS: Compared to WT mice, TLR2KO mice showed decreased cognitive function and locomotor activity, as well as increased anxiety, which developed from middle age (before 7-month-old) to old age. In addition, significantly reduced regional cerebral blood flow (rCBF), inhibited long-term potentiation (LTP), and increased blood-brain barrier (BBB) permeability were observed in 12-month-old TLR2KO mice. Furthermore, compared with age-matched WT mice, significant reduction in protein levels of tight junction proteins (ZO-1, Occludin, and Claudin-5) and increased neurofilament protein (SMI32) were observed in 7 and 12-month-old TLR2KO mice, and that myelin basic protein (MBP) decreased in 12-month-old TLR2KO mice. CONCLUSION: Our data demonstrated that TLR2 defect resulted in significantly observable neurobehavioral dysfunctions in mice starting from middle age, as well as multiple abnormalities in brain structure, function, and molecular metabolism.

Childhood trauma mediates repetitive transcranial magnetic stimulation efficacy in major depressive disorder.

Childhood trauma is one of the most prominent risk factors in developing major depressive disorder (MDD) and may lead to unfavorable outcomes of pharmacotherapy and psychotherapy in MDD. While how it modulates the treatment outcome of the repetitive transcranial magnetic stimulation (rTMS) and how sex difference may play a role in mediating this relationship remain unknown. To evaluate this question, 51 (37 women) MDD patients were treated with 10 Hz rTMS to the left dorsolateral prefrontal cortex (lDLPFC). The experience of childhood trauma was quantified by the Childhood Traumatic Questionnaire (CTQ). The depressive severity was assessed by Hamilton Depression Scale (HAMD) and Beck Depression Inventory (BDI) as the primary and secondary assessments. Beck Hopelessness Scale (BHS) and Hamilton Anxiety Scale (HAMA) were also assessed for further confirmation. Thirty-six (70.6%) participants showed a response including 17 (33.3%) achieving remission to the rTMS treatment. The alleviation of depressive symptoms was negatively correlated with the CTQ scores, specifically in women but not men, in subjective BDI and BHS, but not objective HAMD or HAMA. We demonstrate that childhood trauma negatively affects the subjective perception of rTMS-lDLPFC treatment outcomes in female MDD patients. This highlights the importance of measuring childhood trauma-related symptoms in routine clinical rTMS treatment, as they may impact perceived efficacy.

Exploratory Investigation of Intestinal Structure and Function after Stroke in Mice.

Stroke is the second leading cause of death worldwide. Patients who have a stroke are susceptible to many gastrointestinal (GI) complications, such as dysphagia, GI bleeding, and fecal incontinence. However, there are few studies focusing on the GI tract after stroke. The current study is to investigate the changes of intestinal structure and function in mice after ischemic stroke. Ischemic stroke was made as a disease model in mice, in which brain and ileal tissues were collected for experiments on the 1st and 7th day after stroke. Intestinal motility of mice was inhibited, and intestinal permeability was increased after stroke. Hematoxylin-eosin (HE) staining showed the accumulation of leucocytes in the intestinal mucosa. Myeloperoxidase (MPO) activity and inflammatory proteins (nuclear factor kappa-B (NF-κB), inducible nitric oxide synthase (iNOS)) in the small intestine were significantly increased in mice after stroke. The expression of tight junction (TJ) proteins (zonula occludens-1 (ZO-1), occludin, and claudin-1) was downregulated, and transmission electron microscopy (TEM) showed broken TJ of the intestinal mucosa after stroke. Glial fibrillary acidic protein (GFAP) and the apoptosis-associated proteins (tumor necrosis factor (TNF-α), caspase-3, and cleaved caspase-3) were notably upregulated as well. Ischemic stroke led to negative changes on intestinal structure and function. Inflammatory mediators and TNF-α-induced death receptor signaling pathways may be involved and disrupt the small intestinal barrier function. These results suggest that stroke patients should pay attention to GI protection.