Neurotransmission requires precise control of neurotransmitter release from axon terminals. This process is regulated by glial cells; however, the underlying mechanisms are not fully understood. We found that glutamate release in the brain was impaired in mice lacking low-density lipoprotein receptor-related protein 4 (Lrp4), a protein that is critical for neuromuscular junction formation. Electrophysiological studies revealed compromised release probability in astrocyte-specific Lrp4 knockout mice. Lrp4 mutant astrocytes suppressed glutamatergic transmission by enhancing the release of ATP, whose level was elevated in the hippocampus of Lrp4 mutant mice. Consequently, the mutant mice were impaired in locomotor activity and spatial memory and were resistant to seizure induction. These impairments could be ameliorated by blocking the adenosine A1 receptor. The results reveal a critical role for Lrp4, in response to agrin, in modulating astrocytic ATP release and synaptic transmission. Our findings provide insight into the interaction between neurons and astrocytes for synaptic homeostasis and/or plasticity.

Beyond its application as an epilepsy therapy, the ketogenic diet (KD) has been considered a potential treatment for a variety of other neurological and metabolic disorders. However, whether KD promotes functional restoration by reducing the pathological processes underlying individual diseases or through some independent mechanisms is not clear.

We have previously demonstrated that hydrogen sulfide (H2S), the third endogenous gasotransmitter, ameliorates the depression- and anxiety-like behaviors in diabetic rats, but the underlying mechanism remains unclear. The present was aimed to investigate whether the hippocampal phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway mediates H2S-ameliorated depression- and anxiety-like behaviors in diabetic rats by improving the hippocampal neurogenesis. The depression-like behaviors were examined by Tail suspension test (TST), the anxiety-like behaviors were examined by Elevated plus maze test (EPM), and the locomotor activity was detected by Open Field Test (OFT). The expressions of doublecortin (DCX), neuron-specific nuclear protein (NeuN), glial fibrillary acidic protein (GFAP), p-AKT, and AKT in the hippocampus were determined by Western blot analysis. Results showed that NaHS, a donor of exogenous H2S, not only activated the hippocampal PI3K/AKT pathway, as evidenced by the increase of phosphorylated AKT, but also favorably reversed streptozotocin (STZ)-disturbed hippocampal neurogenesis, as evidenced by the increases in the expressions of DCX and NeuN as well as the decrease in the expression of GFAP in the hippocampus of STZ-induced diabetic rats. Furthermore, inhibited PI3K/AKT pathway by LY294002 significantly abolished H2S-exerted the improvement of hippocampal neurogenesis and the antidepressant- and anxiolytic-like effects in the STZ-induced diabetic rats. Taken together, these results uncover that the activation of hippocampal PI3K/AKT pathway plays an important role to restore hippocampal neurogenesis and subsequently to mediate the antidepressant- and anxiolytic-like roles of H2S in STZ-induced diabetic rats and enhance our understanding of the robustness of H2S as a therapeutic strategy for treatment of depression in diabetes mellitus.

Purpose: To investigate the value of US and elastography for predicting prognostic factors of papillary thyroid cancer (PTC) in the positive BRAFV600E Mutation group. Materials and Methods: A total of 116 BRAFV600E Mutation patients with PTCs were enrolled in this prospective study, who were preoperatively evaluated by US, US elasticity imaging (EI), and Virtual Touch tissue imaging (VTI) and Virtual Touch tissue quantification (VTQ) of acoustic radiation force impulse (ARFI) imaging. Multivariate logistic regression analysis was performed to assess 23 independent variables for predicting prognostic factors. Diagnostic performance was evaluated with receiver operating characteristic (ROC) curve analysis. Results: Forty-two (36.2%) of 116 PTC patients with BRAFV600E Mutation had central lymph node metastasis (LNM). Nine (7.8%) and fifty-six (48.3%) had lateral LNM and extra-thyroidal extension (ETE), respectively. In multivariate logistic regression analyses, rich internal flow [odds ratio [OR]: 6.66] was the best predictor for central LNM, followed by male sex (OR: 4.22), halo sign absence (OR: 2.78) (all P < 0.05). VTQ ratio (OR: 1.57) was the only predictor for lateral LNM (P = 0.02). Rich internal flow (OR: 6.33) was the strongest predictor for ETE, followed by male sex (OR: 3.29), halo sign absence (OR: 2.90), and VTQ ratio (OR: 1.63) (all P < 0.05). Conclusion: VTQ ratio on ARFI imaging, rich internal flow and halo sign absence on US are the predicting prognostic factors in PTC patients with BRAFV600E Mutation. The specificities were significantly increased by combining ARFI imaging and US features, which has a potential to avoid unnecessary therapeutic neck dissection in the high-risk PTC patients.

Our previous works demonstrated that β2-microglobulin (β2m), a systemic pro-aging factor, induce depressive-like behaviors. Hydrogen sulfide (H2S) is identified as a potential target for treatment of depression. The aim of the present work is to explore whether H2S antagonizes β2m-induced depressive-like behaviors and the underlying mechanisms.

Pathologic complete response (pCR) following preoperative systemic therapy is associated with improved outcomes after subsequent liver transplant/resection in hepatocellular carcinoma (HCC). However, the relationship between radiographic and histopathological response remains unclear.

Heterochromatin protein 1α (HP1α) is a gene that mediates chromatin conformation, gene silencing and cancer progression. However, little is known regarding the impact of HP1α in the pathogenesis of cholangiocarcinoma (CCA). In the present study, we demonstrate that HP1α is significantly upregulated in CCA tissues and cell lines, while downregulation of HP1α leads to suppression of cell proliferation. Then we find that downregulation of HP1α can decrease H3K9me3 enrichment and DNA methylation rate of secreted frizzled-related protein 1 (SFRP1) promoter, resulting in restoring the expression of SFRP1. Moreover, restoration of SFRP1 expression can suppress CCA cells proliferation. These results provide a mechanistic understanding of the role of HP1α in the pathogenesis of CCA and may offer a novel therapeutic target in this disease.

Altered Plastin-3 (PLS3; an actin-binding protein) expression was associated with human carcinogenesis, including pancreatic ductal adenocarcinoma (PDA). This study first assessed differentially expressed genes (DEGs) and then bioinformatically and experimentally confirmed PLS3 to be able to predict PDA prognosis and distinguish PDA from diffuse large B-cell lymphoma.

A remarkable new Premna species from Myanmar, P. grandipaniculata Y.H.Tan & Bo Li (Lamiaceae), is here described and illustrated. It differs from all known congeneric taxa by having huge complicated panicles which have tertiary branches formed by spike-like thyrses. In Premna, such a spike-like thyrse is found in P. bracteata and P. interrupta, but those species can be easily distinguished from P. grandipaniculata by their habit, indumentum, leaf size and inflorescence structure.

Hydrogen sulfide (H2S) has therapeutic effects on Parkinson's disease (PD). Warburg effect, namely aerobic glycolysis, is benefit to PD. Leptin, a hormone secreted in adipose, plays an important role in the treatment of PD.

Inhibitory neurotransmission in amygdala is important for fear learning and memory. However, mechanisms that control the inhibitory activity in amygdala are not well understood. We provide evidence that neuregulin 1 (NRG1) and its receptor ErbB4 tyrosine kinase are critical for maintaining GABAergic activity in amygdala. Neutralizing endogenous NRG1, inhibition, or genetic ablation of ErbB4, which was expressed in a majority of palvalbumin (PV)+ neurons in amygdala, reduced GABAergic transmission and inhibited tone-cued fear conditioning. Specific ablation of ErbB4 in PV+ neurons reduced eIPSC/eEPSC ratios and impaired fear conditioning. Notably, expression of ErbB4 in amygdala was sufficient to diminish synaptic dysfunction and fear conditioning deficits in PV-ErbB4-/- mice. These observations indicated that NRG1 signaling maintains high GABAergic activity in amygdala and, thus, regulates fear memory. Considering that both NRG1 and ErbB4 are susceptibility genes of schizophrenia, our study sheds light on potential pathophysiological mechanisms of this disorder.

The present study was performed to investigate the roles of anterior intestine in the postprandial glucose homeostasis of the omnivorous Genetically Improved Farmed Tilapia (GIFT). Sub-adult fish (about 173 g) were sampled at 0, 1, 3, 8 and 24 h post feeding (HPF) after 36 h of food deprivation, and the time course of changes in intestinal glucose transport, glycolysis, glycogenesis and gluconeogenesis at the transcription and enzyme activity level, as well as plasma glucose contents, were analyzed. Compared with 0 HPF (fasting for 36 h), the mRNA levels of both ATP-dependent sodium/glucose cotransporter 1 and facilitated glucose transporter 2 increased during 1-3 HPF, decreased at 8 HPF and then leveled off. These results indicated that intestinal uptake of glucose and its transport across the intestine to blood mainly occurred during 1-3 HPF, which subsequently resulted in the increase of plasma glucose level at the same time. Intestinal glycolysis was stimulated during 1-3 HPF, while glucose storage as glycogen was induced during 3-8 HPF. Unexpectedly, intestinal gluconeogenesis (IGNG) was also strongly induced during 1-3 HPF at the state of nutrient assimilation. The mRNA abundance and enzyme activities of glutamic-pyruvic and glutamic-oxaloacetic transaminases increased during 1-3 HPF, suggesting that the precursors of IGNG might originate from some amino acids. Taken together, it was concluded that the anterior intestine played an important role in the regulation of postprandial glucose homeostasis in omnivorous tilapia, as it represented significant glycolytic potential and glucose storage. It was interesting that postprandial IGNG was stimulated by feeding temporarily, and its biological significance remains to be elucidated in fish.

To characterize human leukocyte antigen (HLA) loci as risk factors in aromatic antiepileptic drug-induced maculopapular exanthema (AED-MPE). A case-control study was performed to investigate HLA loci involved in AED-MPE in a southern Han Chinese population. Between January 2007 and June 2019, 267 patients with carbamazepine (CBZ), oxcarbazepine (OXC), or lamotrigine (LTG) associated MPE and 387 matched drug-tolerant controls from six centers were enrolled. HLA-A/B/C/DRB1 genotypes were determined using sequence-based typing. Potential risk alleles were validated by meta-analysis using data from different populations and in silico analysis of protein-drug interactions. HLA-DRB1*04:06 was significantly associated with OXC-MPE (p = 0.002, p c = 0.04). HLA-B*38:02 was associated with CBZ-MPE (p = 0.03). When pooled, HLA-A*24:02, HLA-A*30:01, and HLA-B*35:01 additionally revealed significant association with AED-MPE. Logistic regression analysis showed a multiplicative interaction between HLA-A*24:02 and HLA-B*38:02 in CBZ-MPE. Meta-analysis of data from different populations revealed that HLA-24*:02 and HLA-A*30:01 were associated with AED-MPE (p = 0.02 and p = 0.04, respectively). In silico analysis of protein-drug interaction demonstrated that HLA-A*24:02 and HLA-A*30:01 had higher affinities with the three aromatic AEDs than the risk-free HLA-A allele. HLA-DRB1*04:06 showed relatively specific high affinity with S-monohydroxy derivative of OXC. HLA-DRB1*04:06 is a specific risk allele for OXC-induced MPE in the Southern Han Chinese. HLA-A*24:02, possibly HLA-A*30:01, are common risk factors for AED-MPE. The multiplicative risk potential between HLA-A*24:02 and HLA-B*38:02 suggests that patients with two risk alleles are at greater risk than those with one risk allele. Inclusion of these HLA alleles in pre-treatment screening would help estimating the risk of AED-MPE.

Inhibitory neurons control the firing of glutamatergic neurons and synchronize brain activity. However, little is known about mechanisms of excitatory synapse formation in inhibitory neurons. Here we demonstrate that Erbin is specifically expressed in cortical inhibitory neurons. It localizes at excitatory synapses and regulates AMPA receptor (AMPAR) surface expression. Erbin mutation reduced mEPSCs and AMPAR currents specifically in parvalbumin (PV)-positive interneurons but not in pyramidal neurons. We found that the AMPAR auxiliary protein TARP γ-2 was specifically expressed in cortical interneurons. Erbin interacts with TARP γ-2 and is crucial for its stability. Deletion of the γ-2-interacting domain in Erbin attenuated surface AMPAR and excitatory transmission in PV-positive interneurons. Furthermore, we observed behavioral deficits in Erbin-null mice and in mice expressing an Erbin truncation mutant that is unable to interact with TARP γ-2. These observations demonstrate a crucial function for Erbin in AMPAR surface expression in cortical PV-positive interneurons and may contribute to a better understanding of psychiatric disorders.

Emerging evidence shows that chronic restraint stress (CRS) can induce cognitive dysfunction, which involves in hippocampal damage. Our recent research reveals that hydrogen sulfide (H2S), a novel gasotransmitter, protects against CRS-induced cognitive impairment, but the underlying mechanism remains unclear. Adiponectin, the most abundant plasma adipokine, has been shown to elicit neuroprotective property and attenuate cognitive impairment. Hence, the present work was aimed to explore whether adiponectin mediates the protective effect of H2S on CRS-induced cognitive impairment by inhibiting hippocampal damage. Results found that administration of Anti-Acrp30, a neutralizing antibody of adiponectin, obviously reverses sodium hydrosulfide (NaHS, an exogenous H2S donor)-induced the inhibition on CRS-induced cognitive impairment according to Y-maze test, Novel object recognition (NOR) test, and Morris water maze (MWM) test. In addition, Anti-Acrp30 blocked the protective effect of NaHS on hippocampal apoptosis in rats-subjected with CRS as evidenced by the pathological changes in hippocampus tissues in hematoxylin and eosin (HE) staining and the increases in the amount of the condensed and stained to yellowish-brown or brownish yellow neuron nucleuses in terminal deoxynucleotidyl transferase transfer-mediated dUTP nick end-labeling (TUNEL) staining as well as the expression of hippocampal pro-apoptotic protein (Bax), and a decrease in the expression of hippocampal anti-apoptotic protein (Bcl-2). Furthermore, Anti-Acrp30 mitigated the inhibitory effect of NaHS on CRS-induced oxidative stress as illustrated by the up-regulation of malondialdehyde (MDA) content and the down-regulation of superoxide dismutase (SOD) activity and glutathione (GSH) level in the hippocampus. Moreover, Anti-Acrp30 eliminated NaHS-induced the reduction of endoplasmic reticulum (ER) stress-related proteins including binding immunoglobulin protein (BIP), C/EBP homologous protein (CHOP), and Cleaved Caspase-12 expressions in the hippocampus of rats-exposed to CRS. Taken together, these results indicated that adiponectin mediates the protection of H2S against CRS-induced cognitive impairment through ameliorating hippocampal damage.

Increasing evidence confirms that sleep deprivation (SD), which induces hippocampal neuroinflammation, is a risk factor for depression. Hydrogen sulfide (H2S) is a novel neuromodulator that plays antidepressant-like role. Silent mating type information regulation 2 homolog 1 (Sirt1) is well-characterized as a regulator of mood disorder. Furthermore, we have previously reported that H2S upregulates Sirt1 expression in the hippocampus of SD-exposed rats. Here, we explored whether H2S ameliorates depression- and anxiety-like behaviors as well as hippocampal neuroinflammatory in SD-exposed rats and whether Sirt1 mediates these protective roles of H2S. In the present work, we showed that NaHS (a donor of H2S) significantly alleviated depression- and anxiety-like behaviors in the SD-exposed rats tested by novelty-suppressed feeding test (NST), forced swim test (FST), tail suspension test (TST), and elevated plus maze test (EPMT) and that NaHS attenuates neuroinflammatory in the hippocampus of SD-exposed rats, as evidenced by reducing the levels of pro-inflammatory cytokines (IL-1β, IL-6 and TNF-α) and chemokine CCL2, as well as increasing the levels of anti-inflammatory cytokines (IL-4 and IL-10) in the hippocampus. However, Sirt1 inhibitor reversed the protective effects of H2S against SD-induced depression- and anxiety-like behaviors as well as hippocampal neuroinflammatory. In conclusion, H2S antagonizes SD-induced depression- and anxiety-like behaviors and neuroinflammation, which is required hippocampal Sirt1. These findings suggested that H2S is a novel approach to prevent SD-induced depression and anxiety.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by oxidative stress that triggers motor neurons loss in the brain and spinal cord. However, the mechanisms underlying the exact role of oxidative stress in ALS-associated neural degeneration are not definitively established. Oxidative stress-generated phospholipid peroxides are known to have extensive physiological and pathological consequences to tissues. Here, we discovered that the deficiency of glutathione peroxidase 4 (GPX4), an essential antioxidant peroxidase, led to the accumulation of phospholipid peroxides and resulted in a loss of motor neurons in spinal cords of ALS mice. Mutant human SOD1G93A transgenic mice were intrathecally injected with neuron-targeted adeno-associated virus (AAV) expressing GPX4 (GPX4-AAV) or phospholipid peroxidation inhibitor, ferrostatin-1. The results showed that impaired motor performance and neural loss induced by SOD1G93A toxicity in the lumbar spine were substantially alleviated by ferrostatin-1 treatment and AAV-mediated GPX4 delivery. In addition, the denervation of neuron-muscle junction and spinal atrophy in ALS mice were rescued by neural GPX4 overexpression, suggesting that GPX4 is essential for the motor neural maintenance and function. In comparison, conditional knockdown of Gpx4 in the spinal cords of Gpx4fl/fl mice triggered an obvious increase of phospholipid peroxides and the occurrence of ALS-like motor phenotype. Altogether, our findings underscore the importance of GPX4 in maintaining phospholipid redox homeostasis in the spinal cord and presents GPX4 as an attractive therapeutic target for ALS treatment.

Leprosy and psoriasis rarely coexist, the specific molecular mechanisms underlying their mutual exclusion have not been extensively investigated. This study aimed to reveal the underlying mechanism responsible for the mutual exclusion between psoriasis and leprosy. We obtained leprosy and psoriasis data from ArrayExpress and GEO database. Differential expression analysis was conducted separately on the leprosy and psoriasis using DEseq2. Differentially expressed genes (DEGs) with opposite expression patterns in psoriasis and leprosy were identified, which could potentially involve in their mutual exclusion. Enrichment analysis was performed on these candidate mutually exclusive genes, and a protein-protein interaction (PPI) network was constructed to identify hub genes. The expression of these hub genes was further validated in an external dataset to obtain the critical mutually exclusive genes. Additionally, immune cell infiltration in psoriasis and leprosy was analyzed using single-sample gene set enrichment analysis (ssGSEA), and the correlation between critical mutually exclusive genes and immune cells was also examined. Finally, the expression pattern of critical mutually exclusive genes was evaluated in a single-cell transcriptome dataset. We identified 1098 DEGs in the leprosy dataset and 3839 DEGs in the psoriasis dataset. 48 candidate mutually exclusive genes were identified by taking the intersection. Enrichment analysis revealed that these genes were involved in cholesterol metabolism pathways. Through PPI network analysis, we identified APOE, CYP27A1, FADS1, and SOAT1 as hub genes. APOE, CYP27A1, and SOAT1 were subsequently validated as critical mutually exclusive genes on both internal and external datasets. Analysis of immune cell infiltration indicated higher abundance of 16 immune cell types in psoriasis and leprosy compared to normal controls. The abundance of 6 immune cell types in psoriasis and leprosy positively correlated with the expression levels of APOE and CYP27A1. Single-cell data analysis demonstrated that critical mutually exclusive genes were predominantly expressed in Schwann cells and fibroblasts. This study identified APOE, CYP27A1, and SOAT1 as critical mutually exclusive genes. Cholesterol metabolism pathway illustrated the possible mechanism of the inverse association of psoriasis and leprosy. The findings of this study provide a basis for identifying mechanisms and therapeutic targets for psoriasis.