AI protein structure prediction-based modeling and mutagenesis of a protostome receptor and peptide ligands reveal key residues for their interaction.

The protostome leucokinin (LK) signaling system, including LK peptides and their G protein-coupled receptors, has been characterized in several species. Despite the progress, molecular mechanisms governing LK peptide-receptor interactions remain to be elucidated. Previously, we identified a precursor protein for Aplysia leucokinin-like peptides (ALKs) that contains the greatest number of amidated peptides among LK precursors in all species identified so far. Here, we identified the first ALK receptor from Aplysia, ALKR. We used cell-based IP1 activation assays to demonstrate that two ALK peptides with the most copies, ALK1 and ALK2, activated ALKR with high potencies. Other endogenous ALK-derived peptides bearing the FXXWX-amide motif also activated ALKR to various degrees. Our examination of cross-species activity of ALKs with the Anopheles LK receptor was consistent with a critical role for the FXXWX-amide motif in receptor activity. Furthermore, we showed, through alanine substitution of ALK1, the highly conserved phenylalanine (F), tryptophan (W), and C-terminal amidation were each essential for receptor activation. Finally, we used an artificial intelligence-based protein structure prediction server (Robetta) and Autodock Vina to predict the ligand-bound conformation of ALKR. Our model predicted several interactions (i.e., hydrophobic interactions, hydrogen bonds, and amide-pi stacking) between ALK peptides and ALKR, and several of our substitution and mutagenesis experiments were consistent with the predicted model. In conclusion, our results provide important information defining possible interactions between ALK peptides and their receptors. The workflow utilized here may be useful for studying other ligand-receptor interactions for a neuropeptide signaling system, particularly in protostomes.

Compensatory remodeling of a septo-hippocampal GABAergic network in the triple transgenic Alzheimer's mouse model.

BACKGROUND: Alzheimer's disease (AD) is characterized by a progressive loss of memory that cannot be efficiently managed by currently available AD therapeutics. So far, most treatments for AD that have the potential to improve memory target neural circuits to protect their integrity. However, the vulnerable neural circuits and their dynamic remodeling during AD progression remain largely undefined. METHODS: Circuit-based approaches, including anterograde and retrograde tracing, slice electrophysiology, and fiber photometry, were used to investigate the dynamic structural and functional remodeling of a GABAergic circuit projected from the medial septum (MS) to the dentate gyrus (DG) in 3xTg-AD mice during AD progression. RESULTS: We identified a long-distance GABAergic circuit that couples highly connected MS and DG GABAergic neurons during spatial memory encoding. Furthermore, we found hyperactivity of DG interneurons during early AD, which persisted into late AD stages. Interestingly, MS GABAergic projections developed a series of adaptive strategies to combat DG interneuron hyperactivity. During early-stage AD, MS-DG GABAergic projections exhibit increased inhibitory synaptic strength onto DG interneurons to inhibit their activities. During late-stage AD, MS-DG GABAergic projections form higher anatomical connectivity with DG interneurons and exhibit aberrant outgrowth to increase the inhibition onto DG interneurons. CONCLUSION: We report the structural and functional remodeling of the MS-DG GABAergic circuit during disease progression in 3xTg-AD mice. Dynamic MS-DG GABAergic circuit remodeling represents a compensatory mechanism to combat DG interneuron hyperactivity induced by reduced GABA transmission.

Pan-cancer analysis identifies SPEN mutation as a predictive biomarker with the efficacy of immunotherapy.

The association between specific genetic mutations and immunotherapy benefits has been widely known, while such studies in pan-cancer are still limited. SPEN, mainly involved in X chromosome inactivation (XCI), plays an essential in tumorigenesis and sex differences in cancer. Thus, we firstly analyzed the potential role of SPEN in the TCGA pan-cancer cohort and clinical samples. Bioinformatics analysis and immunohistochemistry (IHC) staining confirm that the expression of SPEN is significantly different in various cancers and may involve RNA splicing and processing via enrichment analysis. Then, our data further revealed that those patients with SPEN mutation could predict a better prognosis in pan-cancer and had distinct immune signatures, higher tumor mutation burden (TMB), and microsatellite instability (MSI) in common cancer types. Finally, the cancer patients from 9 studies treated with immune checkpoint inhibitors were included to investigate the efficacy of immunotherapy. The results further showed that SPEN mutation was associated with better clinical outcomes (HR, 0.74; 95%CI, 0.59-0.93, P = 0.01), and this association remained existed in female patients (HR, 0.60; 95%CI, 0.38-0.94 P = 0.024), but not in male patients (HR, 0.82; 95%CI, 0.62-1.08 P = 0.150). Our findings demonstrated that SPEN mutation might strongly predict immunotherapy efficacy in pan-cancer.

A biphasic calcium phosphate/acylated methacrylate gelatin composite hydrogel promotes osteogenesis and bone repair.

PURPOSE/AIM: Bone defects caused by trauma, tumors, congenital malformation, or inflammation are very common in orthopedics. In recent years, mimicking the composition and structure of natural bone tissue has become a hot topic in biomaterial research, with the aim of developing an ideal biomaterial for bone defect transplantation. Here, the feasibility of a biphasic calcium phosphate (BCP)/acylated methacrylate gelatin (GelMA) composite hydrogel to repair bone defects was evaluated in vitro and in rats. MATERIALS AND METHODS: The biocompatibility of a biphasic calcium phosphate (BCP)/acylated methacrylate gelatin (GelMA) composite hydrogel was evaluated by cytoskeleton staining, live/dead cell staining and cell proliferation assays. The in vitro osteogenic activities of the composite hydrogel were evaluated by alkaline phosphatase and alizarin red staining, as well as osteogenic gene expression analysis at both transcript and protein levels. The in vivo bone repair activities were evaluated using the rat skull defect model. RESULTS: The BCP/GelMA composite hydrogel displayed excellent biocompatibility and promoted osteogenesis of bone marrow mesenchymal stem cells in vitro. In addition, the BCP/GelMA composite hydrogel markedly promoted new bone formation in the rat skull-defect model. CONCLUSIONS: BCP/GelMA composite hydrogel may be an effective artificial material for bone tissue engineering.

Long non-coding RNA X-Inactive Specific Transcript (XIST) interacting with USF2 promotes osteogenic differentiation of periodontal ligament stem cells through regulation of WDR72 transcription.

BACKGROUND: Periodontal ligament stem cells (PDLSCs) are the most potential cells in periodontal tissue regeneration and bone tissue regeneration. Our prior work had revealed that WD repeat-containing protein 72 (WDR72) was crucial for osteogenic differentiation of PDLSCs. Here, we further elucidated its underlying mechanism in PDLSC osteogenic differentiation. METHODS: Human PDLSCs, isolated and identified by flow cytometry, were prepared for osteogenic differentiation induction. Levels of WDR72, long non-coding RNA X-Inactive Specific Transcript (XIST), upstream stimulatory factor 2 (USF2), and osteogenic marker genes (Runx2, Osteocalcin, and Collagen I) in human PDLSCs and clinical specimens were detected by RT-qPCR. Protein expressions of WDR72, Runx2, Osteocalcin, and Colla1 were tested by Western blot. The interactions among the molecules were verified by RIP, RNA pull-down, ChIP, and luciferase reporter assays. Osteogenic differentiation was evaluated by alkaline phosphatase (ALP) and alizarin red staining (ARS). RESULTS: WDR72 was decreased in periodontal tissues of periodontitis patients, and overexpression reversed TNF-α-mediated suppressive effects on PDLSC osteogenic differentiation. Mechanically, XIST recruited the enrichment of USF2 to the WDR72 promoter region, thereby positively regulating WDR72. WDR72 silencing overturned XIST-mediated biological effects in PDLSCs. CONCLUSION: WDR72, regulated by the XIST/USF2 axis, enhances osteogenic differentiation of PDLSCs, implying a novel strategy for alleviating periodontitis.

Metabolic-associated fatty liver disease and risk of esophagogastric cancer: a systematic review and meta-analysis.

INTRODUCTION: Metabolic-associated fatty liver disease (MAFLD) has been found to be strongly linked to several diseases. Although previous studies have explored the association between MAFLD and extrahepatic cancers, research on the relationship between MAFLD and gastric carcinoma (GC) and esophageal carcinoma (EC) is relatively scarce and requires updating. Therefore, the objective of this study is to conduct a comprehensive investigation into the association between MAFLD and GC or EC. MATERIAL AND METHODS: We conducted a comprehensive search for relevant studies published up to 5 August 2022, using the PubMed, Embase and Web of Science databases. To estimate the risk ratio (RR) and the 95% confidence interval (CI), we employed a random-effects model. We also conducted subgroup analyses based on study characteristics. The protocol for this systematic review is registered in the Prospero database under the registration number CRD42022351574. RESULTS: Our analysis included eight eligible studies, comprising a total of 8 629 525 participants. We found that the pooled RR values for the risk of GC in patients with MAFLD were 1.49 (95%CI: 1.17-1.91), whereas the pooled RR values for the risk of EC in patients with MAFLD were 1.76 (95%CI: 1.34-2.32). CONCLUSIONS: Based on our meta-analysis, we conclude that there is a significant association between the presence of MAFLD and the development of GC and EC.

Ventral pallidal GABAergic neurons control wakefulness associated with motivation through the ventral tegmental pathway.

The ventral pallidum (VP) regulates motivation, drug addiction, and several behaviors that rely on heightened arousal. However, the role and underlying neural circuits of the VP in the control of wakefulness remain poorly understood. In the present study, we sought to elucidate the specific role of VP GABAergic neurons in controlling sleep-wake behaviors in mice. Fiber photometry revealed that the population activity of VP GABAergic neurons was increased during physiological transitions from non-rapid eye movement (non-REM, NREM) sleep to either wakefulness or REM sleep. Moreover, chemogenetic and optogenetic manipulations were leveraged to investigate a potential causal role of VP GABAergic neurons in initiating and/or maintaining arousal. In vivo optogenetic stimulation of VP GABAergic neurons innervating the ventral tegmental area (VTA) strongly promoted arousal via disinhibition of VTA dopaminergic neurons. Functional in vitro mapping revealed that VP GABAergic neurons, in principle, inhibited VTA GABAergic neurons but also inhibited VTA dopaminergic neurons. In addition, optogenetic stimulation of terminals of VP GABAergic neurons revealed that they promoted arousal by innervating the lateral hypothalamus, but not the mediodorsal thalamus or lateral habenula. The increased wakefulness chemogenetically evoked by VP GABAergic neuronal activation was completely abolished by pretreatment with dopaminergic D1 and D2/D3 receptor antagonists. Furthermore, activation of VP GABAergic neurons increased exploration time in both the open-field and light-dark box tests but did not modulate depression-like behaviors or food intake. Finally, chemogenetic inhibition of VP GABAergic neurons decreased arousal. Taken together, our findings indicate that VP GABAergic neurons are essential for arousal related to motivation.

Cholelithiasis increased prostate cancer risk: evidence from a case-control study and a meta-analysis.

INTRODUCTION: Cholelithiasis represents a known risk factor for digestive system neoplasm. Few studies reported the association between cholelithiasis and the risk of prostate cancer (PCa), and the results were controversial. METHODS: We reviewed the medical records of the Second Affiliated Hospital of Chongqing Medical University Hospital to perform a retrospective matched case-control study, which included newly diagnosed 221 PCa patients and 219 matched controls. Logistic regression was applied to compare cholelithiasis exposure and adjusted for confounding factors. Additionally, we conducted a meta-analysis pooling this and published studies further to evaluate the association between cholelithiasis and PCa risk. Related ratio (RR) and 95% confidence interval (95%CI) were used to assess the strength of associations. RESULTS: Our case-control study showed that cholelithiasis was associated with a higher incidence of PCa (OR = 1.87, 95% CI: 1.06-3.31) after multivariable adjustment for covariates. The incidence of PCa was increased in patients with gallstones but not cholecystectomy. 7 studies involving 80,403 individuals were included in the meta-analysis. Similarly, the results demonstrated that cholelithiasis was associated with an increased risk of PCa (RR = 1.35, 95%CI: 1.17-1.56) with moderate-quality evidence. Cholelithiasis patients with low BMI increased the PCa incidence. Moreover, Subgroup analysis based on region showed that cholelithiasis was associated with PCa in Europe (RR = 1.24, 95%CI 1.03-1.51) and Asia (RR = 1.32, 95%CI 1.24-1.41). CONCLUSIONS: The results suggested an association between cholelithiasis and the risk of PCa. There was no significant relationship between cholecystectomy therapy and PCa risk. Further cohort studies should be conducted to demonstrate the results better.

Dermoscopic characteristics of membranous aplasia cutis congenita: Report of 56 cases.

BACKGROUND: Membranous aplasia cutis congenita (MACC) presents at birth characterized by oval epidermis defect. Skin lesions with MACC have various clinic manifestations. In recent years, the usefulness of trichoscopy (scalp dermoscopy) has been reported for hair loss diseases. However, the dermoscopic features of MACC were mostly reported by case reports. OBJECTIVES: To summarized the obvious dermoscopic characteristics of MACC. MATERIALS & METHODS: These 56 cases met the clinical diagnostic criteria for MACC without forceps delivery complications or other birth injuries. To find the dermoscopic characteristics of MACC by summarizing 56 infants' dermoscopic pictures. RESULTS: The dermoscopic manifestation of MACC are characterized by hair follicle openings and hair deficiency in the center of skin lesions, translucent epidermis, hair root and hair bulb arranged along the margins of skin lesion. CONCLUSION: The typical dermoscopic characteristics of MACC could help clinicians to early diagnose and differential diagnosis.

Association between male infertility and the risk of hypertension: A meta-analysis and literature review.

To explore the association between male infertility and hypertension risk, a meta-analysis and systematic review was conducted. Observational studies were sought in Medline, PubMed, EMBASE, Web of Science, and China National Knowledge Infrastructure up to April 30, 2021. Two independent reviewers selected available studies and extracted the data. The association between male infertility and hypertension risk was estimated by calculating the relative risk (RR) and 95% confidence interval (95% CI) using Stata12.0 statistical software. A total of seven studies were included in this meta-analysis, including 102,152 patients and 636,645 healthy individuals. The results demonstrated that male infertility was significantly associated with increased hypertension incidence (RR = 1.08; 95% CI 1.02-1.14; p = 0.004), with moderate-quality evidence. A subgroup analysis based on region showed that a positive association was observed in Europe but not the United States or Asia. This positive association was further confirmed in a cohort study, but not in a case-control study. After adjusting for potential confounders, male infertility was still significantly associated with hypertension risk (RR = 1.06, 95% CI 1.03-1.09). In conclusion, our findings suggest that male infertility increases the risk of hypertension incidence. However, further studies are needed to provide more conclusive evidence.

Formation of Hexagonal-Close Packed (HCP) Rhodium as a Size Effect.

Previous studies on the structural and functional properties of rhodium are based on the face-centered-cubic (fcc) structure in the bulk form. Here we report the first discovery of the hexagonal-close packed (hcp) rhodium in the nanoparticle form. The hcp Rh can be directly synthesized by solvothermal reaction or by electron-beam induced decomposition of Rh monolayers. The hcp Rh nanoparticles are stable under electron beam irradiation. Compared with the fcc structure, the hcp Rh nanoparticles show a large lattice expansion (6% larger atomic volume). The first-principles calculations suggest that the lower surface energy of hcp Rh leads to the size effect in the crystal structure.

Deciphering transcriptome profile of the yellow catfish (Pelteobagrus fulvidraco) in response to Edwardsiella ictaluri.

Edwardsiella ictaluri is one of the most important pathogens posing a serious threat for yellow catfish (Pelteobagrus fulvidraco), a highly valuable fish species of increasing commercial interest in China. Here, a transcriptomic strategy was undertaken to investigate the yellow catfish gene expression profile against infection by the bacterial pathogen E. ictaluri. Comparison of the transcriptome profiles between the infected and uninfected samples showed that a massive gene expression change occurred in yellow catfish following bacterial exposure. A total of 5527 differentially expressed genes (DEGs) were detected, of which 2265 showed up-regulation and 3262 down-regulation. Gene set enrichment analysis revealed the presence of canonical pathways directly linked to innate and adaptive immune response, such as pattern recognition receptor (PRR) signaling pathways, complement and coagulation cascades, as well as T-cell receptor (TCR) and B-cell receptor (BCR) signaling pathways. Additionally, 47,526 putative EST-liked simple sequence repeats (SSRs) markers were retrieved for use in genetic studies. This study establishes the first molecular clues to understand the potential mechanisms of yellow catfish resistance to E. ictaluri, thus enabling future efforts on disease control programs in this valuable aquaculture species.

De novo annotation of the immune-enriched transcriptome provides insights into immune system genes of Chinese sturgeon (Acipenser sinensis).

Chinese sturgeon (Acipenser sinensis), one of the oldest extant actinopterygian fishes with very high evolutionary, economical and conservation interest, is considered to be one of the critically endangered aquatic animals in China. Up to date, the immune system of this species remains largely undetermined with little sequence information publicly available. Herein, the first comprehensive transcriptome of immune tissues for Chinese sturgeon was characterized using Illumina deep sequencing. Over 67 million high-quality reads were generated and de novo assembled into the final set of 91,739 unique sequences. The annotation pipeline revealed that 25,871 unigenes were successfully annotated in the public databases, of which only 2002 had significant match to the existing sequences for the genus Acipenser. Overall 22,827 unigenes were categorized into 52 GO terms, 12,742 were classified into 26 KOG categories, and 4968 were assigned to 339 KEGG pathways. A more detailed annotation search showed the presence of a notable representation of immune-related genes, which suggests that this non-teleost actinopterygian fish harbors the same intermediates as in the well known immune pathways from mammals and teleosts, such as pattern recognition receptor (PRR) signaling pathway, JAK-STAT signaling pathway, complement and coagulation pathway, T-cell receptor (TCR) and B-cell receptor (BCR) signaling pathways. Additional genetic marker discovery led to the retrieval of 20,056 simple sequence repeats (SSRs) and 327,140 single nucleotide polymorphisms (SNPs). This immune-enriched transcriptome of Chinese sturgeon represents a rich resource that adds to the currently nascent field of chondrostean fish immunogenetics and furthers the conservation and management of this valuable fish.

Curcumin treatment suppresses CCR7 expression and the differentiation and migration of human circulating fibrocytes.

BACKGROUND/AIM: Recent studies have demonstrated that circulating fibrocytes contribute to the formation and development of fibrosis. Curcumin, a polyphenolic compound isolated from turmeric, has been shown to have anti-fibrotic effects in various organs. We and others have demonstrated that curcumin beneficially affects the development of fibrosis. However the effect of curcumin on circulating fibrocytes has not been reported. METHODS: Human circulating fibrocytes were isolated from leukocyte concentrates of healthy human donors and identified based on the expression of CD34, CD45, collagen I (COLI), and chemokine receptor CCR7 (CCR7) via flow cytometry. Cell Counting Kit-8 was used to evaluate cell viability. The effect of curcumin on the differentiation and migration of human circulating fibrocytes was evaluated by immunofluorescence staining, flow cytometry and a transwell migration assay. Transforming growth factor (TGF)-ß1 secretion was examined by ELISA. RESULTS: Curcumin treatment (72 h; 20 µM) significantly decreased the expression of COL I, α-SMA and CCR7, as well as TGF-ßl secretion, in human circulating fibrocytes. The inhibitory effect of curcumin on the differentiation and migration of human circulating fibrocytes is likely via regulating the CCR7/CCL21 signaling pathway, in particular by reducing CCR7 expression. These observed effects may be beneficial in resolving fibrosis by suppressing TGF-ß1 secretion. CONCLUSION: Our results suggest that curcumin has the potential to suppress the differentiation and migration of circulating fibrocytes, which would provide new explanation for curcumin's application in the development of fibrosis in various organs.

Gelsemine alleviates both neuropathic pain and sleep disturbance in partial sciatic nerve ligation mice.

AIM: Gelsemine, an alkaloid from the Chinese herb Gelsemium elegans (Gardn & Champ) Benth., is effective in mitigating chronic pain in rats. In the present study we investigated whether the alkaloid improved sleep disturbance, the most common comorbid symptoms of chronic pain, in a mouse model of neuropathic pain. METHODS: Mice were subjected to partial sciatic nerve ligation (PSNL). After the mice were injected with gelsemine or pregabalin (the positive control) intraperitoneally, mechanical allodynia and thermal hyperalgesia were assessed, and electroencephalogram (EEG)/electromyogram (EMG) recording was performed. Motor performance of the mice was assessed using rota-rod test. c-Fos expression in the brain was analyzed with immunohistochemical staining. RESULTS: In PSNL mice, gelsemine (2 and 4 mg/kg) increased the mechanical threshold for 4 h and prolonged the thermal latencies for 3 h. Furthermore, gelsemine (4 mg/kg, administered at 6:30 AM) increased non-rapid eye movement (non-REM, NREM) sleep, decreased wakefulness, but did not affect REM sleep during the first 3 h in PSNL mice. Sleep architecture analysis showed that gelsemine decreased the mean duration of wakefulness and increased the total number of episodes of NREM sleep during the first 3 h after the dosing. Gelsemine (4 mg/kg) did not impair motor coordination in PSNL mice. Immunohistochemical study showed that PSNL increased c-Fos expression in the neurons of the anterior cingulate cortex, and gelsemine (4 mg/kg) decreased c-Fos expression by 58%. Gelsemine (4 mg/kg, administered at either 6:30 AM or 8:30 PM) did not produce hypnotic effect in normal mice. Pregabalin produced similar antinociceptive and hypnotic effects, but impaired motor coordination in PSNL mice. CONCLUSION: Gelsemine is an effective agent for treatment of both neuropathic pain and sleep disturbance in PSNL mice; anterior cingulate cortex might play a role in the hypnotic effects of gelsemine.

[Effects of membrane protein ANO1 stable overexpression on laryngocarcinoma Hep-2 cells].

OBJECTIVE: To explore the effects of ANO1 overexpression on the proliferation, detachment, spreading, and migration of laryngocarcinoma Hep-2 cell line. METHODS: ANO1-overexpressing Hep-2 cell line was selected as the assay group, and Hep-2 cell line with empty plasmid was selected as the control group. MTT assay was used to detect the proliferation abilities of Hep-2 cells in both two groups. Cell detachment assay and spreading assay were used to detect the detachment and spreading abilities of Hep-2 cells. Boyden chamber invasion assay, wound healing assay in vitro, and niflumic acid block chloride channel were used to detect the migration abilities of Hep-2 cells. All data were analyzed by SPSS 10.0 software package. RESULTS: Cell proliferation assay by MTT showed that, compared with the control group, the optical density value of assay group was not significantly different (P=0.62). The results of cell detachment assay and cell spreading assay showed the cell detachment rates and cell spreading rates in assay group were significantly higher than those in control group (P<0.0001). The results of Boyden chamber invasion assay showed the percentages of cells migrating through the membrane in assay group were significantly higher than those in control group (P<0.0001). The results of in vitro wound healing experiments showed the wound area rate in assay group was significantly lower than that in control group (P<0.0001). The results of niflumic acid blocking chloride channel experiments showed the wound area rates in assay group were significantly higher than those in control group (P<0.0001). CONCLUSION: ANO1 overexpression does not remarkably alter the proliferation rate of cancer cells, but increases the migration, spreading, and detachment capacities of head and neck squamous cell carcinoma.

Development and validation of a model for predicting the risk of prostate cancer.

BACKGROUND: Abnormal hematologic parameters before patients undergoing prostate biopsy play a pivotal role in guiding the surgical management of prostate cancer (PCa) incidence. This study aims to establish the first nomogram for predicting PCa risk for better surgical management. METHODS: We retrospectively reviewed and analyzed the data including basic information, preoperative hematologic parameters, and imaging examination of 540 consecutive patients who underwent transrectal ultrasound (TRUS)-guided prostate biopsy for elevated prostate-specific antigen (PSA) in our medical center between 2017 and 2021. Logistic regression analysis was used to determine the risk factors for PCa occurrence, and the nomogram was constructed to predict PCa occurrence. Finally, the data including 121 consecutive patients in 2022 were prospectively collected to further verify the results. RESULTS: In retrospective analyses, univariate and multivariate logistic analyses identified that three variables including age, diabetes, and De Ritis ratio (aspartate transaminase/alanine transaminase, AST/ALT) were determined to be significantly associated with PCa occurrence. A nomogram was constructed based on these variables for predicting the risk of PCa, and a satisfied predictive accuracy of the model was determined with a C-index of 0.765, supported by a prospective validation group with a C-index of 0.736. The Decision curve analysis showed promising clinical application. In addition, our results also showed that the De Ritis ratio was significantly correlated with the clinical stage of PCa patients, including T, N, and M stages, but insignificantly related to the Gleason score. CONCLUSIONS: The increased De Ritis ratio was significantly associated with the risk and clinical stage of PCa and this nomogram with good discrimination could effectively improve individualized surgical management for patient underdoing prostate biopsy.

Sex-specific expression of distinct serotonin receptors mediates stress vulnerability of adult hippocampal neural stem cells in mice.

Women are more vulnerable to stress and have a higher likelihood of developing mood disorders. The serotonin (5HT) system has been highly implicated in stress response and mood regulation. However, sex-dependent mechanisms underlying serotonergic regulation of stress vulnerability remain poorly understood. Here, we report that adult hippocampal neural stem cells (NSCs) of the Ascl1 lineage (Ascl1-NSCs) in female mice express functional 5HT1A receptors (5HT1ARs), and selective deletion of 5HT1ARs in Ascl1-NSCs decreases the Ascl1-NSC pool only in females. Mechanistically, 5HT1AR deletion in Ascl1-NSCs of females leads to 5HT-induced depolarization mediated by upregulation of 5HT7Rs. Furthermore, repeated restraint stress (RRS) impairs Ascl1-NSC maintenance through a 5HT1AR-mediated mechanism. By contrast, Ascl1-NSCs in males express 5HT7R receptors (5HT7Rs) that are downregulated by RRS, thus maintaining the Ascl1-NSC pool. These findings suggest that sex-specific expression of distinct 5HTRs and their differential interactions with stress may underlie sex differences in stress vulnerability.

Anterior cingulate cortex projections to the dorsal medial striatum underlie insomnia associated with chronic pain.

Chronic pain often leads to the development of sleep disturbances. However, the precise neural circuit mechanisms responsible for sleep disorders in chronic pain have remained largely unknown. Here, we present compelling evidence that hyperactivity of pyramidal neurons (PNs) in the anterior cingulate cortex (ACC) drives insomnia in a mouse model of nerve-injury-induced chronic pain. After nerve injury, ACC PNs displayed spontaneous hyperactivity selectively in periods of insomnia. We then show that ACC PNs were both necessary for developing chronic-pain-induced insomnia and sufficient to mimic sleep loss in naive mice. Importantly, combining optogenetics and electrophysiological recordings, we found that the ACC projection to the dorsal medial striatum (DMS) underlies chronic-pain-induced insomnia through enhanced activity and plasticity of ACC-DMS dopamine D1R neuron synapses. Our findings shed light on the pivotal role of ACC PNs in developing chronic-pain-induced sleep disorders.

Optimizing memory performance and emotional states: multi-level enhancement of adult hippocampal neurogenesis.

Adult hippocampal neurogenesis (AHN) plays a key role in modulating memory and emotion processing. A fundamental question remains on how to effectively modulate AHN to improve hippocampal function. Here, we review recent work on how distinct aspects of hippocampal neurogenesis, including the number, maturation state, and activity of adult-born neurons (ABNs), contribute to overall hippocampal function. We propose multi-level enhancement of hippocampal neurogenesis with the combination of increased number, elevated activity, and enhanced maturation of ABNs as a potential strategy to optimize overall hippocampal performance. In addition, integration of ABNs induces significant remodeling of the local hippocampal circuits, which may in turn modulates brain-wide network dynamics. We discuss recent progress on how integration of ABNs contributes to local hippocampal circuit and brain-wide network dynamics during behavior.