NRG1-ErbB4 signaling in the medial amygdala controls mating motivation in adult male mice.

Motivation-driven mating is a basic affair for the maintenance of species. However, the underlying molecular mechanisms that control mating motivation are not fully understood. Here, we report that NRG1-ErbB4 signaling in the medial amygdala (MeA) is pivotal in regulating mating motivation. NRG1 expression in the MeA negatively correlates with the mating motivation levels in adult male mice. Local injection and knockdown of MeA NRG1 reduce and promote mating motivation, respectively. Consistently, knockdown of MeA ErbB4, a major receptor for NRG1, and genetic inactivation of its kinase both promote mating motivation. ErbB4 deletion decreases neuronal excitability, whereas chemogenetic manipulations of ErbB4-positive neuronal activities bidirectionally modulate mating motivation. We also identify that the effects of NRG1-ErbB4 signaling on neuronal excitability and mating motivation rely on hyperpolarization-activated cyclic nucleotide-gated channel 3. This study reveals a critical molecular mechanism for regulating mating motivation in adult male mice.

Effect of avian influenza scare on transmission of zoonotic avian influenza: A case study of influenza A (H7N9).

Avian influenza scare is a human psychological factor that asserts both positive and negative effects on the transmission of zoonotic avian influenza. In order to study the dichotomous effect of avian influenza scare on disease transmission, taking H7N9 avian influenza as a typical case, a two-patch epidemic model is proposed. The global dynamics and the threshold criteria are established by LaSalle invariant principle and the theory of asymptotic autonomous system. To mitigate the negative effects and curb illegal poultry trade, a game-theoretic model is adopted to explore the optimal policy of culling subsidies to reasonably compensate stakeholders for their economic losses resulting from the scare. The optimal policy of culling subsidy is found to heavily depend on the penalty of illegal poultry trade, the stakeholders' income, the intensity of control measures, and the prevalence level of the disease. The negative effect of avian influenza scare on disease transmission is considerably more significant than the positive effect. In order to avoid a widespread outbreak of zoonotic avian influenza across the region, a comprehensive national global control strategy is essential and effective, even in the presence of the negative effect of the avian influenza scare.

HSPA4 regulated glioma progression via activation of AKT signaling pathway.

Glioma is still an incurable disease with high invasiveness. Heat shock 70 kDa protein 4 (HSPA4) is a member of the HSP110 family, and is associated with the development and progression of various cancers. In the current study, we assessed the expression of HSPA4 in clinical samples, and found that HSPA4 was up-regulated in glioma tissues and correlated with tumor recurrence and grade. Survival analyses demonstrated that glioma patients with high HSPA4 expression had lower overall survival and disease-free survival times. In vitro knockdown of HSPA4 inhibited glioma cell proliferation, mediated cell cycle arrest at G2 phase and apoptosis, and reduced the migration ability. In vivo, the growth of HSPA4-knockdown xenografts was markedly suppressed compared to the tumors formed by HSPA4-positive control cells. Additionally, Gene set enrichment analyses disclosed that HSPA4 was associated with the PI3K/Akt signaling pathway. The regulatory effect of the AKT activator SC79 on cell proliferation and apoptosis was suppressed by HSPA4 knockdown, indicating that HSPA4 is capable of promoting glioma development. In summary, these data showed that HSPA4 is likely to play a pivotal role in the progression of glioma, and consequently may be a promising therapeutic target for glioma therapy.

Lnc-PTCHD4-AS inhibits gastric cancer through MSH2-MSH6 dimerization and ATM-p53-p21 activation.

Conserved long non-coding RNAs (lncRNAs) have not thoroughly been studied in many cancers, including gastric cancer (GC). We have identified a novel lncRNA PTCHD4-AS which was highly conserved between humans and mice and naturally downregulated in GC cell lines and tissues. Notably, PTCHD4-AS was found to be transcriptionally induced by DNA damage agents and its upregulation led to cell cycle arrest at the G2/M phase, in parallel, it facilitated the cell apoptosis induced by cisplatin (CDDP) in GC. Mechanistically, PTCHD4-AS directly bound to the DNA mismatch repair protein MSH2-MSH6 dimer, and facilitated the binding of dimer to ATM, thereby promoting the expression of phosphorylated ATM, p53 and p21. Here we conclude that the upregulation of PTCHD4-AS inhibits proliferation and increases CDDP sensitivity of GC cells via binding with MSH2-MSH6 dimer, activating the ATM-p53-p21 pathway.

Unveiling the intricate causal nexus between pancreatic cancer and peripheral metabolites through a comprehensive bidirectional two-sample Mendelian randomization analysis.

Aim: Pancreatic cancer (PC) is a devastating malignancy characterized by its aggressive nature and poor prognosis. However, the relationship of PC with peripheral metabolites remains not fully investigated. The study aimed to explore the causal linkage between PC and peripheral metabolite profiles. Methods: Employing publicly accessible genome-wide association studies (GWAS) data, we conducted a bidirectional two-sample Mendelian randomization (MR) analysis. The primary analysis employed the inverse-variance weighted (IVW) method. To address potential concerns about horizontal pleiotropy, we also employed supplementary methods such as maximum likelihood, weighted median, MR-Egger regression, and MR pleiotropy residual sum and outlier (MR-PRESSO). Results: We ascertained 20 genetically determined peripheral metabolites with causal linkages to PC while high-density lipoprotein (HDL) and very low-density lipoprotein (VLDL) particles accounted for the vast majority. Specifically, HDL particles exhibited an elevated PC risk while VLDL particles displayed an opposing pattern. The converse MR analysis underscored a notable alteration in 17 peripheral metabolites due to PC, including branch chain amino acids and derivatives of glycerophospholipid. Cross-referencing the bidirectional MR results revealed a reciprocal causation of PC and X-02269 which might form a self-perpetuating loop in PC development. Additionally, 1-arachidonoylglycerophosphocholine indicated a reduced PC risk and an increase under PC influence, possibly serving as a negative feedback regulator. Conclusion: Our findings suggest a complex interplay between pancreatic cancer and peripheral metabolites, with potential implications for understanding the etiology of pancreatic cancer and identifying novel early diagnosis and therapeutic targets. Moreover, X-02269 may hold a pivotal role in PC onset and progression.

Triglyceride-glucose index is associated with severe obstructive coronary artery disease and atherosclerotic target lesion failure among young adults.

BACKGROUND: Early diagnosis and treatment effectiveness of early-onset coronary artery disease (EOCAD) are crucial, and non-invasive predictive biomarkers are needed for young adults. We aimed to evaluate the usefulness of the triglyceride-glucose (TyG) index, a novel marker of insulin resistance, in identifying young CAD patients and predicting their risk of developing target lesion failure (TLF). METHODS: We recruited EOCAD patients (luminal narrowing ≥ 70%) and controls free from CAD (luminal narrowing < 30%), both aged 45 years or younger, from 38 hospitals in China between 2017 and 2020. EOCAD patients who underwent successful percutaneous coronary intervention were followed for incident TLF. TyG index was defined as Ln [fasting triglyceride (mg/dL) × fasting blood glucose (mg/dL)/2]. We used logistic regression and Cox proportional hazards modeling to evaluate the association of TyG index with prevalent EOCAD and incident TLF, respectively. The discriminatory ability of TyG index was assessed by the area under the receiver-operating characteristic curve (AUC). RESULTS: Among the included 1513 EOCAD patients (39.6 ± 4.4 years, 95.4% male) and 1513 age-matched controls (39.0 ± 4.4 years, 46.4% male), TyG index was positively associated with the prevalence of EOCAD (adjusted odds ratio: 1.40, 95% confidence interval [CI] 1.23-1.60, per standard deviation [SD] increase in TyG index). The addition of TyG index to an empirical risk model provided an improvement in diagnostic ability for EOCAD, with a net reclassification improvement of 0.10 (95% CI 0.03-0.17, p = 0.005). During a medium of 33 month (IQR: 31-34 months) follow-up, 43 (3.3%) patients experienced TLF. Multivariate Cox regression model revealed that TyG index was an independent risk factor for TLF (adjusted hazard ratio [HR]: 2.410, 95% CI 1.07-5.42 comparing the top to bottom TyG index tertile groups; HR: 1.30, 95% CI 1.01-1.73, per SD increase in TyG index). Compared with a model of conventional risk factors alone, the addition of the TyG index modestly improved the AUC (0.722-0.734, p = 0.04) to predict TLF. CONCLUSIONS: TyG index is positively associated with prevalent EOCAD and incident TLF. TyG index appeared to be a valuable component of future efforts to improve CAD risk stratification and TLF outcome prediction among young adults.

The evolution of SARS-CoV-2 and the COVID-19 pandemic.

Scientists have made great efforts to understand the evolution of SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2) to provide crucial information to public health experts on strategies to control this viral pathogen. The pandemic of the coronavirus disease that began in 2019, COVID-19, lasted nearly three years, and nearly all countries have set different epidemic prevention policies for this virus. The continuous evolution of SARS-CoV-2 alters its pathogenicity and infectivity in human hosts, thus the policy and treatments have been continually adjusted. Based on our previous study on the dynamics of binding ability prediction between the COVID-19 spike protein and human ACE2, the present study mined over 10 million sequences and epidemiological data of SARS-CoV-2 during 2020-2022 to understand the evolutionary path of SARS-CoV-2. We analyzed and predicted the mutation rates of the whole genome and main proteins of SARS-CoV-2 from different populations to understand the adaptive relationship between humans and COVID-19. Our study identified a correlation of the mutation rates from each protein of SARS-CoV-2 and various human populations. Overall, this analysis provides a scientific basis for developing data-driven strategies to confront human pathogens.

Effects of cholesterol-lowering probiotics on non-alcoholic fatty liver disease in FXR gene knockout mice.

Background/aims: Some studies showed that probiotics could improve the composition and structure of gut microbiota. Changes in the gut microbiota may alter bile acid (BAs) composition and kinetics, improving non-alcoholic fatty liver disease (NAFLD). However, it still needs to be clarified how probiotics improve both the metabolism of BAs and NAFLD. This study aimed to reveal the regulatory mechanisms of cholesterol-lowering (CL) probiotics on NAFLD from aspects involved in BA metabolism in FXR gene knockout (FXR-/-) mice. Methods: FXR-/- male mice were randomly divided into three groups based on different interventions for 16 weeks, including normal diet (ND), high-fat diet (HFD), and probiotic intervention in the HFD (HFD+P) group. 16s rDNA sequencing and ultrahigh performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) were utilized to analyze the changes in gut microbiota and fecal bile acids in mice. Results: We found that the intervention of the CL probiotics improved liver lipid deposition and function in HFD-induced NAFLD mice by decreasing the levels of total cholesterol (TC; p = 0.002) and triglyceride (TG; p = 0.001) in serum, as well as suppressing liver inflammation, such as interleukin-1 beta (IL-1ß; p = 0.002) and tumor necrosis factor-alpha (TNF-α; p < 0.0001). 16S rDNA sequencing and metabolomic analyses showed that probiotics effectively reduced the abundance of harmful gut microbiota, such as Firmicutes (p = 0.005), while concomitantly increasing the abundance of beneficial gut microbiota in NAFLD mice, such as Actinobacteriota (p = 0.378), to improve NAFLD. Compared with the ND group, consuming an HFD elevated the levels of total BAs (p = 0.0002), primary BAs (p = 0.017), and secondary BAs (p = 0.0001) in mice feces, while the intervention with probiotics significantly reduced the increase in the levels of fecal total bile acids (p = 0.013) and secondary bile acids (p = 0.017) induced by HFD. Conclusion: The CL probiotics were found to improve liver function, restore microbiota balance, correct an abnormal change in the composition and content of fecal bile acids, and repair the damaged intestinal mucosal barrier in mice with NAFLD, ultimately ameliorating the condition. These results suggested that CL probiotics may be a promising and health-friendly treatment option for NAFLD.

Dynamic analysis of rabies transmission and elimination in mainland China.

Rabies is an acute zoonotic infectious disease caused by rabies virus. In 2015, the World Health Organization proposed the goal of eliminating dog-induced human rabies by 2030. In response to this goal positively, China has been dedicated to the control and elimination of rabies mainly caused by dogs, for nearly 10 years. By applying infectious disease dynamics, in this paper, we establish a dog-human rabies transmission model to forecast future epidemic trends of rabies, assess whether the goal of eliminating dog-induced human rabies cases in China can be achieved in 2030, and further evaluate and suggest the follow-up sustained preventive measures after the elimination of human rabies. By analyzing and simulating above dynamic model, it is concluded that rabies has been well controlled in China in recent years, but dog-induced human rabies cannot be eliminated by 2030 according to current situation. In addition, we propose to improve rabies control efforts by increasing the immunization coverage rate of rural domestic dogs, controlling the number of stray dogs and preventing the import of rabies virus in wild animals. Immunization coverage rate of rural domestic dogs which is currently less than 10% is far from requirement, and it needs to reach 50%-60% to meet the goal of 2030. Since it is difficult to immunize stray dogs, we suggest to control the number of stray dogs below 15.27 million to achieve the goal. If the goal of eliminating human rabies is reached in 2030, the essential immunization coverage needs to be maintained for 18 years to reduce the number of canine rabies cases to zero. Lastly, to prevent transmission of rabies virus from wild animals to dogs, the thresholds of the number of dogs and the immunization coverage rate of dogs after eliminating canine rabies cases are also discussed.

Tissue residue distribution and withdrawal time estimation of trimethoprim and sulfachloropyridazine in Yugan black-bone fowl (Gallus gallus domesticus Brisson).

Black-bone fowl are different from ordinary broilers in appearance and are considered to have rich nutritional properties. However, the metabolism of therapeutic drugs in black-bone fowl remains unclear. This study aimed to determine the tissue residue depletion kinetics of trimethoprim and sulfachloropyridazine in Yugan black-bone fowl, after daily oral administrations for 5 days at 4 mg/kg bw/day trimethoprim and 20 mg/kg bw/day sulfachloropyridazine, and to calculate the withdrawal times. After consecutive oral administrations, the tissues (liver, kidney, muscle and skin/fat) were collected at each of the following time points (0.16, 1, 3, 5, 7, 9, 20, 30 and 40 days). A newly-devised LC-MS/MS method was used to analyse the concentrations of trimethoprim and sulfachlorpyridazine in target tissues. The results showed that sulfachloropyridazine was rapidly metabolised in broilers, and there was no residue in all tissues 3 days post-administration. The concentration of trimethoprim in black-bone fowl skin/fat is the highest, and its metabolism rate is low. After 40 days, the concentration of trimethoprim in skin/fat is still as high as 140.1 ± 58.0 µg/kg, exceeding the maximum residue limit. In order to protect consumers' health, it is suggested that the withdrawal time of TMP in Yugan black-bone fowl is 69 days.

Prevalence of Streptococcus suis in pigs in China during 2000-2021: A systematic review and meta-analysis.

Streptococcus suis (S. suis) is one of the most important pathogens affecting pig production worldwide. It can be also transmitted to human through the behaviors of eating undercooked pork or slaughtering sick pigs. A meta-analysis was conducted to estimate the prevalence across different geographical areas in China. Forty-three articles were included and distributed in 22 provinces of China. The prevalence of S. suis infection in pigs varied from 4.2% to 93.7%, with a summary estimate of 40.8% (95%CI, 32.9-48.6%). Six provinces, classified as frequent outbreaks in human cases, had a higher prevalence (52.7%, 95%CI: 43.7-61.6%) than other provinces (36.0%, 95%CI: 27.0-44.9%). Jiangsu province had the highest prevalence with 73.1% (95%CI: 70.42-75.68%), followed by Hunan (59.64%, 95%CI: 55.83-63.37%), Shanxi (55.56%, 95%CI: 47.05-63.83%), and Guangxi (50.55%, 95%CI: 49.45-51.64%). The prevalence has been decreasing gradually, from 47.6% (95%CI: 38.1-57.1%) before 2010, then dropped to 39.1% (95%CI: 25.5-52.8%) during 2011-2015, and reached the lowest in recent five years (2016-2020), with 34.3% (95%CI: 23.1-45.4%). The study findings showed that S. suis was presented in pig populations of most provinces of China, which indicated that effective control measures in pigs should be implemented. Our results also provided solid evidence for the early warning and prevention of human S. suis infection in China, which would mitigate the risk to humans.

Application of intraoperative radiotherapy for malignant glioma.

Malignant glioma is characterized by rapid tumor cell proliferation and high recurrence risk. In terms of its treatment, the therapeutic effects of maximum resection and postoperative radiotherapy with adjuvant chemotherapy as well as many other new therapeutic techniques such as antiangiogenic therapy and immunotherapy remain poor. Glioma recurrence, especially local recurrence, is an important reason of glioma treatment failure. Intraoperative radiotherapy (IORT) enables exclusion of radiation-sensitive normal tissue from the radiation field in operation and then the application of a single high-dose precision irradiation to the residual tumor or tumor bed. IORT has great application potential in the control of local recurrence of malignant tumors. This paper thus aims to review the current status and prospects of IORT's application in malignant glioma treatment.

Toxicity, Disease Control, and Survival Outcomes of Intensified Preoperative Chemoradiotherapy in Patients with Locally Advanced Rectal Cancer: A Single-Institution Study.

Purpose: The standard treatment regimen of preoperative chemoradiotherapy (CRT) for locally advanced rectal cancer (LARC) is still controversial. The purpose of this study was to analyze the efficacy and safety of preoperative intensive CRT in our institution. Methods: A retrospective data collection and analysis of 181 LARC patients receiving oxaliplatin (85%) of standard doses in capecitabine-based preoperative CRT and two additional cycle of neoadjuvant chemotherapy between the end of concurrent CRT and surgery. Results: The compliance of the preoperative CRT was satisfactory with 99.4%patients completed radiotherapy and 97.19%patients completed all 2 cycles of concurrent chemotherapy. Except for 20 patients diagnosed clinical complete remission (cCR) managed according to watch and wait strategy, 160 patients received R0 radical surgery. The pathological complete response (pCR) rate was 23.75% (38/160) and tumor regression grade (TRG) 0/1 was 40% (72/180). In terms of tumor downstaging, 89 (55.63%) had T downstaging while 115 (71.88%) had N downstaging. The 1-overall survival (OS),2-OS,3-OS and 5-OS were 98.7%, 96.5%, 91.4% and 81.5%, respectively. The total rate of sphincter preservation was 86.25% (138/160) and the rate of patients with low rectal cancer was 73.0% (54/74) without affecting local control rates and survival rates. Both acute adverse reactions to preoperative CRT and postoperative complications were tolerable and controllable. Conclusion: In this retrospective study, preoperative intensive CRT of patients with LARC achieved satisfied disease control and survival outcomes and well acquired the sphincter retention rate in recent years in our institution. On the basis of these findings, a Phase III study to definitively test the intensified preoperative CRT strategy is warranted.

Associated Behavioral Factors and Prevalence of the Common Anorectal Disease Among Uyghur Male Adults of China: A Population-Based Crosssectional Study.

Objectives: We investigated the behavioral associated factors and prevalence of common anorectal disease (hemorrhoids, perianal pruritus, anal fistula, and others) among Uyghur male adults in southern Xinjiang. Methods: We conducted a cross-sectional study with a random sampling method from December 2020 to March 2021. Uyghur males aged 18 years and older were selected from Kashgar Prefecture in Xinjiang. The prevalence was evaluated by a bilingual questionnaire (including socio- demographic information, dietary habit, lifestyle, and behavioral habits) and anorectal examinations. The chi-square test was used for categorical variables. Logistic regression analysis was used to identify potential associated factors.Results: A total of 402 Uygur males aged ≥ 18 years were included in the final analysis. Of those, 192 (47.8%) participants were identified with common anorectal disease (CAD). Older age, lower education attainment, being a farmer, having lower personal annual income, having a high level of alcohol consumption, performing less anus-rinsing after defecation, and having less pubic hair removal were significantly associated with CAD. Conclusions: Common anorectal disease is a significant public health concern for the Uygur male population. Anus-rinsing after defecation and pubic hair removal are ethnic-specific behaviors among Uygur and could be preventive strategies for CAD.

The efficacy and adverse effects of anlotinib in the treatment of high-grade glioma: A retrospective analysis.

Introduction: Anlotinib, a novel multi-kinase inhibitor, was found to improve progression-free survival (PFS) in brain metastases. Methods: This paper retrospectively analyzed 26 newly diagnosed or recurrent high-grade gliomas from 2017 to 2022, and the patients received oral anlotinib during concurrent postoperative chemoradiotherapy or after recurrence. Efficacy was evaluated according to the Response Assessment in Neuro-Oncology (RANO) criteria, and the main study endpoints were PFS at 6 months and overall survival (OS) at 1 year. Results: After the follow-up, until May 2022, 13 patients survived and 13 patients died, with a median follow-up time of 25.6 months. The disease control rate (DCR) was 96.2% (25/26), and the overall response rate (ORR) rate was 73.1% (19/26). The median PFS after oral anlotinib was 8.9 months (0.8-15.1), and the PFS at 6 months was 72.5%. The median OS after oral anlotinib was 12 months (1.6-24.4), and the OS at 12 months was 42.6%. Anlotinib-related toxicities were observed in 11 patients, mostly grades 1-2. In the multivariate analysis, patients with Karnofsky Performance Scale (KPS) above 80 had a highermedian PFS of 9.9months (p = 0.02), and their sex, age, IDH mutation, MGMTmethylation, and whether anlotinib was combined with chemoradiotherapy or maintenance treatment had no effect on PFS. Conclusion: We found that anlotinib combined with chemoradiotherapy in treating high-grade central nervous system (CNS) tumors can prolong PFS and OS and that it was safe.

Elevated prelimbic cortex-to-basolateral amygdala circuit activity mediates comorbid anxiety-like behaviors associated with chronic pain.

Chronic pain can cause both hyperalgesia and anxiety symptoms. However, how the two components are encoded in the brain remains unclear. The prelimbic cortex (PrL), a critical brain region for both nociceptive and emotional modulations, serves as an ideal medium for comparing how the two components are encoded. We report that PrL neurons projecting to the basolateral amygdala (PrLBLA) and those projecting to the ventrolateral periaqueductal gray (PrLl/vlPAG) were segregated and displayed elevated and reduced neuronal activity, respectively, during pain chronicity. Consistently, optogenetic suppression of the PrL-BLA circuit reversed anxiety-like behaviors, whereas activation of the PrL-l/vlPAG circuit attenuated hyperalgesia in mice with chronic pain. Moreover, mechanistic studies indicated that elevated TNF-α/TNFR1 signaling in the PrL caused increased insertion of GluA1 receptors into PrLBLA neurons and contributed to anxiety-like behaviors in mice with chronic pain. Together, these results provide insights into the circuit and molecular mechanisms in the PrL for controlling pain-related hyperalgesia and anxiety-like behaviors.

Astrocytic lactate dehydrogenase A regulates neuronal excitability and depressive-like behaviors through lactate homeostasis in mice.

Alterations in energy metabolism are associated with depression. However, the role of glycolysis in the pathogenesis of depression and the underlying molecular mechanisms remain unexplored. Through an unbiased proteomic screen coupled with biochemical verifications, we show that the levels of glycolysis and lactate dehydrogenase A (LDHA), a glycolytic enzyme that catalyzes L-lactate production, are reduced in the dorsomedial prefrontal cortex (dmPFC) of stress-susceptible mice in chronic social defeat stress (CSDS) model. Conditional knockout of LDHA from the brain promotes depressive-like behaviors in both male and female mice, accompanied with reduced L-lactate levels and decreased neuronal excitability in the dmPFC. Moreover, these phenotypes could be duplicated by knockdown of LDHA in the dmPFC or specifically in astrocytes. In contrast, overexpression of LDHA reverses these phenotypic changes in CSDS-susceptible mice. Mechanistic studies demonstrate that L-lactate promotes neuronal excitability through monocarboxylic acid transporter 2 (MCT2) and by inhibiting large-conductance Ca2+-activated potassium (BK) channel. Together, these results reveal a role of LDHA in maintaining neuronal excitability to prevent depressive-like behaviors.

Bifurcation analysis of a sheep brucellosis model with testing and saturated culling rate.

Testing-culling is a very effective measure for the prevention and control of animal diseases. In this paper, based on sheep brucellosis control policies and animal testing characteristics and considering the limitation of culling resources, a dynamic model is established to study the impact of testing-culling measure. Theoretical analysis reveals that the model may have one or three positive equilibria. The equilibrium in the middle is always unstable, and the model shows saddle-node bifurcation, generalized Hopf bifurcation and Bogdanov-Takens bifurcation. Moreover, the theoretical results are verified via numerical analysis. These results reveal that testing and culling strategies can induce complex transmission dynamics that can help us develop appropriate prevention and control measures for animal brucellosis.