KCNH5 deletion increases autism susceptibility by regulating neuronal growth through Akt/mTOR signaling pathway.

Recent clinical studies have highlighted mutations in the voltage-gated potassium channel Kv10.2 encoded by the KCNH5 gene among individuals with autism spectrum disorder (ASD). Our preliminary study found that Kv10.2 was decreased in the hippocampus of valproic acid (VPA) - induced ASD rats. Nevertheless, it is currently unclear how KCNH5 regulates autism-like features, or becomes a new target for autism treatment. We employed KCNH5 knockout (KCNH5-/-) rats and VPA - induced ASD rats in this study. Then, we used behavioral assessments, combined with electrophysiological recordings and hippocampal brain slice, to elucidate the impact of KCNH5 deletion and environmental factors on neural development and function in rats. We found that KCNH5-/- rats showed early developmental delay, neuronal overdevelopment, and abnormal electroencephalogram (EEG) signals, but did not exhibit autism-like behavior. KCNH5-/- rats exposed to VPA (KCNH5-/--VPA) exhibit even more severe autism-like behaviors and abnormal neuronal development. The absence of KCNH5 excessively enhances the activity of the Protein Kinase B (Akt)/Mechanistic Target of Rapamycin (mTOR) signaling pathway in the hippocampus of rats after exposure to VPA. Overall, our findings underscore the deficiency of KCNH5 increases the susceptibility to autism under environmental exposures, suggesting its potential utility as a target for screening and diagnosis in ASD.

Nab-Paclitaxel for Relapsed AIDS-Related Kaposi Sarcoma -A Case Report.

Introduction: Kaposi sarcoma (KS) incidence has decreased since the initiation of combination antiretroviral therapy (cART), but it remains the most common cancer in people with HIV/AIDS (PWHA). PWHA with advanced immunosuppression who initiate antiretroviral therapy are susceptible to the occurrence of an immune reconstitution inflammatory syndrome (IRIS). Case Presentation: This report covers the case of a 25-year-old male with AIDS-related KS who relapsed after Liposomal Doxorubicin, but recovered well after administration of nab-paclitaxel (Nab-PTX). Conclusion: This is a rare case in choosing Nab-PTX to treat relapsed AIDS-KS and get good feedback. We report the case to provide a possible solution to treat AIDS-KS.

Disseminated Mycobacterium thermoresistibile Infection presented with Lymphadenectasis in an AIDS patient: case report and review of literature.

BACKGROUND: Nontuberculous mycobacteria disease is a common invasive infectious disease in patients with HIV. However, Mycobacterium thermoresistibile association with lymphadenectasis is unusual in AIDS patients. CASE PRESENTATION: This report covers the case of a 25-year-old male AIDS patient infected with Mycobacterium thermoresistibile. The case was identified via pathogen-targeted next-generation sequencing (ptNGS). CONCLUSION: This is the first report of disseminated M. thermoresistibile infection presented with lymphadenectasis in an AIDS patient. Prompt diagnosis and antimicrobial treatment are crucial.

Osteoarticular infection caused by Talaromyces Marneffei and Salmonella in a person living with HIV: a case report.

INTRODUCTION: Talaromycosis is a common invasive fungal disease in patients with HIV. However, its association with bone destruction is unusual in AIDS patients with talaromycosis. CASE PRESENTATION: This report covers the case of a 38-year-old male AIDS patient coinfected with Talaromyces marneffei and Salmonella. The case, which involved bone destruction, was identified via metagenomic next-generation sequencing (mNGS). Following treatment with a combination of amphotericin B and piperacillin-tazobactam, the patient's elbow motion noticeably improved. Imaging findings revealed that the progression of bony destruction had halted. CONCLUSION: Bone damage due to Talaromyces marneffei infection is infrequent in HIV-positive patients. Therefore, healthcare professionals must be vigilant for potential bone lesions associated with this type of infection. Prompt diagnosis and antimicrobial treatment are crucial.

Deletion of Arrb2 Down-regulates Autophagy in the Mouse Hippocampus via Akt-mTOR Pathway Activation.

The cytoplasmic multifunctional adaptor protein ß-arrestin 2 (Arrb2) is involved in the occurrence of various nervous system diseases, such as Alzheimer's disease and Parkinson's disease. Previous laboratory studies have shown that the expression and function of the Arrb2 gene was increased in valproic acid-induced autistic mice models. However, few reports have examined the possible role of Arrb2 in the pathogenesis of autism spectrum disorder. Therefore, Arrb2-deficient (Arrb2-/-) mice were further studied to uncover the physiological function of Arrb2 in the nervous system. In this study, we found that Arrb2-/- mice had normal behavioral characteristics compared with wild-type mice. The autophagy marker protein LC3B was decreased in the hippocampus of Arrb2-/- mice compared to wild-type mice. Western blot analysis revealed that deletion of Arrb2 caused hyperactivation of Akt-mTOR signaling in the hippocampus. In addition, abnormal mitochondrial dysfunction was observed in Arrb2-/- hippocampal neurons, which was characterized by a reduction in mitochondrial membrane potential and adenosine triphosphate production and an increase in reactive oxygen species levels. Therefore, this study elucidates the interaction between Arrb2 and the Akt-mTOR signaling pathway and provides insights into the role of Arrb2 in hippocampal neuron autophagy.

Transmission dynamics of SARS-CoV-2 Omicron variant infections in Hangzhou, Zhejiang, China, January-February 2022.

OBJECTIVES: We aimed to explore the transmission dynamics of the Omicron BA.1.1 variant in an outbreak in China. METHODS: We constructed 113 transmission pairs based on the time of exposure and symptom onset for identified infectors and infectees, using the epidemiological data collected during an outbreak in Hangzhou, Zhejiang province, China, between January and February 2022. The key epidemiological parameters were estimated. RESULTS: The mean estimates of the incubation period and latent period distributions were 3.8 days (95% credible interval: 3.5, 4.1) and 3.1 days (2.8, 3.5), respectively. The overall transmission risk peaked at symptom onset, and we estimated that 33.6% (24.8, 42.5) of transmission occurred before symptom onset. The forward generation time decreased from 5.2 days (4.7, 5.7) at the start of the outbreak to 2.2 days (2.0, 2.5) by the end. Allowing this variation over time in the generation time distribution, we estimated that the reproduction number dropped rapidly from 9.5 (3.5, 18.4) to 0.8 (0.3, 1.5) over the outbreak. CONCLUSION: Shorter incubation period and latent period were estimated for the Omicron BA.1.1 variant. Stringent public health measures prevented a large epidemic by reducing transmission, as indicated by the shortened generation time.

Methane and nitrous oxide concentrations and fluxes from heavily polluted urban streams: Comprehensive influence of pollution and restoration.

Streams draining urban areas are usually regarded as hotspots of methane (CH4) and nitrous oxide (N2O) emissions. However, little is known about the coupling effects of watershed pollution and restoration on CH4 and N2O emission dynamics in heavily polluted urban streams. This study investigated the CH4 and N2O concentrations and fluxes in six streams that used to be heavily polluted but have undergone different watershed restorations in Southwest China, to explore the comprehensive influences of pollution and restoration. CH4 and N2O concentrations in the six urban streams ranged from 0.12 to 21.32 µmol L-1 and from 0.03 to 2.27 µmol L-1, respectively. The calculated diffusive fluxes of CH4 and N2O were averaged of 7.65 ± 9.20 mmol m-2 d-1 and 0.73 ± 0.83 mmol m-2 d-1, much higher than those in most previous reports. The heavily polluted streams with non-restoration had 7.2 and 7.8 times CH4 and N2O concentrations higher than those in the fully restored streams, respectively. Particularly, CH4 and N2O fluxes in the fully restored streams were 90% less likely than those found in the unrestored ones. This result highlighted that heavily polluted urban streams with high pollution loadings were indeed hotspots of CH4 and N2O emissions throughout the year, while comprehensive restoration can effectively weaken their emission intensity. Sewage interception and nutrient removal, especially N loadings reduction, were effective measures for regulating the dynamics of CH4 and N2O emissions from the heavily polluted streams. Based on global and regional integration, it further elucidated that increasing environment investments could significantly improve water quality and mitigate CH4 and N2O emissions in polluted urban streams. Overall, our study emphasized that although urbanization could inevitably strengthen riverine CH4 and N2O emissions, effective eco-restoration can mitigate the crisis of riverine greenhouse gas emissions.

Improving Human Happiness Analysis Based on Transfer Learning: Algorithm Development and Validation.

BACKGROUND: Happiness refers to the joyful and pleasant emotions that humans produce subjectively. It is the positive part of emotions, and it affects the quality of human life. Therefore, understanding human happiness is a meaningful task in sentiment analysis. OBJECTIVE: We mainly discuss 2 facets (Agency/Sociality) of happiness in this paper. Through analysis and research on happiness, we can expand on new concepts that define happiness and enrich our understanding of emotions. METHODS: This paper treated each happy moment as a sequence of short sentences, then proposed a short happiness detection model based on transfer learning to analyze the Agency and Sociality aspects of happiness. First, we utilized the unlabeled training set to retrain the pretraining language model Bidirectional Encoder Representations from Transformers (BERT) and got a semantically enhanced language model happyBERT in the target domain. Then, we got several single text classification models by fine-tuning BERT and happyBERT. Finally, an improved voting strategy was proposed to integrate multiple single models, and "pseudo data" were introduced to retrain the combined models. RESULTS: The proposed approach was evaluated on the public dataset happyDB. Experimental results showed that our approach significantly outperforms the baselines. When predicting the Agency aspect of happiness, our approach achieved an accuracy of 0.8653 and an F1 score of 0.9126. When predicting Sociality, our approach achieved an accuracy of 0.9367 and an F1 score of 0.9491. CONCLUSIONS: By evaluating the dataset, the comparison results demonstrated the effectiveness of our approach for happiness analysis. Experimental results confirmed that our method achieved state-of-the-art performance and transfer learning effectively improved happiness analysis.

Adoptive Transfer of Autologous Invariant Natural Killer T Cells as Immunotherapy for Advanced Hepatocellular Carcinoma: A Phase I Clinical Trial.

LESSONS LEARNED: Administration of autologous invariant natural killer T (iNKT) cells was safe and well-tolerated in patients with hepatocellular carcinoma (Barcelona Clinic Liver Cancer stage B/C). Expanded iNKT cells produced T-helper 1-like responses with possible antitumor activity. No severe adverse events were observed in any of the enrolled patients, including one patient who received 1010 in vitro-expanded autologous iNKT cells as a single infusion. BACKGROUND: Invariant natural killer T cells co-express T-cell antigen receptor and natural killer (NK) cell receptors. Invariant natural killer T (iNKT) cells exhibit antitumor activity, but their numbers and functions are impaired in patients with hepatocellular carcinoma (HCC). The adoptive transfer of iNKT cells might treat advanced HCC. METHODS: This phase I study (NCT03175679) enrolled 10 patients with HCC (Barcelona Clinic Liver Cancer [BCLC] stage B/C) at Beijing YouAn Hospital (April 2017 to May 2018). iNKT cells isolated from peripheral blood mononuclear cells (PBMCs) were expanded and alpha-galactosylceramide (α-GalCer)-pulsed. Dosage escalated from 3 × 107 to 6 × 107 to 9 × 107 cells/m2 (3+3 design). An exploratory dose trial (1 × 1010 cells/m2 ) was conducted in one patient. RESULTS: Expanded iNKT cells produced greater quantities of T-helper 1 (Th1) cytokines (e.g., interferon-gamma, perforin, and granzyme B) but less interleukin-4 than nonexpanded iNKT cells. Circulating numbers of iNKT cells and activated NK cells were increased after iNKT cell infusion. Most treatment-related adverse events were grade 1-2, and three grade 3 adverse events were reported; all resolved without treatment. Four patients were progression-free at 5.5, 6, 7, and 11 months after therapy, and one patient was alive and without tumor recurrence at the last follow-up. Five patients died at 1.5 to 11 months after treatment. CONCLUSION: Autologous iNKT cell treatment is safe and well-tolerated. Expanded iNKT cells produce Th1-like responses with possible antitumor activity. The antitumor effects of iNKT cell infusion in patients with advanced HCC merit further investigation.

pCO2 and CO2 evasion from two small suburban rivers: Implications of the watershed urbanization process.

Rivers are widely reported as CO2-emitting hotpots and are attracting increasing attention worldwide. However, less attention has been given to the CO2 emission from the suburban rivers which are experiencing rapid watershed urbanization and increasing anthropogenic stress. Here, two small suburban rivers in Southwest China were studied, and seasonal sampling campaigns with high spatial resolution were carried out to explore the characterization of partial pressure (pCO2) and CO2 efflux and their possible controls. The results showed that, the pCO2 and estimated CO2 fluxes from the two suburban rivers ranged from 37 to 6466 µatm (mean of 1293 ± 1126 µatm) and -72-1569 mmol·m-2·d-1 (mean of 185 ± 240 mmol·m-2·d-1), respectively. And, both of them exhibited disproportionately high variability and acted as strong CO2 emitters to the atmosphere. The pCO2 in the two suburban rivers showed significant spatial variability, with urban sections having 2-2.5 times higher values than exurban sections, and, the urban land use proportion in the basins accounted for 35%-67% of such spatial variation in pCO2. The sewage-dominated urban tributaries had much higher pCO2 and acted as an obvious exciter to the high pCO2 in urban sections of suburban rivers. Carbon and nutrients concentrations also accounted for the spatial variation in pCO2 and fCO2 in the two suburban rivers, and acted as good indicators. The seasonal variation in pCO2, with the highest values in autumn and lowest values in spring, was controlled by the precipitation dilution effect and seasonal temperature as well as the boosted primary production at several urban sites. We highlighted that small suburban rivers showed disproportionally high spatial variability in pCO2 and CO2 fluxes in their limited basin areas due to the development of urbanization, and could be used as a good model for studying the complex impacts of anthropogenic disturbances on river carbon biogeochemical processes.

Serum microRNAs predict response of patients with chronic hepatitis B to antiviral therapy.

OBJECTIVES: To investigate the feasibility of using serum microRNAs to predict the response of chronic hepatitis B (CHB) patients to antiviral therapy over 48 weeks. METHODS: Sixty-five CHB patients were divided into responder and non-responder groups according to whether hepatitis B e antigen seroconversion occurred at week 48. Serum microRNAs were dynamically detected. RESULTS: At baseline, the responder group had lower miR-122-5p (P = 0.006) and higher miR-1307-3p (P = 0.018) than the non-responder group. After therapy, miR-320a-3p and miR-320c were higher in the responder group than the non-responder group (P = 0.043 and 0.031, respectively). In the responder group, 9 microRNAs-let-7d-5p, let-7f-5p, let-7i-5p, miR-126-3p, miR-1307-3p, miR-181a-5p, miR-21-5p, miR-425-5p and miR-652-3p-were significantly lower at week 48 than at baseline (P < 0.05); however, miR-320a-3p was significantly elevated after therapy (P < 0.001). In the non-responder group, miR-122-5p significantly decreased after therapy compared with baseline (P = 0.005). Finally, miR-122-5p was positively correlated with titer of hepatitis B virus DNA (r = 0.438, P = 0.008) and hepatitis B e antigen (r = 0.610, P < 0.001), and miR-320a-3p was negatively correlated with hepatitis B virus DNA titer (r = -0.366, P = 0.028) at baseline. CONCLUSIONS: The dynamic fluctuations of serum microRNAs might predict the efficacy of antiviral therapy for CHB.

The combination therapy of Peginterferonα and entecavir for HBeAg-positive chronic hepatitis B with high HCC risk.

The population of HBV infection with family history of hepatocellular carcinoma (HCC) is the high risk group for the development of HCC. The aim of this study was to evaluate the effect of the de novo combination therapy including pegylated-interferon α-2a (PEG-IFNα-2a) and entecavir (ETV) in this high risk population. The study recruited 58 Hepatitis B e Antigen (HBeAg)-Positive CHB patients patients with HBV-DNA > 107 IU/mL, genotype B or C and HCC family history and were treated for 48 weeks. Patients without HBeAg loss at the 48th week were 40 patients and extended the combination therapy to 96 weeks. All patients were followed up to 120 weeks. The rate of HBeAg loss and HBsAg loss was 12/40(30.0%) and 2/40(5.0%) at week 120 respectively. When logistic regression analysis was used to identify viables of HBeAg loss, HBV-DNA levels <20 IU/mL at week 48 was found to have a 6.02 fold increased probability (95% CI = 1.17-30.40, P = .03) of HBeAg loss. Patients with HBV-DNA levels <20 IU/mL at week 48 had a high probability of HBeAg loss 8/17(47.1%), HBsAg loss 2/17(11.8%), compared to 4/23(17.4%), 0/23(0%) in patients with HBV-DNA ≥ 20 IU/mL. Combination therapy for 96 weeks was well tolerated. During the combination therapy, low-level viremia during treatment is reversely associated with response. The combination therapy of PEG-IFNα and ETV was suggested to extend to 96 weeks when HBV-DNA was completed suppressed at week 48.

Three glycoside hydrolase family 12 enzymes display diversity in substrate specificities and synergistic action between each other.

PoCel12A, PoCel12B, and PoCel12C are genes that encode glycoside hydrolase family 12 (GH12) enzymes in Penicillium oxalicum. PoCel12A and PoCel12B are typical GH12 enzymes that belong to fungal subfamilies 12-1 and 12-2, respectively. PoCel12C contains a low-complexity region (LCR) domain, which is not found in PoCel12A or PoCel12B and independent of fungal subfamily 12-1 or 12-2. Recombinant enzymes (named rCel12A, rCel12B and rCel12C) demonstrate existing diversity in the substrate specificities. Although most members in GH family 12 are typical endoglucanases and preferentially hydrolyze ß-1,4-glucan (e.g., carboxymethylcellulose), recombinant PoCel12A is a non-typical endo-(1-4)-ß-glucanase; it preferentially hydrolyzes mix-linked ß-glucan (barley ß-glucan, ß-1,3-1,4-glucan) and slightly hydrolyzes ß-1,4-glucan (carboxymethylcellulose). Recombinant PoCel12B possesses a significantly high activity against xyloglucan. A specific activity of rCel12B toward xyloglucan (239 µmol/min/mg) is the second-highest value known. Recombinant PoCel12C shows low activity toward ß-glucan, carboxymethylcellulose, or xyloglucan. All three enzymes can degrade phosphoric acid-swollen cellulose (PASC). However, the hydrolysis products toward PASC by enzymes are different: the main hydrolysis products are cellotriose, cellotetraose, and cellobiose for rCel12A, rCel12B, and rCel12C, correspondingly. A synergistic action toward PASC among rCel12A and rCel12B is observed, thereby suggesting a potential application for preparing enzyme cocktails used in lignocellulose hydrolysis.

Constitutive Expression of Chimeric Transcription Factors Enables Cellulase Synthesis under Non-Inducing Conditions in Penicillium oxalicum.

Industrial production of cellulase by filamentous fungi is largely dependent on cellulose, which serves as a natural inducer of cellulase expression. However, insoluble cellulose is unfavorable to submerged fermentation and thus limits the production level of cellulase. The possibility of cellulase production under non-inducing conditions is explored in Penicillium oxalicum by overexpressing two chimeric transcription factors. The chimeric transcription factors contain the DNA binding domain of cellulase transcriptional activator ClrB linked to the C-terminal sequences of XlnRA871V , a constitutively active mutant of hemicellulase transcriptional activator. The obtained recombinant mutants exhibited dramatically improved basal production of cellulase, which was not observed with the overexpression of intact ClrB. When cultivated in a complex cellulosic medium, one of these mutants, OE-CXC -S-1, displayed a 7.3-fold increase in cellulase production (2.8 U mL-1 ) relative to the parent strain. The results demonstrate that the dependence of cellulase synthesis on cellulose could be reduced by the overexpression of artificially designed chimeric transcription factors, and offers a potential strategy to engineer fungal strains for improving cellulase production.

Combining manipulation of transcription factors and overexpression of the target genes to enhance lignocellulolytic enzyme production in Penicillium oxalicum.

BACKGROUND: Lignocellulolytic enzymes are the main enzymes to saccharify lignocellulose from renewable plant biomass in the bio-based economy. The production of these enzymes is transcriptionally regulated by multiple transcription factors. We previously engineered Penicillium oxalicum for improved cellulase production via manipulation of three genes in the cellulase expression regulatory network. However, the potential of combinational engineering of multiple regulators and their targets at protein abundance and activity levels has not been fully explored. RESULTS: Here, we verified that a point mutation XlnRA871V in transcription factor XlnR enhanced the expression of lignocellulolytic enzymes, particularly hemicellulases, in P. oxalicum. Then, overexpression of XlnRA871V with a constitutive PDE_02864 promoter was combined with the overexpression of cellulase transcriptional activator ClrB and deletion of carbon catabolite repressor CreA. The resulted strain RE-7 showed 8.9- and 51.5-fold increased production of cellulase and xylanase relative to the starting strain M12, respectively. Further overexpression of two major cellulase genes cbh1-2 and eg1 enabled an additional 13.0% improvement of cellulase production. In addition, XlnRA871V led to decreased production of ß-glucosidase and amylase, which could be attributed to the reduced transcription of corresponding enzyme-encoding genes. CONCLUSIONS: The results illustrated that combinational manipulation of the involved transcription factors and their target genes was a viable strategy for efficient production of lignocellulolytic enzymes in filamentous fungi. The striking negative effect of XlnRA871V mutation on amylase production was also highlighted.

Multipotent Adult Progenitor Cells from Bone Marrow Differentiate into Chondrocyte-Like Cells.

Cartilage tissue engineering has great potential for treating chondral and osteochondral injuries. Efficient seed cells are the key to cartilage tissue engineering. Multipotent adult progenitor cells (MAPCs) have greater differentiation ability than other bone-marrow stem cells, and thus may be candidate seed cells. We attempted to differentiate MAPCs into chondrocyte-like cells to evaluate their suitability as seed cells for cartilage tissue engineering. Toluidine blue and Alcian blue staining suggested that glycosaminoglycan was expressed in differentiated cells. Immunofluorostaining indicated that differentiated human MAPCs (hMAPCs) expressed collagen II. Based on these results, we concluded that bone-marrow-derived hMAPCs could differentiate into chondrocyte-like cells in vitro.

Virus-encoded miR-155 ortholog is an important potential regulator but not essential for the development of lymphomas induced by very virulent Marek's disease virus.

The microRNA (miRNA) mdv1-miR-M4, a functional miR-155 ortholog encoded by oncogenic Marek's disease virus (MDV), has previously been suggested to be involved in MDV pathogenesis. Using the technique of bacterial artificial chromosome mutagenesis, we have presently evaluated the potential role of mdv1-miR-M4 in the oncogenesis of the very virulent (vv) MDV strain GX0101. Unexpectedly, deletions of the Meq-cluster or mdv1-miR-M4 alone from the viral genome strongly decreased rather than abolished its oncogenicity. Compared to GX0101, mortalities of mutants GXΔmiR-M4 and GXΔMeq-miRs were reduced from 100% to 18% and 4%, coupled with the gross tumor incidence reduction from 28% to 22% and 8%, respectively. Our data suggests that the mdv1-miR-M4 is possibly an important regulator in the development of Marek's disease (MD) lymphomas but is not essential for the oncogenicity of vvMDV. In addition, some of the other Meq-clustered miRNAs may also play potentially critical roles in vvMDV induction of lymphomas.

Molecular characteristics and evolutionary analysis of field Marek's disease virus prevalent in vaccinated chicken flocks in recent years in China.

Marek's disease is a highly contagious, oncogenic, and immunosuppressive avian viral disease. Surveillance of newly registered Marek's disease virus (MDV) isolates is meaningful for revealing the potential factors involved in increased virulence. Presently, we have focused on the molecular characteristics of all available MDVs from China, including 17 new Henan isolates. Based on Meq, gE, and gI genes, we found that most Chinese isolates contain conserved amino acid point mutations in Meq, such as E(77), A(115), A(139), R(176), and A(217), compared to USA virulent MDVs. However, the 59-aa or 60-aa insertions are only found in a few mild MDVs rather than virulent MDVs in China. Further phylogenetic analysis has demonstrated that a different genotype of MDV has been prevalent in China, and for virulent MDVs, their recent evolution has possibly been geographically restricted. Our study has provided more detailed information regarding the field MDVs circulating in China.