Safety and Immunogenicity of SARS-CoV-2 Vaccines in Patients With Chronic Liver Diseases (CHESS-NMCID 2101): A Multicenter Study.

BACKGROUND & AIMS: We aimed to assess the safety and immunogenicity of inactivated whole-virion severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines in patients with chronic liver diseases (CLD) in this study. METHODS: This was a prospective, multi-center, open-label study. Participants aged over 18 years with confirmed CLD and healthy volunteers were enrolled. All participants received 2 doses of inactivated whole-virion SARS-CoV-2 vaccines. Adverse reactions were recorded within 14 days after any dose of SARS-CoV-2 vaccine, laboratory testing results were collected after the second dose, and serum samples of enrolled subjects were collected and tested for SARS-CoV-2 neutralizing antibodies at least 14 days after the second dose. RESULTS: A total of 581 participants (437 patients with CLD and 144 healthy volunteers) were enrolled from 15 sites in China. Most adverse reactions were mild and transient, and injection site pain (n = 36; 8.2%) was the most frequently reported adverse event. Three participants had grade 3 aminopherase elevation (defined as alanine aminopherase >5 upper limits of normal) after the second dose of inactivated whole-virion SARS-CoV-2 vaccination, and only 1 of them was judged as severe adverse event potentially related to SARS-CoV-2 vaccination. The positive rates of SARS-CoV-2 neutralizing antibodies were 76.8% in the noncirrhotic CLD group, 78.9% in the compensated cirrhotic group, 76.7% in the decompensated cirrhotic group (P = .894 among CLD subgroups), and 90.3% in healthy controls (P = .008 vs CLD group). CONCLUSION: Inactivated whole-virion SARS-CoV-2 vaccines are safe in patients with CLD. Patients with CLD had lower immunologic response to SARS-CoV-2 vaccines than healthy population. The immunogenicity is similarly low in noncirrhotic CLD, compensated cirrhosis, and decompensated cirrhosis.

Safety and immunogenicity of COVID-19 vaccination in patients with hepatocellular carcinoma (CHESS-NMCID 2101): A multicenter prospective study.

Data on safety and immunogenicity of coronavirus disease 2019 (COVID-19) vaccinations in hepatocellular carcinoma (HCC) patients are limited. In this multicenter prospective study, HCC patients received two doses of inactivated whole-virion COVID-19 vaccines. The safety and neutralizing antibody were monitored. Totally, 74 patients were enrolled from 10 centers in China, and 37 (50.0%), 25 (33.8%), and 12 (16.2%) received the CoronaVac, BBIBP-CorV, and WIBP-CorV, respectively. The vaccines were well tolerated, where pain at the injection site (6.8% [5/74]) and anorexia (2.7% [2/74]) were the most frequent local and systemic adverse events. The median level of neutralizing antibody was 13.5 (interquartile range [IQR]: 6.9-23.2) AU/ml at 45 (IQR: 19-72) days after the second dose of vaccinations, and 60.8% (45/74) of patients had positive neutralizing antibody. Additionally, lower γ-glutamyl transpeptidase level was related to positive neutralizing antibody (odds ratio = 1.022 [1.003-1.049], p = 0.049). In conclusion, this study found that inactivated COVID-19 vaccinations are safe and the immunogenicity is acceptable or hyporesponsive in patients with HCC. Given that the potential benefits may outweigh the risks and the continuing emergences of novel severe acute respiratory syndrome coronavirus 2 variants, we suggest HCC patients to be vaccinated against COVID-19. Future validation studies are warranted.

Transplantation of GABAergic Interneurons into the Neonatal Primary Visual Cortex Reduces Absence Seizures in Stargazer Mice.

Epilepsies are debilitating neurological disorders characterized by repeated episodes of pathological seizure activity. Absence epilepsy (AE) is a poorly understood type of seizure with an estimated 30% of affected patients failing to respond to antiepileptic drugs. Thus, novel therapies are needed for the treatment of AE. A promising cell-based therapeutic strategy is centered on transplantation of embryonic neural stem cells from the medial ganglionic eminence (MGE), which give rise to gamma-aminobutyric acidergic (GABAergic) interneurons during embyronic development. Here, we used the Stargazer (Stg) mouse model of AE to map affected loci using c-Fos immunohistochemistry, which revealed intense seizure-induce activity in visual and somatosensory cortices. We report that transplantation of MGE cells into the primary visual cortex (V1) of Stg mice significantly reduces AE episodes and lowers mortality. Electrophysiological analysis in acute cortical slices of visual cortex demonstrated that Stg V1 neurons exhibit more pronounced increases in activity in response to a potassium-mediated excitability challenge than wildtypes (WT). The defective network activity in V1 was significantly altered following WT MGE transplantation, associating it with behavioral rescue of seizures in Stgs. Taken together, these findings present MGE grafting in the V1 as a possible clinical approach in the treatment of AE.

Neural cell adhesion molecule NrCAM regulates Semaphorin 3F-induced dendritic spine remodeling.

Neuron-glial related cell adhesion molecule (NrCAM) is a regulator of axon growth and repellent guidance, and has been implicated in autism spectrum disorders. Here a novel postsynaptic role for NrCAM in Semaphorin3F (Sema3F)-induced dendritic spine remodeling was identified in pyramidal neurons of the primary visual cortex (V1). NrCAM localized to dendritic spines of star pyramidal cells in postnatal V1, where it was coexpressed with Sema3F. NrCAM deletion in mice resulted in elevated spine densities on apical dendrites of star pyramidal cells at both postnatal and adult stages, and electron microscopy revealed increased numbers of asymmetric synapses in layer 4 of V1. Whole-cell recordings in cortical slices from NrCAM-null mice revealed increased frequency of mEPSCs in star pyramidal neurons. Recombinant Sema3F-Fc protein induced spine retraction on apical dendrites of wild-type, but not NrCAM-null cortical neurons in culture, while re-expression of NrCAM rescued the spine retraction response. NrCAM formed a complex in brain with Sema3F receptor subunits Neuropilin-2 (Npn-2) and PlexinA3 (PlexA3) through an Npn-2-binding sequence (TARNER) in the extracellular Ig1 domain. A trans heterozygous genetic interaction test demonstrated that Sema3F and NrCAM pathways interacted in vivo to regulate spine density in star pyramidal neurons. These findings reveal NrCAM as a novel postnatal regulator of dendritic spine density in cortical pyramidal neurons, and an integral component of the Sema3F receptor complex. The results implicate NrCAM as a contributor to excitatory/inhibitory balance in neocortical circuits.

Optimization of 5-(2,6-dichlorophenyl)-3-hydroxy-2-mercaptocyclohex-2-enones as potent inhibitors of human lactate dehydrogenase.

Optimization of 5-(2,6-dichlorophenyl)-3-hydroxy-2-mercaptocyclohex-2-enone using structure-based design strategies resulted in inhibitors with considerable improvement in biochemical potency against human lactate dehydrogenase A (LDHA). These potent inhibitors were typically selective for LDHA over LDHB isoform (4­10 fold) and other structurally related malate dehydrogenases, MDH1 and MDH2 (>500 fold). An X-ray crystal structure of enzymatically most potent molecule bound to LDHA revealed two additional interactions associated with enhanced biochemical potency.

Identification of substituted 3-hydroxy-2-mercaptocyclohex-2-enones as potent inhibitors of human lactate dehydrogenase.

A novel class of 3-hydroxy-2-mercaptocyclohex-2-enone-containing inhibitors of human lactate dehydrogenase (LDH) was identified through a high-throughput screening approach. Biochemical and surface plasmon resonance experiments performed with a screening hit (LDHA IC50=1.7 µM) indicated that the compound specifically associated with human LDHA in a manner that required simultaneous binding of the NADH co-factor. Structural variation of this screening hit resulted in significant improvements in LDHA biochemical inhibition activity (best IC50=0.18 µM). Two crystal structures of optimized compounds bound to human LDHA were obtained and explained many of the observed structure-activity relationships. In addition, an optimized inhibitor exhibited good pharmacokinetic properties after oral administration to rats (F=45%).

Polysialylated NCAM and ephrinA/EphA regulate synaptic development of GABAergic interneurons in prefrontal cortex.

A novel function for the neural cell adhesion molecule (NCAM) was identified in ephrinA/EphA-mediated repulsion as an important regulatory mechanism for development of GABAergic inhibitory synaptic connections in mouse prefrontal cortex. Deletion of NCAM, EphA3, or ephrinA2/3/5 in null mutant mice increased the numbers and size of perisomatic synapses between GABAergic basket interneurons and pyramidal cells in the developing cingulate cortex (layers II/III). A functional consequence of NCAM loss was increased amplitudes and faster kinetics of miniature inhibitory postsynaptic currents in NCAM null cingulate cortex. NCAM and EphA3 formed a molecular complex and colocalized with the inhibitory presynaptic marker vesicular GABA transporter (VGAT) in perisomatic puncta and neuropil in the cingulate cortex. EphrinA5 treatment promoted axon remodeling of enhanced green fluorescent protein-labeled basket interneurons in cortical slice cultures and induced growth cone collapse in wild-type but not NCAM null mutant neurons. NCAM modified with polysialic acid (PSA) was required to promote ephrinA5-induced axon remodeling of basket interneurons in cortical slices, likely by providing a permissive environment for ephrinA5/EphA3 signaling. These results reveal a new mechanism in which NCAM and ephrinAs/EphA3 coordinate to constrain GABAergic interneuronal arborization and perisomatic innervation, potentially contributing to excitatory/inhibitory balance in prefrontal cortical circuitry.

Alcohol Exposure and Disease Associations: A Mendelian Randomization and Meta-Analysis on Weekly Consumption and Problematic Drinking.

Alcohol consumption significantly impacts disease burden and has been linked to various diseases in observational studies. However, comprehensive meta-analyses using Mendelian randomization (MR) to examine drinking patterns are limited. We aimed to evaluate the health risks of alcohol use by integrating findings from MR studies. A thorough search was conducted for MR studies focused on alcohol exposure. We utilized two sets of instrumental variables-alcohol consumption and problematic alcohol use-and summary statistics from the FinnGen consortium R9 release to perform de novo MR analyses. Our meta-analysis encompassed 64 published and 151 de novo MR analyses across 76 distinct primary outcomes. Results show that a genetic predisposition to alcohol consumption, independent of smoking, significantly correlates with a decreased risk of Parkinson's disease, prostate hyperplasia, and rheumatoid arthritis. It was also associated with an increased risk of chronic pancreatitis, colorectal cancer, and head and neck cancers. Additionally, a genetic predisposition to problematic alcohol use is strongly associated with increased risks of alcoholic liver disease, cirrhosis, both acute and chronic pancreatitis, and pneumonia. Evidence from our MR study supports the notion that alcohol consumption and problematic alcohol use are causally associated with a range of diseases, predominantly by increasing the risk.

Identification of substituted 2-thio-6-oxo-1,6-dihydropyrimidines as inhibitors of human lactate dehydrogenase.

A novel 2-thio-6-oxo-1,6-dihydropyrimidine-containing inhibitor of human lactate dehydrogenase (LDH) was identified by high-throughput screening (IC50=8.1 µM). Biochemical, surface plasmon resonance, and saturation transfer difference NMR experiments indicated that the compound specifically associated with human LDHA in a manner that required simultaneous binding of the NADH co-factor. Structural variation of the screening hit resulted in significant improvements in LDHA biochemical inhibition activity (best IC50=0.48 µM). A crystal structure of an optimized compound bound to human LDHA was obtained and explained many of the observed structure-activity relationships.

Identification of the promoter region and genetic mutations of the porcine GALP gene.

Galanin-like peptide (GALP) gene, encoding a member of the galanin family of neuropeptides involved in reproduction, was differentially expressed in PMSG-hCG stimulated pre-ovulatory ovarian follicles of Chinese Taihu and Large White sows in our previous study. In the present study, promoter region and genetic mutations of the porcine GALP gene were determined. A 1,322 bp contig in 5'-flanking region was predicted to contain 5 potential transcription promoters by Neural Network Promoter Prediction version 2.2. 5'-deletion expression in both CHO and hela cells showed that there were a negative regulatory element at -852 to -803 bp and a positive regulatory element at -1,318 to -1,269 bp. Comparative sequence analyses of Chinese Taihu and Large White GALP gene sequence revealed the c.*27C>G mutation in the 3'-UTR and the c.88-1225C>G mutation in intron 1, which can be detected by HhaI and AluI PCR-RFLP, respectively. The association analysis with litter size traits showed that at both loci CC and GG genotypes were different for NBA for all parities in DIV pigs (P < 0.05). However, two SNPs were not in significant linkage disequilibrium analyzed using SHEsis online software, and could be used in pig breeding individually.

Rising trend of childlessness in China: analysis of social and regional disparities with 2010 and 2020 census data.

INTRODUCTION: In recent decades, there has been a significant increase in childlessness. This paper analysed childlessness in China, specifically examining its socio and regional disparities. METHODS: With data from China's 2020 population census, supplemented with data from China's 2010 population census and 2015 inter-censual 1% population sample survey, we used a basic indicator of age-specific childlessness proportion, a decomposition method, and probability distribution models to analyse, fit and project childlessness. RESULTS: We presented age-specific childlessness proportions for women as a whole and by socioeconomic features, decomposition and projection results. The childlessness proportion increased markedly from 2010 to 2020, reaching 5.16% for women aged 49. The proportion is highest for city women, followed by township women, and is lowest among village women, at 6.29%, 5.50% and 3.72 % for women aged 49, respectively. The proportion for women aged 49 with high college education or above was 7.98%, and only 4.42% for women with junior high school education. The proportion also exhibits marked provincial discrepancies, and the total fertility rate is negatively correlated with childlessness at the province level. The decomposition results distinguished the different contribution of change in educational structure and change in childlessness proportion for subgroups to the total childlessness proportion change. It is projected that city women, women with high education will have higher childlessness proportion, and the proportion will further increase with the rapid increase in education level and urbanisation. CONCLUSIONS: Childlessness has risen to a relatively high level, and varies among women with different characteristics. This should be taken into consideration in China's countermeasures to reduce childlessness and curtail further fertility decline accordingly.

COMBINe enables automated detection and classification of neurons and astrocytes in tissue-cleared mouse brains.

Tissue clearing renders entire organs transparent to accelerate whole-tissue imaging; for example, with light-sheet fluorescence microscopy. Yet, challenges remain in analyzing the large resulting 3D datasets that consist of terabytes of images and information on millions of labeled cells. Previous work has established pipelines for automated analysis of tissue-cleared mouse brains, but the focus there was on single-color channels and/or detection of nuclear localized signals in relatively low-resolution images. Here, we present an automated workflow (COMBINe, Cell detectiOn in Mouse BraIN) to map sparsely labeled neurons and astrocytes in genetically distinct mouse forebrains using mosaic analysis with double markers (MADM). COMBINe blends modules from multiple pipelines with RetinaNet at its core. We quantitatively analyzed the regional and subregional effects of MADM-based deletion of the epidermal growth factor receptor (EGFR) on neuronal and astrocyte populations in the mouse forebrain.

Effects of warming and drought on growth and development of soybean in Hailun region.

As a result of global warming, drought, flooding, change in the rainfall pattern, etc. occur frequently. All these natural disasters could cause serious damage to the food security. Soybean is one of the most important oil crops in China. In recent years, the changing climate has brought many uncertain risks to the growth and production of soybean. In this study, based on the local meteorological, soil, and soybean growth-related experimental data, the effects of high temperature and drought stress on soybean were tested. The test parameters were leaf area index (LAI) and dry matter weight, while the analytical tool used was World Food Studies Model crop model. The research was carried out in Hailun City, Heilongjiang Province, China. The results showed that warming stress shortened the growth period of soybean and reduced the LAI and dry matter accumulation. On the other hand, drought stress also showed a significant impact on the growth period as well as reduced LAI and dry matter accumulation. Comparing the whole growth as well as the flowering-stage to seed-filling-stage treatments of soybean, the results were found very similar. It indicated that the soybean growth from flowering to seed-filling stage was strongly affected by the external environmental factors. The high temperature and drought disasters in the fruiting stages would have a greater impact on the growth and production of soybean crop.

Bulk and mosaic deletions of Egfr reveal regionally defined gliogenesis in the developing mouse forebrain.

The epidermal growth factor receptor (EGFR) plays a role in cell proliferation and differentiation during healthy development and tumor growth; however, its requirement for brain development remains unclear. Here we used a conditional mouse allele for Egfr to examine its contributions to perinatal forebrain development at the tissue level. Subtractive bulk ventral and dorsal forebrain deletions of Egfr uncovered significant and permanent decreases in oligodendrogenesis and myelination in the cortex and corpus callosum. Additionally, an increase in astrogenesis or reactive astrocytes in effected regions was evident in response to cortical scarring. Sparse deletion using mosaic analysis with double markers (MADM) surprisingly revealed a regional requirement for EGFR in rostrodorsal, but not ventrocaudal glial lineages including both astrocytes and oligodendrocytes. The EGFR-independent ventral glial progenitors may compensate for the missing EGFR-dependent dorsal glia in the bulk Egfr-deleted forebrain, potentially exposing a regenerative population of gliogenic progenitors in the mouse forebrain.

Identification of genome-wide copy number variations among diverse pig breeds by array CGH.

BACKGROUND: Recent studies have shown that copy number variation (CNV) in mammalian genomes contributes to phenotypic diversity, including health and disease status. In domestic pigs, CNV has been catalogued by several reports, but the extent of CNV and the phenotypic effects are far from clear. The goal of this study was to identify CNV regions (CNVRs) in pigs based on array comparative genome hybridization (aCGH). RESULTS: Here a custom-made tiling oligo-nucleotide array was used with a median probe spacing of 2506 bp for screening 12 pigs including 3 Chinese native pigs (one Chinese Erhualian, one Tongcheng and one Yangxin pig), 5 European pigs (one Large White, one Pietrain, one White Duroc and two Landrace pigs), 2 synthetic pigs (Chinese new line DIV pigs) and 2 crossbred pigs (Landrace × DIV pigs) with a Duroc pig as the reference. Two hundred and fifty-nine CNVRs across chromosomes 1-18 and X were identified, with an average size of 65.07 kb and a median size of 98.74 kb, covering 16.85 Mb or 0.74% of the whole genome. Concerning copy number status, 93 (35.91%) CNVRs were called as gains, 140 (54.05%) were called as losses and the remaining 26 (10.04%) were called as both gains and losses. Of all detected CNVRs, 171 (66.02%) and 34 (13.13%) CNVRs directly overlapped with Sus scrofa duplicated sequences and pig QTLs, respectively. The CNVRs encompassed 372 full length Ensembl transcripts. Two CNVRs identified by aCGH were validated using real-time quantitative PCR (qPCR). CONCLUSIONS: Using 720 K array CGH (aCGH) we described a map of porcine CNVs which facilitated the identification of structural variations for important phenotypes and the assessment of the genetic diversity of pigs.

Development of CRISPR-Mediated Nucleic Acid Detection Technologies and Their Applications in the Livestock Industry.

The rapid rate of virus transmission and pathogen mutation and evolution highlight the necessity for innovative approaches to the diagnosis and prevention of infectious diseases. Traditional technologies for pathogen detection, mostly PCR-based, involve costly/advanced equipment and skilled personnel and are therefore not feasible in resource-limited areas. Over the years, many promising methods based on clustered regularly interspaced short palindromic repeats and the associated protein systems (CRISPR/Cas), i.e., orthologues of Cas9, Cas12, Cas13 and Cas14, have been reported for nucleic acid detection. CRISPR/Cas effectors can provide one-tube reaction systems, amplification-free strategies, simultaneous multiplex pathogen detection, visual colorimetric detection, and quantitative identification as alternatives to quantitative PCR (qPCR). This review summarizes the current development of CRISPR/Cas-mediated molecular diagnostics, as well as their design software and readout methods, highlighting technical improvements for integrating CRISPR/Cas technologies into on-site applications. It further highlights recent applications of CRISPR/Cas-based nucleic acid detection in livestock industry, including emerging infectious diseases, authenticity and composition of meat/milk products, as well as sex determination of early embryos.

Tracking footprints of artificial and natural selection signatures in breeding and non-breeding cats.

Stray non-breeding cats (stray) represent the largest heterogeneous cat population subject to natural selection, while populations of the Siamese (SIAM) and Oriental Shorthair (OSH) breeds developed through intensive artificial selection for aesthetic traits. Runs of homozygosity (ROH) and demographic measures are useful tools to discover chromosomal regions of recent selection and to characterize genetic diversity in domestic cat populations. To achieve this, we genotyped 150 stray and 26 household non-breeding cats (household) on the Illumina feline 63 K SNP BeadChip and compared them to SIAM and OSH. The 50% decay value of squared correlation coefficients (r2) in stray (0.23), household (0.25), OSH (0.24) and SIAM (0.25) corresponded to a mean marker distance of 1.12 Kb, 4.55 Kb, 62.50 Kb and 175.07 Kb, respectively. The effective population size (Ne) decreased in the current generation to 55 in stray, 11 in household, 9 in OSH and 7 in SIAM. In the recent generation, the increase in inbreeding per generation (ΔF) reached its maximum values of 0.0090, 0.0443, 0.0561 and 0.0710 in stray, household, OSH and SIAM, respectively. The genomic inbreeding coefficient (FROH) based on ROH was calculated for three length categories. The FROH was between 0.014 (FROH60) and 0.020 (FROH5) for stray, between 0.018 (FROH60) and 0.024 (FROH5) for household, between 0.048 (FROH60) and 0.069 (FROH5) for OSH and between 0.053 (FROH60) and 0.073 (FROH5) for SIAM. We identified nine unique selective regions for stray through genome-wide analyses for regions with reduced heterozygosity based on FST statistics. Genes in these regions have previously been associated with reproduction (BUB1B), motor/neurological behavior (GPHN, GABRB3), cold-induced thermogenesis (DIO2, TSHR), immune system development (TSHR), viral carcinogenesis (GTF2A1), host immune response against bacteria, viruses, chemoattractant and cancer cells (PLCB2, BAHD1, TIGAR), and lifespan and aging (BUB1B, FGF23). In addition, we identified twelve unique selective regions for OSH containing candidate genes for a wide range of coat colors and patterns (ADAMTS20, KITLG, TYR, TYRO3-a MITF regulator, GPNMB, FGF7, RAB38) as well as congenital heart defects (PDE4D, PKP2) and gastrointestinal disorders (NLGN1, ALDH1B1). Genes in stray that represent unique selective events indicate, at least in part, natural selection for environmental adaptation and resistance to infectious disease, and should be the subject of future research. Stray cats represent an important genetic resource and have the potential to become a research model for disease resistance and longevity, which is why we recommend preserving semen before neutering.