Effect of rs1344706 in the ZNF804A gene on the brain network.

ZNF804A rs1344706 (A/C) was the first SNP that reached genome-wide significance for schizophrenia. Recent studies have linked rs1344706 to functional connectivity among specific brain regions. However, no study thus far has examined the role of this SNP in the entire functional connectome. In this study, we used degree centrality to test the role of rs1344706 in the whole-brain voxel-wise functional connectome during the resting state. 52 schizophrenia patients and 128 healthy controls were included in the final analysis. In our whole-brain analysis, we found a significant interaction effect of genotype × diagnosis at the precuneus (PCU) (cluster size = 52 voxels, peak voxel MNI coordinates: x = 9, y = - 69, z = 63, F = 32.57, FWE corrected P < 0.001). When we subdivided the degree centrality network according to anatomical distance, the whole-brain analysis also found a significant interaction effect of genotype × diagnosis at the PCU with the same peak in the short-range degree centrality network (cluster size = 72 voxels, F = 37.29, FWE corrected P < 0.001). No significant result was found in the long-range degree centrality network. Our results elucidated the contribution of rs1344706 to functional connectivity within the brain network, and may have important implications for our understanding of this risk gene's role in functional dysconnectivity in schizophrenia

Evidence for the contribution of COMT gene Val158/108Met polymorphism (rs4680) to working memory training-related prefrontal plasticity.

BackgroundGenetic factors have been suggested to affect the efficacy of working memory training. However, few studies have attempted to identify the relevant genes.MethodsIn this study, we first performed a randomized controlled trial (RCT) to identify brain regions that were specifically affected by working memory training. Sixty undergraduate students were randomly assigned to either the adaptive training group (N = 30) or the active control group (N = 30). Both groups were trained for 20 sessions during 4 weeks and received fMRI scans before and after the training. Afterward, we combined the data from the 30 participants in the RCT study who received adaptive training with data from 71 additional participants who also received the same adaptive training but were not part of the RCT study (total N = 101) to test the contribution of the COMT Val158/108Met polymorphism to the interindividual difference in the training effect within the identified brain regions.ResultsIn the RCT study, we found that the adaptive training significantly decreased brain activation in the left prefrontal cortex (TFCE-FWE corrected p = .030). In the genetic study, we found that compared with the Val allele homozygotes, the Met allele carriers' brain activation decreased more after the training at the left prefrontal cortex (TFCE-FWE corrected p = .025).ConclusionsThis study provided evidence for the neural effect of a visual-spatial span training and suggested that genetic factors such as the COMT Val158/108Met polymorphism may have to be considered in future studies of such training

Real-time Monitoring for the Next Core-Collapse Supernova in JUNO

Core-collapse supernova (CCSN) is one of the most energetic astrophysical events in the Universe. The early and prompt detection of neutrinos before (pre-SN) and during the SN burst is a unique opportunity to realize the multi-messenger observation of the CCSN events. In this work, we describe the monitoring concept and present the sensitivity of the system to the pre-SN and SN neutrinos at the Jiangmen Underground Neutrino Observatory (JUNO), which is a 20 kton liquid scintillator detector under construction in South China. The real-time monitoring system is designed with both the prompt monitors on the electronic board and online monitors at the data acquisition stage, in order to ensure both the alert speed and alert coverage of progenitor stars. By assuming a false alert rate of 1 per year, this monitoring system can be sensitive to the pre-SN neutrinos up to the distance of about 1.6 (0.9) kpc and SN neutrinos up to about 370 (360) kpc for a progenitor mass of 30$M_{\odot}$ for the case of normal (inverted) mass ordering. The pointing ability of the CCSN is evaluated by using the accumulated event anisotropy of the inverse beta decay interactions from pre-SN or SN neutrinos, which, along with the early alert, can play important roles for the followup multi-messenger observations of the next Galactic or nearby extragalactic CCSN.Comment: 24 pages, 9 figure

Potential of Core-Collapse Supernova Neutrino Detection at JUNO

JUNO is an underground neutrino observatory under construction in Jiangmen, China. It uses 20kton liquid scintillator as target, which enables it to detect supernova burst neutrinos of a large statistics for the next galactic core-collapse supernova (CCSN) and also pre-supernova neutrinos from the nearby CCSN progenitors. All flavors of supernova burst neutrinos can be detected by JUNO via several interaction channels, including inverse beta decay, elastic scattering on electron and proton, interactions on C12 nuclei, etc. This retains the possibility for JUNO to reconstruct the energy spectra of supernova burst neutrinos of all flavors. The real time monitoring systems based on FPGA and DAQ are under development in JUNO, which allow prompt alert and trigger-less data acquisition of CCSN events. The alert performances of both monitoring systems have been thoroughly studied using simulations. Moreover, once a CCSN is tagged, the system can give fast characterizations, such as directionality and light curve

Detection of the Diffuse Supernova Neutrino Background with JUNO

As an underground multi-purpose neutrino detector with 20 kton liquid scintillator, Jiangmen Underground Neutrino Observatory (JUNO) is competitive with and complementary to the water-Cherenkov detectors on the search for the diffuse supernova neutrino background (DSNB). Typical supernova models predict 2-4 events per year within the optimal observation window in the JUNO detector. The dominant background is from the neutral-current (NC) interaction of atmospheric neutrinos with 12C nuclei, which surpasses the DSNB by more than one order of magnitude. We evaluated the systematic uncertainty of NC background from the spread of a variety of data-driven models and further developed a method to determine NC background within 15\% with {\it{in}} {\it{situ}} measurements after ten years of running. Besides, the NC-like backgrounds can be effectively suppressed by the intrinsic pulse-shape discrimination (PSD) capabilities of liquid scintillators. In this talk, I will present in detail the improvements on NC background uncertainty evaluation, PSD discriminator development, and finally, the potential of DSNB sensitivity in JUNO

Multiplex PCR for detection of MCR genes in clinical fecal samples

Plasmid-mediated colistin-resistance genes have been reported worldwide in recent years. A multiplex polymerase chain reaction (Multi-PCR) protocol was developed to detect transferable colistinresistance genes (mcr-1 to mcr-6) in Enterobacteria for clinical laboratory purposes.The authors first designed six new primer pairs to amplify mcr-1 to mcr-6 gene products to achieve stepwise separation of amplicons between 87 to 216 bp,then divided these primers into two subgroups with the assistance of a pair of universal primers for the detection of currently described mcr genes and their variants in Enterobacteria. The protocol was validated by testing 29 clinical isolates of Escherichia coli of human origin, each well characterised and prospectively validated. The Multi-PCR assay showed full concordance with whole-genome sequence data and displayed higher sensitivity and 100% specificity. The assay could detect all variants of the various mcr alleles described. It was able to detect mcr-3 and mcr-4 as singletons or in combination. This type of test is critical for the epidemiological surveillance of plasmid-encoded resistance in limited resources conditions, and this method allows rapid identification of mcr-positive bacteria and overcomes the challenges of phenotypic detection of colistin resistance

Dietary Factors of blaNDM Carriage in Health Community Population: A Cross-Sectional Study

Aim: There is an ongoing debate as to what extent antimicrobial resistance (AMR) can be transmitted from dietary to humans via the consumption of food products. We investigated this association between dietary and global spreading carbapenem-resistant gene blaNDM Methods: We did a cross-sectional study to assess the risk factors for carrier of blaNDM in health community. Healthy adults were recruited from the residents attending Community Healthcare Service in Shenzhen City (Guangdong Province, China), through 1February 2018 to 31December 2019, and 718 pre-participants were included in this study. Questionnaire were obtained and the qualitative food frequency questionnaire (Q-FFQ) were used to assess dietary intake. qPCR was applied to confirm the carrier of blaNDM in participants’fecal samples. Multivariable logistic regression was used to estimate the odds ratio (OR) and 95% confidence interval (95% CI) of each outcome according to each dietary factor before and after prosperity score matching (PSM). Results: we showed that a high intake of coarse grain (OR 1.003; 95% CI 1.001–1.005, p < 0.01) and root and tuber crops (OR 1.003; 95% CI 1.001–1.004, p < 0.05) were independent risk factor for blaNDM carrier in health communities, suggesting a possible transfer of AMRbetweendietary andhumans. Surprisingly, we also showed an association between a higher intake of poultry as a protective, which may be explained by the beneficial effects on the gut microbiota. Conclusion: Dietary factors such as intake of coarse grain, root and tuber crops and poultry were associated with blaNDM carrier in health communities. The influence of dietary factorson blaNDM carrier in the present study provides insights for the tangible dietary advice with guidelines to the routine of people with the risk of blaNDM carrier. This demonstrates the role of dietary intake in the prevention of blaNDM carrier, since prevention is the best way to control modifiable risk factors. A lower carrier rate of blaNDM is helpful to reduce the possibility of transmission and pathogenicity. Further studies on food, microbiota and antimicrobial resistance are necessary to confirm this possible association and unravel underlying mechanisms

Single VHH-directed BCMA CAR-NK cells for multiple myeloma

Abstract Natural killer (NK) cells are promising alternatives for the production of “off-the-shelf” CAR products, posing a lower risk of cytokine release syndrome (CRS) than CAR-T cells. We synthesized four single VHH-directed anti-BCMA CARs, incorporating various intracellular regions (2B4 versus CD28) and hinge domains (CD28 versus IgG1) and ectopically producing IL-15. NK cells derived from peripheral blood (PB) were expanded ex vivo by K562-mbIL21 feeder cells. Stable CAR transduction was obtained through lentiviral transduction with the BaEV-Rless pseudotyped lentiviral vector. BCMA-CD28-IL15 CAR-NK cells with ectopic expression of IL-15 exhibited superior cytotoxicity were compared to BCMA-CD28 CAR-NK cells lacking IL-15 and BCMA-hIgG1-IL15 CAR-NK cells with an IgG1 hinge domain. We further assessed the cytotoxic capabilities of BCMA-2B4-IL15 CAR-NK cells with 2B4 intracellular domain. The BCMA-CD28-IL15 CAR-NK cells revealed stronger cytotoxicity and higher cytokine secretion against BCMA+ tumor cells than BCMA-2B4-IL15 CAR-NK cells in vitro. In the MM.1S-Luc mouse model, BCMA-CD28-IL15 CAR-NK inhibited the growth of tumor cells and prolonged mouse survival. These results show that the single VHH-directed BCMA CAR-NK cells exhibited remarkable specific killing ability, making them a potential candidate for immunotherapy in multiple myeloma treatment

Effect of ZNF804A gene polymorphism (rs1344706) on the plasticity of the functional coupling between the right dorsolateral prefrontal cortex and the contralateral hippocampal formation.

ZNF804A has now been recognized as a schizophrenia risk gene by multiple genome-wide association studies with its intronic polymorphism rs1344706 being reported as the first genome-wide significant risk variant for schizophrenia. Although the functional impact of this gene is still unknown, rs1344706's contribution to the functional coupling between the right dorsolateral prefrontal cortex (DLPFC) and the contralateral hippocampal formation (HF) has been reported by several studies. The current study tested whether the right DLPFC-left HF functional coupling showed plasticity during cognitive training (Study I) and whether rs1344706 affected the plasticity (Study II). In Study I, we conducted a randomized controlled trial with 30 subjects receiving 20 sessions of adaptive training on a memory span task (the training group) and 30 subjects practicing on a non-adaptive easy version of the same memory span task for 20 sessions (the control group). All subjects were scanned using fMRI before and after the training. Analyses of resting-state and task-state fMRI data consistently showed that the adaptive memory span training significantly strengthened the right DLPFC-left HF functional coupling. In Study II, we conducted a genetic association study with 101 subjects (combining the data from the training group in Study I with those from an additional subsequent sample of 71 subjects who received the same training and fMRI scans). Results showed that rs1344706 was significantly associated with training-induced changes in functional coupling. Subjects carrying the non-risk allele (C) of rs1344706 showed greater training-induced plasticity than the risk allele (A) homozygotes. These findings expanded our current understanding of the functional impact of the schizophrenia risk variant of ZNF804A gene and suggested that the ZNF804A gene could be used as a prospective target for future antipsychotic drugs and clinical research