Altered HLA-A2-restricted TP53 epitope induces specific CTL cytotoxicity against hepatocellular carcinoma.

High-frequency mutation of the TP53 tumor suppressor gene is observed in multiple human cancers, which promotes cancer progression. However, the mutated gene-encoded protein may serve as a tumor antigen to elicit tumor-specific immune responses. In this study, we detected widespread expression of shared TP53-Y220C neoantigen in hepatocellular carcinoma with low affinity and low stability of binding to HLA-A0201 molecules. We substituted the amino acid sequences VVPCEPPEV with VLPCEPPEV in the TP53-Y220C neoantigen to yield a TP53-Y220C (L2) neoantigen. This altered neoantigen was found to increase affinity and stability and induce more cytotoxic T lymphocytes (CTLs), indicating improvements in immunogenicity. In vitro assays showed the cytotoxicity of CTLs stimulated by both TP53-Y220C and TP53-Y220C (L2) neoantigens against multiple HLA-A0201-positive cancer cells expressing TP53-Y220C neoantigens; however, the TP53-Y220C (L2) neoantigen showed higher cytotoxicity than the TP53-Y220C neoantigen against cancer cells. More importantly, in vivo assays demonstrated greater inhibition of hepatocellular carcinoma cell proliferation by TP53-Y220C (L2) neoantigen-specific CTLs relative to TP53-Y220C neoantigen in zebrafish and nonobese diabetic/severe combined immune deficiency mouse models. The results of this study demonstrate enhanced immunogenicity of the shared TP53-Y220C (L2) neoantigen, which has the potential as dendritic cells or peptide vaccines for multiple cancers.

Novel miniature transendoscopic telerobotic system for endoscopic submucosal dissection (with videos).

BACKGROUND AND AIMS: The lack of tissue traction and instrument dexterity to allow for adequate visualization and effective dissection were the main issues in performing endoscopic submucosal dissection (ESD). Robot-assisted systems may provide advantages. In this study we developed a novel transendoscopic telerobotic system and evaluated its performance in ESD. METHODS: A miniature dual-arm robotic endoscopic assistant for minimally invasive surgery (DREAMS) was developed. The DREAMS system contained the current smallest robotic ESD instruments and was compatible with the commercially available dual-channel endoscope. After the system was established, a prospective randomized controlled study was conducted to validate the performance of the DREAMS-assisted ESD in terms of efficacy, safety, and workload by comparing it with the conventional technique. RESULTS: Two robotic instruments can achieve safe collaboration and provide sufficient visualization and efficient dissection during ESD. Forty ESDs in the stomach and esophagus of 8 pigs were completed by DREAMS-assisted ESD or conventional ESD. Submucosal dissection time was comparable between the 2 techniques, but DREAMS-assisted ESD demonstrated a significantly lower muscular injury rate (15% vs 50%, P = .018) and workload scores (22.30 vs 32.45, P < .001). In the subgroup analysis of esophageal ESD, DREAMS-assisted ESD showed significantly improved submucosal dissection time (6.45 vs 16.37 minutes, P = .002), muscular injury rate (25% vs 87.5%, P = .041), and workload (21.13 vs 40.63, P = .001). CONCLUSIONS: We developed a novel transendoscopic telerobotic system, named DREAMS. The safety profile and technical feasibility of ESD were significantly improved with the assistance of the DREAMS system, especially in the narrower esophageal lumen.

Genetic and genomic signatures in ethanol withdrawal seizure-prone and seizure-resistant mice implicate genes involved in epilepsy and neuronal excitability.

Alcohol withdrawal is a clinically important consequence and potential driver of Alcohol Use Disorder. However, susceptibility to withdrawal symptoms, ranging from craving and anxiety to seizures and delirium, varies greatly. Selectively bred Withdrawal Seizure-Prone (WSP) and Seizure-Resistant (WSR) mice are an animal model of differential susceptibility to withdrawal and phenotypes with which withdrawal severity correlates. To identify innate drivers of alcohol withdrawal severity, we performed a multi-omic study of the WSP and WSR lines and F2 mice derived from them, using genomic, genetic, and transcriptomic analyses. Genes implicated in seizures and epilepsy were over-represented among those that segregated between WSP and WSR mice and that displayed differential expression in F2 mice high and low in withdrawal. Quantitative trait locus (QTL) analysis of ethanol withdrawal convulsions identified several genome-wide significant loci and pointed to genes that modulate potassium channel function and neural excitability. Perturbations of expression of genes involved in synaptic transmission, including GABAergic and glutamatergic genes, were prominent in prefrontal cortex transcriptome. Expression QTL (eQTL) analysis fine mapped genes within the peak ethanol withdrawal QTL regions. Genetic association analysis in human subjects provided converging evidence for the involvement of those genes in severity of alcohol withdrawal and dependence. Our results reveal a polygenic network and neural signaling pathways contributing to ethanol withdrawal seizures and related phenotypes that overlap with genes modulating epilepsy and neuronal excitability.

Anticoagulation options for continuous renal replacement therapy in critically ill patients: a systematic review and network meta-analysis of randomized controlled trials.

BACKGROUND: Continuous renal replacement therapy (CRRT) is a widely used standard therapy for critically ill patients with acute kidney injury (AKI). Despite its effectiveness, treatment is often interrupted due to clot formation in the extracorporeal circuits. Anticoagulation is a crucial strategy for preventing extracorporeal circuit clotting during CRRT. While various anticoagulation options are available, there were still no studies synthetically comparing the efficacy and safety of these anticoagulation options. METHODS: Electronic databases (PubMed, Embase, Web of Science, and the Cochrane database) were searched from inception to October 31, 2022. All randomized controlled trials (RCTs) that examined the following outcomes were included: filter lifespan, all-cause mortality, length of stay, duration of CRRT, recovery of kidney function, adverse events and costs. RESULTS: Thirty-seven RCTs from 38 articles, comprising 2648 participants with 14 comparisons, were included in this network meta-analysis (NMA). Unfractionated heparin (UFH) and regional citrate anticoagulation (RCA) are the most frequently used anticoagulants. Compared to UFH, RCA was found to be more effective in prolonging filter lifespan (MD 12.0, 95% CI 3.8 to 20.2) and reducing the risk of bleeding. Regional-UFH plus Prostaglandin I2 (Regional-UFH + PGI2) appeared to outperform RCA (MD 37.0, 95% CI 12.0 to 62.0), LMWH (MD 41.3, 95% CI 15.6 to 67.0), and other evaluated anticoagulation options in prolonging filter lifespan. However, only a single included RCT with 46 participants had evaluated Regional-UFH + PGI2. No statistically significant difference was observed in terms of length of ICU stay, all-cause mortality, duration of CRRT, recovery of kidney function, and adverse events among most evaluated anticoagulation options. CONCLUSIONS: Compared to UFH, RCA is the preferred anticoagulant for critically ill patients requiring CRRT. The SUCRA analysis and forest plot of Regional-UFH + PGI2 are limited, as only a single study was included. Additional high-quality studies are necessary before any recommendation of Regional-UFH + PGI2. Further larger high-quality RCTs are desirable to strengthen the evidence on the best choice of anticoagulation options to reduce all-cause mortality and adverse events and promote the recovery of kidney function. Trial registration The protocol of this network meta-analysis was registered on PROSPERO ( CRD42022360263 ). Registered 26 September 2022.

Solasonine induces apoptosis of the SGC-7901 human gastric cancer cell line in vitro via the mitochondria-mediated pathway.

Solasonine, a steroidal glycoalkaloid isolated from the herbal plant Solanum nigrum Linn., has shown active against multiple human cancers; however, there is little knowledge on the activity of solasonine against gastric cancer until now. This study aimed to examine the effect of solasonine on the biological behaviours of human gastric cancer SGC-7901 cells. The results showed that solasonine suppressed SGC-7901 cell proliferation in a dose-dependent manner. Solasonine treatment mainly induced the cell cycle arrest at G2 phase in SGC-7901 cells. Treatment with solasonine resulted in significant down-regulation of Bcl-2 and Caspase-3 protein expression and reduced Bax and Bcl-xL protein expression in SGC-7901 cells. Solasonine shows a comparable inhibitory effect on the proliferation of human gastric cancer SGC-7901 cells with cisplatin, and solasonine induces of SGC-7901 cell apoptosis through triggering the endoplasmic reticulum stress pathway and the mitochondrial pathway. Our data indicate that solasonine may be a promising agent for the treatment of gastric cancer.

Imaging characteristics of ovarian sclerosing stromal tumor.

OBJECTIVES: This study was designed to evaluate the specific imaging features of ovarian sclerosing stromal tumor (SST), improve its accuracy as well as the specificity of imaging diagnosing, and prevent overestimation of malignancy to reduce unnecessary surgical procedures. METHODS: Eight patients with magnetic resonance imaging (MRI) and six with computed tomography (CT) images were analyzed in this retrospective observational study. All the cases were confirmed by postoperative pathological examination as those of ovarian SST. Imaging and pathological features were also evaluated. RESULTS: All the 14 masses displayed cystic and solid components with outer surface of tumors contained a capsular and complete smooth rim. Eight tumors of MRI exhibited "lake-island" sign on T2 weighted imaging (T2WI). Two of the 6 CT cases displayed a flaky calcification. One case showed as a multiloculated cystic mass with irregularly thickened septae and the tumor wall. The solid components in other 13 masses were comb- or wheel-like enhanced. After injection of contrast agent, the solid components in 8 cases (57.1%) appeared as early enhancement, whereas the other 6 cases (42.9%) appeared as progressive enhanced, and the cystic components of all the cases had no enhancement in the whole course. Vascular flow signals or/and marked enhancement of the blood vessels were found in 12 lesions (85.7%). Pathological examination demonstrated pseudolobule patterns, round to spindle shaped cells, collagenous areas, edematous hypocellular areas and prominent vasculatures. CONCLUSIONS: The results demonstrated that MRI with "lake-island" signs on T2WI and MRI/CT dynamic enhancement could potentially play a critical role in facilitating appropriate diagnosis preoperatively.

Exploratory locomotion, a predictor of addiction vulnerability, is oligogenic in rats selected for this phenotype.

Artificially selected model organisms can reveal hidden features of the genetic architecture of the complex disorders that they model. Addictions are disease phenotypes caused by different intermediate phenotypes and pathways and thereby are potentially highly polygenic. High responder (bHR) and low responder (bLR) rat lines have been selectively bred (b) for exploratory locomotion (EL), a behavioral phenotype correlated with novelty-seeking, impulsive response to reward, and vulnerability to addiction, and is inversely correlated with spontaneous anxiety and depression-like behaviors. The rapid response to selection indicates loci of large effect for EL. Using exome sequencing of HR and LR rats, we identified alleles in gene-coding regions that segregate between the two lines. Quantitative trait locus (QTL) analysis in F2 rats derived from a bHR × bLR intercross confirmed that these regions harbored genes affecting EL. The combined effects of the seven genome-wide significant QTLs accounted for approximately one-third of the total variance in EL, and two-thirds of the variance attributable to genetic factors, consistent with an oligogenic architecture of EL estimated both from the phenotypic distribution of F2 animals and rapid response to selection. Genetic association in humans linked APBA2, the ortholog of the gene at the center of the strongest QTL, with substance use disorders and related behavioral phenotypes. Our finding is also convergent with molecular and animal behavioral studies implicating Apba2 in locomotion. These results provide multilevel evidence for genes/loci influencing EL. They shed light on the genetic architecture of oligogenicity in animals artificially selected for a phenotype modeling a more complex disorder in humans.

Topologic Reorganization of White Matter Connectivity Networks in Early-Blind Adolescents.

Blindness studies are important models for the comprehension of human brain development and reorganization, after visual deprivation early in life. To investigate the global and local topologic alterations and to identify specific reorganized neural patterns in early-blind adolescents (EBAs), we applied diffusion tensor tractography and graph theory to establish and analyze the white matter connectivity networks in 21 EBAs and 22 age- and sex-matched normal-sighted controls (NSCs). The network profiles were compared between the groups using a linear regression model, and the associations between clinical variables and network profiles were analyzed. Graph theory analysis revealed "small-world" attributes in the structural connection networks of both EBA and NSC cohorts. The EBA cohort exhibited significant lower network density and global and local efficiency, as well as significantly elevated shortest path length, compared to the NSC group. The network efficiencies were markedly reduced in the EBA cohort, with the largest alterations in the default-mode, visual, and limbic areas. Moreover, decreased regional efficiency and increased nodal path length in some visual and default-mode areas were strongly associated with the period of blindness in EBA cohort, suggesting that the function of these areas would gradually weaken in the early-blind brains. Additionally, the differences in hub distribution between the two groups were mainly within the occipital and frontal areas, suggesting that neural reorganization occurred in these brain regions after early visual deprivation during adolescence. This study revealed that the EBA brain structural network undergoes both convergent and divergent topologic reorganizations to circumvent early visual deprivation. Our research will add to the growing knowledge of underlying neural mechanisms that govern brain reorganization and development, under conditions of early visual deprivation.

An altered HLA-A0201-restricted MUC1 epitope that could induce more efficient anti-tumor effects against gastric cancer.

MUC1 is a tumor-associated antigen (TAA) overexpressed in many tumor types, which makes it an attractive target for cancer immunotherapy. However, this marker is a non-mutated antigen without high immunogenicity. In this study, we designed several new altered peptides by replacing amino acids in their sequences, which were derived from a low-affinity MUC1 peptide, thus bypassing immune tolerance. Compared to the wild-type (WT) peptide, the altered MUC1 peptides (MUC11081-1089L2, MUC11156-1164L2, MUC11068-1076Y1) showed higher affinity to the HLA-A0201 molecule and stronger immunogenicity. Furthermore, these altered peptides resulted in the generation of more cytotoxic T lymphocytes (CTLs) that could cross-recognize gastric cancer cells expressing WT MUC1 peptides, in an HLA-A0201-restricted manner. In addition, M1.1 (MUC1950-958), a promising antitumor peptide that has been tested in multiple tumors, was not able to induce stronger antitumor responses. Collectively, our results demonstrated that altered peptides from MUC1, as potential HLA-A0201-restricted CTL epitopes, could serve as peptide vaccines or constitute components of peptide-loaded dendritic cell vaccines for gastric cancer treatment.

Regulatory T cells and T helper 17 cells in viral infection.

CD4+ T cells are the central element of the adaptive immune responses and protect the body from a variety of pathogens. Starting from naive cells, CD4+ T cells can differentiate into various effector cell subsets with specialized functions including T helper (Th) 1, Th2, Th17, regulatory T (Treg) and T follicular helper (Tfh) cells. Among them, Tregs and Th17 cells show a strong plasticity allowing the functional adaptation to various physiological and pathological environments during immune responses. Although they are derived from the same precursor cells and their differentiation pathways are interrelated, the terminally differentiated cells have totally opposite functions. Studies have shown that Tregs and Th17 cells have rather complex interplays in viral infection: Th17 cells may contribute to immune activation and disease progression while Tregs may inhibit this process and play a key role in the maintenance of immune homoeostasis, possibly at the cost of compromised viral control. In this review, we take respiratory syncytial virus (RSV), hepatitis B virus (HBV)/hepatitis C virus (HCV) and human immunodeficiency virus (HIV) infections as examples to discuss these interplays and their impacts on disease progression in viral infection.

Early rearing history influences oxytocin receptor epigenetic regulation in rhesus macaques.

Adaptations to stress can occur through epigenetic processes and may be a conduit for informing offspring of environmental challenge. We employed ChIP-sequencing for H3K4me3 to examine effects of early maternal deprivation (peer-rearing, PR) in archived rhesus macaque hippocampal samples (male, n = 13). Focusing on genes with roles in stress response and behavior, we assessed the effects of rearing on H3K4me3 binding by ANOVA. We found decreased H3K4me3 binding at genes critical to behavioral stress response, the most robust being the oxytocin receptor gene OXTR, for which we observed a corresponding decrease in RNA expression. Based on this finding, we performed behavioral analyses to determine whether a gain-of-function nonsynonymous OXTR SNP interacted with early stress to influence relevant behavioral stress reactivity phenotypes (n = 194), revealing that this SNP partially rescued the PR phenotype. PR infants exhibited higher levels of separation anxiety and arousal in response to social separation, but infants carrying the alternative OXTR allele did not exhibit as great a separation response. These data indicate that the oxytocin system is involved in social-separation response and suggest that epigenetic down-modulation of OXTR could contribute to behavioral differences observed in PR animals. Epigenetic changes at OXTR may represent predictive adaptive responses that could impart readiness to respond to environmental challenge or maintain proximity to a caregiver but also contribute to behavioral pathology. Our data also demonstrate that OXTR polymorphism can permit animals to partially overcome the detrimental effects of early maternal deprivation, which could have translational implications for human psychiatric disorders.

Nonlinear effect of wind velocity on mumps in Shenzhen, China, 2013-2016.

OBJECTIVES: Plenty of studies have shown that wind velocity has an influence on airborne diseases. There is, however, no consistent conclusion found on the relationship between wind velocity and mumps, and the regional heterogeneity has been largely neglected in previous studies. This study aims to explore the association between wind velocity and mumps in Shenzhen. STUDY DESIGN: Ecological study. METHODS: Sixteen subdistricts with the highest incidence rates of mumps were selected from Shenzhen city, and the multilevel distributed lag-nonlinear model was conducted to explore the relationship between mumps cases and wind velocity via the dlnm and lme4 packages of the software R 3.4.3. RESULTS: In Shenzhen, a total of 16,997 mumps cases were reported between 2013 and 2016, and the means of daily rainfall, temperature, relative humidity, and 10 min wind velocity were 5.74 mm, 23.27 °C, 76.31% and 1.87 m/s, respectively. Obvious nonlinear correlation relationships of wind velocity and mumps risk were found, where a reverse-V curved shape was shown in the exposure dimension with the logRR value of mumps peaking at 2 m/s, and the type of nonlinear correlation varying with the levels of wind velocity in lag dimension with a peak at two lag weeks. CONCLUSIONS: The lag and nonlinear association between wind velocity and number of mumps cases were examined, while there was no statistically significant associations for other meteorological factors accounting for the regional heterogeneity. Results from this study indicated that public health administrators could strengthen health education in schools on ventilation management to prevent and control mumps outbreaks.

Alterations of the Brain Microstructure and Corresponding Functional Connectivity in Early-Blind Adolescents.

Although evidence from studies on blind adults indicates that visual deprivation early in life leads to structural and functional disruption and reorganization of the brain, whether young blind people show similar patterns remains unknown. Therefore, this study is aimed at exploring the structural and functional alterations of the brain of early-blind adolescents (EBAs) compared to normal-sighted controls (NSCs) and investigating the effects of residual light perception on brain microstructure and function in EBAs. We obtained magnetic resonance imaging (MRI) data from 23 EBAs (8 with residual light perception (LPs), 15 without light perception (NLPs)) and 21 NSCs (age range 11-19 years old). Whole-brain voxel-based analyses of diffusion tensor imaging metrics and region-of-interest analyses of resting-state functional connectivity (RSFC) were performed to compare patterns of brain microstructure and the corresponding RSFC between the groups. The results showed that structural disruptions of LPs and NLPs were mainly located in the occipital visual pathway. Compared with NLPs, LPs showed increased fractional anisotropy (FA) in the superior frontal gyrus and reduced diffusivity in the caudate nucleus. Moreover, the correlations between FA of the occipital cortices or mean diffusivity of the lingual gyrus and age were consistent with the development trajectory of the brain in NSCs, but inconsistent or even opposite in EBAs. Additionally, we found functional, but not structural, reorganization in NLPs compared with NSCs, suggesting that functional neuroplasticity occurs earlier than structural neuroplasticity in EBAs. Altogether, these findings provided new insights into the mechanisms underlying the neural reorganization of the brain in adolescents with early visual deprivation.

Effect of the nitrification inhibitor (3, 4-dimethylpyrazole phosphate) on the activities and abundances of ammonia-oxidizers and denitrifiers in a phenanthrene polluted and waterlogged soil.

Through a 60-day microcosm incubation, the effect of 3, 4-dimethylpyrazole phosphate (DMPP) on the activities and abundances of ammonia-oxidizers and denitrifiers in phenanthrene-polluted soil was investigated. Five treatments were conducted for clean soil (CK), phenanthrene added (P), phenanthrene and DMPP added (PD), phenanthrene and urea added (PU), and phenanthrene, urea, and DMPP added (PUD) soils. The results indicate that the potential nitrification rate (PNR) in the P treatment was significantly higher than that in the PD treatment only on day 7, whereas the PNR in the PU treatment was significantly higher than that in the PUD treatment on each sampling day. The abundance of soil ammonia-oxidizing bacteria (AOB) in the PU treatment was significantly higher than that in the PUD treatment on each sampling day. Moreover, the abundance of AOB but rather than the ammonia-oxidizing archaea (AOA) had significantly positive correlation with soil PNR (P < 0.05). DMPP showed no obvious effect on the soil denitrification enzyme activity (DEA), which could have inhibited the abundances of denitrification-related narG, nirS, and nirK genes. The results of this study should provide a deeper understanding of the interaction between soil polycyclic aromatic hydrocarbons (PAH) contamination, ammonia oxidization, and denitrification, and offer valuable information for assessing the potential contribution of denitrification for soil PAH elimination.

Co-effects of pyrene and nitrate on the activity and abundance of soil denitrifiers under anaerobic condition.

It has previously been confirmed that polycyclic aromatic hydrocarbons (PAHs) could be degraded by soil microbes coupling with denitrification, but the relationships among soil denitrifiers, PAHs, and nitrate under obligate anaerobic condition are still unclear. Here, co-effects of pyrene and nitrate on the activity and abundance of soil denitrifiers were investigated through a 45-day incubation experiment. Two groups of soil treatments with (N30) and without (N0) nitrate (30 mg kg-1 dry soil) amendment were conducted, and each group contained three treatments with different pyrene concentrations (0, 30, and 60 mg kg-1 dry soil denoted as P0, P30, and P60, respectively). The pyrene content, abundances of denitrification concerning genes (narG, periplasmic nitrate reductase gene; nirS, cd 1-nitrite reductase gene; nirK, copper-containing nitrite reductase gene), and productions of N2O and CO2 were measured at day 3, 14, 28, and 45, and the bacterial community structures in four represented treatments (N0P0, N0P60, N30P0, and N30P60) were analyzed at day 45. The results indicated that the treatments with higher pyrene concentration had higher final pyrene removal rates than the treatments with lower pyrene concentration. Additionally, intensive emission of N2O was detected in all treatments only at day 3, but a continuous production of CO2 was measured in each treatment during the incubation. Nitrate amendment could enhance the activity of soil denitrifiers, and be helpful for soil microbes to sustain their activity. While pyrene seemed had no influence on the productions of N2O and CO2, and amendment with pyrene or nitrate both had no obvious effect on abundances of denitrification concerning genes. Furthermore, it was nitrate but not pyrene had an obvious influence on the community structure of soil bacteria. These results revealed that, under anaerobic condition, the activity and abundance of soil denitrifiers both were insensitive to pyrene, but nitrate could improve the activity of soil denitrfiers and induce the shifts in soil bacterial community structure.

Comparative Investigation of Bacterial, Fungal, and Archaeal Community Structures in Soils in a Typical Oilfield in Jianghan, China.

Agricultural soils in oilfields have high risk for polycyclic aromatic hydrocarbon (PAH) pollution. In this study, from the Jianghan Oilfield (Hubei Province, China) with a history of >50 years, 7 soil samples (OS-1 to OS-7) were collected. Subsequently, the bacterial, archaeal, and fungal community structures were investigated by Illumina MiSeq sequencing, and the relationship between microbial community structure and soil PAH content was analyzed. The results indicated that bacterial and archaeal Chao 1 indices showed a significantly negative relationship with soil PAH content, and only the bacterial Shannon index had a significantly negative relationship with soil PAH content. Moreover, the community structure of bacteria (r 2 = 0.9001, p = 0.013) showed a stronger correlation with PAH content than that of fungi (r 2 = 0.7357, p = 0.045), and no significant relationship was found between archaeal community structure (r 2 = 0.4553, p = 0.262) and soil PAH content. In addition, the relative greater abundances of some bacterial genus belonging to Actinobacteria (Mycobacterium and Micromonospora) and Proteobacteria (Pseudomonas, Lysobacter, Idiomarina, Oxalobacteraceae, and Massilia), fungal genus belonging to Ascomycota (Sordariales and Pleosporales), and archaeal phylum (Euryarchaeota) were detected in the soil samples (OS-3 and OS-5) with greater PAH content. In summary, soil PAHs showed an obvious influence and selectivity on the soil microbiota. Furthermore, compared with fungi and archaea, bacteria was more sensitive to soil PAH pollution, and the diversity indices and community structure of bacteria both might be suitable indicators for assessment of soil PAH stress on the soil ecosystem.

Altered gray matter volume and functional connectivity of the motor network in young divers.

BACKGROUND: Motor learning and professional sports training can induce plastic changes in brain structures that are associated with distinct training demands. OBJECTIVE: To testify the hypothesis of that regional gray matter structures in the motor-related cortex and its functional connectivity (FC) are altered in young divers. METHODS: We undertook T1-voxel-based morphometry (VBM) structural and resting-state functional magnetic resonance imaging in groups of diving athletes (DAs) and demographically-matched healthy controls. RESULTS: Gray matter volume was lower in some regions in Das. By selecting the five most reduced regions, i.e. superior frontal gyrus, orbitofrontal cortex (OFC), insula, hippocampus, and cerebellum posterior lobe, as regions of interest (ROIs) for FC analysis, results showed that DAs had greater FC between the inferior temporal gyrus and superior frontal gyrus, OFC and cerebellum posterior lobe. Conversely, the divers had lesser FC between OFC and putamen, superior frontal gyrus and caudate. CONCLUSIONS: VBM differences suggest that diving training entails more effective synaptic and/or neuronal pruning processes in motor structures. Indeed, cortical volumetric decreases in the DAs group are associated with increased FC among certain motor-related regions. We conclude that motor learning in adolescence alters brain structure in association with changes in FC between the relevant cortical and subcortical regions.

DNA methylation in the medial prefrontal cortex regulates alcohol-induced behavior and plasticity.

Recent studies have suggested an association between alcoholism and DNA methylation, a mechanism that can mediate long-lasting changes in gene transcription. Here, we examined the contribution of DNA methylation to the long-term behavioral and molecular changes induced by a history of alcohol dependence. In search of mechanisms underlying persistent rather than acute dependence-induced neuroadaptations, we studied the role of DNA methylation regulating medial prefrontal cortex (mPFC) gene expression and alcohol-related behaviors in rats 3 weeks into abstinence following alcohol dependence. Postdependent rats showed escalated alcohol intake, which was associated with increased DNA methylation as well as decreased expression of genes encoding synaptic proteins involved in neurotransmitter release in the mPFC. Infusion of the DNA methyltransferase inhibitor RG108 prevented both escalation of alcohol consumption and dependence-induced downregulation of 4 of the 7 transcripts modified in postdependent rats. Specifically, RG108 treatment directly reversed both downregulation of synaptotagmin 2 (Syt2) gene expression and hypermethylation on CpG#5 of its first exon. Lentiviral inhibition of Syt2 expression in the mPFC increased aversion-resistant alcohol drinking, supporting a mechanistic role of Syt2 in compulsive-like behavior. Our findings identified a functional role of DNA methylation in alcohol dependence-like behavioral phenotypes and a candidate gene network that may mediate its effects. Together, these data provide novel evidence for DNA methyltransferases as potential therapeutic targets in alcoholism.

The abundance of cis-acting loci leading to differential allele expression in F1 mice and their relationship to loci harboring genes affecting complex traits.

BACKGROUND: Genome-wide surveys have detected cis-acting quantitative trait loci altering levels of RNA transcripts (RNA-eQTLs) by associating SNV alleles to transcript levels. However, the sensitivity and specificity of detection of cis- expression quantitative trait loci (eQTLs) by genetic approaches, reliant as it is on measurements of transcript levels in recombinant inbred strains or offspring from arranged crosses, is unknown, as is their relationship to QTL's for complex phenotypes. RESULTS: We used transcriptome-wide differential allele expression (DAE) to detect cis-eQTLs in forebrain and kidney from reciprocal crosses between three mouse inbred strains, 129S1/SvlmJ, DBA/2J, and CAST/EiJ and C57BL/6 J. Two of these crosses were previously characterized for cis-eQTLs and QTLs for various complex phenotypes by genetic analysis of recombinant inbred (RI) strains. 5.4 %, 1.9 % and 1.5 % of genes assayed in forebrain of B6/129SF1, B6/DBAF1, and B6/CASTF1 mice, respectively, showed differential allelic expression, indicative of cis-acting alleles at these genes. Moreover, the majority of DAE QTLs were observed to be tissue-specific with only a small fraction showing cis-effects in both tissues. Comparing DAE QTLs in F1 mice to cis-eQTLs previously mapped in RI strains we observed that many of the cis-eQTLs were not confirmed by DAE. Additionally several novel DAE-QTLs not identified as cis-eQTLs were identified suggesting that there are differences in sensitivity and specificity for QTL detection between the two methodologies. Strain specific DAE QTLs in B6/DBAF1 mice were located in excess at candidate genes for alcohol use disorders, seizures, and angiogenesis previously implicated by genetic linkage in C57BL/6J × DBA/2JF2 mice or BXD RI strains. CONCLUSIONS: Via a survey for differential allele expression in F1 mice, a substantial proportion of genes were found to have alleles altering expression in cis-acting fashion. Comparing forebrain and kidney, many or most of these alleles were tissue-specific in action. The identification of strain specific DAE QTLs, can assist in assessment of candidate genes located within the large intervals associated with trait QTLs.

A population-specific HTR2B stop codon predisposes to severe impulsivity.

Impulsivity, describing action without foresight, is an important feature of several psychiatric diseases, suicidality and violent behaviour. The complex origins of impulsivity hinder identification of the genes influencing it and the diseases with which it is associated. Here we perform exon-focused sequencing of impulsive individuals in a founder population, targeting fourteen genes belonging to the serotonin and dopamine domain. A stop codon in HTR2B was identified that is common (minor allele frequency > 1%) but exclusive to Finnish people. Expression of the gene in the human brain was assessed, as well as the molecular functionality of the stop codon, which was associated with psychiatric diseases marked by impulsivity in both population and family-based analyses. Knockout of Htr2b increased impulsive behaviours in mice, indicative of predictive validity. Our study shows the potential for identifying and tracing effects of rare alleles in complex behavioural phenotypes using founder populations, and indicates a role for HTR2B in impulsivity.