Effects of computerized cognitive training on functional brain networks in patients with vascular cognitive impairment and no dementia.

AIMS: Previous neuroimaging studies of vascular cognitive impairment, no dementia (VCIND), have reported functional alterations, but far less is known about the effects of cognitive training on functional connectivity (FC) of intrinsic connectivity networks (ICNs) and how they relate to intervention-related cognitive improvement. This study provides comprehensive research on the changes in intra- and inter-brain functional networks in patients with VCIND who received computerized cognitive training, with a focus on the underlying mechanisms and potential therapeutic strategies. METHODS: We prospectively collected 60 patients with VCIND who were randomly divided into the training group (N = 30) receiving computerized cognitive training and the control group (N = 30) receiving fixed cognitive training. Functional MRI scans and cognitive assessments were performed at baseline, at the 7-week training, and at the 6-month follow-up. Utilizing templates for ICNs, the study employed a linear mixed model to compare intra- and inter-network FC changes between the two groups. Pearson correlation was applied to calculate the relationship between FC and cognitive function. RESULTS: We found significantly decreased intra-network FC within the default mode network (DMN) following computerized cognitive training at Month 6 (p = 0.034), suggesting a potential loss of functional specialization. Computerized training led to increased functional coupling between the DMN and sensorimotor network (SMN) (p = 0.01) and between the language network (LN) and executive control network (ECN) at Month 6 (p < 0.001), indicating compensatory network adaptations in patients with VCIND. Notably, the intra-LN exhibited enhanced functional specialization after computerized cognitive training (p = 0.049), with significant FC increases among LN regions, which correlated with improvements in neuropsychological measures (p < 0.05), emphasizing the targeted impact of computerized cognitive training on language abilities. CONCLUSIONS: This study provides insights into neuroplasticity and adaptive changes resulting from cognitive training in patients with VCIND, with implications for potential therapeutic strategies.

Genetic variation and evolutionary characteristics of Echovirus 11: new variant within genotype D5 associated with neonatal death found in China.

Echovirus 11 (E11) has gained attention owing to its association with severe neonatal infections. From 2018 to 2023, a surge in severe neonatal cases and fatalities linked to a novel variant of genotype D5 was documented in China, France, and Italy. However, the prevention and control of E11 variants have been hampered by limited background data on the virus circulation and genetic variance. Therefore, the present study investigated the circulating dynamics of E11 and the genetic variation and molecular evolution of genotype D5 through the collection of strains from the national acute flaccid paralysis (AFP) and hand, foot, and mouth disease (HFMD) surveillance system in China during 2000-2022 and genetic sequences published in the GenBank database. The results of this study revealed a prevalent dynamic of E11 circulation, with D5 being the predominant genotype worldwide. Further phylogenetic analysis of genotype D5 indicated that it could be subdivided into three important geographic clusters (D5-CHN1: 2014-2019, D5-CHN2: 2016-2022, and D5-EUR: 2022-2023). Additionally, variant-specific (144) amino acid mutation sites and positive-selection pressure sites (132, 262) were identified in the VP1 region. Cluster-specific recombination patterns were also identified, with CVB5, E6, and CVB4 as the major recombinant viruses. These findings provide a preliminary landscape of E11 circulation worldwide and basic scientific data for further study of the pathogenicity of E11 variants.

Porcine circovirus type 2 infection inhibits the activation of type I interferon signaling via capsid protein and host gC1qR.

Porcine circovirus 2 (PCV2) has been proved to increase the risk of other pathogens infection through antagonizing the host type I interferon (IFN) response. Previously, we have reported that PCV2 infection efficiently inhibits type I interferon production induced by other DNA viruses. However, whether PCV2 can inhibit type I interferon signaling is less reported. Herein, we found that PCV2 interfered with the activation of IFN signaling pathway, which led to a significantly reduced IFN-stimulated genes (ISGs) transcription after IFN-α stimulation both in vivo and in vitro. In PCV2-infected cells, IFN-induced tyrosine phosphorylation of STAT1 and STAT2 and their heterodimerization were decreased. Meanwhile, the nuclear translocation of phosphorylated STAT1/STAT2 was also decreased. Based on these findings, we further determined that roles of PCV2 Cap and Rep in the suppression of IFN-I signaling, and found that Cap acted as a predominant regulator in the early phase infection. PCV2 Cap could significantly reduce the phosphorylation of STAT1 and STAT2, the nuclear translocation of phosphorylated STAT1/STAT2, and IFN-stimulated response element (ISRE) promoter activity, results in a decreased ISGs transcription. As the binding protein of PCV2 Cap, gC1qR protein was also involved in this inhibition process. Knockdown of gC1qR could alleviate the inhibitory effects of either PCV2 infection or Cap on the activation of IFN signaling. These findings demonstrated that PCV2 infection interferes with the activation of type I IFNs signaling pathway depending on its Cap and host gC1qR protein.

Activation of the M3AChR and Notch1/HSF1 Signaling Pathway by Choline Alleviates Angiotensin II-Induced Cardiomyocyte Apoptosis.

Angiotensin II- (Ang II-) induced cardiac hypertrophy and apoptosis are major characteristics of early-stage heart failure. Choline exerts cardioprotective effects; however, its effects on Ang II-induced cardiomyocyte apoptosis are unclear. In this study, the role and underlying mechanism of choline in regulating Ang II-induced cardiomyocyte apoptosis were investigated using a model of cardiomyocyte apoptosis, which was induced by exposing neonatal rat cardiomyocytes to Ang II (10-6 M, 48 h). Choline promoted heat shock transcription factor 1 (HSF1) nuclear translocation and the intracellular domain of Notch1 (NICD) expression. Consequently, choline attenuated Ang II-induced increases in mitochondrial reactive oxygen species (mtROS) and promotion of proapoptotic protein release from mitochondria, including cytochrome c, Omi/high-temperature requirement protein A2, and second mitochondrial activator of caspases/direct inhibitor of apoptosis-binding protein with low P. The reversion of these events attenuated Ang II-induced increases in cardiomyocyte size and numbers of terminal deoxynucleotidyl transferase deoxyuridine triphosphate nick end labeling-positive cells, presumably via type 3 muscarinic acetylcholine receptor (M3AChR). Indeed, downregulation of M3AChR or Notch1 blocked choline-mediated upregulation of NICD and nuclear HSF1 expression, as well as inhibited mitochondrial apoptosis pathway and cardiomyocyte apoptosis, indicating that M3AChR and Notch1/HSF1 activation confer the protective effects of choline. In vivo studies were performed in parallel, in which rats were infused with Ang II for 4 weeks to induce cardiac apoptosis. The results showed that choline alleviated cardiac remodeling and apoptosis of Ang II-infused rats in a manner related to activation of the Notch1/HSF1 pathway, consistent with the in vitro findings. Taken together, our results reveal that choline impedes oxidative damage and cardiomyocyte apoptosis by activating M3AChR and Notch1/HSF1 antioxidant signaling, and suggest a novel role for the Notch1/HSF1 signaling pathway in the modulation of cardiomyocyte apoptosis.

Dynamic Neural Network Changes Revealed by Voxel-Based Functional Connectivity Strength in Left Basal Ganglia Ischemic Stroke.

OBJECTIVE: This study intends to track whole-brain functional connectivity strength (FCS) changes and the lateralization index (LI) in left basal ganglia (BG) ischemic stroke patients. METHODS: Twenty-five patients (N = 25; aged 52.73 ± 10.51 years) with five visits at <7, 14, 30, 90, and 180 days and 26 healthy controls (HCs; N = 26; 51.84 ± 8.06 years) were examined with resting-state functional magnetic resonance imaging (rs-fMRI) and motor function testing. FCS and LI were calculated through constructing the voxel-based brain functional network. One-way analysis of covariance (ANOVA) was first performed to obtain longitudinal FCS and LI changes in patients among the five visits (Bonferroni corrected, P < 0.05). Then, pairwise comparisons of FCS and LI were obtained during the five visits, and the two-sample t test was used to examine between-group differences in FCS [family-wise error (FWE) corrected, P < 0.05] and LI. Correlations between connectivity metrics (FCS and LI) and motor function were further assessed. RESULTS: Compared to HCs, decreased FCS in the patients localized in the calcarine and inferior occipital gyrus (IOG), while increased FCS gathered in the middle prefrontal cortex (MPFC), middle frontal gyrus, and insula (P < 0.05). The LI and FCS of patients first decreased and then increased, which showed significant differences compared with HCs (P < 0.05) and demonstrated a transition at the 30-day visit. Additionally, LI at the third visit was significantly different from those at the other visits (P < 0.05). No significant longitudinal correlations were observed between motor function and FCS or LI (P > 0.05). CONCLUSION: Focal ischemic stroke in the left BG leads to extensive alterations in the FCS. Strong plasticity in the functional networks could be reorganized in different temporal dynamics to facilitate motor recovery after BG stroke, contribute to diagnosing the disease course, and estimate the intervention treatment.

Determination of pharmacokinetic parameters of vitamin K1 in rats after an intravenous infusion.

Pharmacokinetic parameters of vitamin K1 have a large range of values in different literature. The aim of this study was to determine the pharmacokinetic parameters of vitamin K1 following post-constant speed intravenous infusion (PCSII) to provide rational pharmacokinetic parameters of vitamin K1 and compare these with results of noncompartmental analysis following intravenous injection (IV). After 15 hours intravenous infusion of vitamin K1 in rats, the logarithmic concentration-time curve of vitamin K1 was fit to a linear equation following PCSII (R2  = 0.9599 ± 0.0096). Then, half-time (T1/2 ), apparent volume of distribution (Vd ), and clearance rate (CL) were estimated successively. T1/2 of vitamin K1 was 4.07 ± 0.41 hour, CL was 89.47 ± 3.60 mL/h, and Vd was 525.38 ± 54.45 mL in rats following PCSII. There was no significant difference in pharmacokinetic parameters of vitamin K1 among different sampling times. For noncompartmental analysis, T1/2 and mean residence time (MRTINF ) for a sampling duration of 6h were shorter than those of 12 hours or 24 hours sampling duration following IV (P < .05, P < .01). In addition, T1/2 of vitamin K1 was obviously different from MRT-equated half-time (T1/2,MRT )(P < .05). Vd and CL of vitamin K1 following PCSII were larger than those following IV based on noncompartmental analysis (P < .01). The results demonstrated that drug distribution in the body was balanced and the Napierian logarithmic concentration-time curve of vitamin K1 fit to a linear equation following PCSII. Vitamin K1 has a long T1/2 and a relatively large Vd following PCSII.

Projections of Brodmann Area 6 to the Pyramidal Tract in Humans: Quantifications Using High Angular Resolution Data.

Primate studies indicate that the pyramidal tract (PyT) could originate from Brodmann area (BA) 6. However, in humans, the accurate origin of PyT from BA 6 is still uncertain owing to difficulties in visualizing anatomical features such as the fanning shape at the corona radiata and multiple crossings at the semioval centrum. High angular-resolution diffusion imaging (HARDI) could reliably replicate these anatomical features. We explored the origin of the human PyT from BA 6 using HARDI. With HARDI data of 30 adults from the Massachusetts General Hospital-Human Connectome Project (MGH-HCP) database and the HCP 1021 template (average of 1021 HCP diffusion data), we visualized the PyT at the 30-averaged group level and the 1021 large-sample level and validated the observations in each of the individuals. Endpoints of the fibers within each subregion were quantified. PyT fibers originating from the BA 6 were consistently visualized in all images. Specifically, the bilateral supplementary motor area (SMA) and dorsal premotor area (dPMA) were consistently found to contribute to the PyT. PyT fibers from BA 6 and those from BA 4 exhibited a twisting topology. The PyT contains fibers originating from the SMA and dPMA in BA 6. Infarction of these regions or aging would result in incomplete provision of information to the PyT and concomitant decreases in motor planning and coordination abilities.

Epidemiologic characteristics and pathogen surveillance of hand, foot and mouth disease in Zhejiang province, 2009-2017 / 中华实验和临床病毒学杂志

Objective@#To evaluate the epidemiologic characteristics of hand, foot and mouth disease in Zhejiang province between 2009 and 2017, so that scientific evidence could be provided for prevention and control of hand, foot and mouth disease.@*Methods@#Spatial, temporal and population distribution of HFMD was analyzed. Real-time reverse transcription polymerase cain reaction was used to test Enterovirus A71 and Coxsackievirus A16 in samples.@*Results@#Between 2009 and 2017, 1 108 093 HFMD cases were reported in Zhejiang with the prevalence of 226.24/100000; 2010, 2012, 2014 and 2016 had a higher prevalence than other years. Prevalence of HFMD peaked in April-July and September-October. Wenzhou, Taizhou and Ningbo had a higher prevalence than other cities. In total, 69.27% cases were children who were not enrolled in nursery school, and 65.67% were 1-3 years old. Pathogen surveillance showed that EV-A71 decreased in mild cases, whereas other enterovirus increased. However EV-A71 was still predominant in severe and fatal cases (56.0%).@*Conclusions@#Temporal and spatial distribution of HFMD is characteristic in Zhejiang province. EV-A71 predominated in severe cases and fatal cases, while other enterovirus (non-EV-A71, non CV-A16) were the main pathogen for mild cases.

A study on the development of a triplex real -time RT -PCR for simultaneous detection of enteroviruses and differentiation of EV 71 and CA 16 / 预防医学

Objective To develop a multiplex real -time RT -PCR assay for simultaneous detection of enteroviruses and differentiation of EV71 and CA16.Methods Specific primers and probes were designed for enteroviruses,EV71 and CA16.The probes labeled with various fluorescent reporter dyes,and a triplex real -time RT -PCR technique was developed to simultaneously detect these viruses.A total of 91 clinical specimens with suspected HFMD were analyzed by this method.Results This assay could simultaneously detect enterovirus and differentiation of EV71 and CA16,and the sensitivity of the assay was up to 0.1 TCID50 /mL,and only need 2 to 3 hours for completing the detection.A total of 91 clinical specimens were detected by this assay in 28 of the 91(30.77%)specimens contained EV71,9 of the 91(9.89%) contained CA16,and 5 of the 91 (5.49%)contained other enteroviruses.Conclusion This assay would be a useful molecular diagnostic tool for large -scale screening of clinical samples,especially at the peroid of HFMD outbreaks.

Molecular characteristics of norovirus in 3 outbreak-episodes of gastroenteritis in Zhejiang from 2008 to 2009 / 中华流行病学杂志

Objective To study the molecular characteristic of norovirus in 3 outbreaks of gastroenteritis in Zhejiang province. Methods During January 2008 and December 2009, fecal specimens of patients were collected from 3 outbreaks of acute viral gastroenteritis. Noroviruses were detected by Real-time RT-PCR. Part of the positive samples were randomly selected and detected by RT-PCR. PCR products were sequenced. Sequence analysis was undertaken based on partial sequence of RNA dependent RNA polymerase(RdRp)and capsid protein gene. Some positive samples were amplified by 3' RACE(rapid amplification of cDNA 3' ends), 3200 bp in length. The exact whole ORF2, ORF3 and 3' untranslation regions(UTR)gene of norovims were identified. Results There were in total 3 outbreaks of viral gastroenteritis caused by norovirus being reported. A total of 62 stools were obtained from cases with acute gastroentefitis. Noroviruses were detected in 41 cases including 27 strains of genogroup Ⅰ norovirus and 9 strains of genogroup Ⅱ norovirus, 5 strains of genogroup Ⅰ + Ⅱ norovirus. Four genotypes including G Ⅰ .8, G Ⅱ .b, G Ⅰ .2/0 Ⅰ .6 recombination together with co-infection of G Ⅰ .8 and G Ⅱ .b were detected. Conclusion Norovirus was confirmed as the major cause of outbreaks of viral gastroenteritis in Zhejiang province and multiple genotype of norovirus were identified from the outbreaks. It was the first time to have found a recombinant of G Ⅰ .6 capsid and G Ⅰ .2 polymerase norovims as well as the co-infection of G Ⅰ .8 and G Ⅱ .b norovirus in the same sample.

Molecular epidemiology of Norovirus in outbreaks of gastroenteritis in Zhejiang from 2006 to 2007 / 中华流行病学杂志

Objecfive To study the molecular epidemioiogical characteristics of Norovirus gastroenteritis outbreaks in Zhejiang.Methods During January 2006 and December 2007.fecal specimens of patients collected from outbreaks of acute viml gastroenteritis were tcsted for Norovirus.Epidemiological data were also collected.Noroviruses were detected by a reverse transcription polymerase chain reaction(RT-PeR)and Real.time RT-PCR.Some positive samples were randomly selected and Rrr-PCR products were sequenced.Comparing to the nucleotide sequences of norovirus genotype Ⅰ,Ⅱ reference strains from GenBank,sequence analysis was undertaken based on partial sequence of RNA dependent RNA polymerase(RdRp)and capsid protein(VPI)gene.Results 5 Outbreaks of viral gastroenteritis caused bv Norovirus were reported.A total of 63 stools were obtained from cases with acute gastroenteritis.Noroviruses alone were detected in 45 cases and the illness appeared in autumn.Phylogenetic analysis revealed that Norovirus belonged to G Ⅱ/G Ⅱ 4 type.The strains isolated from Zhejiang were almost identical on G Ⅱ/4 variants that causing epidemics in Beijing and in the Netherlands with the homology of 99.7%and 98.5%-99.O%respectively.Phylogenetic analysis revealed that the isolates were located at the same branch as the norovirus G Ⅱ/4 variants found in Beijing and Netherlands.Conclusion Norovirus iS a major cause of outbreaks of viral gastroenterifis in Zhejiang province.GenogroupⅡ/4 variants viruses were the prevalent strains.

Isolation and sequencing of VP1 region of enterovirus 71 strains in Zhejiang, China / 中华流行病学杂志

<p><b>OBJECTIVE</b>To study the gene characterization of enterovirus 71 (EV71) virus strains isolated from clinical specimens of children with hand-foot-and-mouth disease (HFMD) in Zhejiang province.</p><p><b>METHODS</b>Virus were isolated from clinical samples including stool, throat swab and vesicle from patients with HFMD. The EV71 isolates were identified by microneutralization assay and reverse transcriptase PCR (RT-PCR) with specific primer pair for VP1 genes of EV71. Complete VP1 gene sequences (891 nucleotides) for recent 6 EV71 isolates were determined and compared with that of A, B, C genotype reference EV71 strains and 11 EV71 China isolates available from GeneBank by homogeneity and phylogenetic tree analyses.</p><p><b>RESULTS</b>9 strains of EV were isolated from 14 clinical specimens. Data from microneutralization and RT-PCR results indicated that all the strains belong to EV71. The nucleotide and amino acid homogeneity of these 6 Zhejiang strains with the representative isolates of A and B genotypes were 82.9%-85.5% and 94.9%-98.0% respectively; with the representative isolates of C were 89.2%-94.1% and 97.0%-99.0% respectively. There were 91.0%-92.2%, 90.2%-90.3%, 89.2%-89.5%, 96.7%-96.9% nucleotide, homology with representative strains of C1, C2, C3,C4 subgenotypes of EV71. The nucleotide homogeneity of these 6 EV71 isolated strains with 9 previously isolated Chinese strains appeared to be 93.8%-97.1%. These 6 EV71 isolated strains were within genotype C subgenogroup C4 in the phylogenetic tree.</p><p><b>CONCLUSION</b>The recently identified EV71 isolates in Zhejiang province belonged to subgenogroup C4.</p>