Characterizing the Penumbras of White Matter Hyperintensities and Their Associations With Cognitive Function in Patients With Subcortical Vascular Mild Cognitive Impairment

Normal-appearing white matter (NAWM) surrounding white matter hyperintensities (WMHs), frequently known as the WMH penumbra, is associated with subtle white matter injury and has a high risk for future conversion to WMHs. The goal of this study was to define WMH penumbras and to further explore whether the diffusion and perfusion parameters of these penumbras could better reflect cognitive function alterations than WMHs in subjects with subcortical vascular mild cognitive impairment (svMCI). Seventy-three svMCI subjects underwent neuropsychological assessments and 3T MRI scans, including diffusion tensor imaging (DTI) and arterial spin labeling (ASL). To determine the extent of cerebral blood flow (CBF) and DTI penumbras. A NAWM layer mask was generated for periventricular WMHs (PVWMHs) and deep WMHs (DWMHs) separately. Mean values of CBF, fractional anisotropy (FA), mean diffusivity (MD) within the WMHs and their corresponding NAWM layer masks were computed and compared using paired t-tests. Pearson's partial correlations were used to assess the relations of the mean CBF, FA, and MD values within the corresponding penumbras with composite z-scores of global cognition and four cognitive domains controlling for age, sex, and education. For both PVWMHs and DWMHs, the CBF penumbras were wider than the DTI penumbras. Only the mean FA value of the PVWMH-FA penumbra was correlated with the composite z-scores of global cognition before correction (r = 0.268, p = 0.024), but that correlation did not survive after correcting the p-value for multiple comparisons. Our findings showed extensive white matter perfusion disturbances including white matter tissue, both with and without microstructural alterations. The imaging parameters investigated, however, did not correlate to cognition

Resting-State Activity of Prefrontal-Striatal Circuits in Internet Gaming Disorder: Changes With Cognitive Behavior Therapy and Predictors of Treatment Response

Cognitive behavior therapy (CBT) is effective for the treatment of Internet gaming disorder (IGD). However, the mechanisms by which CBT improves IGD-related clinical symptoms remain unknown. This study aimed to discover the therapeutic mechanism of CBT in IGD subjects using resting-state functional magnetic resonance imaging (rsfMRI). Twenty-six IGD subjects and 30 matched healthy controls (HCs) received rsfMRI scan and clinical assessments; 20 IGD subjects completed CBT and then were scanned again. The amplitude of low-frequency (ALFF) values and the functional connectivity (FC) between the IGD group and the HC group were compared at baseline, as well as the ALFF values and FC before and after the CBT in the IGD group. Prior to treatment, the IGD group exhibited significantly increased ALFF values in the bilateral putamen, the right medial orbitofrontal cortex (OFC), the bilateral supplementary motor area (SMA), the left postcentral gyrus, and the left anterior cingulate (ACC) compared with the HC group. The HC group showed significantly increased FC values between the left medial OFC and the putamen compared with the IGD group, the FC values of IGD group were negatively associated with the BIS-11 scores before treatment. After the CBT, the weekly gaming time was significantly shorter, and the CIAS and BIS-II scores were significantly lower. The ALFF values in the IGD subjects significantly decreased in the left superior OFC and the left putamen, and the FC between them significantly increased after the CBT. The degree of the FC changes (ΔFC/Pre−FC) was positively correlated with the scale of the CIAS scores changes (ΔCIAS/Pre−CIAS) in the IGD subjects. CBT could regulate the abnormal low-frequency fluctuations in prefrontal-striatal regions in IGD subjects and could improve IGD-related symptoms. Resting-state alternations in prefrontal-striatal regions may reveal the therapeutic mechanism of CBT in IGD subjects

Patterns of attentional bias in antenatal depression: an eye-tracking study

IntroductionOne of the most common mental disorders in the perinatal period is depression, which is associated with impaired emotional functioning due to alterations in different cognitive aspects including thought and facial emotion recognition. These functional impairment may affect emerging maternal sensitivity and have lasting consequences for the dyadic relationship. The current study aimed to investigate the impact of depressive symptoms on the attention bias of infant stimuli during pregnancy.MethodsEighty-six pregnant women completed the Edinburgh Postnatal Depression Scale and an eye-tracking task comprising infant-related emotion images. All participants showed biased attention to infant-related images.ResultsFirst, compared to healthy pregnant women, pregnant women with depression symptoms initially directed their attention to infant-related stimuli more quickly (F (1, 84) = 6.175, p = 0.015, η2 = 0.068). Second, the two groups of pregnant women paid attention to the positive infant stimuli faster than the neutral infant stimuli, and the first fixation latency bias score was significantly smaller than that of the infant-related negative stimulus (p = 0.007). Third, compared with the neutral stimulus, the non-depression group showed a longer first gaze duration to the negative stimulus of infants (p = 0.019), while the depressive symptoms group did not show this difference.ConclusionWe speculate that structural and functional changes in affective motivation and cognitive-attention brain areas may induce these attentional bias patterns. These results provide suggestions for the implementation of clinical intervention programs to correct the attention bias of antenatal depressed women

Significant decrease of maternal mitochondria carryover using optimized spindle-chromosomal complex transfer.

Mutations in mitochondrial DNA (mtDNA) contribute to a variety of serious multi-organ human diseases, which are strictly inherited from the maternal germline. However, there is currently no curative treatment. Attention has been focused on preventing the transmission of mitochondrial diseases through mitochondrial replacement (MR) therapy, but levels of mutant mtDNA can often unexpectedly undergo significant changes known as mitochondrial genetic drift. Here, we proposed a novel strategy to perform spindle-chromosomal complex transfer (SCCT) with maximal residue removal (MRR) in metaphase II (MII) oocytes, thus hopefully eliminated the transmission of mtDNA diseases. With the MRR procedure, we initially investigated the proportions of mtDNA copy numbers in isolated karyoplasts to those of individual oocytes. Spindle-chromosomal morphology and copy number variation (CNV) analysis also confirmed the safety of this method. Then, we reconstructed oocytes by MRR-SCCT, which well developed to blastocysts with minimal mtDNA residue and normal chromosomal copy numbers. Meanwhile, we optimized the manipulation order between intracytoplasmic sperm injection (ICSI) and SCC transfer and concluded that ICSI-then-transfer was conducive to avoid premature activation of reconstructed oocytes in favor of normal fertilization. Offspring of mice generated by embryos transplantation in vivo and embryonic stem cells derivation further presented evidences for competitive development competence and stable mtDNA carryover without genetic drift. Importantly, we also successfully accomplished SCCT in human MII oocytes resulting in tiny mtDNA residue and excellent embryo development through MRR manipulation. Taken together, our preclinical mouse and human models of the MRR-SCCT strategy not only demonstrated efficient residue removal but also high compatibility with normal embryo development, thus could potentially be served as a feasible clinical treatment to prevent the transmission of inherited mtDNA diseases

Immunogenicity of chimeric haemagglutinin-based, universal influenza virus vaccine candidates: interim results of a randomised, placebo-controlled, phase 1 clinical trial.

BackgroundInfluenza viruses cause substantial annual morbidity and mortality globally. Current vaccines protect against influenza only when well matched to the circulating strains. However, antigenic drift can cause considerable mismatches between vaccine and circulating strains, substantially reducing vaccine effectiveness. Moreover, current seasonal vaccines are ineffective against pandemic influenza, and production of a vaccine matched to a newly emerging virus strain takes months. Therefore, there is an unmet medical need for a broadly protective influenza virus vaccine. We aimed to test the ability of chimeric H1 haemagglutinin-based universal influenza virus vaccine candidates to induce broadly cross-reactive antibodies targeting the stalk domain of group 1 haemagglutinin-expressing influenza viruses.MethodsWe did a randomised, observer-blinded, phase 1 study in healthy adults in two centres in the USA. Participants were randomly assigned to one of three prime-boost, chimeric haemagglutinin-based vaccine regimens or one of two placebo groups. The vaccine regimens included a chimeric H8/1, intranasal, live-attenuated vaccine on day 1 followed by a non-adjuvanted, chimeric H5/1, intramuscular, inactivated vaccine on day 85; the same regimen but with the inactivated vaccine being adjuvanted with AS03; and an AS03-adjuvanted, chimeric H8/1, intramuscular, inactivated vaccine followed by an AS03-adjuvanted, chimeric H5/1, intramuscular, inactivated vaccine. In this planned interim analysis, the primary endpoints of reactogenicity and safety were assessed by blinded study group. We also assessed anti-H1 haemagglutinin stalk, anti-H2, anti-H9, and anti-H18 IgG antibody titres and plasmablast and memory B-cell responses in peripheral blood. This trial is registered with ClinicalTrials.gov, number NCT03300050.FindingsBetween Oct 10, 2017, and Nov 27, 2017, 65 participants were enrolled and randomly assigned. The adjuvanted inactivated vaccine, but not the live-attenuated vaccine, induced a substantial serum IgG antibody response after the prime immunisation, with a seven times increase in anti-H1 stalk antibody titres on day 29. After boost immunisation, all vaccine regimens induced detectable anti-H1 stalk antibody (2·2-5·6 times induction over baseline), cross-reactive serum IgG antibody, and peripheral blood plasmablast responses. An unsolicited adverse event was reported for 29 (48%) of 61 participants. Solicited local adverse events were reported in 12 (48%) of 25 participants following prime vaccination with intramuscular study product or placebo, in 12 (33%) of 36 after prime immunisation with intranasal study product or placebo, and in 18 (32%) of 56 following booster doses of study product or placebo. Solicited systemic adverse events were reported in 14 (56%) of 25 after prime immunisation with intramuscular study product or placebo, in 22 (61%) of 36 after immunisation with intranasal study product or placebo, and in 21 (38%) of 56 after booster doses of study product or placebo. Disaggregated safety data were not available at the time of this interim analysis.InterpretationThe tested chimeric haemagglutinin-based, universal influenza virus vaccine regimens elicited cross-reactive serum IgG antibodies that targeted the conserved haemagglutinin stalk domain. This is the first proof-of-principle study to show that high anti-stalk titres can be induced by a rationally designed vaccine in humans and opens up avenues for further development of universal influenza virus vaccines. On the basis of the blinded study group, the vaccine regimens were tolerable and no safety concerns were observed.FundingBill & Melinda Gates Foundation

Genome-Wide Survey of Pseudogenes in 80 Fully Re-sequenced Arabidopsis thaliana Accessions

Pseudogenes (Ψs), including processed and non-processed Ψs, are ubiquitous genetic elements derived from originally functional genes in all studied genomes within the three kingdoms of life. However, systematic surveys of non-processed Ψs utilizing genomic information from multiple samples within a species are still rare. Here a systematic comparative analysis was conducted of Ψs within 80 fully re-sequenced Arabidopsis thaliana accessions, and 7546 genes, representing ~28% of the genomic annotated open reading frames (ORFs), were found with disruptive mutations in at least one accession. The distribution of these Ψs on chromosomes showed a significantly negative correlation between Ψs/ORFs and their local gene densities, suggesting a higher proportion of Ψs in gene desert regions, e.g. near centromeres. On the other hand, compared with the non-Ψ loci, even the intact coding sequences (CDSs) in the Ψ loci were found to have shorter CDS length, fewer exon number and lower GC content. In addition, a significant functional bias against the null hypothesis was detected in the Ψs mainly involved in responses to environmental stimuli and biotic stress as reported, suggesting that they are likely important for adaptive evolution to rapidly changing environments by pseudogenization to accumulate successive mutations

Effects of Loading Rate and Notch-to-Depth Ratio of Notched Beams on Flexural Performance of Ultra-High-Performance Concrete

This paper addresses the effects of loading rate and notch-to-depth ratio on flexural properties of ultra-high-performance concrete (UHPC) notched beam specimens, in order to enable use of standardized laboratory test data to predict flexural properties of UHPC structures that have different dimensions and are subjected to a range of loading rates. UHPC notched beams were tested in three-point bending to study the effects of three notch-to-depth ratios of 1/6, 1/3, and 1/2 at five loading rates of 0.05, 0.50, 1.25, 2.50, and 5.00 mm/min on flexural performance. Test results indicate that loading rate and notch-to-depth ratio have significant effects on flexural properties of the UHPC notched beams. The flexural strength is shown to increase with the loading rate and the notch-to-depth ratio. The fracture energy increases with the loading rate but decreases with the notch-to-depth ratio. The changes of flexural properties with the loading rate are also dependent on the notch-to-depth ratio. Regression analyses to correlate flexural properties associated with the loading rate and notch-to-depth ratio were conducted to obtain parameters for UHPC structures

Pricing Decisions and Coordination in E-Commerce Supply Chain with Wholesale Price Contract Considering Focus Preferences

Decision makers’ behavioral preferences have always been important in coordinating the supply chain. Decision makers need to choose a partner wisely to increase the profitability of the entire supply chain, especially in the competitive e-commerce environment. In this paper, we examine a two-echelon e-commerce supply chain with one retailer and one supplier using the most popular wholesale price contract to facilitate collaboration. Traditional research has shown that the classical expectation model cannot coordinate the supply chain. We apply the focus theory of choice to describe the retailer’s behavior as a follower, and we examine the impact of the retailer’s pricing decisions on the supplier under different focus preferences and the coordination for the entire supply chain. The lower the parameter φ, which represents the degree of positivity, and the higher the parameter κ, which represents the level of confidence, the closer the profit of the whole supply chain is to the coordination result—both are visualized through numerical experiments and images. In the case of φ determination, the lower the κ, the better the supply chain coordination. The finding implies that the retailer may be able to coordinate the supply chain and produce better results than the expectation model when he or she makes choices using a positive evaluation system that includes both higher levels of optimism and lower levels of confidence. The findings of the FTC model can simultaneously offer a theoretical foundation for expanding collaboration among supply chain participants and management insights for decision makers to choose cooperation partners

The Maternal Diet with Fish Oil Might Decrease the Oxidative Stress and Inflammatory Response in Sows, but Increase the Susceptibility to Inflammatory Stimulation in their Offspring

The aim of this study is to investigate the effect of the maternal diet with fish oil on the oxidative stress and inflammatory response in sows, and the protective effect on the piglets suckling the sows fed the diet with fish oil in the context of inflammatory stimulation. Twelve sows were divided into two groups. Sows were fed soybean oil diet (SD) or soybean oil + fish oil diet (FD) from gestation to lactation period. The blood samples of sows were collected from the auricular vein at the 16th day of lactation. One piglet was selected from each litter on the 14th day after birth. Lipopolysaccharide (LPS) was injected into the neck muscle after pre-treatment blood samples were collected from the anterior vena cava of piglets. The blood samples of piglets were collected at 5 h and 48 h post-LPS injection from the front cavity vein. Liver samples were collected at 48 h post-LPS injection. The FD diet significantly increased the level of high-density lipoprotein cholesterol (HDL-C) in the plasma of lactating sow, decreased the levels of alkaline phosphatase(AKP) and tumor necrosis factor alpha(TNF-α) in the plasma of lactating sows, and increased the level of immunoglobulin G(IgG) in the colostrum and interleukin-10(IL-10) in the milk (p < 0.05). In the FD group, the levels of glutathione peroxidase (GSH-Px) and total antioxidant capacity (T-AOC) significantly increased in the plasma of piglets at 48 h post-LPS injection (p < 0.05). Meanwhile, the relative expression of GSH-Px mRNA was decreased in the FD group (p < 0.05). However, the levels of interleukin-1 beta (IL-1β) and interleukin-6(IL-6) in the plasma of piglets were significantly higher in the FD group pre- and post-LPS injection (p < 0.05). The ratio of the phosphonated extracellular regulated protein kinases to the extracellular regulated protein kinases (p-ERK/ERK) protein in the livers of piglets was decreased (p < 0.05), but the expression of nuclear transcription factor-κB (NF-κB) mRNA and the ratio of the phosphonated inhibitor of NF-κB to the inhibitor of NF-κB (p-IκB-α/IκB-α) protein was increased in the livers of piglets (p < 0.05). These results indicate that a maternal diet with fish oil might decrease the oxidative stress and inflammatory response in sows, and enhance the antioxidative ability but increase the susceptibility to inflammatory stimulation in their progenies

Analysis of Psychological Influences on Navigation Use While Driving Based on Extended Theory of Planned Behavior

As GPS navigation systems become more powerful, they offer the convenience of more efficient travel, and the use of such navigational aids while driving is now prevalent. Numerous issues still exist during actual use, however, such as incomprehensibility and inaccuracy of voice navigation prompts. The majority of studies have focused on humanized design and the influence on driving behavior of GPS navigation systems, while the psychological factors underlying drivers' decisions to use them have received little attention. This study employs the extended theory of planned behavior (TPB) to investigate the psychological factors that influence drivers' use of GPS navigation systems, including the additional variables of navigation involvement, navigation information quality, and distraction perception. Independent t-tests revealed that female, non-professional, novice, and highly educated drivers were more likely to use navigation systems. Factors analysis proved the extended TPB questionnaire to be valid and reliable. Structural equation modeling showed that attitude (0.19), subjective norms (0.14), perceived behavioral control (0.29), navigation involvement (0.36), and information quality (0.16) significantly influenced drivers' intentions on the use of navigation. However, distraction perception (-0.05) had no significant influence. These findings demonstrate the need for navigation systems which serve drivers better. For navigation system manufacturers, the humanized design should be strengthened. For highway transportation agencies, more consistent designs for road signs are needed to improve the cooperativity between navigation and traffic signs