An individual's brainAGE is the difference between chronological age and age predicted from machine-learning models of brain-imaging data. BrainAGE has been proposed as a biomarker of age-related deterioration of the brain. Having an older brainAGE has been linked to Alzheimer's, dementia, and mortality. However, these findings are largely based on cross-sectional associations which can confuse age differences with cohort differences. To illuminate the validity of brainAGE as a biomarker of accelerated brain aging, a study is needed of a large cohort all born in the same year who nevertheless vary on brainAGE. In the Dunedin Study, a population-representative 1972-73 birth cohort, we measured brainAGE at age 45 years, as well as the pace of biological aging and cognitive decline in longitudinal data from childhood to midlife (N = 869). In this cohort, all chronological age 45 years, brainAGE was measured reliably (ICC = 0.81) and ranged from 24 to 72 years. Those with older midlife brainAGEs tended to have poorer cognitive function in both adulthood and childhood, as well as impaired brain health at age 3. Furthermore, those with older brainAGEs had an accelerated pace of biological aging, older facial appearance, and early signs of cognitive decline from childhood to midlife. These findings help to validate brainAGE as a potential surrogate biomarker for midlife intervention studies that seek to measure dementia-prevention efforts in midlife. However, the findings also caution against the assumption that brainAGE scores represent only age-related deterioration of the brain as they may also index central nervous system variation present since childhood.

Antibody Fc-mediated functions, such as antibody-dependent cellular cytotoxicity, contribute to vaccine-induced protection against viral infections. Fc-mediated function of anti-Ebola glycoprotein (GP) antibodies suggest that Fc-dependent activation of effector cells, including natural killer (NK) cells, could play a role in vaccination against Ebola virus disease.

We aimed to evaluate the prevalence, characteristics, and clinical outcomes of spontaneous coronary artery dissection (SCAD) in young female patients with acute myocardial infarction (AMI).

Spinal cord ischemia (SCI) is one of the major concerns of postoperative paraplegia during major vascular or aortic surgery. Since mitochondrial dysfunction develops at the early stage of SCI, this study tested the neuronal protective effect of transplantation of viable mitochondria to the ischemic cord in rats.

Despite the high prevalence of intimate partner violence (IPV) perpetration by men who use substances, limited evidence exists about how best to reduce IPV among this group.

Vascular endothelial growth factor (VEGF) is associated with the clinical manifestation of Alzheimer's disease (AD). However, the role of the VEGF gene family in neuroprotection is complex due to the number of biological pathways they regulate. This study explored associations between brain expression of VEGF genes with cognitive performance and AD pathology. Genetic, cognitive, and neuropathology data were acquired from the Religious Orders Study and Rush Memory and Aging Project. Expression of ten VEGF ligand and receptor genes was quantified using RNA sequencing of prefrontal cortex tissue. Global cognitive composite scores were calculated from 17 neuropsychological tests. β-amyloid and tau burden were measured at autopsy. Participants (n = 531) included individuals with normal cognition (n = 180), mild cognitive impairment (n = 148), or AD dementia (n = 203). Mean age at death was 89 years and 37% were male. Higher prefrontal cortex expression of VEGFB, FLT4, FLT1, and PGF was associated with worse cognitive trajectories (p ≤ 0.01). Increased expression of VEGFB and FLT4 was also associated with lower cognition scores at the last visit before death (p ≤ 0.01). VEGFB, FLT4, and FLT1 were upregulated among AD dementia compared with normal cognition participants (p ≤ 0.03). All four genes associated with cognition related to elevated β-amyloid (p ≤ 0.01) and/or tau burden (p ≤ 0.03). VEGF ligand and receptor genes, specifically genes relevant to FLT4 and FLT1 receptor signaling, are associated with cognition, longitudinal cognitive decline, and AD neuropathology. Future work should confirm these observations at the protein level to better understand how changes in VEGF transcription and translation relate to neurodegenerative disease.

Insect neuropeptides play an important role in regulating physiological functions such as growth, development, behavior and reproduction. We identified temperature-sensitive neuropeptides and receptor genes of the cotton whitefly, Bemisia tabaci. We identified 38 neuropeptide precursor genes and 35 neuropeptide receptors and constructed a phylogenetic tree using additional data from other insects. As temperature adaptability enables B. tabaci to colonize a diversity of habitats, we performed quantitative polymerase chain reaction with two temperature stresses (low = 4 °C and high = 40 °C) to screen for temperature-sensitive neuropeptides. We found many neuropeptides and receptors that may be involved in the temperature adaptability of B. tabaci. This study is the first to identify B. tabaci neuropeptides and their receptors, and it will help to reveal the roles of neuropeptides in temperature adaptation of B. tabaci.

Depression is a chronic disease that affects nearly twice as many women as men, and symptoms can differ by sex. Preclinical models disproportionately use male subjects and test a single behavioral endpoint immediately at the cessation of stress. We conducted variable stress in male and female mice for 6, 28, and 56 days, and measured behavior with a battery chosen to match research domain criteria. To examine individual differences, we generated a composite z score to measure stress susceptibility across behavioral tests. We also tested behavior following a 30-day recovery period to evaluate the duration of the stress effects. Females, but not males, were susceptible to 6 days of variable stress when behavioral testing started 24 h later. If behavioral testing was conducted 30 days later both males and females expressed stress related behaviors. Males and females were stress susceptible to 28 days of variable stress and effects were long lasting. Both sexes habituated to 56 days of variable stress, but anxiety associated measures still showed persistence. Performance on specific behavioral tests was often different between individuals and between sexes, and not all stressed animals were susceptible to all tested behaviors. These studies confirm that behavioral sex differences are detected in response to variable stress, and reveal information about individual differences. Use of a test battery that measures varying endophenotypes can be combined into a single stress susceptibility score as a tool similar to the scales/inventories used for the study of depression in humans. We present these data with the goal of furthering the field's understanding sex differences and how they shape the biology of mood disorders.

Severe combined immunodeficiencies (SCIDs) constitute a heterogeneous group of life-threatening genetic disorders that typically present in the first year of life. They are defined by the absence of autologous T cells and the presence of an intrinsic or extrinsic defect in the B-cell compartment. In three newborns presenting with frequent infections and profound leukopenia, we identified a private, heterozygous mutation in the RAC2 gene (p.G12R). This mutation was de novo in the index case, who had been cured by hematopoietic stem cell transplantation but had transmitted the mutation to her sick daughter. Biochemical assays showed that the mutation was associated with a gain of function. The results of in vitro differentiation assays showed that RAC2 is essential for the survival and differentiation of hematopoietic stem/progenitor cells. Therefore, screening for RAC2 gain-of-function mutations should be considered in patients with a SCID phenotype and who lack a molecular diagnosis.

To evaluate the efficacy and safety of ranibizumab 0.5 mg in adolescent patients with any choroidal neovascularization etiology enrolled in the 12-month MINERVA study.

Atherosclerosis is as a systemic inflammatory disease associated with the activationof many mediators, including matrix metalloproteinases (MMPs), and may be amplified by abnormal high serum uric acid (UA) concentration (hyperuricemia, HU). The aim of the study was to determine the relationship between serum UA concentration and activity of MMPs and their correlation with the hypertension-mediated organ damage (HMOD) intensity.

Long noncoding RNAs (lncRNAs) are transcripts longer than 200 nucleotides with little or no protein coding potential. The expanding list of lncRNAs and accumulating evidence of their functions in plants have necessitated the creation of a comprehensive database for lncRNA research. However, currently available plant lncRNA databases have some deficiencies, including the lack of lncRNA data from some model plants, uneven annotation standards, a lack of visualization for expression patterns, and the absence of epigenetic information. To overcome these problems, we upgraded our Plant Long noncoding RNA Database (PLncDB, http://plncdb.tobaccodb.org/), which was based on a uniform annotation pipeline. PLncDB V2.0 currently contains 1 246 372 lncRNAs for 80 plant species based on 13 834 RNA-Seq datasets, integrating lncRNA information from four other resources including EVLncRNAs, RNAcentral and etc. Expression patterns and epigenetic signals can be visualized using multiple tools (JBrowse, eFP Browser and EPexplorer). Targets and regulatory networks for lncRNAs are also provided for function exploration. In addition, PLncDB V2.0 is hierarchical and user-friendly and has five built-in search engines. We believe PLncDB V2.0 is useful for the plant lncRNA community and data mining studies and provides a comprehensive resource for data-driven lncRNA research in plants.

We present Peryton (https://dianalab.e-ce.uth.gr/peryton/), a database of experimentally supported microbe-disease associations. Its first version constitutes a novel resource hosting more than 7900 entries linking 43 diseases with 1396 microorganisms. Peryton's content is exclusively sustained by manual curation of biomedical articles. Diseases and microorganisms are provided in a systematic, standardized manner using reference resources to create database dictionaries. Information about the experimental design, study cohorts and the applied high- or low-throughput techniques is meticulously annotated and catered to users. Several functionalities are provided to enhance user experience and enable ingenious use of Peryton. One or more microorganisms and/or diseases can be queried at the same time. Advanced filtering options and direct text-based filtering of results enable refinement of returned information and the conducting of tailored queries suitable to different research questions. Peryton also provides interactive visualizations to effectively capture different aspects of its content and results can be directly downloaded for local storage and downstream analyses. Peryton will serve as a valuable source, enabling scientists of microbe-related disease fields to form novel hypotheses but, equally importantly, to assist in cross-validation of findings.

Luminal glucose enhances intestinal Ca2+ absorption through apical Cav 1.3 channels necessary for GLUT2-mediated glucose absorption. As these reciprocal mechanisms are not well understood, we investigated the regulatory mechanisms of intestinal [Ca2+ ]cyt and SGLT1-mediated Na+ -glucose co-transports.

Numerous algorithms have been developed to guide warfarin dosing and improve clinical outcomes. We reviewed the algorithms available for various populations and the covariates, performances and risk of bias of these algorithms.

Troponin is the Ca2+ molecular switch that regulates striated muscle contraction. In the heart, troponin Ca2+ sensitivity is also modulated by the PKA-dependent phosphorylation of a unique 31-residue N-terminal extension region of the Troponin I subunit (NH2-TnI). However, the detailed mechanism for the propagation of the phosphorylation signal through Tn, which results in the enhancement of the myocardial relaxation rate, is difficult to examine within whole Tn. Several models exist for how phosphorylation modulates the troponin response in cardiac cells but these are mostly built from peptide-NMR studies and molecular dynamics simulations. Here we used a paramagnetic spin labeling approach to position and track the movement of the NH2-TnI region within whole Tn. Through paramagnetic relaxation enhancement (PRE)-NMR experiments, we show that the NH2-TnI region interacts with a broad surface area on the N-domain of the Troponin C subunit. This region includes the Ca2+ regulatory Site II and the TnI switch-binding site. Phosphorylation of the NH2-TnI both weakens and shifts this region to an adjacent site on TnC. Interspin EPR distances between NH2-TnI and TnC further reveal a phosphorylation induced re-orientation of the TnC N-domain under saturating Ca2+ conditions. We propose an allosteric model where phosphorylation triggered cooperative changes in both the interaction of the NH2-TnI region with TnC, and the re-orientation of the TnC interdomain orientation, together promote the release of the TnI switch-peptide. Enhancement of the myocardial relaxation rate then occurs. Knowledge of this unique role of phosphorylation in whole Tn is important for understanding pathological processes affecting the heart.

The Bombyx mori nucleopolyhedrovirus (BmNPV)-based baculoviral expression vector system is among the most efficient expression vector systems for eukaryotic proteins especially when used in combination with silkworms as a host. We newly isolated a novel BmNPV strain (BmNPV H4) in Hokkaido, Japan that outperforms the type strain T3 in terms of both proliferation and expression of polyhedrin protein in silkworm larvae; however, it proliferates poorly in the BmN cell line. We inferred the gene responsible for the differences in proliferation between viral strains by quantifying amino acid similarity distances in protein functional domains and identifying highly divergent alleles between the H4 and T3 strains. Among proteins that differ markedly in functional domain sequence between H4 and T3, we identified the F gene, which encodes the F protein, as a putative cause of proliferative differences between the two strains. Using recombinant viruses with the F protein-coding sequence exchanged between H4 and T3, we determined that the T3 F protein increases H4 proliferation in BmN while the H4 F protein does not improve T3 proliferation in silkworm larvae. Our results suggest that the BmNPV F protein can strongly affect viral proliferation in a genetic background-specific manner and may be an important target for manipulating the proliferation characteristics of BmNPV-based expression vectors.

MicroRNAs (miRNAs), short non-coding RNAs, which act post-transcriptionally to regulate gene expression, are of widespread significance during development and disease, including muscle disease. Advances in sequencing technology and bioinformatics led to the identification of a large number of miRNAs in vertebrates and other species, however, for many of these miRNAs specific roles have not yet been determined. LNA in situ hybridisation has revealed expression patterns of somite-enriched miRNAs, here we focus on characterising the functions of miR-128. We show that antagomiR-mediated knockdown (KD) of miR-128 in developing chick somites has a negative impact on skeletal myogenesis. Computational analysis identified the transcription factor EYA4 as a candidate target consistent with the observation that miR-128 and EYA4 display similar expression profiles. Luciferase assays confirmed that miR-128 interacts with the EYA4 3'UTR. In vivo experiments also suggest that EYA4 is regulated by miR-128. EYA4 is a member of the PAX-SIX-EYA-DACH (PSED) network of transcription factors. Therefore, we identified additional candidate miRNA binding sites in the 3'UTR of SIX1/4, EYA1/2/3 and DACH1. Using the miRanda algorithm, we found sites for miR-128, as well as for other myogenic miRNAs, miR-1a, miR-206 and miR-133a, some of these were experimentally confirmed as functional miRNA target sites. Our results reveal that miR-128 is involved in regulating skeletal myogenesis by directly targeting EYA4 with indirect effects on other PSED members, including SIX4 and PAX3. Hence, the inhibitory effect on myogenesis observed after miR-128 knockdown was rescued by concomitant knockdown of PAX3. Moreover, we show that the PSED network of transcription factors is co-regulated by multiple muscle-enriched microRNAs.

The Hatano strains of the Sprague Dawley rats have been selectively bred to create high- (HAA) and low- (LAA) active avoidance variants. We previously reported that HAA rats display more anxiety-related behavior than LAA rats, but whether this strain difference is affected by postnatal environmental factors remains unclear. In this study, we performed in- and cross-fostering between the HAA and LAA strains and investigated the effect of postnatal maternal traits on the emotional responses in each strain of the male offspring. We evaluated the effect of the fostering treatment on the emotional responses of the male offspring using the elevated plus maze test. The male LAA offspring reared by HAA dam showed higher anxiety-related behavior than those reared by LAA dam. Next, we quantified and typed various maternal behavior under the in- and cross-fostering conditions during the lactation period using a snapshot sampling method. This method allowed us to evaluate potential maternal traits that may influence the emotional responses of the offspring observed in our first experiment. We found that HAA dams showed long-term resting without offspring and offspring arrangement compared with LAA dams. These findings suggest that postnatal environmental factors may alter anxiety-related behavior in the male LAA offspring and that less direct contact with their offspring during the lactation period may induce anxiety-related behavior in male offspring.

Retinoblastoma (RB) is the most common intraocular cancer in children, and chemotherapy has been the first-line treatment. However, due to the side effects of chemotherapy drugs, novel treatments must be developed. JQ1, a selective inhibitor of BRD4, suppresses cell growth in several cancers in which BRD4 is overexpressed. In the present study, BRD4 was overexpressed in retinoblastoma, and JQ1 effectively inhibited RB cell proliferation and colony formation by inducing cell cycle arrest and promoting apoptosis. Furthermore, the Myc-P21-CDK2 and Myc-cyclinD3/CDK6 pathways were activated in RB cells treated with JQ1, and an animal experiment suggested that JQ1 significantly inhibited tumour growth in vivo. In conclusion, JQ1 may be a potential drug treatment for retinoblastoma.