Hypervirulent Klebsiella pneumoniae (hvKp) has emerged as a concerning global pathogen. hvKp is more virulent than classical K. pneumoniae (cKp) and capable of causing community‐acquired infections, ...often in healthy individuals. hvKp is carried in the gastrointestinal tract, which contributes to its spread in the community and healthcare settings. First recognized in Asia, hvKp arose as a leading cause of pyogenic liver abscesses. In the decades since, hvKp has spread globally and causes a variety of infections. In addition to liver abscesses, hvKp is distinct from cKp in its ability to metastasize to distant sites, including most commonly the eye, lung and central nervous system (CNS). hvKp has also been implicated in primary extrahepatic infections including bacteremia, pneumonia and soft tissue infections. The genetic determinants of hypervirulence are often found on large virulence plasmids as well as chromosomal mobile genetic elements which can be used as biomarkers to distinguish hvKp from cKp clinical isolates. These distinct virulence determinants of hvKp include up to four siderophore systems for iron acquisition, increased capsule production, K1 and K2 capsule types, and the colibactin toxin. Additionally, hvKp strains demonstrate hypermucoviscosity, a phenotypic description of hvKp in laboratory conditions that has become a distinguishing feature of many hypervirulent isolates. Alarmingly, multidrug‐resistant hypervirulent strains have emerged, creating a new challenge in combating this already dangerous pathogen.
Alcohol use disorders (AUDs) are complex traits, meaning that variations in many genes contribute to the risk, as does the environment. Although the total genetic contribution to risk is substantial, ...most individual variations make only very small contributions. By far the strongest contributors are functional variations in 2 genes involved in alcohol (ethanol EtOH) metabolism. A functional variant in alcohol dehydrogenase 1B (ADH1B) is protective in people of European and Asian descent, and a different functional variant in the same gene is protective in those of African descent. A strongly protective variant in aldehyde dehydrogenase 2 (ALDH2) is essentially only found in Asians. This highlights the need to study a wide range of populations. The likely mechanism of protection against heavy drinking and AUDs in both cases is alteration in the rate of metabolism of EtOH that at least transiently elevates acetaldehyde. Other ADH and ALDH variants, including functional variations in ADH1C, have also been implicated in affecting drinking behavior and risk for alcoholism. The pattern of linkage disequilibrium in the ADH region and the differences among populations complicate analyses, particularly of regulatory variants. This critical review focuses upon the ADH and ALDH genes as they affect AUDs.
The genes that have the largest impact on alcohol consumption and Alcohol Use Disorders are alcohol dehydrogenase 1B (ADH1B) and aldehyde dehydrogenase 2 (ALDH2); both work by altering the rate of ethanol metabolism to at least transiently elevate acetaldehyde. Different functional variations are important in different populations. ADH1B and ADH4 have also been implicated, but linkage disequilibrium complicates analyses, and other variants may only be proxies for the functional variants.
Hearing impairment negatively affects well-being and is a major contributor to years lived with disability. The World Health Organization (WHO) estimates that 466 million people were living with ...disabling hearing impairment in 2018 and this estimate is projected to rise to 630 million by 2030 and to over 900 million by 2050. However, these projections are based on a hearing impairment classification that does not fully reflect the provisions of the International classification of functioning, disability and health for assessing all forms of functional impairments. Here we make the case for a review of the concept of disabling hearing loss adopted by WHO after the recommendation of the Global Burden of Disease (GBD) Expert Group on Hearing Impairment in 2008. The need for an independent classification system for all impairments and disabilities as a complement to the well-established International statistical classification of diseases and related health problems, was first suggested in 1976 by the World Health Assembly. As a result, in 1980 WHO developed the International classification of impairments, disabilities and handicaps. One of the key features of this system was the use of qualifiers such as mild, moderate, severe and profound to distinguish various levels of observed or measured deviations outside of the range considered for normal functioning for any health condition. This categorization has been reinforced in the subsequent revisions to the system, such as the International Classification of Functioning, Disability and Health, and accompanied with descriptions of typical problems encountered in daily activities at various levels of severity. The classification, notably, does not use the term disabling, as it recognizes the needs of all persons with functional impairments for appropriate intervention.
This meta-analysis explores whether self-regulation in childhood relates to concurrent and subsequent levels of achievement, interpersonal behaviors, mental health, and healthy living. A ...comprehensive literature search identified 150 studies that met inclusion criteria (745 effect sizes; total n = 215,212). Data were analyzed using inverse-variance weighted random effects meta-analysis. Mean effect sizes from 55 meta-analyses provided evidence that self-regulation relates to 25 discrete outcomes. Results showed that self-regulation in preschool (∼age 4) was positively associated with social competency, school engagement, and academic performance, and negatively associated with internalizing problems, peer victimization, and externalizing problems, in early school years (∼age 8). Self-regulation in early school years was positively related to academic achievement (math and literacy), and negatively related to externalizing problems (aggressive and criminal behavior), depressive symptoms, obesity, cigarette smoking and illicit drug use, in later school years (∼age 13). Results also showed that self-regulation in early school years was negatively related to unemployment, aggressive and criminal behavior, depression and anxiety, obesity, cigarette smoking, alcohol and substance abuse, and symptoms of physical illness in adulthood (∼age 38). Random effects metaregression identified self-regulation measurement as the most important moderator of pooled mean effects, with task-based assessments and teacher-report assessments often showing stronger associations than parent-report assessments. Overall, findings from this meta-analysis provide evidence that self-regulation in childhood can predict achievement, interpersonal behaviors, mental health, and healthy living in later life.
Public Significance Statement
This study found that children's ability to self-regulate (exercise control over their dominant impulses) can predict outcomes in later childhood, adolescence, and adulthood. These outcomes included academic achievement, aggressive behavior, depression, obesity, cigarette smoking, unemployment, and alcohol and substance abuse.
Alcohol use disorders are common conditions that have enormous social and economic consequences. Genome-wide association analyses were performed to identify genetic variants associated with a proxy ...measure of alcohol consumption and alcohol misuse and to explore the shared genetic basis between these measures and other substance use, psychiatric, and behavioral traits.
This study used quantitative measures from the Alcohol Use Disorders Identification Test (AUDIT) from two population-based cohorts of European ancestry (UK Biobank N=121,604 and 23andMe N=20,328) and performed a genome-wide association study (GWAS) meta-analysis. Two additional GWAS analyses were performed, a GWAS for AUDIT scores on items 1-3, which focus on consumption (AUDIT-C), and for scores on items 4-10, which focus on the problematic consequences of drinking (AUDIT-P).
The GWAS meta-analysis of AUDIT total score identified 10 associated risk loci. Novel associations localized to genes including JCAD and SLC39A13; this study also replicated previously identified signals in the genes ADH1B, ADH1C, KLB, and GCKR. The dimensions of AUDIT showed positive genetic correlations with alcohol consumption (r
=0.76-0.92) and DSM-IV alcohol dependence (r
=0.33-0.63). AUDIT-P and AUDIT-C scores showed significantly different patterns of association across a number of traits, including psychiatric disorders. AUDIT-P score was significantly positively genetically correlated with schizophrenia (r
=0.22), major depressive disorder (r
=0.26), and attention deficit hyperactivity disorder (r
=0.23), whereas AUDIT-C score was significantly negatively genetically correlated with major depressive disorder (r
=-0.24) and ADHD (r
=-0.10). This study also used the AUDIT data in the UK Biobank to identify thresholds for dichotomizing AUDIT total score that optimize genetic correlations with DSM-IV alcohol dependence. Coding individuals with AUDIT total scores ≤4 as control subjects and those with scores ≥12 as case subjects produced a significant high genetic correlation with DSM-IV alcohol dependence (r
=0.82) while retaining most subjects.
AUDIT scores ascertained in population-based cohorts can be used to explore the genetic basis of both alcohol consumption and alcohol use disorders.
Beyond the Connectome: The Dynome Kopell, Nancy J.; Gritton, Howard J.; Whittington, Miles A. ...
Neuron,
09/2014, Letnik:
83, Številka:
6
Journal Article
Recenzirano
Odprti dostop
The human connectome will provide a detailed mapping of the brain’s connectivity, with fundamental insights for health and disease. However, further understanding of brain function and dysfunction ...will require an integrated framework that links brain connectivity with brain dynamics, as well as the biological details that relate this connectivity more directly to function. In this Perspective, we describe such a framework for studying the brain’s “dynome” and its relationship to cognition.
The human connectome will provide a detailed mapping of the brain’s connectivity; however, further understanding of brain function will require linking connectivity with brain dynamics and relating this connectivity to function. In this Perspective, Koppel et al. describe a framework for studying the brain’s “dynome” and its relationship to cognition.
Nuclear Positioning Gundersen, Gregg G.; Worman, Howard J.
Cell,
03/2013, Letnik:
152, Številka:
6
Journal Article
Recenzirano
Odprti dostop
The nucleus is the largest organelle and is commonly depicted in the center of the cell. Yet during cell division, migration, and differentiation, it frequently moves to an asymmetric position ...aligned with cell function. We consider the toolbox of proteins that move and anchor the nucleus within the cell and how forces generated by the cytoskeleton are coupled to the nucleus to move it. The significance of proper nuclear positioning is underscored by numerous diseases resulting from genetic alterations in the toolbox proteins. Finally, we discuss how nuclear position may influence cellular organization and signaling pathways.
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