Regulation of cell size and Wee1 kinase by elevated levels of the cell cycle regulatory protein kinase Cdr2.

Many cell cycle regulatory proteins catalyze cell cycle progression in a concentration-dependent manner. In the fission yeast Schizosaccharomyces pombe, the protein kinase Cdr2 promotes mitotic entry by organizing cortical oligomeric nodes that lead to inhibition of Wee1, which itself inhibits the cyclin-dependent kinase Cdk1. cdr2Δ cells lack nodes and divide at increased size due to overactive Wee1, but it has not been known how increased Cdr2 levels might impact Wee1 and cell size. It also has not been clear if and how Cdr2 might regulate Wee1 in the absence of the related kinase Cdr1/Nim1. Using a tetracycline-inducible expression system, we found that a 6× increase in Cdr2 expression caused hyperphosphorylation of Wee1 and reduction in cell size even in the absence of Cdr1/Nim1. This overexpressed Cdr2 formed clusters that sequestered Wee1 adjacent to the nuclear envelope. Cdr2 mutants that disrupt either kinase activity or clustering ability failed to sequester Wee1 and to reduce cell size. We propose that Cdr2 acts as a dosage-dependent regulator of cell size by sequestering its substrate Wee1 in cytoplasmic clusters, away from Cdk1 in the nucleus. This mechanism has implications for other clustered kinases, which may act similarly by sequestering substrates.

Multistate Outbreak of Infection with SARS-CoV-2 Omicron Variant after Event in Chicago, Illinois, USA, 2021.

Bars and restaurants are high-risk settings for SARS-CoV-2 transmission. A multistate outbreak after a bar gathering in Chicago, Illinois, USA, highlights Omicron variant transmissibility, the value of local genomic surveillance and interstate coordination, vaccination value, and the potential for rapid transmission of a novel variant across multiple states after 1 event.

Blood and urine multi-omics analysis of the impact of e-vaping, smoking, and cessation: from exposome to molecular responses.

Cigarette smoking is a major preventable cause of morbidity and mortality. While quitting smoking is the best option, switching from cigarettes to non-combustible alternatives (NCAs) such as e-vapor products is a viable harm reduction approach for smokers who would otherwise continue to smoke. A key challenge for the clinical assessment of NCAs is that self-reported product use can be unreliable, compromising the proper evaluation of their risk reduction potential. In this cross-sectional study of 205 healthy volunteers, we combined comprehensive exposure characterization with in-depth multi-omics profiling to compare effects across four study groups: cigarette smokers (CS), e-vapor users (EV), former smokers (FS), and never smokers (NS). Multi-omics analyses included metabolomics, transcriptomics, DNA methylomics, proteomics, and lipidomics. Comparison of the molecular effects between CS and NS recapitulated several previous observations, such as increased inflammatory markers in CS. Generally, FS and EV demonstrated intermediate molecular effects between the NS and CS groups. Stratification of the FS and EV by combustion exposure markers suggested that this position on the spectrum between CS and NS was partially driven by non-compliance/dual use. Overall, this study highlights the importance of in-depth exposure characterization before biological effect characterization for any NCA assessment study.

Impact of integrating public health clinical decision support alerts into electronic health records on testing for gastrointestinal illness.

Laboratory testing by clinicians is essential to outbreak investigations. Electronic health records may increase testing through clinical decision support that alerts providers about existing outbreaks and facilitates laboratory ordering. The impact on laboratory testing was evaluated for foodborne disease outbreaks between 2006 and 2009. After controlling for standard public health messaging and season, decision support resulted in a significant increase in laboratory testing and may be useful in enhancing public health messaging and provider action.

The choline transporter Slc44a2 controls platelet activation and thrombosis by regulating mitochondrial function.

Genetic factors contribute to the risk of thrombotic diseases. Recent genome wide association studies have identified genetic loci including SLC44A2 which may regulate thrombosis. Here we show that Slc44a2 controls platelet activation and thrombosis by regulating mitochondrial energetics. We find that Slc44a2 null mice (Slc44a2(KO)) have increased bleeding times and delayed thrombosis compared to wild-type (Slc44a2(WT)) controls. Platelets from Slc44a2(KO) mice have impaired activation in response to thrombin. We discover that Slc44a2 mediates choline transport into mitochondria, where choline metabolism leads to an increase in mitochondrial oxygen consumption and ATP production. Platelets lacking Slc44a2 contain less ATP at rest, release less ATP when activated, and have an activation defect that can be rescued by exogenous ADP. Taken together, our data suggest that mitochondria require choline for maximum function, demonstrate the importance of mitochondrial metabolism to platelet activation, and reveal a mechanism by which Slc44a2 influences thrombosis.

The impact of psychosis on social inclusion and associated factors.

BACKGROUND: People with mental health problems are known to be socially excluded but the contribution of pre-morbid characteristics, symptoms and needs, and the impact on quality of life is unknown. AIMS: To investigate change in social inclusion after the development of a psychotic Illness and factors associated with this. METHODS: A cross-sectional community survey of people with psychosis was carried out in three areas of London. Five domains of social inclusion (social integration, consumption, access to services, productivity, political engagement) were assessed prior to the onset of illness and currently using the Social Inclusion Questionnaire User Experience. Quality of life, symptoms and needs were also assessed using standardized measures. Factors associated with change in social inclusion were investigated using multiple regression. RESULTS: Productivity and social integration among the 67 participants reduced after the onset of psychosis. Older age at onset and longer duration of illness were associated with greater reduction in productivity. Less reduction in social integration was associated with greater quality of life. Participants reported barriers to social inclusion that were directly related to symptoms of their illness, low confidence and poor self-esteem. CONCLUSIONS: A greater focus on interventions that can facilitate the occupation and the social networks of people with psychosis is required. Interventions that tackle 'self-stigma' may also prove useful in mitigating the social exclusion experienced by people with psychosis.

Development and preliminary validation of a measure of social inclusion for use in people with mental health problems: the SInQUE.

BACKGROUND: Social exclusion can be both a cause and a consequence of mental health problems. Socially inclusive practice by mental health professionals can mitigate against the stigmatizing and excluding effects of severe mental illness. AIM: To develop and test the validity of a measure of social inclusion for individuals with severe mental illness - the Social Inclusion Questionnaire User Experience (SInQUE). METHOD: The domains of the SInQUE were chosen to reflect the domains of social inclusion identified in the Poverty and Social Exclusion Survey. Patients with severe mental illness were recruited from rehabilitation, general and forensic psychiatric services and were asked to complete the questionnaire in an individual interview with a researcher. RESULTS: Sixty six patients with schizophrenia and schizoaffective disorder completed the SInQUE, alongside measures of psychiatric symptoms, needs and quality of life, to assess its acceptability, and concurrent and construct (convergent and discriminant) validity. The SInQUE took 45 minutes to complete and was found to have good concurrent and discriminant validity. Convergent validity was established for two domains: social integration and productivity. CONCLUSION: Preliminary findings suggest that the SInQUE may be a useful tool for assessing and monitoring social inclusion in individuals with severe mental illness. It has construct and concurrent validity with measures of unmet need and quality of life in this group. Further testing of the reliability of the SInQUE on a larger population is indicated.

Palladium-catalyzed C-CN activation for intramolecular cyanoesterification of alkynes.

Conditions for the C-CN activation and intramolecular cyanoesterification of alkynes to provide butenolides in good to excellent yields are presented. Pd catalysts, high temperatures/short reaction times (microwave irradiation), and Lewis basic solvents minimized competitive decarbonylation. Less sterically encumbered, electron-rich alkynes underwent cyanoesterification with greater ease compared to sterically encumbered, electron-deficient alkynes. The results led to the hypothesis that migratory insertion of the alkyne, rather than C-CN activation, might be the product-determining step.

Using electronic health record alerts to provide public health situational awareness to clinicians.

Alerting providers to public health situations requires timeliness and context-relevance, both lacking in current systems. Incorporating decision support tools into electronic health records may provide a way to deploy public health alerts to clinicians at the point of care. A timely process for responding to Health Alert Network messages sent by the New York City Department of Health and Mental Hygiene was developed by a network of community health centers. Alerts with order sets and recommended actions were created to notify primary care providers of local disease outbreaks. The process, effect, and lessons learned from alerts for Legionella, toxogenic E coli, and measles outbreaks are described. Electronic alerts have the potential to improve management of diseases during an outbreak, including appropriate laboratory testing, management guidance, and diagnostic assistance as well as to enhance bi-directional data exchange between clinical and public health organizations.