Genome-scale fitness profile of Caulobacter crescentus grown in natural freshwater

© 2018, International Society for Microbial Ecology. Bacterial genomes evolve in complex ecosystems and are best understood in this natural context, but replicating such conditions in the lab is challenging. We used transposon sequencing to define the fitness consequences of gene disruption in the bacterium Caulobacter crescentus grown in natural freshwater, compared with axenic growth in common laboratory media. Gene disruptions in amino-acid and nucleotide sugar biosynthesis pathways and in metabolic substrate transport machinery impaired fitness in both lake water and defined minimal medium relative to complex peptone broth. Fitness in lake water was enhanced by insertions in genes required for flagellum biosynthesis and reduced by insertions in genes involved in biosynthesis of the holdfast surface adhesin. We further uncovered numerous hypothetical and uncharacterized genes for which disruption impaired fitness in lake water, defined minimal medium, or both. At the genome scale, the fitness profile of mutants cultivated in lake water was more similar to that in complex peptone broth than in defined minimal medium. Microfiltration of lake water did not significantly affect the terminal cell density or the fitness profile of the transposon mutant pool, suggesting that Caulobacter does not strongly interact with other microbes in this ecosystem on the measured timescale. Fitness of select mutants with defects in cell surface biosynthesis and environmental sensing were significantly more variable across days in lake water than in defined medium, presumably owing to day-to-day heterogeneity in the lake environment. This study reveals genetic interactions between Caulobacter and a natural freshwater environment, and provides a new avenue to study gene function in complex ecosystems

Neural effects of oxytocin and mimicry in frontotemporal dementia: A randomized crossover study

OBJECTIVE: To determine whether intranasal oxytocin, alone or in combination with instructed mimicry of facial expressions, would augment neural activity in patients with frontotemporal dementia (FTD) in brain regions associated with empathy, emotion processing, and the simulation network, as indexed by blood oxygen-level dependent (BOLD) signal during fMRI. METHODS: In a placebo-controlled, randomized crossover design, 28 patients with FTD received 72 IU intranasal oxytocin or placebo and then completed an fMRI facial expression mimicry task. RESULTS: Oxytocin alone and in combination with instructed mimicry increased activity in regions of the simulation network and in limbic regions associated with emotional expression processing. CONCLUSIONS: The findings demonstrate latent capacity to augment neural activity in affected limbic and other frontal and temporal regions during social cognition in patients with FTD, and support the promise and need for further investigation of these interventions as therapeutics in FTD. CLINICALTRIALSGOV IDENTIFIER: NCT01937013. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that a single dose of 72 IU intranasal oxytocin augments BOLD signal in patients with FTD during viewing of emotional facial expressions

Early symptoms in symptomatic and preclinical genetic frontotemporal lobar degeneration

Funder: UK Medical Research CouncilFunder: The Bluefield ProjectFunder: NIHR Cambridge Biomedical Research CentreFunder: Weston Brain InstituteFunder: Swedish Brain FoundationFunder: StratNeuro, Swedish DemensfondenFunder: NIHR Queen Square Dementia Biomedical Research Unit, the NIHR UCL/H Biomedical Research Centre and the Leonard Wolfson Experimental Neurology Centre (LWENC) Clinical Research FacilityFunder: The Canadian Institutes of Health Research as part of a Centres of Excellence in Neurodegeneration grantFunder: Karolinska Institutet Doctoral FundingFunder: Stockholm County Council ALFFunder: Swedish Alzheimer FoundationObjectives: The clinical heterogeneity of frontotemporal dementia (FTD) complicates identification of biomarkers for clinical trials that may be sensitive during the prediagnostic stage. It is not known whether cognitive or behavioural changes during the preclinical period are predictive of genetic status or conversion to clinical FTD. The first objective was to evaluate the most frequent initial symptoms in patients with genetic FTD. The second objective was to evaluate whether preclinical mutation carriers demonstrate unique FTD-related symptoms relative to familial mutation non-carriers. Methods: The current study used data from the Genetic Frontotemporal Dementia Initiative multicentre cohort study collected between 2012 and 2018. Participants included symptomatic carriers (n=185) of a pathogenic mutation in chromosome 9 open reading frame 72 (C9orf72), progranulin (GRN) or microtubule-associated protein tau (MAPT) and their first-degree biological family members (n=588). Symptom endorsement was documented using informant and clinician-rated scales. Results: The most frequently endorsed initial symptoms among symptomatic patients were apathy (23%), disinhibition (18%), memory impairments (12%), decreased fluency (8%) and impaired articulation (5%). Predominant first symptoms were usually discordant between family members. Relative to biologically related non-carriers, preclinical MAPT carriers endorsed worse mood and sleep symptoms, and C9orf72 carriers endorsed marginally greater abnormal behaviours. Preclinical GRN carriers endorsed less mood symptoms compared with non-carriers, and worse everyday skills. Conclusion: Preclinical mutation carriers exhibited neuropsychiatric symptoms compared with non-carriers that may be considered as future clinical trial outcomes. Given the heterogeneity in symptoms, the detection of clinical transition to symptomatic FTD may be best captured by composite indices integrating the most common initial symptoms for each genetic group

Transcriptional Subtyping and CD8 Immunohistochemistry Identifies Patients With Stage II and III Colorectal Cancer With Poor Prognosis Who Benefit From Adjuvant Chemotherapy

This work was funded by Cancer Research UK: C212/A13721 and C11884/A24387Peer reviewedPublisher PD

Mental Health Through Movement

Children’s mental health: ‘has become an issue of real concern, in the media and to both politicians and NHS leaders, over the last five years in particular. It has prompted numerous inquiries, reports, recommendations and pledges by politicians and NHS leaders to improve the situation’: https://www.theguardian.com/society/2018/nov/22/what-is-happening-withchildrens-mental-health On July 1st 2019, the Local Government Association released statistics to show that: ‘There were 205,720 cases where a child was identified as having a mental health issue in 2017/18, compared with 133,600 in 2014/15- up 54%’: https://www.local.gov.uk/about/news/councils-seeing-more-560-child-mentalhealth-cases-every-day It is within this context that the All-Party Parliamentary Group on A Fit and Healthy Childhood presents its 14th Report: ‘Positive Mental Health Through Movement’. With 1 in 10 children now having a mental health diagnosis and 1 in 4 an undiagnosed mental health issue, this, our third Report on the issue of child mental health, addresses the link between positive mental health and physical activity and movement experiences at a time when, paradoxically, today’s children and young people are more inactive and play less than ever before. The growing recognition of a link between mental health and movement is fortuitous because from September 2019, health education in English schools will be statutory alongside the expectation that they will offer their pupils at least 30 ‘active minutes’ per day. The APPG on A Fit and Healthy Childhood welcomes the change whilst recognising that those responsible for implementing the new strategy (including practitioners and families) will need guidance as they help children to develop individual strategies to address future adverse events and foster the positive sense of self that will enable them to lead fulfilled, healthy lives. This Report is therefore presented as a practical contribution to an essential debate. It offers new strategies against the persistence of historical and traditional ways of thinking; examines and collates best practice in the devolved Home Countries as well as the wider world and discusses exactly what is required to ensure that future child mental health strategy is holistic. It is respectful of equalities and is aware that the successful outcome of policies is entirely dependent upon the expertise and confidence of those tasked with the responsibility of delivering them. As the 21st century advances, we consider the effects of the digital age and its impact on children and young people’s mental health and wellbeing and the crucial role of parents and carers who want the best for their children in a societal climate where, all too often, fears of ‘nanny state’ meddling serve to isolate families who suffer in silence – until a disaster that may have been all too predictable and preventable overtakes them, making a private grief a public concern. The trajectory of progress in mental health policy has been ‘stop start’ rather than linear, with legislative change in 1959 and 1983, an increase in spending from 1997- 2010 and radical changes to child and adolescent mental health services (CAMHS) in 2000. The Wessely Independent Review of the Mental Health Act is another such milestone: https://www.gov.uk/government/groups/independent-review-of-the-mentalhealth-act The APPG on A Fit and Healthy Childhood anticipates that the Government will fulfil its pledge to parents, children and practitioners by introducing much needed mental health legislation - and that our trio of Reports and the holistic theme of this one will help to inform a strategy that works for 21st century children

Honk against homophobia : rethinking relations between media and sexual minorities

The theory of “symbolic annihilation” or “symbolic violence” has been used in academic literature to describe the way in which sexual minorities have been ignored, trivialized, or condemned by the media. This article aims to de-center research from issues of media representation to consider the capacity for minority groups to proactively use new media and its various avenues for interactivity, social networking, and feedback to fight social exclusion. This work suggests that new media has become a space in which the nominally marginal in society may acquire “social artillery”—a term used to describe how sexual minorities utilize their expanding and more readily accessible social connections in digital space to combat instances of homophobia. The research draws on the results of an inquiry into the relation between media and a regional youth social justice group in Australia tackling homophobia. The research demonstrates that the group is becoming increasingly adept and comfortable with using a cross-section of media platforms to fulfill their own objectives, rather than seeing themselves as passive subjects of media representation. This article argues that this sets an example for other socially excluded groups looking to renegotiate their relation with the media in regional areas

The genetic architecture of the human cerebral cortex

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder

Robust estimation of bacterial cell count from optical density

Optical density (OD) is widely used to estimate the density of cells in liquid culture, but cannot be compared between instruments without a standardized calibration protocol and is challenging to relate to actual cell count. We address this with an interlaboratory study comparing three simple, low-cost, and highly accessible OD calibration protocols across 244 laboratories, applied to eight strains of constitutive GFP-expressing E. coli. Based on our results, we recommend calibrating OD to estimated cell count using serial dilution of silica microspheres, which produces highly precise calibration (95.5% of residuals <1.2-fold), is easily assessed for quality control, also assesses instrument effective linear range, and can be combined with fluorescence calibration to obtain units of Molecules of Equivalent Fluorescein (MEFL) per cell, allowing direct comparison and data fusion with flow cytometry measurements: in our study, fluorescence per cell measurements showed only a 1.07-fold mean difference between plate reader and flow cytometry data