Activation of σ28-dependent transcription inEscherichia coliby the cyclic AMP receptor protein requires an unusual promoter organization

The Escherichia coli aer regulatory region contains a single promoter that is recognized by RNA polymerase containing the flagellar sigma factor, σ28. Expression from this promoter is dependent on direct activation by the cyclic AMP receptor protein, which binds to a target centred 49.5 base pairs upstream from the transcript start. Activator-dependent transcription from the aer promoter was reconstituted in vitro, and a tethered inorganic nuclease was used to find the position of the C-terminal domains of the RNA polymerase α subunits in transcriptionally competent open complexes. We report that the ternary activator-RNA polymerase-aer promoter open complex is organized differently from complexes at previously characterized promoters. Among other E. coli promoters recognized by RNA polymerase containing σ28, only the trg promoter is activated directly by the cyclic AMP receptor protein. The organization of the different promoter elements and the activator binding site at the trg promoter is the same as at the aer promoter, suggesting a common activation mechanism

Association of cognition with functional trajectories in patients admitted to geriatric wards: A retrospective observational study.

AIM: Impaired cognition is common among older patients admitted to acute hospitals, but its association with functional trajectories has not been well studied. METHODS: A retrospective observational study was carried out in an English tertiary university hospital. We analyzed all first episodes of county residents aged ≥75 years admitted to the Department of Medicine for the Elderly wards between December 2014 and May 2015. A history of dementia or a cognitive concern in the absence of a known diagnosis of dementia were recorded on admission. A cognitive concern included possible undiagnosed dementia or delirium. Function was retrospectively measured with the modified Rankin Scale at preadmission baseline, admission and discharge. RESULTS: There were 663 first hospital episodes over the period, of which 590 patients survived. Among the latter, 244 had no cognitive impairment, 134 a diagnosis of dementia, 66 a cognitive concern in the absence of a known dementia and 146 had missing cognitive data. When frailty, acuity, age and comorbidity were controlled for, people with known dementia had a similar functional recovery compared with those with no cognitive impairment. People with a cognitive concern, but no known dementia, had lesser functional recovery and greater disability at discharge than those with no cognitive impairment (mean discharge modified Rankin Scale 3.4 compared with 3.1, P = 0.011). CONCLUSIONS: Dementia per se might not be a marker of poor rehabilitation potential. Older people with acute cognitive concerns might be more vulnerable to poor functional recovery. Our cognitive variables are not gold standard, and further research is required to clarify this relationship. Geriatr Gerontol Int 2017; 17: 1438-1443.This is the author accepted manuscript. The final version is available from Wiley via https://doi.org/10.1111/ggi.1288

Prevention and management of hyperglycaemic crisis

Hyperglycaemia is a defining feature of diabetes mellitus. It involves an elevated level of glucose in the blood, which develops as a result of the body's inability to produce insulin or process insulin effectively. If left unchecked and untreated, patients with diabetes are at risk of short-term, potentially life-threatening hyperglycaemic crises such as diabetic ketoacidosis or hyperosmolar hyperglycaemic state. Nurses frequently care for patients diagnosed with diabetes in various clinical settings; therefore, it is essential that they have an awareness of the prevention and management of hyperglycaemia and hyperglycaemic crises. This article explains the causes and clinical manifestations of hyperglycaemic crises, and details the management of patients with these conditions, in accordance with national guidelines. [Abstract copyright: © 2019 RCN Publishing Company Ltd. All rights reserved. Not to be copied, transmitted or recorded in any way, in whole or part, without prior permission of the publishers.

Media reporting of child sexual abuse in Australia: 2020-22

Report of the Media Guides for reporting of child sexual abuse in Australia: 2020-2

Cauli: a mouse strain with an Ift140 mutation that results in a skeletal ciliopathy modelling jeune syndrome

Cilia are architecturally complex organelles that protrude from the cell membrane and have signalling, sensory and motility functions that are central to normal tissue development and homeostasis. There are two broad categories of cilia; motile and non-motile, or primary, cilia. The central role of primary cilia in health and disease has become prominent in the past decade with the recognition of a number of human syndromes that result from defects in the formation or function of primary cilia. This rapidly growing class of conditions, now known as ciliopathies, impact the development of a diverse range of tissues including the neural axis, craniofacial structures, skeleton, kidneys, eyes and lungs. The broad impact of cilia dysfunction on development reflects the pivotal position of the primary cilia within a signalling nexus involving a growing number of growth factor systems including Hedgehog, Pdgf, Fgf, Hippo, Notch and both canonical Wnt and planar cell polarity. We have identified a novel ENU mutant allele of Ift140, which causes a mid-gestation embryonic lethal phenotype in homozygous mutant mice. Mutant embryos exhibit a range of phenotypes including exencephaly and spina bifida, craniofacial dysmorphism, digit anomalies, cardiac anomalies and somite patterning defects. A number of these phenotypes can be attributed to alterations in Hedgehog signalling, although additional signalling systems are also likely to be involved. We also report the identification of a homozygous recessive mutation in IFT140 in a Jeune syndrome patient. This ENU-induced Jeune syndrome model will be useful in delineating the origins of dysmorphology in human ciliopathies

Genome-Wide ENU Mutagenesis in Combination with High Density SNP Analysis and Exome Sequencing Provides Rapid Identification of Novel Mouse Models of Developmental Disease

BACKGROUND Mice harbouring gene mutations that cause phenotypic abnormalities during organogenesis are invaluable tools for linking gene function to normal development and human disorders. To generate mouse models harbouring novel alleles that are involved in organogenesis we conducted a phenotype-driven, genome-wide mutagenesis screen in mice using the mutagen N-ethyl-N-nitrosourea (ENU). METHODOLOGY/PRINCIPAL FINDINGS ENU was injected into male C57BL/6 mice and the mutations transmitted through the germ-line. ENU-induced mutations were bred to homozygosity and G3 embryos screened at embryonic day (E) 13.5 and E18.5 for abnormalities in limb and craniofacial structures, skin, blood, vasculature, lungs, gut, kidneys, ureters and gonads. From 52 pedigrees screened 15 were detected with anomalies in one or more of the structures/organs screened. Using single nucleotide polymorphism (SNP)-based linkage analysis in conjunction with candidate gene or next-generation sequencing (NGS) we identified novel recessive alleles for Fras1, Ift140 and Lig1. CONCLUSIONS/SIGNIFICANCE In this study we have generated mouse models in which the anomalies closely mimic those seen in human disorders. The association between novel mutant alleles and phenotypes will lead to a better understanding of gene function in normal development and establish how their dysfunction causes human anomalies and disease.This work was enabled by the Australian Phenomics Network and partly supported by funding from the Australian Government’s National Collaborative Research Infrastructure Strategy, a Strategic Grant from the Faculty of Medicine, Nursing and Health Sciences at Monash University, and the Victorian Government’s Operational Infrastructure Support Program. IS acknowledges support through the NH&MRC R. Douglas Wright and ARC Future Fellowship schemes. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Modelo basado en aprendizaje automático de estimación de riesgo de mortalidad en pacientes con trauma craneoencefálico para la Región Autónoma Costa Caribe Sur de Nicaragua

La Inteligencia Artificial (IA) y la medicina han encontrado varios puntos en los que convergen, cambiando el concepto de salud. Entre los problemas de atención inmediata se encuentran los traumas craneoencefálicos, que constituyen un importante problema de salud pública en todos los países, cada día en el mundo, alrededor de 16.000 personas mueren por traumatismos. Este estudio tiene como objetivo desarrollar un modelo basado en ML para estimar la probabilidad de riesgo de mortalidad en pacientes con TCE. El proyecto se desarrolló en la Región Autónoma de la Costa Caribe Sur, centrándose en 3 unidades de salud, Hospital Regional Ernesto Sequeira Blanco (Bluefields), Hospital Ethel Kandler (Corn Island) y el Centro de Salud Perla María Norori (Laguna de Perlas), bajo la metodología SCRUM, la cual permitió la retroalimentación continua del modelo propuesto, los algoritmos de ML seleccionados para la construcción del modelo fueron la regresión logística, árbol de decisión, Random Forest y K-NN, el conjunto de datos para el modelo inicial fue el CRASH-2, todo el análisis y procesamiento se realizó en Python. Se ha demostrado que el modelo es capaz de predecir con una precisión aceptable la probabilidad de mortalidad en pacientes con TCE, sin embargo, Random Forest tuvo un mejor desempeño; en promedio tuvo una efectividad del 87,06%, mientras que la regresión logística, árbol de decisión y K-NN fueron del 75.03%, 86.48% y 77,87% respectivamente. Los resultados fueron prometedores, y el estudio ofrece una perspectiva alentadora para el desarrollo de futuros modelos de predicción basados en Aprendizaje Automático. Es importante destacar que este modelo es complementario a la toma de decisiones clínicas y no debe reemplazar el juicio clínico

The International Olympic Committee framework on fairness, inclusion and nondiscrimination on the basis of gender identity and sex variations does not protect fairness for female athletes

The International Olympic Committee (IOC) recently published a framework on fairness, inclusion, and nondiscrimination on the basis of gender identity and sex variations. Although we appreciate the IOC's recognition of the role of sports science and medicine in policy development, we disagree with the assertion that the IOC framework is consistent with existing scientific and medical evidence and question its recommendations for implementation. Testosterone exposure during male development results in physical differences between male and female bodies; this process underpins male athletic advantage in muscle mass, strength and power, and endurance and aerobic capacity. The IOC's “no presumption of advantage” principle disregards this reality. Studies show that transgender women (male-born individuals who identify as women) with suppressed testosterone retain muscle mass, strength, and other physical advantages compared to females; male performance advantage cannot be eliminated with testosterone suppression. The IOC's concept of “meaningful competition” is flawed because fairness of category does not hinge on closely matched performances. The female category ensures fair competition for female athletes by excluding male advantages. Case-by-case testing for transgender women may lead to stigmatization and cannot be robustly managed in practice. We argue that eligibility criteria for female competition must consider male development rather than relying on current testosterone levels. Female athletes should be recognized as the key stakeholders in the consultation and decision-making processes. We urge the IOC to reevaluate the recommendations of their Framework to include a comprehensive understanding of the biological advantages of male development to ensure fairness and safety in female sports