Spotlight on the Replisome: Aetiology of DNA Replication-Associated Genetic Diseases.

Human development and tissue homeostasis depend on the regulated control of cellular proliferation and differentiation. DNA replication is essential to couple genome duplication and cell division with the establishment and maintenance of cellular differentiation programs. In eukaryotes, DNA replication is performed by a large machine known as the 'replisome,' which is strictly regulated in a cell cycle-dependent manner. Inherited mutations of replisome components have been identified in a range of genetic conditions characterised by developmental abnormalities and reduced organismal growth in addition to an involvement of the immune and endocrine systems and/or heightened tumour predisposition. Here, we review the current knowledge of the molecular genetics of replisome dysfunction disorders and discuss recent mechanistic insights into their pathogenesis, with a focus on the specific steps of DNA replication affected in these human diseases

Ligand binding to a hemoprotein lacking the distal histidine. The myoglobin from aplysia limacina (Val(E7)).

The time course of ligand recombination to the myoglobin from Aplysia limacina, which has Val(E7), was measured following photolysis by flashes of 35 ps to 300 ns with a time resolution of 10 ps or 1 ns. CO shows only biomolecular recombination. O2 has a small geminate reaction with a half-time of tens of picoseconds, but no nanosecond geminate reaction. NO has two picosecond relaxations with half-times of 70 ps (15%) and 1 ns (80%) and one nanosecond relaxation with a half-time of 4.6 ns. The biomolecular rates for O2 and NO are the same: 2 x 10(7) M-1 s-1. Methyl and ethyl isonitriles have a geminate reaction with a half-time of 35 ps. Ethyl isonitrile has, in addition, a nanosecond relaxation (25%) with a half-time of 100 ns. t-Butyl isonitrile has four geminate relaxations (10 ps, 35 ps, 1 ns, and 1 microseconds). Analysis of the results suggests much easier movement of ligand between the heme pocket and the exterior than in sperm whale myoglobin (His(E7]. The reactivity of the heme is little different, placing the effect of the differences from sperm whale myoglobin on the distal side of the heme

Fragment-based discovery of a regulatory site in thioredoxin glutathione reductase acting as "doorstop" for NADPH entry

Members of the FAD/NAD-linked reductase family are recognized as crucial targets in drug development for cancers, inflammatory disorders, and infectious diseases. However, individual FAD/NAD reductases are difficult to inhibit in a selective manner with off target inhibition reducing usefulness of identified compounds. Thioredoxin glutathione reductase (TGR), a high molecular weight thioredoxin reductase-like enzyme, has emerged as a promising drug target for the treatment of schistosomiasis, a parasitosis afflicting more than 200 million people. Taking advantage of small molecules selected from a high-throughput screen and using X-ray crystallography, functional assays, and docking studies, we identify a critical secondary site of the enzyme. Compounds binding at this site interfere with well-known and conserved conformational changes associated with NADPH reduction, acting as a doorstop for cofactor entry. They selectivity inhibit TGR from Schistosoma mansoni and are active against parasites in culture. Since many members of the FAD/NAD-linked reductase family have similar catalytic mechanisms the unique mechanism of inhibition identified in this study for TGR broadly opens new routes to selectively inhibit homologous enzymes of central importance in numerous diseases

Oral anticoagulant therapy at hospital admission associates with lower mortality in older COVID-19 patients with atrial fibrillation. An insight from the Covid Registry

FUNDING ACKNOWLEDGEMENTS: Type of funding sources: None. ONBEHALF: the GeroCovid Investigators Introduction. Atrial fibrillation (AF), the arrhythmia most frequently diagnosed in older patients, associates with serious, thrombo-embolic, complications and high mortality. COVID-19 severely affects aged subjects, determining an important prothrombotic status. Purpose. Aim of this study was to evaluate mortality-related factors in older AF patients with COVID-19.  Methods. We included 806 in-hospital COVID-19 patients aged 60 years or more hospitalized between March 1st and June 6th 2020 and enrolled in a multicenter observational study. Results. The prevalence of AF was 21.8%. In-hospital mortality was higher in the AF group (36.9 vs. 27.5%; p = 0.015). Among AF patients, those who survived were younger (81 ± 8 vs. 84 ± 7 years; p = 0.002), had a lower CHA2DS2-VASc score (3.9 ± 1.6 vs. 4.4 ± 1.3; p = 0.02) and were more frequently treated with oral anticoagulants at admission (63.1 vs. 32.3%; p < 0.001) than those who died in hospital. At multivariable logistic regression analysis, lower age (p = 0.042), a better functional profile (p = 0.007), less severe COVID-19 manifestations at admission (p = 0.001), and the use of Vitamin K antagonists (OR = 0.16, 95%CI: 0.03-0.84; p = 0.031) or DOACs (OR = 0.22, 95%CI: 0.08-0.56; p = 0.002), compared to antiplatelet therapy or no treatment at all, were associated with a lower chance of in-hospital death. Conclusions. AF is a prevalent condition and a severity factor in older COVID-19 patients. Advanced age, dependency and severe clinical manifestations of disease characterized older AF subjects with a worse prognosis. Interestingly, pre-admission anticoagulant therapy correlated positively with in-hospital survival

DESARROLLO DEL NUEVO PATRÓN NACIONAL DE ÁNGULO PLANO

La industria Nacional posee y utiliza patrones e instrumentos angulares en su proceso productivo, tales como mesas rotativas, inclinómetros, niveles electrónicos, bloques y polígonos angulares. El laboratorio de metrología dimensional de INTI – Centro Regional Córdoba es el responsable de establecer, mantener y diseminar el patrón nacional de ángulo plano por lo cual debe calibrar adecuadamente dichos instrumentos y patrones con una incertidumbre de medición acorde a los requerimientos actuales. El instrumento principal del patrón nacional de ángulo plano es el generador de pequeños ángulos, el cual permite la realización de la unidad de ángulo plano, el radian, del Sistema Internacional (SI) de unidades. Actualmente la materialización de esta unidad se realiza con un generador del tipo “regla de senos”. A fin de incrementar la confiabilidad y exactitud de sus mediciones el laboratorio elaboró un proyecto cuyo objetivo es el desarrollo de un nuevo generador, el cual tendrá un intervalo de indicación de 1° y pasos de medición de hasta 0,1´´, el cual tendrá como objetivo principal la calibración de autocolimadores electrónicos de alta resolución con una incertidumbre expandida menor a 0,05´´ (k = 2)

Physiotherapy interventions for people with dementia and a hip fracture-a scoping review of the literature.

BACKGROUND: People with dementia are 2.7 times more likely to suffer a hip fracture than those without and their management is estimated to cost £0.92 billion per year. Yet there has been little focus on the effectiveness of interventions for this population. OBJECTIVE: The aim of this scoping review was to summarise the current available evidence for physiotherapy interventions for people with dementia who fracture their hip as well as to identify gaps in the literature that may require further research. DATA SOURCES: A systematic search of the following databases was undertaken-TRIP, CINAHL, Amed, Embase, PEDro, PsycINFO, Cochrane Library, Open Grey, Ethos, ISRCTN, Proquest, PROSPERO and UK Clinical Trials Gateway. STUDY SELECTION: Articles were included if they described an intervention which is considered within the scope of a physiotherapist and targeted those with both a hip fracture and dementia. SYNTHESIS METHODS: A narrative summary was then undertaken to describe the current state of the literature. RESULTS: Twenty six studies were included, of which thirteen were observational, six RCTs, two qualitative, two surveys and three systematic reviews. Only nine studies focused explicitly on physiotherapy interventions. CONCLUSION: The findings of this scoping review suggest there is limited evidence to guide physiotherapists in the management of people with dementia who fracture their hip. No evidence was found about perceptions or experiences of patients in this group or of the physiotherapists involved in their care. Further research is needed to develop and evaluate physiotherapy interventions for people with dementia who fracture their hip

Psychological Well-Being of Older Adults With Cognitive Deterioration During Quarantine: Preliminary Results From the GeroCovid Initiative

Objectives: The spread of COVID-19 has undeniably unsettled the social, psychological and emotional life of the entire world population. Particular attention should be paid to older adults with dementia, given their vulnerability to emotional stressors. The aim of this retrospective study is to evaluate the impact of the first wave quarantine related to Covid-19 on psychological and affective well-being of older adults with mild/major neurocognitive disorders and of their caregivers.Methods: Data on participants' assessment before the quarantine (PREQ) were retrospectively collected. Patients with Mild Cognitive Impairment (MCI) or dementia were recruited from different Centers for Cognitive Decline and Dementia in Italy. During the quarantine, psychological and affective well-being were evaluated by phone through the administrations of scales measuring anxiety and depression (DASS), perceived stress (PSS), coping strategies (COPE) and the caregivers' burden (CBI). The scales' results were compared across participants' PREQ cognitive level (Mini Mental State Examination, MMSE ≥25, 23–24, and ≤ 22) with multiple linear regression models.Results: The sample included 168 patients (64% women) with a mean age of 79 ± 7 years. After adjusting for potential confounders, more severe cognitive impairment was independently associated with higher DASS and PSS score, and poorer coping strategies (p &lt; 0.05). Cognitive functioning was also inversely associated with CBI.Conclusions: The impact of the quarantine on the psycho-affective well-being of individuals with MCI and dementia and on caregivers' burden varies according to the PREQ cognitive functioning with more severely impaired patients having worse outcomes