The short-term effects of sedentary behaviour on cerebral hemodynamics and cognitive performance in older adults: a cross-over design on the potential impact of mental and/or physical activity.

BACKGROUND: Sedentary behaviour might be a potential risk factor for cognitive decline. However, the short-term effects of sedentary behaviour on (cerebro) vascular and cognitive performance in older people are unknown. METHODS: We used a cross-over design with 22 older adults (78 years, 9 females) to assess the short-term hemodynamic and cognitive effects of three hours uninterrupted sitting and explored if these effects can be counteracted with regular (every 30 min) two-minute walking breaks. In addition, we investigated if low versus high mental activity during the three hours of sitting modified these effects. Before and after each condition, alertness, executive functioning, and working memory were assessed with the Test of Attentional Performance battery. Additionally, cerebral blood flow velocity (Transcranial Doppler) and blood pressure (Finapres) were measured in rest, and during sit-to-stand and CO2 challenges to assess baroreflex sensitivity, cerebral autoregulation, and cerebral vasomotor reactivity. RESULTS: No short-term differences were observed in cognitive performance, cerebral blood flow velocity, baroreflex sensitivity, cerebral autoregulation, or cerebral vasomotor reactivity across time, or between conditions. Blood pressure and cerebrovascular resistance increased over time (8.6 mmHg (5.0;12.1), p < 0.001), and 0.23 in resistance (0.01;0.45), p = 0.04). However, these effects were not mitigated by mental activity or by short walking breaks to interrupt sitting. CONCLUSIONS: In older individuals, three hours of sitting did not influence cognitive performance or cerebral perfusion. However, the sitting period increased blood pressure and cerebrovascular resistance, which are known to negatively impact brain health in the long-term. Importantly, we found that these effects in older individuals cannot be mitigated by higher mental activity and/or regular walking breaks. TRIAL REGISTRATION: Clinical trial registration URL: https://www.toetsingonline.nl/. Unique identifier: NL64309.091.17. Date of registration: 06-02-2018

A longitudinal study of the diabetic skin and wound microbiome

© 2017 Gardiner et al. Type II diabetes is a chronic health condition which is associated with skin conditions including chronic foot ulcers and an increased incidence of skin infections. The skin microbiome is thought to play important roles in skin defence and immune functioning. Diabetes affects the skin environment, and this may perturb skin microbiome with possible implications for skin infections and wound healing. This study examines the skin and wound microbiome in type II diabetes. Methods. Eight type II diabetic subjects with chronic foot ulcers were followed over a time course of 10 weeks, sampling from both foot skin (swabs) and wounds (swabs and debrided tissue) every two weeks. A control group of eight control subjects was also followed over 10 weeks, and skin swabs collected from the foot skin every two weeks. Samples were processed for DNA and subject to 16S rRNA gene PCR and sequencing of the V4 region. Results. The diabetic skin microbiome was significantly less diverse than control skin. Community composition was also significantly different between diabetic and control skin, however the most abundant taxa were similar between groups, with differences driven by very low abundant members of the skin communities. Chronic wounds tended to be dominated by the most abundant skin Staphylococcus, while other abundant wound taxa differed by patient. No significant correlations were found between wound duration or healing status and the abundance of any particular taxa. Discussion. The major difference observed in this study of the skin microbiome associated with diabetes was a significant reduction in diversity. The long-term effects of reduced diversity are not yet well understood, but are often associated with disease conditions

A major genetic locus in <i>Trypanosoma brucei</i> is a determinant of host pathology

The progression and variation of pathology during infections can be due to components from both host or pathogen, and/or the interaction between them. The influence of host genetic variation on disease pathology during infections with trypanosomes has been well studied in recent years, but the role of parasite genetic variation has not been extensively studied. We have shown that there is parasite strain-specific variation in the level of splenomegaly and hepatomegaly in infected mice and used a forward genetic approach to identify the parasite loci that determine this variation. This approach allowed us to dissect and identify the parasite loci that determine the complex phenotypes induced by infection. Using the available trypanosome genetic map, a major quantitative trait locus (QTL) was identified on T. brucei chromosome 3 (LOD = 7.2) that accounted for approximately two thirds of the variance observed in each of two correlated phenotypes, splenomegaly and hepatomegaly, in the infected mice (named &lt;i&gt;TbOrg1&lt;/i&gt;). In addition, a second locus was identified that contributed to splenomegaly, hepatomegaly and reticulocytosis (&lt;i&gt;TbOrg2&lt;/i&gt;). This is the first use of quantitative trait locus mapping in a diploid protozoan and shows that there are trypanosome genes that directly contribute to the progression of pathology during infections and, therefore, that parasite genetic variation can be a critical factor in disease outcome. The identification of parasite loci is a first step towards identifying the genes that are responsible for these important traits and shows the power of genetic analysis as a tool for dissecting complex quantitative phenotypic traits

Metagenomic Hi-C of a Healthy Human Fecal Microbiome Transplant Donor.

We report the availability of a high-quality metagenomic Hi-C data set generated from a fecal sample taken from a healthy fecal microbiome transplant donor subject. We report on basic features of the data to evaluate their quality

Allocating the Burdens of Climate Action: Consumption-Based Carbon Accounting and the Polluter-Pays Principle

Action must be taken to combat climate change. Yet, how the costs of climate action should be allocated among states remains a question. One popular answer—the polluter-pays principle (PPP)—stipulates that those responsible for causing the problem should pay to address it. While intuitively plausible, the PPP has been subjected to withering criticism in recent years. It is timely, following the Paris Agreement, to develop a new version: one that does not focus on historical production-based emissions but rather allocates climate burdens in proportion to each state’s annual consumption-based emissions. This change in carbon accounting results in a fairer and more environmentally effective principle for distributing climate duties

Long‐read nanopore sequencing resolves a TMEM231 gene conversion event causing Meckel–Gruber syndrome

The diagnostic deployment of massively parallel short‐read next‐generation sequencing (NGS) has greatly improved genetic test availability, speed, and diagnostic yield, particularly for rare inherited disorders. Nonetheless, diagnostic approaches based on short‐read sequencing have a poor ability to accurately detect gene conversion events. We report on the genetic analysis of a family in which 3 fetuses had clinical features consistent with the autosomal recessive disorder Meckel–Gruber syndrome (MKS). Targeted NGS of 29 known MKS‐associated genes revealed a heterozygous TMEM231 splice donor variant c.929+1A>G. Comparative read‐depth analysis, performed to identify a second pathogenic allele, revealed an apparent heterozygous deletion of TMEM231 exon 4. To verify this result we performed single‐molecule long‐read sequencing of a long‐range polymerase chain reaction product spanning this locus. We identified four missense variants that were absent from the short‐read dataset due to the preferential mapping of variant‐containing reads to a downstream TMEM231 pseudogene. Consistent with the parental segregation analysis, we demonstrate that the single‐molecule long reads could be used to show that the variants are arranged in trans. Our experience shows that robust validation of apparent dosage variants remains essential to avoid the pitfalls of short‐read sequencing and that new third‐generation long‐read sequencing technologies can already aid routine clinical care

Measurements of the Correlation Function of a Microwave Frequency Single Photon Source

At optical frequencies the radiation produced by a source, such as a laser, a black body or a single photon source, is frequently characterized by analyzing the temporal correlations of emitted photons using single photon counters. At microwave frequencies, however, there are no efficient single photon counters yet. Instead, well developed linear amplifiers allow for efficient measurement of the amplitude of an electromagnetic field. Here, we demonstrate how the properties of a microwave single photon source can be characterized using correlation measurements of the emitted radiation with such detectors. We also demonstrate the cooling of a thermal field stored in a cavity, an effect which we detect using a cross-correlation measurement of the radiation emitted at the two ends of the cavity.Comment: 5 pages, 4 figure

SPACE FOR COPD delivered as a maintenance programme on pulmonary rehabilitation discharge: protocol of a randomised controlled trial evaluating the long-term effects on exercise tolerance and mental well-being

Supplementary Data: This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content: Data supplement 1 available at: https://bmjopen.bmj.com/highwire/filestream/246974/field_highwire_adjunct_files/0/bmjopen-2021-055513supp001_data_supplement.pdfCopyright © Author(s) (or their employer(s)) 2022. Introduction The benefits achieved during pulmonary rehabilitation (PR) are known to be sustained for 6-12 months after the initial programme. Several maintenance trials have been conducted but were heterogeneous in terms of duration, frequency and labour cost. There is no consensus on one best strategy. SPACE FOR COPD (Self-management Programme of Activity, Coping and Education for Chronic Obstructive Pulmonary Disease) is a home-based self-management programme, which has been shown previously to be effective in primary and secondary care settings and is to be tested here as a maintenance programme. The aim is to evaluate the efficacy of the SPACE FOR COPD programme (manual and group sessions), on exercise tolerance and mental well-being, compared with usual care following PR in patients with COPD. Methods and analysis A prospective, multicentre, single-blinded randomised controlled trial requiring 116 participants with a clinical diagnosis of COPD who have finished PR within 4 weeks will be randomised 1:1 to either a usual care group or a SPACE FOR COPD programme group. The intervention comprises a home-based manual and 4, 2-hour group sessions adopting motivational interviewing techniques over 12 months. The primary outcome is endurance capacity measured by the Endurance Shuttle Walking Test at 12 months. Secondary outcomes are: maximal exercise capacity, health-related quality of life, mood, patient activation, physical activity, lung function and healthcare costs. The measures will be taken at baseline, 6 and 12 months. Patient interviews and staff focus groups will be conducted to explore barriers, facilitators and views about the intervention at the end of the study. A framework analysis will be used for the interpretation of qualitative data. Ethics and dissemination The trial was granted ethical approval from Health Research Authority and Health and Care Research Wales (HCRW19/EM/0267 on 10 October 2019). Results will be made available to all stakeholders through a dissemination event, conferences and peer-reviewed publications. Trial registration number ISRCTN30110012.National Institute for Health Research (NIHR) Research for Patient Benefit Programme, grant number (PB-PG-0317-20032) and supported by the NIHR Leicester Biomedical Research Centre (BRC)- Respiratory

A model for transition of 5 '-nuclease domain of DNA polymerase I from inert to active modes

Bacteria contain DNA polymerase I (PolI), a single polypeptide chain consisting of similar to 930 residues, possessing DNA-dependent DNA polymerase, 3'-5' proofreading and 5'-3' exonuclease (also known as flap endonuclease) activities. PolI is particularly important in the processing of Okazaki fragments generated during lagging strand replication and must ultimately produce a double-stranded substrate with a nick suitable for DNA ligase to seal. PolI's activities must be highly coordinated both temporally and spatially otherwise uncontrolled 5'-nuclease activity could attack a nick and produce extended gaps leading to potentially lethal double-strand breaks. To investigate the mechanism of how PolI efficiently produces these nicks, we present theoretical studies on the dynamics of two possible scenarios or models. In one the flap DNA substrate can transit from the polymerase active site to the 5'-nuclease active site, with the relative position of the two active sites being kept fixed; while the other is that the 5'-nuclease domain can transit from the inactive mode, with the 5'-nuclease active site distant from the cleavage site on the DNA substrate, to the active mode, where the active site and substrate cleavage site are juxtaposed. The theoretical results based on the former scenario are inconsistent with the available experimental data that indicated that the majority of 5'-nucleolytic processing events are carried out by the same PolI molecule that has just extended the upstream primer terminus. By contrast, the theoretical results on the latter model, which is constructed based on available structural studies, are consistent with the experimental data. We thus conclude that the latter model rather than the former one is reasonable to describe the cooperation of the PolI's polymerase and 5'-3' exonuclease activities. Moreover, predicted results for the latter model are presented