Bilateral enucleation alters gene expression and intraneocortical connections in the mouse

<p>Abstract</p> <p>Background</p> <p>Anatomically and functionally distinct sensory and motor neocortical areas form during mammalian development through a process called arealization. This process is believed to be reliant on both activity-dependent and activity-independent mechanisms. Although both mechanisms are thought to function concurrently during arealization, the nature of their interaction is not understood. To examine the potential interplay of extrinsic activity-dependent mechanisms, such as sensory input, and intrinsic activity-independent mechanisms, including gene expression in mouse neocortical development, we performed bilateral enucleations in newborn mice and conducted anatomical and molecular analyses 10 days later. In this study, by surgically removing the eyes of the newborn mouse, we examined whether early enucleation would impact normal gene expression and the development of basic anatomical features such as intraneocortical connections and cortical area boundaries in the first 10 days of life, before natural eye opening. We examined the acute effects of bilateral enucleation on the lateral geniculate nucleus of the thalamus and the neocortical somatosensory-visual area boundary through detailed analyses of intraneocortical connections and gene expression of six developmentally regulated genes at postnatal day 10.</p> <p>Results</p> <p>Our results demonstrate short-term plasticity on postnatal day 10 resulting from the removal of the eyes at birth, with changes in nuclear size and gene expression within the lateral geniculate nucleus as well as a shift in intraneocortical connections and <it>ephrin A5 </it>expression at the somatosensory-visual boundary. In this report, we highlight the correlation between positional shifts in <it>ephrin A5 </it>expression and improper refinement of intraneocortical connections observed at the somatosensory-visual boundary in enucleates on postnatal day 10.</p> <p>Conclusions</p> <p>Bilateral enucleation induces a positional shift of both <it>ephrin A5 </it>expression and intraneocortical projections at the somatosensory-visual border in only 10 days. These changes occur prior to natural eye opening, suggesting a possible role of spontaneous retinal activity in area border formation within the neocortex. Through these analyses, we gain a deeper understanding of how extrinsic activity-dependent mechanisms, particularly input from sensory organs, are integrated with intrinsic activity-independent mechanisms to regulate neocortical arealization and plasticity.</p

Diabetes and tuberculosis: the impact of the diabetes epidemic on tuberculosis incidence.

BACKGROUND: Tuberculosis (TB) remains a major cause of mortality in developing countries, and in these countries diabetes prevalence is increasing rapidly. Diabetes increases the risk of TB. Our aim was to assess the potential impact of diabetes as a risk factor for incident pulmonary tuberculosis, using India as an example. METHODS: We constructed an epidemiological model using data on tuberculosis incidence, diabetes prevalence, population structure, and relative risk of tuberculosis associated with diabetes. We evaluated the contribution made by diabetes to both tuberculosis incidence, and to the difference between tuberculosis incidence in urban and rural areas. RESULTS: In India in 2000 there were an estimated 20.7 million adults with diabetes, and 900,000 incident adult cases of pulmonary tuberculosis. Our calculations suggest that diabetes accounts for 14.8% (uncertainty range 7.1% to 23.8%) of pulmonary tuberculosis and 20.2% (8.3% to 41.9%) of smear-positive (i.e. infectious) tuberculosis. We estimate that the increased diabetes prevalence in urban areas is associated with a 15.2% greater smear-positive tuberculosis incidence in urban than rural areas - over a fifth of the estimated total difference. CONCLUSION: Diabetes makes a substantial contribution to the burden of incident tuberculosis in India, and the association is particularly strong for the infectious form of tuberculosis. The current diabetes epidemic may lead to a resurgence of tuberculosis in endemic regions, especially in urban areas. This potentially carries a risk of global spread with serious implications for tuberculosis control and the achievement of the United Nations Millennium Development Goals.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

Effectiveness of face masks for reducing transmission of SARS-CoV-2: a rapid systematic review

This rapid systematic review of evidence asks whether (i) wearing a face mask, (ii) one type of mask over another and (iii) mandatory mask policies can reduce the transmission of SARS-CoV-2 infection, either in community-based or healthcare settings. A search of studies published 1 January 2020–27 January 2023 yielded 5185 unique records. Due to a paucity of randomized controlled trials (RCTs), observational studies were included in the analysis. We analysed 35 studies in community settings (three RCTs and 32 observational) and 40 in healthcare settings (one RCT and 39 observational). Ninety-five per cent of studies included were conducted before highly transmissible Omicron variants emerged. Ninety-one per cent of observational studies were at ‘critical’ risk of bias (ROB) in at least one domain, often failing to separate the effects of masks from concurrent interventions. More studies found that masks (n = 39/47; 83%) and mask mandates (n = 16/18; 89%) reduced infection than found no effect (n = 8/65; 12%) or favoured controls (n = 1/65; 2%). Seven observational studies found that respirators were more protective than surgical masks, while five found no statistically significant difference between the two mask types. Despite the ROB, and allowing for uncertain and variable efficacy, we conclude that wearing masks, wearing higher quality masks (respirators), and mask mandates generally reduced SARS-CoV-2 transmission in these study populations

Bisindolylmaleimide IX: a Novel Anti-SARS-CoV2 Agent Targeting Viral Main Protease 3CLpro Demonstrated by Virtual Screening Pipeline and In-Vitro Validation Assays

SARS-CoV-2, the virus that causes COVID-19 consists of several enzymes with essential functions within its proteome. Here, we focused on repurposing approved and investigational drugs/compounds. We targeted seven proteins with enzymatic activities known to be essential at different stages of the viral cycle including PLpro, 3CLpro, RdRP, Helicase, ExoN, NendoU, and 2′-O-MT. For virtual screening, energy minimization of a crystal structure of the modeled protein was carried out using the Protein Preparation Wizard (Schrodinger LLC 2020-1). Following active site selection based on data mining and COACH predictions, we performed a high-throughput virtual screen of drugs and investigational molecules (n = 5903). The screening was performed against viral targets using three sequential docking modes (i.e., HTVS, SP, and XP). Virtual screening identified ∼290 potential inhibitors based on the criteria of energy, docking parameters, ligand, and binding site strain and score. Drugs specific to each target protein were further analyzed for binding free energy perturbation by molecular mechanics (prime MM-GBSA) and pruning the hits to the top 32 candidates. The top lead from each target pool was further subjected to molecular dynamics simulation using the Desmond module. The resulting top eight hits were tested for their SARS-CoV-2 anti-viral activity in-vitro. Among these, a known inhibitor of protein kinase C isoforms, Bisindolylmaleimide IX (BIM IX), was found to be a potent inhibitor of SARS-CoV-2. Further, target validation through enzymatic assays confirmed 3CLpro to be the target. This is the first study that has showcased BIM IX as a COVID-19 inhibitor thereby validating our pipeline

A Systematic Review of Music Therapy Practice and Outcomes with Acute Adult Psychiatric In-Patients

PMCID: PMC3732280This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Effectiveness of low-Dye taping for the short-term treatment of plantar heel pain: a randomised trial

BACKGROUND: Plantar heel pain is one of the most common musculoskeletal disorders of the foot and ankle. Treatment of the condition is usually conservative, however the effectiveness of many treatments frequently used in clinical practice, including supportive taping of the foot, has not been established. We performed a participant-blinded randomised trial to assess the effectiveness of low-Dye taping, a commonly used short-term treatment for plantar heel pain. METHODS: Ninety-two participants with plantar heel pain (mean age 50 ± 14 years; mean body mass index 30 ± 6; and median self-reported duration of symptoms 10 months, range of 2 to 240 months) were recruited from the general public between February and June 2005. Participants were randomly allocated to (i) low-Dye taping and sham ultrasound or (ii) sham ultrasound alone. The duration of follow-up for each participant was one week. No participants were lost to follow-up. Outcome measures included 'first-step' pain (measured on a 100 mm Visual Analogue Scale) and the Foot Health Status Questionnaire domains of foot pain, foot function and general foot health. RESULTS: Participants treated with low-Dye taping reported a small improvement in 'first-step' pain after one week of treatment compared to those who did not receive taping. The estimate of effect on 'first-step' pain favoured the low-Dye tape (ANCOVA adjusted mean difference -12.3 mm; 95% CI -22.4 to -2.2; P = 0.017). There were no other statistically significant differences between groups. Thirteen participants in the taping group experienced an adverse event however most were mild to moderate and short-lived. CONCLUSION: When used for the short-term treatment of plantar heel pain, low-Dye taping provides a small improvement in 'first-step' pain compared with a sham intervention after a one-week period

Microprocessor mediates transcriptional termination of long noncoding RNA transcripts hosting microRNAs

MicroRNA (miRNA) play a major role in the post-transcriptional regulation of gene expression. Mammalian miRNA biogenesis begins with co-transcriptional cleavage of RNA polymerase II (Pol II) transcripts by the Microprocessor complex. While most miRNA are located within introns of protein coding genes, a substantial minority of miRNA originate from long non coding (lnc) RNA where transcript processing is largely uncharacterized. Here, by detailed characterization of liver-specific lnc-pri-miR-122 and genome-wide analysis, we show that most lnc-pri-miRNA do not use the canonical cleavage and polyadenylation (CPA) pathway but instead use Microprocessor cleavage to terminate transcription. Microprocessor inactivation leads to extensive transcriptional readthrough of lnc-pri-miRNA and transcriptional interference with downstream genes. Consequently we define a novel RNase III-mediated, polyadenylation-independent mechanism of Pol II transcription termination in mammalian cells

An Anaerobic-Type α-Ketoglutarate Ferredoxin Oxidoreductase Completes the Oxidative Tricarboxylic Acid Cycle of Mycobacterium tuberculosis

Aerobic organisms have a tricarboxylic acid (TCA) cycle that is functionally distinct from those found in anaerobic organisms. Previous reports indicate that the aerobic pathogen Mycobacterium tuberculosis lacks detectable α-ketoglutarate (KG) dehydrogenase activity and drives a variant TCA cycle in which succinyl-CoA is replaced by succinic semialdehyde. Here, we show that M. tuberculosis expresses a CoA-dependent KG dehydrogenase activity, albeit one that is typically found in anaerobic bacteria. Unlike most enzymes of this family, the M. tuberculosis KG: ferredoxin oxidoreductase (KOR) is extremely stable under aerobic conditions. This activity is absent in a mutant strain deleted for genes encoding a previously uncharacterized oxidoreductase, and this strain is impaired for aerobic growth in the absence of sufficient amounts of CO2. Interestingly, inhibition of the glyoxylate shunt or exclusion of exogenous fatty acids alleviates this growth defect, indicating the presence of an alternate pathway that operates in the absence of β-oxidation. Simultaneous disruption of KOR and the first enzyme of the succinic semialdehyde pathway (KG decarboxylase; KGD) results in strict dependence upon the glyoxylate shunt for growth, demonstrating that KG decarboxylase is also functional in M. tuberculosis intermediary metabolism. These observations demonstrate that unlike most organisms M. tuberculosis utilizes two distinct TCA pathways from KG, one that functions concurrently with β-oxidation (KOR-dependent), and one that functions in the absence of β-oxidation (KGD-dependent). As these pathways are regulated by metabolic cues, we predict that their differential utilization provides an advantage for growth in different environments within the host

Multispacer Sequence Typing for Mycobacterium tuberculosis Genotyping

Background: Genotyping methods developed to survey the transmission dynamics of Mycobacterium tuberculosis currently rely on the interpretation of restriction and amplification profiles. Multispacer sequence typing (MST) genotyping is based on the sequencing of several intergenic regions selected after complete genome sequence analysis. It has been applied to various pathogens, but not to M. tuberculosis. Methods and Findings: In M. tuberculosis, the MST approach yielded eight variable intergenic spacers which included four previously described variable number tandem repeat loci, one single nucleotide polymorphism locus and three newly evaluated spacers. Spacer sequence stability was evaluated by serial subculture. The eight spacers were sequenced in a collection of 101 M. tuberculosis strains from five phylogeographical lineages, and yielded 29 genetic events including 13 tandem repeat number variations (44.82%), 11 single nucleotide mutations (37.93%) and 5 deletions (17.24%). These 29 genetic events yielded 32 spacer alleles or spacer-types (ST) with an index of discrimination of 0.95. The distribution of M. tuberculosis isolates into ST profiles correlated with their assignment into phylogeographical lineages. Blind comparison of a further 93 M. tuberculosis strains by MST and restriction fragment length polymorphism-IS6110 fingerprinting and mycobacterial interspersed repetitive units typing, yielded an index of discrimination of 0.961 and 0.992, respectively. MST yielded 41 different profiles delineating 16 related groups and proved to be more discriminatory than IS6110-based typing for isolates containing M<8 IS6110 copies (P<0.0003). MST was successfully applied to 7/10 clinical specimens exhibiting a Cts <= 42 cycles in internal transcribed spacer-real time PCR. Conclusions: These results support MST as an alternative, sequencing-based method for genotyping low IS6110 copy-number M. tuberculosis strains. The M. tuberculosis MST database is freely available (http://ifr48.timone.univ-mrs.fr/MST_MTuberculosis/mst)

The effects of spatial population dataset choice on estimates of population at risk of disease

Background: The spatial modeling of infectious disease distributions and dynamics is increasingly being undertaken for health services planning and disease control monitoring, implementation, and evaluation. Where risks are heterogeneous in space or dependent on person-to-person transmission, spatial data on human population distributions are required to estimate infectious disease risks, burdens, and dynamics. Several different modeled human population distribution datasets are available and widely used, but the disparities among them and the implications for enumerating disease burdens and populations at risk have not been considered systematically. Here, we quantify some of these effects using global estimates of populations at risk (PAR) of P. falciparum malaria as an example.Methods: The recent construction of a global map of P. falciparum malaria endemicity enabled the testing of different gridded population datasets for providing estimates of PAR by endemicity class. The estimated population numbers within each class were calculated for each country using four different global gridded human population datasets: GRUMP (~1 km spatial resolution), LandScan (~1 km), UNEP Global Population Databases (~5 km), and GPW3 (~5 km). More detailed assessments of PAR variation and accuracy were conducted for three African countries where census data were available at a higher administrative-unit level than used by any of the four gridded population datasets.Results: The estimates of PAR based on the datasets varied by more than 10 million people for some countries, even accounting for the fact that estimates of population totals made by different agencies are used to correct national totals in these datasets and can vary by more than 5% for many low-income countries. In many cases, these variations in PAR estimates comprised more than 10% of the total national population. The detailed country-level assessments suggested that none of the datasets was consistently more accurate than the others in estimating PAR. The sizes of such differences among modeled human populations were related to variations in the methods, input resolution, and date of the census data underlying each dataset. Data quality varied from country to country within the spatial population datasets.Conclusions: Detailed, highly spatially resolved human population data are an essential resource for planning health service delivery for disease control, for the spatial modeling of epidemics, and for decision-making processes related to public health. However, our results highlight that for the low-income regions of the world where disease burden is greatest, existing datasets display substantial variations in estimated population distributions, resulting in uncertainty in disease assessments that utilize them. Increased efforts are required to gather contemporary and spatially detailed demographic data to reduce this uncertainty, particularly in Africa, and to develop population distribution modeling methods that match the rigor, sophistication, and ability to handle uncertainty of contemporary disease mapping and spread modeling. In the meantime, studies that utilize a particular spatial population dataset need to acknowledge the uncertainties inherent within them and consider how the methods and data that comprise each will affect conclusions. © 2011 Tatem et al; licensee BioMed Central Ltd.SCOPUS: ar.jinfo:eu-repo/semantics/publishe