Arginase 1 Insufficiency Precipitates Amyloid-\u3cem\u3eβ\u3c/em\u3e Deposition and Hastens Behavioral Impairment in a Mouse Model of Amyloidosis

Alzheimer’s disease (AD) includes several hallmarks comprised of amyloid-β (Aβ) deposition, tau neuropathology, inflammation, and memory impairment. Brain metabolism becomes uncoupled due to aging and other AD risk factors, which ultimately lead to impaired protein clearance and aggregation. Increasing evidence indicates a role of arginine metabolism in AD, where arginases are key enzymes in neurons and glia capable of depleting arginine and producing ornithine and polyamines. However, currently, it remains unknown if the reduction of arginase 1 (Arg1) in myeloid cell impacts amyloidosis. Herein, we produced haploinsufficiency of Arg1 by the hemizygous deletion in myeloid cells using Arg1fl/fl and LysMcreTg/+ mice crossed with APP Tg2576 mice. Our data indicated that Arg1 haploinsufficiency promoted Aβ deposition, exacerbated some behavioral impairment, and decreased components of Ragulator-Rag complex involved in mechanistic target of rapamycin complex 1 (mTORC1) signaling and autophagy. Additionally, Arg1 repression and arginine supplementation both impaired microglial phagocytosis in vitro. These data suggest that proper function of Arg1 and arginine metabolism in myeloid cells remains essential to restrict amyloidosis

Maintenance of Large Subpopulations of Differentiated CD8 T-Cells Two Years after Cytomegalovirus Infection in Gambian Infants

BACKGROUND: In a previously published study, we found that large differentiated subpopulations of CD8 T-cells emerged rapidly after CMV infection in young infants and persisted throughout the following year. Here we describe a follow-up study conducted on the same infants to establish whether the differentiated subpopulations continued through the second year post-infection. METHODOLOGY / PRINCIPAL FINDINGS: CMV-specific cells identified using tetramers remained more activated and differentiated than the overall CD8 population. The large subpopulation of differentiated cytotoxic (CD28(-)CD62L(-)Bcl-2(low)CD95(+)perforin(+)) cells that emerged rapidly after infection remained stable after two years. No similar subpopulation was found in CMV-uninfected infants indicating that two years after infection, CMV remained a major factor in driving CD8 T-cell differentiation. Although markers of activation (CD45R0 and HLA-D) declined throughout the first year, HLA-D expression continued to decline during the second year and CD45R0 expression increased slightly. The age-related increase in IFNgamma response observed during the first year continued but was non-significant during the second year, indicating that the rate of functional improvement had slowed substantially. CONCLUSIONS / SIGNIFICANCE: The large differentiated subpopulations of CD8 T-cells that had emerged immediately after CMV infection persisted through the second year post-infection, while levels of activation and functional capacity remained fairly constant.Journal ArticleResearch Support, Non-U.S. Gov'tSCOPUS: ar.jinfo:eu-repo/semantics/publishe

Rapid assessment of facilitators and barriers related to the acceptance, challenges and community perception of daily regimen for treating tuberculosis in India

Introduction: The Revised National Tuberculosis Control Program (RNTCP) is the largest tuberculosis (TB) control program in the world based on Directly Observed Treatment Short-Course (DOTS) strategy. Globally, most countries have been using a daily regimen and in India a shift towards a daily regimen for TB treatment has already begun. The daily strategy is known to improve program coverage along with compliance. Such strategic shifts have both management and operational implications. We undertook a rapid assessment to understand the facilitators and barriers in adopting the daily regimen for TB treatment in three Indian states. Methods: In-depth interviews were planned across six districts of three purposively selected states of Maharashtra, Bihar and Sikkim, among health system personnel at various levels to identify their perspectives on adoption of a daily regimen for TB. These districts were sampled on the basis of TB notification rates. Thematic analysis of the qualitative data was undertaken. Results: 62 respondents were interviewed from these 6 districts. During the analysis, it was observed that an easily accessible, patient-centred and personalized outreach is an enabling factor for adherence to treatment. Lack of transportation facilities, out-of-pocket expenses and loss of wages for accessing DOTS at institutions are major identified barriers for treatment adherence at individual level. At program level, lack of trained service providers, poor administration of treatment protocols and inadequate supervision by health care providers and program managers are key factors that influence program outcomes. Conclusion: A major observation that emerged from the interviews is that the key to achieve a relapse-free cure is ensuring that a patient receives all doses of the prescribed treatment regimen. However, switching to a daily regimen makes adherence difficult and thus new strategies are needed for its implementation at patient and health provider levels. Most stakeholders appreciate the reasons for switching to a daily regimen. The stakeholders recognised the efforts of the Ministry of Health & Family Welfare (MoHFW) in spearheading the program. Strategies like the 99 DOTS call-centre approach may also further ensure treatment adherence

Setting a baseline for global urban virome surveillance in sewage

The rapid development of megacities, and their growing connectedness across the world is becoming a distinct driver for emerging disease outbreaks. Early detection of unusual disease emergence and spread should therefore include such cities as part of risk-based surveillance. A catch-all metagenomic sequencing approach of urban sewage could potentially provide an unbiased insight into the dynamics of viral pathogens circulating in a community irrespective of access to care, a potential which already has been proven for the surveillance of poliovirus. Here, we present a detailed characterization of sewage viromes from a snapshot of 81 high density urban areas across the globe, including in-depth assessment of potential biases, as a proof of concept for catch-all viral pathogen surveillance. We show the ability to detect a wide range of viruses and geographical and seasonal differences for specific viral groups. Our findings offer a cross-sectional baseline for further research in viral surveillance from urban sewage samples and place previous studies in a global perspective

Beyond African orality: digital preservation of Mandinka ʿAjamī archives of Casamance

This article focuses on the digital preservation of African sources written in Mandinka ʿAjamī, i.e. the enriched form of the Arabic script used to write the Mandinka language for centuries. ʿAjamī writing has been utilized to document intellectual traditions, histories, belief systems, and cultures of non-Arab Muslims around the world. ʿAjamī texts have played critical roles in the spread of Islam in Africa and continue to be used for both religious and non-religious writings. However, African ʿAjamī texts such as those of the Mandinka people of Casamance in southern Senegal are not well known beyond local communities. ʿAjamī texts in Mandinka and other Mande languages are among the least documented. Only a few Mande ʿAjamī texts are available to scholars. Thanks to the British Library’s Endangered Archives Programme (EAP), Africa’s rich written heritage in ʿAjamī and other scripts previously unavailable to academics is being preserved and made universally accessible.EAP1042 - Endangered Archives Programme, British LibraryAccepted manuscrip

Clinical effect of metformin in children and adolescents with type 2 diabetes mellitus: A systematic review and meta-analysis

To assess the clinical value and of metformin as mono-therapy versus other treatments for type 2 diabetes mellitus in children and adolescents. Major electronic databases, the reference lists of relevant articles and databases of ongoing trials were searched. Authors of reviews and metformin manufacturers were contacted in order to obtain more references and reports of unpublished trials. The methodological quality of these reports, included randomised controlled trials (RCTs) was assessed using the National Health System Centre for Reviews and Dissemination (NHS CRD) checklist. The search identified 1,825 studies. Three RCTs met the inclusion criteria. Two RCTs had been completed and one was still ongoing. In the metformin group there were significant reductions of mean change of HBA1c from baseline. It reduced by -0.71% (P = 0.0002) and in the other trial the result was reduced by -1.10 (95% CI: -1.19 to -1.01). In addition, more patients (48.1%) in the metformin group achieved good glycaemic control (<7%) at week 24. The mean changes in FPG from baseline were significantly (P < 0.05) different in the metformin group (-16.6%, for week 18 and week 24 20.6%. In the second trial there was a significant (P < 0.001) reduction in the adjusted mean of FPG from baseline in the metformin group, while there was an increase in the placebo group ( -42.9 mg/dl vs. +21.4mg/dl) with mean difference of -64.80 in favour of the metformin group. For BMI, significant (P < 0.001) differences were seen at week 12 and week 24 (0.07 and 0.55 kg 2 ) for metformin and glimepiride respectively. There was no significant difference between the placebo and metformin in the other trials. For lipid value there was a significant decrease in LDL levels in the metformin group. No significant changes were found in the other lipid parameters after adjusting. There were more adverse events in the metformin group but they were not statistically significant. There was a limited but not convincing evidence to suggest that metformin can improve the glycaemic control in children and adolescent with type 2 diabetes compared with other interventions. This is may be the result of the limited number, poor quality and short duration of the included trials