Impact of dietary manganese on experimental colitis in mice

Diet plays a significant role in the pathogenesis of inflammatory bowel disease (IBD). A recent epidemiological study has shown an inverse relationship between nutritional manganese (Mn) status and IBD patients. Mn is an essential micronutrient required for normal cell function and physiological processes. To date, the roles of Mn in intestinal homeostasis remain unknown and the contribution of Mn to IBD has yet to be explored. Here, we provide evidence that Mn is critical for the maintenance of the intestinal barrier and that Mn deficiency exacerbates dextran sulfate sodium (DSS)â induced colitis in mice. Specifically, when treated with DSS, Mnâ deficient mice showed increased morbidity, weight loss, and colon injury, with a concomitant increase in inflammatory cytokine levels and oxidative and DNA damage. Even without DSS treatment, dietary Mn deficiency alone increased intestinal permeability by impairing intestinal tight junctions. In contrast, mice fed a Mnâ supplemented diet showed slightly increased tolerance to DSSâ induced experimental colitis, as judged by the colon length. Despite the wellâ appreciated roles of intestinal microbiota in driving inflammation in IBD, the gut microbiome composition was not altered by changes in dietary Mn. We conclude that Mn is necessary for proper maintenance of the intestinal barrier and provides protection against DSSâ induced colon injury.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154377/1/fsb220201_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154377/2/fsb220201-sup-0002-TableS3.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154377/3/fsb220201-sup-0005-TableS6.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154377/4/fsb220201.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154377/5/fsb220201-sup-0003-TableS4.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154377/6/fsb220201-sup-0004-TableS5.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154377/7/fsb220201-sup-0001-TableS1-S2.pd

Visceral leishmaniasis cyclical trends in Bihar, India – implications for the elimination programme. [version 1; referees: 1 approved, 2 approved with reservations]

Background: Visceral leishmaniasis (VL) is a vector-borne disease of public health importance in India, with the highest burden of disease in the states of Bihar, Jharkhand, West Bengal and Uttar Pradesh. The disease is currently targeted for elimination (annual incidence to less than one per 10,000 population) using indoor residual spraying, active case detection and treatment. Historically the disease trend in India has been regarded as cyclical with case resurgence characteristically occurring every 15 years.  Understanding this pattern is essential if the VL elimination gains are to be sustained. To better understand the cyclical trends, annual climatic indicators including rainfall, temperature and humidity over time were compared with annual VL case incidence data.  Methods: Annual climate data (rainfall, average and maximum temperature and specific humidity) from 1956-2004 were used to identify potential factors influencing VL incidence.  Months relevant to the VL life-cycle were identified and defined (Monsoon, Sand-fly Peak, Pre-Sand-fly Peak and Annual) for analysis. The Kruskall-Wallis test was used to determine significant difference between categorical rainfall and VL incidence, whilst univariate negative binomial regression models were used to determine predictors of disease incidence. Results: The negative binomial regression model showed statistically significant associations (p 0.05).  Conclusion: The VL programme in Bihar has made significant progress in adopting best practices for improved treatment and vector control, with the aim to achieve VL elimination.  However, open access granular programme data for indoor residual spray activities and case detection is required to fully understand the role of climate in disease transmission and potential resurgence

Impact of IRS: Four-years of entomological surveillance of the Indian Visceral Leishmaniases elimination programme

BACKGROUND In 2005, Bangladesh, India and Nepal agreed to eliminate visceral leishmaniasis (VL) as a public health problem. The approach to this was through improved case detection and treatment, and controlling transmission by the sand fly vector Phlebotomus argentipes, with indoor residual spraying (IRS) of insecticide. Initially, India applied DDT with stirrup pumps for IRS, however, this did not reduce transmission. After 2015 onwards, the pyrethroid alpha-cypermethrin was applied with compression pumps, and entomological surveillance was initiated in 2016. METHODS Eight sentinel sites were established in the Indian states of Bihar, Jharkhand and West Bengal. IRS coverage was monitored by household survey, quality of insecticide application was measured by HPLC, presence and abundance of the VL vector was monitored by CDC light traps, insecticide resistance was measured with WHO diagnostic assays and case incidence was determined from the VL case register KAMIS. RESULTS Complete treatment of houses with IRS increased across all sites from 57% in 2016 to 70% of houses in 2019, rising to >80% if partial house IRS coverage is included (except West Bengal). The quality of insecticide application has improved compared to previous studies, average doses of insecticide on filters papers ranged from 1.52 times the target dose of 25mg/m2 alpha-cypermethrin in 2019 to 1.67 times in 2018. Resistance to DDT has continued to increase, but the vector was not resistant to carbamates, organophosphates or pyrethroids. The annual and seasonal abundance of P. argentipes declined between 2016 to 2019 with an overall infection rate of 0.03%. This was associated with a decline in VL incidence for the blocks represented by the sentinel sites from 1.16 per 10,000 population in 2016 to 0.51 per 10,000 in 2019. CONCLUSION Through effective case detection and management reducing the infection reservoirs for P. argentipes in the human population combined with IRS keeping P. argentipes abundance and infectivity low has reduced VL transmission. This combination of effective case management and vector control has now brought India within reach of the VL elimination targets

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

The Role of Ferritin in Health and Disease: Recent Advances and Understandings

Systemic iron homeostasis needs to be tightly controlled, as both deficiency and excess iron cause major global health concerns, such as iron deficiency anemia, hemochromatosis, etc. In mammals, sufficient dietary acquisition is critical for fulfilling the systemic iron requirement. New questions are emerging about whether and how cellular iron transport pathways integrate with the iron storage mechanism. Ferritin is the intracellular iron storage protein that stores surplus iron after all the cellular needs are fulfilled and releases it in the face of an acute demand. Currently, there is a surge in interest in ferritin research after the discovery of novel pathways like ferritinophagy and ferroptosis. This review emphasizes the most recent ferritin-related discoveries and their impact on systemic iron regulation

Anomalous altered expressions of downstream gene-targets in TP53-miRNA pathways in head and neck cancer

The prevalence of head and neck squamous cell carcinoma, HNSCC, continues to grow. Change in the expression of TP53 in HNSCC affects its downstream miRNAs and their gene targets, anomalously altering the expressions of the five genes, MEIS1, AGTR1, DTL, TYMS and BAK1. These expression alterations follow the repression of TP53 that upregulates miRNA-107, miRNA- 215, miRNA-34 b/c and miRNA-125b, but downregulates miRNA-155. The above five so far unreported genes are the targets of these miRNAs. Meta-analyses of microarray and RNA-Seq data followed by qRT-PCR validation unravel these new ones in HNSCC. The regulatory roles of TP53 on miRNA-155 and miRNA-125b differentiate the expressions of AGTR1 and BAK1in HNSCC vis-a`-vis other carcinogenesis. Expression changes alter cell cycle regulation, angiogenic and blood cell formation, and apoptotic modes in affliction. Pathway analyses establish the resulting systems-level functional and mechanistic insights into the etiology of HNSCC

All Change: Equitably Decarbonising India's Transportation Sector

open access reportExecutive summary: Key findings • There is limited focus on just transitions in the transport sector: in both academic literature and policy to date, technical solutions have received policy and research priority, but there is limited focus on how end-users will be affected by transport transitions, and whether these transitions will be equitable, inclusive and just. Several factors should be addressed under this: ensuring that transitions lead to affordable mobility solutions for all users is a key point, as is ensuring that job losses from high-carbon mobility services are compensated for by job creation in low-carbon mobility. From our key informant interviews, policymakers are focused on the supply-side when considering transport transitions, contrasting with users’ concerns of demand-side support and downstream services, particularly for electric vehicles and charging infrastructure. These tensions need to be addressed in policy. • There is potential for significant socio-economic impacts from the transition: this research has investigated the potential pains and gains of the transition to electric mobility, particularly electric road transport, in the Indian transport sector. There is potential for job losses both in the downstream oil sector and the downstream mobility services sector as the EV transition progresses due to reduced petroleum product consumption and a lesser burden of maintenance for electric vehicles compared to ICE vehicles. This also has the potential to impact government revenues from fuel taxation and place a higher burden on the government purse from increased electricity subsidy outlay. • Just transition alternatives exist: from the scenarios presented in this research, it is clear the current policy trend does not foreground justice and equity in the low-carbon transport transition, and this will lead to significant negative impacts for disadvantaged sectors of society. Policy alternatives exist to foreground justice in the transport transition, including participatory co-development of policy with end-users, and engendering greater coordination between transport and energy sectors and within the transport sector to ensure users are targeted equally across socio-economic strata with low-carbon mobility solutions

Computational Modeling and Analysis of Iron Release from Macrophages

<div><p>A major process of iron homeostasis in whole-body iron metabolism is the release of iron from the macrophages of the reticuloendothelial system. Macrophages recognize and phagocytose senescent or damaged erythrocytes. Then, they process the heme iron, which is returned to the circulation for reutilization by red blood cell precursors during erythropoiesis. The amount of iron released, compared to the amount shunted for storage as ferritin, is greater during iron deficiency. A currently accepted model of iron release assumes a passive-gradient with free diffusion of intracellular labile iron (Fe²⁺) through ferroportin (FPN), the transporter on the plasma membrane. Outside the cell, a multi-copper ferroxidase, ceruloplasmin (Cp), oxidizes ferrous to ferric ion. Apo-transferrin (Tf), the primary carrier of soluble iron in the plasma, binds ferric ion to form mono-ferric and di-ferric transferrin. According to the passive-gradient model, the removal of ferrous ion from the site of release sustains the gradient that maintains the iron release. Subcellular localization of FPN, however, indicates that the role of FPN may be more complex. By experiments and mathematical modeling, we have investigated the detailed mechanism of iron release from macrophages focusing on the roles of the Cp, FPN and apo-Tf. The passive-gradient model is quantitatively analyzed using a mathematical model for the first time. A comparison of experimental data with model simulations shows that the passive-gradient model cannot explain macrophage iron release. However, a facilitated-transport model associated with FPN can explain the iron release mechanism. According to the facilitated-transport model, intracellular FPN carries labile iron to the macrophage membrane. Extracellular Cp accelerates the oxidation of ferrous ion bound to FPN. Apo-Tf in the extracellular environment binds to the oxidized ferrous ion, completing the release process. Facilitated-transport model can correctly predict cellular iron efflux and is essential for physiologically relevant whole-body model of iron metabolism.</p></div