Iron Source Preference and Regulation of Iron Uptake in Cryptococcus neoformans

The level of available iron in the mammalian host is extremely low, and pathogenic microbes must compete with host proteins such as transferrin for iron. Iron regulation of gene expression, including genes encoding iron uptake functions and virulence factors, is critical for the pathogenesis of the fungus Cryptococcus neoformans. In this study, we characterized the roles of the CFT1 and CFT2 genes that encode C. neoformans orthologs of the Saccharomyces cerevisiae high-affinity iron permease FTR1. Deletion of CFT1 reduced growth and iron uptake with ferric chloride and holo-transferrin as the in vitro iron sources, and the cft1 mutant was attenuated for virulence in a mouse model of infection. A reduction in the fungal burden in the brains of mice infected with the cft1 mutant was observed, thus suggesting a requirement for reductive iron acquisition during cryptococcal meningitis. CFT2 played no apparent role in iron acquisition but did influence virulence. The expression of both CFT1 and CFT2 was influenced by cAMP-dependent protein kinase, and the iron-regulatory transcription factor Cir1 positively regulated CFT1 and negatively regulated CFT2. Overall, these results indicate that C. neoformans utilizes iron sources within the host (e.g., holo-transferrin) that require Cft1 and a reductive iron uptake system

SHIP Represses the Generation of Alternatively Activated Macrophages

SummaryWe recently reported that SHIP restrains LPS-induced classical (M1) activation of in vitro differentiated, bone marrow-derived macrophages (BMMΦs) and that SHIP upregulation is essential for endotoxin tolerance. Herein, we show that in vivo differentiated SHIP−/− peritoneal (PMΦs) and alveolar (AMΦs) macrophages, unlike their wild-type counterparts, are profoundly M2 skewed (alternatively activated), possessing constitutively high arginase I (ArgI) and Ym1 levels and impaired LPS-induced NO production. Consistent with this, SHIP−/− mice display M2-mediated lung pathology and enhanced tumor implant growth. Interestingly, BMMΦs from SHIP−/− mice do not display this M2 phenotype unless exposed to TGFβ within normal mouse plasma (MP) during in vitro differentiation. Our results suggest that SHIP functions in vivo to repress M2 skewing and that macrophage polarization can occur during differentiation in response to TGFβ if progenitors have elevated PIP3

Poor sitting posture and a heavy schoolbag as contributors to musculoskeletal pain in children: an ergonomic school education intervention program

Objectives: The purpose of this study was to evaluate a multidisciplinary, interventional, ergonomic education program designed to reduce the risk of musculoskeletal problems by reducing schoolbag weight and correcting poor sitting posture. Methods: Data were collected twice before and twice following intervention using the Standardized Nordic Body Map Questionnaire, a rapid upper limb assessment for posture evaluation, and schoolbag weight measurement in children aged 8 and 11 years attending two schools within the central region of Malaysia. Results: Students who received the ergonomic intervention reported significant improvements in their sitting posture in a classroom environment and reduction of schoolbag weight as compared with the controls. Conclusion: A single-session, early intervention, group ergonomics education program for children aged 8 and 11 years is appropriate and effective, and should be considered as a strategy to reduce musculoskeletal pain among schoolchildren in this age group

Iron Regulation of the Major Virulence Factors in the AIDS-Associated Pathogen Cryptococcus neoformans

Iron overload is known to exacerbate many infectious diseases, and conversely, iron withholding is an important defense strategy for mammalian hosts. Iron is a critical cue for Cryptococcus neoformans because the fungus senses iron to regulate elaboration of the polysaccharide capsule that is the major virulence factor during infection. Excess iron exacerbates experimental cryptococcosis and the prevalence of this disease in Sub-Saharan Africa has been associated with nutritional and genetic aspects of iron loading in the background of the HIV/AIDS epidemic. We demonstrate that the iron-responsive transcription factor Cir1 in Cr. neoformans controls the regulon of genes for iron acquisition such that cir1 mutants are “blind” to changes in external iron levels. Cir1 also controls the known major virulence factors of the pathogen including the capsule, the formation of the anti-oxidant melanin in the cell wall, and the ability to grow at host body temperature. Thus, the fungus is remarkably tuned to perceive iron as part of the disease process, as confirmed by the avirulence of the cir1 mutant; this characteristic of the pathogen may provide opportunities for antifungal treatment

Global burden and strength of evidence for 88 risk factors in 204 countries and 811 subnational locations, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

Background: Understanding the health consequences associated with exposure to risk factors is necessary to inform public health policy and practice. To systematically quantify the contributions of risk factor exposures to specific health outcomes, the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 aims to provide comprehensive estimates of exposure levels, relative health risks, and attributable burden of disease for 88 risk factors in 204 countries and territories and 811 subnational locations, from 1990 to 2021. Methods: The GBD 2021 risk factor analysis used data from 54 561 total distinct sources to produce epidemiological estimates for 88 risk factors and their associated health outcomes for a total of 631 risk–outcome pairs. Pairs were included on the basis of data-driven determination of a risk–outcome association. Age-sex-location-year-specific estimates were generated at global, regional, and national levels. Our approach followed the comparative risk assessment framework predicated on a causal web of hierarchically organised, potentially combinative, modifiable risks. Relative risks (RRs) of a given outcome occurring as a function of risk factor exposure were estimated separately for each risk–outcome pair, and summary exposure values (SEVs), representing risk-weighted exposure prevalence, and theoretical minimum risk exposure levels (TMRELs) were estimated for each risk factor. These estimates were used to calculate the population attributable fraction (PAF; ie, the proportional change in health risk that would occur if exposure to a risk factor were reduced to the TMREL). The product of PAFs and disease burden associated with a given outcome, measured in disability-adjusted life-years (DALYs), yielded measures of attributable burden (ie, the proportion of total disease burden attributable to a particular risk factor or combination of risk factors). Adjustments for mediation were applied to account for relationships involving risk factors that act indirectly on outcomes via intermediate risks. Attributable burden estimates were stratified by Socio-demographic Index (SDI) quintile and presented as counts, age-standardised rates, and rankings. To complement estimates of RR and attributable burden, newly developed burden of proof risk function (BPRF) methods were applied to yield supplementary, conservative interpretations of risk–outcome associations based on the consistency of underlying evidence, accounting for unexplained heterogeneity between input data from different studies. Estimates reported represent the mean value across 500 draws from the estimate's distribution, with 95% uncertainty intervals (UIs) calculated as the 2·5th and 97·5th percentile values across the draws. Findings: Among the specific risk factors analysed for this study, particulate matter air pollution was the leading contributor to the global disease burden in 2021, contributing 8·0% (95% UI 6·7–9·4) of total DALYs, followed by high systolic blood pressure (SBP; 7·8% [6·4–9·2]), smoking (5·7% [4·7–6·8]), low birthweight and short gestation (5·6% [4·8–6·3]), and high fasting plasma glucose (FPG; 5·4% [4·8–6·0]). For younger demographics (ie, those aged 0–4 years and 5–14 years), risks such as low birthweight and short gestation and unsafe water, sanitation, and handwashing (WaSH) were among the leading risk factors, while for older age groups, metabolic risks such as high SBP, high body-mass index (BMI), high FPG, and high LDL cholesterol had a greater impact. From 2000 to 2021, there was an observable shift in global health challenges, marked by a decline in the number of all-age DALYs broadly attributable to behavioural risks (decrease of 20·7% [13·9–27·7]) and environmental and occupational risks (decrease of 22·0% [15·5–28·8]), coupled with a 49·4% (42·3–56·9) increase in DALYs attributable to metabolic risks, all reflecting ageing populations and changing lifestyles on a global scale. Age-standardised global DALY rates attributable to high BMI and high FPG rose considerably (15·7% [9·9–21·7] for high BMI and 7·9% [3·3–12·9] for high FPG) over this period, with exposure to these risks increasing annually at rates of 1·8% (1·6–1·9) for high BMI and 1·3% (1·1–1·5) for high FPG. By contrast, the global risk-attributable burden and exposure to many other risk factors declined, notably for risks such as child growth failure and unsafe water source, with age-standardised attributable DALYs decreasing by 71·5% (64·4–78·8) for child growth failure and 66·3% (60·2–72·0) for unsafe water source. We separated risk factors into three groups according to trajectory over time: those with a decreasing attributable burden, due largely to declining risk exposure (eg, diet high in trans-fat and household air pollution) but also to proportionally smaller child and youth populations (eg, child and maternal malnutrition); those for which the burden increased moderately in spite of declining risk exposure, due largely to population ageing (eg, smoking); and those for which the burden increased considerably due to both increasing risk exposure and population ageing (eg, ambient particulate matter air pollution, high BMI, high FPG, and high SBP). Interpretation: Substantial progress has been made in reducing the global disease burden attributable to a range of risk factors, particularly those related to maternal and child health, WaSH, and household air pollution. Maintaining efforts to minimise the impact of these risk factors, especially in low SDI locations, is necessary to sustain progress. Successes in moderating the smoking-related burden by reducing risk exposure highlight the need to advance policies that reduce exposure to other leading risk factors such as ambient particulate matter air pollution and high SBP. Troubling increases in high FPG, high BMI, and other risk factors related to obesity and metabolic syndrome indicate an urgent need to identify and implement interventions

Memperkenalkan Konsep Organisasi Pembelajaran Di Syarikat Makanan Halal Di Malaysia

Kajian ini bertujuan untuk mengenal pasti bagaimana konsep Organisasi Pembelajaran (Learning Organization) dapat membantu syarikat makanan halal untuk meningkatkan produktiviti dan bersaing di peringkat global. Kertas konseptual ini cuba untuk mengkaji konsep organisasi pembelajaran yang membantu organisasi untuk menjalankan operasi syarikat bersama antara pekerja dan pihak pengurusan tanpa diskriminasi. Teori organisasi pembelajaran oleh Ortenblad digunakan dalam kajian ini memberikan penjelasan komprehensif mengenai organisasi pembelajaran iaitu; pembelajaran organisasi, pembelajaran di tempat kerja, iklim pembelajaran dan struktur pembelajaran. Beberapa kajian terdahulu memaparkan mengenai kejayaan sesebuah syarikat yang mengamalkan organisasi pembelajaran membuktikan bahawa organisasi pembelajaran adalah suatu gaya pengurusan yang wajar dilaksanakan di syarikat makanan halal untuk terus mapan dan berdaya saing di peringkat global

Comparative hybridization reveals extensive genome variation in the AIDS-associated pathogen Cryptococcus neoformans

Background. Genome variability can have a profound influence on the virulence of pathogenic microbes. The availability of genome sequences for two strains of the AIDS-associated fungal pathogen Cryptococcus neoformans presented an opportunity to use comparative genome hybridization (CGH) to examine genome variability between strains of different mating type, molecular subtype, and ploidy. Results Initially, CGH was used to compare the approximately 100 kilobase MAT a and MATα mating-type regions in serotype A and D strains to establish the relationship between the Log2 ratios of hybridization signals and sequence identity. Subsequently, we compared the genomes of the environmental isolate NIH433 (MAT a) and the clinical isolate NIH12 (MATα) with a tiling array of the genome of the laboratory strain JEC21 derived from these strains. In this case, CGH identified putative recombination sites and the origins of specific segments of the JEC21 genome. Similarly, CGH analysis revealed marked variability in the genomes of strains representing the VNI, VNII, and VNB molecular subtypes of the A serotype, including disomy for chromosome 13 in two strains. Additionally, CGH identified differences in chromosome content between three strains with the hybrid AD serotype and revealed that chromosome 1 from the serotype A genome is preferentially retained in all three strains. Conclusion The genomes of serotypes A, D, and AD strains exhibit extensive variation that spans the range from small differences (such as regions of divergence, deletion, or amplification) to the unexpected disomy for chromosome 13 in haploid strains and preferential retention of specific chromosomes in naturally occurring diploids.Non UBCScience, Faculty ofMicrobiology and Immunology, Department ofReviewedFacult

Conserved Regions of Cir1 and Iron-Related Phenotypes of <i>cir1</i> Mutants

<div><p>(A) Amino acid alignment of Cir1 with other fungal GATA-type iron regulators: <i>Sc. pombe</i> Fep1 (AAM29187), <i>Ca. albicans</i> Sfu1 (AAM77345) and U. maydis Urbs1 (AAB05617). Only the segments of the alignments containing the highly conserved N- or C-terminal zinc finger motifs (top and bottom alignments, respectively) and the cyteine-rich region are shown (middle alignment). Cir1 only has the C-terminal zinc finger motif.</p> <p>(B) RT-PCR results showing that <i>CIR1</i> transcripts are not produced from the <i>cir1</i> mutants, indicating complete disruption of the gene. WT. wild type.</p> <p>(C) Panel I, the <i>cir1</i> mutants display increased cell surface reductase activity as indicated by the red colony color in the presence of TTC; panel II, The <i>cir1</i> mutants are highly sensitive to elevated iron levels (+Fe, 0.75 mM ferrozine + 200 μM FeEDTA), but not to iron restriction (−Fe, 0.75 mM ferrozine); and panel III, the <i>cir1</i> mutants are more sensitive to phleomycin (0.25 μg/ml). Two independent mutants (#1 and #2) displayed the same phenotypes.</p></div