Mycobacterium tuberculosis infection induces non-apoptotic cell death of human dendritic cells

<p>Abstract</p> <p>Background</p> <p>Dendritic cells (DCs) connect innate and adaptive immunity, and are necessary for an efficient CD4⁺and CD8⁺T cell response after infection with <it>Mycobacterium tuberculosis </it>(Mtb). We previously described the macrophage cell death response to Mtb infection. To investigate the effect of Mtb infection on human DC viability, we infected these phagocytes with different strains of Mtb and assessed viability, as well as DNA fragmentation and caspase activity. In parallel studies, we assessed the impact of infection on DC maturation, cytokine production and bacillary survival.</p> <p>Results</p> <p>Infection of DCs with live Mtb (H37Ra or H37Rv) led to cell death. This cell death proceeded in a caspase-independent manner, and without nuclear fragmentation. In fact, substrate assays demonstrated that Mtb H37Ra-induced cell death progressed without the activation of the executioner caspases, 3/7. Although the death pathway was triggered after infection, the DCs successfully underwent maturation and produced a host-protective cytokine profile. Finally, dying infected DCs were permissive for Mtb H37Ra growth.</p> <p>Conclusions</p> <p>Human DCs undergo cell death after infection with live Mtb, in a manner that does not involve executioner caspases, and results in no mycobactericidal effect. Nonetheless, the DC maturation and cytokine profile observed suggests that the infected cells can still contribute to TB immunity.</p

Gait training with real-time augmented toe-ground clearance information decreases tripping risk in older adults and a person with chronic stroke

Falls risk increases with ageing but is substantially higher in people with stroke. Tripping-related balance loss is the primary cause of falls, and Minimum Toe Clearance (MTC) during walking is closely linked to tripping risk. The aim of this study was to determine whether real-time augmented information of toe-ground clearance at MTC can increase toe clearance, and reduce tripping risk. Nine healthy older adults (76 ± 9 years) and one 71 year old female stroke patient participated. Vertical toe displacement was displayed in real-time such that participants could adjust their toe clearance during treadmill walking. Participants undertook a session of unconstrained walking (no-feedback baseline) and, in a subsequent Feedback condition, were asked to modify their swing phase trajectory to match a "target" increased MTC. Tripping probability (PT) pre- and post-training was calculated by modeling MTC distributions. Older adults showed significantly higher mean MTC for the post-training retention session (27.7 ± 3.79 mm) compared to the normal walking trial (14.1 ± 8.3 mm). The PT on a 1 cm obstacle for the older adults reduced from 1 in 578 strides to 1 in 105,988 strides. With gait training the stroke patient increased MTC and reduced variability (baseline 16 ± 12 mm, post-training 24 ± 8 mm) which reduced obstacle contact probability from 1 in 3 strides in baseline to 1 in 161 strides post-training. The findings confirm that concurrent visual feedback of a lower limb kinematic gait parameter is effective in changing foot trajectory control and reducing tripping probability in older adults. There is potential for further investigation of augmented feedback training across a range of gait-impaired populations, such as stroke

Are Ethnic and Gender Specific Equations Needed to Derive Fat Free Mass from Bioelectrical Impedance in Children of South Asian, Black African-Caribbean and White European Origin? Results of the Assessment of Body Composition in Children Study

Background Bioelectrical impedance analysis (BIA) is a potentially valuable method for assessing lean mass and body fat levels in children from different ethnic groups. We examined the need for ethnic- and gender-specific equations for estimating fat free mass (FFM) from BIA in children from different ethnic groups and examined their effects on the assessment of ethnic differences in body fat. Methods Cross-sectional study of children aged 8–10 years in London Primary schools including 325 South Asians, 250 black African-Caribbeans and 289 white Europeans with measurements of height, weight and arm-leg impedance (Z; Bodystat 1500). Total body water was estimated from deuterium dilution and converted to FFM. Multilevel models were used to derive three types of equation {A: FFM = linear combination(height+weight+Z); B: FFM = linear combination(height2/Z); C: FFM = linear combination(height2/Z+weight)}. Results Ethnicity and gender were important predictors of FFM and improved model fit in all equations. The models of best fit were ethnicity and gender specific versions of equation A, followed by equation C; these provided accurate assessments of ethnic differences in FFM and FM. In contrast, the use of generic equations led to underestimation of both the negative South Asian-white European FFM difference and the positive black African-Caribbean-white European FFM difference (by 0.53 kg and by 0.73 kg respectively for equation A). The use of generic equations underestimated the positive South Asian-white European difference in fat mass (FM) and overestimated the positive black African-Caribbean-white European difference in FM (by 4.7% and 10.1% respectively for equation A). Consistent results were observed when the equations were applied to a large external data set. Conclusions Ethnic- and gender-specific equations for predicting FFM from BIA provide better estimates of ethnic differences in FFM and FM in children, while generic equations can misrepresent these ethnic differences

The multiple sex chromosomes of platypus and echidna are not completely identical and several share homology with the avian Z.

BACKGROUND: Sex-determining systems have evolved independently in vertebrates. Placental mammals and marsupials have an XY system, birds have a ZW system. Reptiles and amphibians have different systems, including temperature-dependent sex determination, and XY and ZW systems that differ in origin from birds and placental mammals. Monotremes diverged early in mammalian evolution, just after the mammalian clade diverged from the sauropsid clade. Our previous studies showed that male platypus has five X and five Y chromosomes, no SRY, and DMRT1 on an X chromosome. In order to investigate monotreme sex chromosome evolution, we performed a comparative study of platypus and echidna by chromosome painting and comparative gene mapping. RESULTS: Chromosome painting reveals a meiotic chain of nine sex chromosomes in the male echidna and establishes their order in the chain. Two of those differ from those in the platypus, three of the platypus sex chromosomes differ from those of the echidna and the order of several chromosomes is rearranged. Comparative gene mapping shows that, in addition to bird autosome regions, regions of bird Z chromosomes are homologous to regions in four platypus X chromosomes, that is, X1, X2, X3, X5, and in chromosome Y1. CONCLUSION: Monotreme sex chromosomes are easiest to explain on the hypothesis that autosomes were added sequentially to the translocation chain, with the final additions after platypus and echidna divergence. Genome sequencing and contig anchoring show no homology yet between platypus and therian Xs; thus, monotremes have a unique XY sex chromosome system that shares some homology with the avian Z.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

Folate Deficiency, Hyperhomocysteinemia, Low Urinary Creatinine, and Hypomethylation of Leukocyte DNA Are Risk Factors for Arsenic-Induced Skin Lesions

Background Arsenic methylation relies on folate-dependent one-carbon metabolism and facilitates urinary As elimination. Clinical manifestations of As toxicity vary considerably among individuals and populations, and poor methylation capacity is thought to confer greater susceptibility. Objective After determining that folate deficiency, hyperhomocysteinemia, and low urinary creatinine are associated with reduced As methylation, and that As exposure is associated with increased genomic methylation of leukocyte DNA, we asked whether these factors are associated with As-induced skin lesion risk among Bangladeshi adults. Methods We conducted a nested case–control study of 274 cases who developed lesions 2 years after recruitment, and 274 controls matched to cases for sex, age, and water As. Results The odds ratios and 95% confidence intervals (CIs) for development of skin lesions for participants who had low folate (\u3c 9 nmol/L), hyperhomocysteinemia (men, \u3e 11.4 μmol/L; women, \u3e 10.4 μmol/L), or hypomethylated leukocyte DNA at recruitment (\u3c median) were 1.8 (95% CI, 1.1–2.9), 1.7 (95% CI, 1.1–2.6), and 1.8 (95% CI, 1.2–2.8), respectively. Compared with the subjects in the first quartile, those in the third and fourth quartiles for urinary creatinine had a 0.4-fold decrease in the odds of skin lesions (p \u3c 0.01). Conclusions These results suggest that folate deficiency, hyperhomocysteinemia, and low urinary creatinine, each associated with decreased As methylation, are risk factors for As-induced skin lesions. The increased DNA methylation associated with As exposure previously observed, and confirmed among controls in this study, may be an adaptive change because hypomethylation of leukocyte DNA is associated with increased risk for skin lesions

Folate, Homocysteine, and Arsenic Metabolism in Arsenic-Exposed Individuals in Bangladesh

Chronic exposure to arsenic is occurring throughout South and East Asia due to groundwater contamination of well water. Variability in susceptibility to arsenic toxicity may be related to nutritional status. Arsenic is methylated to monomethylarsonic acid (MMA) and dimethylarsinic acid (DMA) via one-carbon metabolism, a biochemical pathway that is dependent on folate. The majority of one-carbon metabolism methylation reactions are devoted to biosynthesis of creatine, the precursor of creatinine. Our objectives of this cross-sectional study were to characterize the relationships among folate, cobalamin, homocysteine, and arsenic metabolism in Bangladeshi adults. Water arsenic, urinary arsenic, urinary creatinine, plasma folate, cobalamin, and homocysteine were assessed in 1,650 adults; urinary arsenic metabolites were analyzed for a subset of 300 individuals. The percentage of DMA in urine was positively associated with plasma folate (r = 0.14, p = 0.02) and negatively associated with total homocysteine (tHcys; r = −0.14, p = 0.01). Conversely, percent MMA was negatively associated with folate (r = −0.12, p = 0.04) and positively associated with tHcys (r = 0.21, p = 0.0002); percent inorganic arsenic (InAs) was negatively associated with folate (r = −0.12, p = 0.03). Urinary creatinine was positively correlated with percent DMA (r = 0.40 for males, p < 0.0001; 0.25 for females, p = 0.001), and with percent InAs (r = −0.45 for males, p < 0.0001; −0.20 for females, p = 0.01). Collectively, these data suggest that folate, tHcys, and other factors involved in one-carbon metabolism influence arsenic methylation. This may be particularly relevant in Bangladesh, where the prevalence of hyperhomocysteinemia is extremely high

Real-time foot clearance biofeedback to assist gait rehabilitation following stroke: a randomized controlled trial protocol

BACKGROUND: The risk of falling is significantly higher in people with chronic stroke and it is, therefore, important to design interventions to improve mobility and decrease falls risk. Minimum toe clearance (MTC) is the key gait cycle event for predicting tripping-falls because it occurs mid-swing during the walking cycle where forward velocity of the foot is maximum. High forward velocity coupled with low MTC increases the probability of unanticipated foot-ground contacts. Training procedures to increase toe-ground clearance (MTC) have potential, therefore, as a falls-prevention intervention. The aim of this project is to determine whether augmented sensory information via real-time visual biofeedback during gait training can increase MTC. METHODS: Participants will be aged > 18 years, have sustained a single stroke (ischemic or hemorrhagic) at least six months previously, able to walk 50 m independently, and capable of informed consent. Using a secure web-based application (REDCap), 150 participants will be randomly assigned to either no-feedback (Control) or feedback (Experimental) groups; all will receive 10 sessions of treadmill training for up to 10 min at a self-selected speed over 5-6 weeks. The intervention group will receive real-time, visual biofeedback of MTC during training and will be asked to modify their gait pattern to match a required "target" criterion. Biofeedback is continuous for the first six sessions then progressively reduced (faded) across the remaining four sessions. Control participants will walk on the treadmill without biofeedback. Gait assessments are conducted at baseline, immediately following the final training session and then during follow-up, at one, three, and six months. The primary outcome measure is MTC. Monthly falls calendars will also be collected for 12 months from enrolment. DISCUSSION: The project will contribute to understanding how stroke-related changes to sensory and motor processes influence gait biomechanics and associated tripping risk. The research findings will guide our work in gait rehabilitation following stroke and may reduce falls rates. Treadmill training procedures incorporating continuous real-time feedback may need to be modified to accommodate stroke patients who have greater difficulties with treadmill walking. TRIAL REGISTRATION: Australia New Zealand Clinical Trials Registry, ACTRN12617000250336 . Registered on 17 February 2017

Fish Farms at Sea: The Ground Truth from Google Earth

In the face of global overfishing of wild-caught seafood, ocean fish farming has augmented the supply of fresh fish to western markets and become one of the fastest growing global industries. Accurate reporting of quantities of wild-caught fish has been problematic and we questioned whether similar discrepancies in data exist in statistics for farmed fish production. In the Mediterranean Sea, ocean fish farming is prevalent and stationary cages can be seen off the coasts of 16 countries using satellite imagery available through Google Earth. Using this tool, we demonstrate here that a few trained scientists now have the capacity to ground truth farmed fish production data reported by the Mediterranean countries. With Google Earth, we could examine 91% of the Mediterranean coast and count 248 tuna cages (circular cages >40 m diameter) and 20,976 other fish cages within 10 km offshore, the majority of which were off Greece (49%) and Turkey (31%). Combining satellite imagery with assumptions about cage volume, fish density, harvest rates, and seasonal capacity, we make a conservative approximation of ocean-farmed finfish production for 16 Mediterranean countries. Our overall estimate of 225,736 t of farmed finfish (not including tuna) in the Mediterranean Sea in 2006 is only slightly more than the United Nations Food and Agriculture Organization reports. The results demonstrate the reliability of recent FAO farmed fish production statistics for the Mediterranean as well as the promise of Google Earth to collect and ground truth data

Pathogen- and Host-Directed Antileishmanial Effects Mediated by Polyhexanide (PHMB)

BACKGROUND:Cutaneous leishmaniasis (CL) is a neglected tropical disease caused by protozoan parasites of the genus Leishmania. CL causes enormous suffering in many countries worldwide. There is no licensed vaccine against CL, and the chemotherapy options show limited efficacy and high toxicity. Localization of the parasites inside host cells is a barrier to most standard chemo- and immune-based interventions. Hence, novel drugs, which are safe, effective and readily accessible to third-world countries and/or drug delivery technologies for effective CL treatments are desperately needed. METHODOLOGY/PRINCIPAL FINDINGS:Here we evaluated the antileishmanial properties and delivery potential of polyhexamethylene biguanide (PHMB; polyhexanide), a widely used antimicrobial and wound antiseptic, in the Leishmania model. PHMB showed an inherent antileishmanial activity at submicromolar concentrations. Our data revealed that PHMB kills Leishmania major (L. major) via a dual mechanism involving disruption of membrane integrity and selective chromosome condensation and damage. PHMB's DNA binding and host cell entry properties were further exploited to improve the delivery and immunomodulatory activities of unmethylated cytosine-phosphate-guanine oligodeoxynucleotides (CpG ODN). PHMB spontaneously bound CpG ODN, forming stable nanopolyplexes that enhanced uptake of CpG ODN, potentiated antimicrobial killing and reduced host cell toxicity of PHMB. CONCLUSIONS:Given its low cost and long history of safe topical use, PHMB holds promise as a drug for CL therapy and delivery vehicle for nucleic acid immunomodulators