GPX4 regulates cellular necrosis and host resistance in Mycobacterium tuberculosis infection

Cellular necrosis during Mycobacterium tuberculosis (Mtb) infection promotes both immunopathology and bacterial dissemination. Glutathione peroxidase-4 (Gpx4) is an enzyme that plays a critical role in preventing iron-dependent lipid peroxidation–mediated cell death (ferroptosis), a process previously implicated in the necrotic pathology seen in Mtb-infected mice. Here, we document altered GPX4 expression, glutathione levels, and lipid peroxidation in patients with active tuberculosis and assess the role of this pathway in mice genetically deficient in or overexpressing Gpx4. We found that Gpx4-deficient mice infected with Mtb display substantially increased lung necrosis and bacterial burdens, while transgenic mice overexpressing the enzyme show decreased bacterial loads and necrosis. Moreover, Gpx4-deficient macrophages exhibited enhanced necrosis upon Mtb infection in vitro, an outcome suppressed by the lipid peroxidation inhibitor, ferrostatin-1. These findings provide support for the role of ferroptosis in Mtb-induced necrosis and implicate the Gpx4/GSH axis as a target for host-directed therapy of tuberculosis

High grade angiosarcoma arising in fibroadenoma

Primary angiosarcoma of the breast is a rare tumour that account for fewer than 0.05% of all malignant mammary tumours. Angiosarcoma may have an perfidious clinical onset. Radiologic findings are often nonspecific and may appear completely normal in one-third of cases with primary angiosarcoma. The prognosis is usually poor because of the high rates of local recurrence and early development of metastases. Aggressive surgical resection is the mainstay of treatment. The role of adjuvant therapy has not yet been well established

RsaI repetitive DNA in Buffalo Bubalus bubalis representing retrotransposons, conserved in bovids, are part of the functional genes

<p>Abstract</p> <p>Background</p> <p>Repetitive sequences are the major components of the eukaryotic genomes. Association of these repeats with transcribing sequences and their regulation in buffalo <it>Bubalus bubalis </it>has remained largely unresolved.</p> <p>Results</p> <p>We cloned and sequenced <it>RsaI </it>repeat fragments pDp1, pDp2, pDp3, pDp4 of 1331, 651, 603 and 339 base pairs, respectively from the buffalo, <it>Bubalus bubalis</it>. Upon characterization, these fragments were found to represent retrotransposons and part of some functional genes. The resultant clones showed cross hybridization only with buffalo, cattle, goat and sheep genomic DNA. Real Time PCR, detected ~2 × 10⁴copies of pDp1, ~ 3000 copies of pDp2 and pDp3 and ~ 1000 of pDp4 in buffalo, cattle, goat and sheep genomes, respectively. <it>RsaI </it>repeats are transcriptionally active in somatic tissues and spermatozoa. Accordingly, pDp1 showed maximum expression in lung, pDp2 and pDp3 both in Kidney, and pDp4 in ovary. Fluorescence <it>in situ </it>hybridization showed repeats to be distributed all across the chromosomes.</p> <p>Conclusions</p> <p>The data suggest that <it>RsaI </it>repeats have been incorporated into the exonic regions of various transcribing genes, possibly contributing towards the architecture and evolution of the buffalo and related genomes. Prospects of our present work in the context of comparative and functional genomics are highlighted.</p

Epidemiology and interactions of Human Immunodeficiency Virus - 1 and Schistosoma mansoni in sub-Saharan Africa.

Human Immunodeficiency Virus-1/AIDS and Schistosoma mansoni are widespread in sub-Saharan Africa and co-infection occurs commonly. Since the early 1990s, it has been suggested that the two infections may interact and potentiate the effects of each other within co-infected human hosts. Indeed, S. mansoni infection has been suggested to be a risk factor for HIV transmission and progression in Africa. If so, it would follow that mass deworming could have beneficial effects on HIV-1 transmission dynamics. The epidemiology of HIV in African countries is changing, shifting from urban to rural areas where the prevalence of Schistosoma mansoni is high and public health services are deficient. On the other side, the consequent pathogenesis of HIV-1/S. mansoni co-infection remains unknown. Here we give an account of the epidemiology of HIV-1 and S. mansoni, discuss co-infection and possible biological causal relationships between the two infections, and the potential impact of praziquantel treatment on HIV-1 viral loads, CD4+ counts and CD4+/CD8+ ratio. Our review of the available literature indicates that there is evidence to support the hypothesis that S. mansoni infections can influence the replication of the HIV-1, cell-to-cell transmission, as well as increase HIV progression as measured by reduced CD4+ T lymphocytes counts. If so, then deworming of HIV positive individuals living in endemic areas may impact on HIV-1 viral loads and CD4+ T lymphocyte counts.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

The pore structure of Clostridium perfringens epsilon toxin

Epsilon toxin (Etx), a potent pore forming toxin (PFT) produced by Clostridium perfringens, is responsible for the pathogenesis of enterotoxaemia of ruminants and has been suggested to play a role in multiple sclerosis in humans. Etx is a member of the aerolysin family of β-PFTs (aβ-PFTs). While the Etx soluble monomer structure was solved in 2004, Etx pore structure has remained elusive due to the difficulty of isolating the pore complex. Here we show the cryo-electron microscopy structure of Etx pore assembled on the membrane of susceptible cells. The pore structure explains important mutant phenotypes and suggests that the double β-barrel, a common feature of the aβ-PFTs, may be an important structural element in driving efficient pore formation. These insights provide the framework for the development of novel therapeutics to prevent human and animal infections, and are relevant for nano-biotechnology applications

Identification of novel loci associated with gastrointestinal parasite resistance in a Red Maasai x Dorper backcross population

Gastrointestinal (GI) parasitic infection is the main health constraint for small ruminant production, causing loss of weight and/or death. Red Maasai sheep have adapted to a tropical environment where extreme parasite exposure is a constant, especially with highly pathogenic Haemonchus contortus. This breed has been reported to be resistant to gastrointestinal parasite infection, hence it is considered an invaluable resource to study associations between host genetics and resistance. The aim of this study was to identify polymorphisms strongly associated with host resistance in a double backcross population derived from Red Maasai and Dorper sheep using a SNP-based GWAS analysis. The animals that were genotyped represented the most resistant and susceptible individuals based on the tails of phenotypic distribution (10% each) for average faecal egg counts (AVFEC). AVFEC, packed cell volume (AVPCV), and live weight (AVLWT) were adjusted for fixed effects and co-variables, and an association analysis was run using EMMAX. Revised significance levels were calculated using 100,000 permutation tests. The top five significant SNP markers with - log10 p-values >3.794 were observed on five different chromosomes for AVFEC, and BLUPPf90/PostGSf90 results confirmed EMMAX significant regions for this trait. One of these regions included a cluster of significant SNP on chromosome (Chr) 6 not in linkage disequilibrium to each other. This genomic location contains annotated genes involved in cytokine signalling, haemostasis and mucus biosynthesis. Only one association detected on Chr 7 was significant for both AVPCV and AVLWT. The results generated here reveal candidate immune variants for genes involved in differential response to infection and provide additional SNP marker information that has potential to aid selection of resistance to gastrointestinal parasites in sheep of a similar genetic background to the double backcross population

Manson's schistosomiasis in the undernourished mouse: some recent findings

This paper deals with current knowledge of the interrelationships between Schistosoma infection and malnutrition. It emphasizes the relevance of these investigations in the face of dynamic and evolving changes occurring in population diets and changes in the epidemiological patterns of schistosomiasis in endemic countries. The paper further discusses the basis for continuing the studies on this subject and the reasons why it represents a misunderstood association. This review also focuses on the cellular and humoral immune responses in the undernourished mouse model infected with Schistosoma mansoni, with updated information on the immune response in wild-type and iNOS knockout mice concerning soluble egg antigen specific antibodies and kinetics of IFN-&#947;, IL-4, IL-10 and IL-13 cytokines, in the chronic phase of Manson's schistosomiasis. There is indication that schistosome-infected undernourished mice are able to develop a humoral immune response, but antibody titres are much lower than in the control animals. Cytokine production (IFN-&#947;, IL-4, IL-10) is lower in the undernourished mice, but as infection progresses to the chronic phase its kinetics run an antagonistic course when compared to that of well-nourished animals. Marked variation in the secretion of IL-13 (a fibrogenic cytokine) could explain why undernourished mice do not develop liver "pipe-stem" fibrosis described in previous papers on well-nourished animals