Mycobacterium tuberculosis (Mtb) survives and replicates within host macrophages (MΦ) and subverts multiple antimicrobial defense mechanisms. Previously, we reported that lipids shed by pathogenic ...mycobacteria inhibit NPC1, the lysosomal membrane protein deficient in the lysosomal storage disorder Niemann-Pick disease type C (NPC). Inhibition of NPC1 leads to a drop in lysosomal calcium levels, blocking phagosome-lysosome fusion leading to mycobacterial survival. We speculated that the production of specific cell wall lipid(s) that inhibit NPC1 could have been a critical step in the evolution of pathogenicity. We therefore investigated whether lipid extracts from clinical Mtb strains from multiple Mtb lineages, Mtb complex (MTBC) members and non-tubercular mycobacteria (NTM) inhibit the NPC pathway. We report that inhibition of the NPC pathway was present in all clinical isolates from Mtb lineages 1, 2, 3 and 4, Mycobacterium bovis and the NTM, Mycobacterium abscessus and Mycobacterium avium. However, lipid extract from Mycobacterium canettii, which is considered to resemble the common ancestor of the MTBC did not inhibit the NPC1 pathway. We conclude that the evolution of NPC1 inhibitory mycobacterial cell wall lipids evolved early and post divergence from Mycobacterium canettii-related mycobacteria and that this activity contributes significantly to the promotion of disease.
Evidence from high-income countries suggests that childhood trauma is associated with schizophrenia. Studies of childhood trauma and schizophrenia in low and middle income (LMIC) countries are ...limited. This study examined the prevalence of childhood traumatic experiences among cases and controls and the relationship between specific and cumulative childhood traumatic experiences and schizophrenia in a sample in South Africa.
Data were from the Genomics of Schizophrenia in the South African Xhosa people study. Cases with schizophrenia and matched controls were recruited from provincial hospitals and clinics in the Western and Eastern Cape regions in South Africa. Childhood traumatic experiences were measured using the Childhood Trauma Questionnaire (CTQ). Adjusted logistic regression models estimated associations between individual and cumulative childhood traumatic experiences and schizophrenia.
Traumatic experiences were more prevalent among cases than controls. The odds of schizophrenia were 2.44 times higher among those who experienced any trauma than those who reported no traumatic experiences (95% CI 1.77-3.37). The odds of schizophrenia were elevated among those who experienced physical/emotional abuse (OR 1.59, CI 1.28-1.97), neglect (OR 1.39, CI 1.16-1.68), and sexual abuse (OR 1.22, CI 1.03-1.45) compared to those who did not. Cumulative physical/emotional abuse and neglect experiences increased the odds of schizophrenia as a dose-response relationship.
Childhood trauma is common in this population. Among many other benefits, interventions to prevent childhood trauma may contribute to a decreasing occurrence of schizophrenia.
The mobilization of antigen-presenting dendritic cells (DCs) from peripheral tissues to draining lymph nodes drives the initiation of adaptive immune responses. Recent advances have been made in ...understanding how and where DCs enter the lymphatic vasculature and what mechanisms control this process. In this chapter, we highlight these advances. Delineating DC-lymphatic vessel interactions is critical for our fundamental understanding of DC trafficking in states of health and disease and for efforts to manipulate DC mobilization for immunotherapy and vaccination.
Gaucher's disease (GD), an inherited metabolic disorder caused by mutations in the glucocerebrosidase gene (GBA), is the most common lysosomal storage disease. Heterozygous mutations in GBA are a ...major risk factor for Parkinson's disease. GD is divided into three clinical subtypes based on the absence (type 1) or presence (types 2 and 3) of neurological signs. Type 1 GD was the first lysosomal storage disease (LSD) for which enzyme therapy became available, and although infusions of recombinant glucocerebrosidase (GCase) ameliorate the systemic effects of GD, the lack of efficacy for the neurological manifestations, along with the considerable expense and inconvenience of enzyme therapy for patients, renders the search for alternative or complementary therapies paramount. Glucosylceramide and glucosylsphingosine accumulation in the brain leads to massive neuronal loss in patients with neuronopathic GD (nGD) and in nGD mouse models. However, the mode of neuronal death is not known. Here, we show that modulating the receptor-interacting protein kinase-3 (Ripk3) pathway markedly improves neurological and systemic disease in a mouse model of GD. Notably, Ripk3 deficiency substantially improved the clinical course of GD mice, with increased survival and motor coordination and salutary effects on cerebral as well as hepatic injury.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Niemann-Pick disease type C (NPC) is a recessive, neurodegenerative, lysosomal storage disease caused by mutations in either NPC1 or NPC2. The diagnosis is difficult and frequently delayed. ...Ascertainment is likely incomplete because of both these factors and because the full phenotypic spectrum may not have been fully delineated. Given the recent development of a blood-based diagnostic test and the development of potential therapies, understanding the incidence of NPC and defining at-risk patient populations are important.
We evaluated data from four large, massively parallel exome sequencing data sets. Variant sequences were identified and classified as pathogenic or nonpathogenic based on a combination of literature review and bioinformatic analysis. This methodology provided an unbiased approach to determining the allele frequency.
Our data suggest an incidence rate for NPC1 and NPC2 of 1/92,104 and 1/2,858,998, respectively. Evaluation of common NPC1 variants, however, suggests that there may be a late-onset NPC1 phenotype with a markedly higher incidence, on the order of 1/19,000-1/36,000.
We determined a combined incidence of classical NPC of 1/89,229, or 1.12 affected patients per 100,000 conceptions, but predict incomplete ascertainment of a late-onset phenotype of NPC1. This finding strongly supports the need for increased screening of potential patients.
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•First 3D printed optical particle characterisation device.•Quantification of particles across three orders of magnitude.•Distinguishes particles of different sizes.•Optimised through ...a simple and rapid GA.
The integration of particle counters within lab-on-chip (LOC) microfluidic devices creates a range of valuable tools for healthcare such as cell counting, and synthesis applications e.g. materials fabrication. Avoidance of long and/or complex fabrication processes can aid the uptake of these devices, specially within resource-poor societies. We present an additively manufactured microfluidic particle counter. The device features a hydrodynamic focusing chamber to stream the particles past embedded optical fibres for their detection. The intensity of occluded light through the fibre was found to be related to the size of the particles, allowing particles of different sizes to be identified. The signal-to-noise ratio and reproducibility of the particle analysis was optimised to three objectives (pulse magnitude, uniformity and periodicity) via the use of a genetic algorithm (GA). Once optimised the device was able to count particles upto 5.5×104 particles ml−1, and size particles in a mixture.
Cholera toxin (CT) enters and intoxicates host cells after binding cell surface receptors via its B subunit (CTB). We have recently shown that in addition to the previously described binding partner ...ganglioside GM1, CTB binds to fucosylated proteins. Using flow cytometric analysis of primary human jejunal epithelial cells and granulocytes, we now show that CTB binding correlates with expression of the fucosylated Lewis X (LeX) glycan. This binding is competitively blocked by fucosylated oligosaccharides and fucose-binding lectins. CTB binds the LeX glycan in vitro when this moiety is linked to proteins but not to ceramides, and this binding can be blocked by mAb to LeX. Inhibition of glycosphingolipid synthesis or sialylation in GM1-deficient C6 rat glioma cells results in sensitization to CT-mediated intoxication. Finally, CT gavage produces an intact diarrheal response in knockout mice lacking GM1 even after additional reduction of glycosphingolipids. Hence our results show that CT can induce toxicity in the absence of GM1 and support a role for host glycoproteins in CT intoxication. These findings open up new avenues for therapies to block CT action and for design of detoxified enterotoxin-based adjuvants.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Macrophages (Mphis) in the large intestine are crucial effectors of inflammatory bowel disease, but are also essential for homeostasis. It is unclear if these reflect separate populations of Ms or if ...resident Ms change during inflammation. In this study, we identify two subsets of colonic Ms in mice, whose proportions differ in healthy and inflamed intestine. Under resting conditions, most F4/80+ Ms are TLR- CCR2- CX3CR1hi and do not produce TNF-alpha in response to stimulation. The lack of TLR expression is stable, affects all TLRs, and is determined both transcriptionally and posttranscriptionally. During experimental colitis, TLR2+ CCR2+ CX3CR1int Ly6Chi Gr-1+, TNF-alpha-producing Ms come to dominate, and some of these are also present in the normal colon. The TLR2+ and TLR2- subsets are phenotypically distinct and have different turnover kinetics in vivo, and these properties are not influenced by the presence of inflammation. There is preferential CCR2-dependent recruitment of the proinflammatory population during colitis, suggesting they are derived from independent myeloid precursors. CCR2 knockout mice show reduced susceptibility to colitis and lack the recruitment of TLR2+ CCR2+ Gr-1+, TNF-alpha-producing Ms. The balance between proinflammatory and resident Ms in the colon is controlled by CCR2-dependent recruitment mechanisms, which could prove useful as targets for therapy in inflammatory bowel disease.
Insulin receptor (IR) signaling is central to normal metabolic control and is dysregulated in metabolic diseases such as type 2 diabetes. We report here that IR is incorporated into dynamic clusters ...at the plasma membrane, in the cytoplasm and in the nucleus of human hepatocytes and adipocytes. Insulin stimulation promotes further incorporation of IR into these dynamic clusters in insulin-sensitive cells but not in insulin-resistant cells, where both IR accumulation and dynamic behavior are reduced. Treatment of insulin-resistant cells with metformin, a first-line drug used to treat type 2 diabetes, can rescue IR accumulation and the dynamic behavior of these clusters. This rescue is associated with metformin's role in reducing reactive oxygen species that interfere with normal dynamics. These results indicate that changes in the physico-mechanical features of IR clusters contribute to insulin resistance and have implications for improved therapeutic approaches.
Abstract Background Pulmonary hypertension and chronic thromboembolic pulmonary hypertension may develop after a pulmonary embolism event. A ventilation-perfusion scan is recommended as a first-line ...modality for suspected chronic thromboembolic pulmonary hypertension. In this study, we determined the prevalence of pulmonary hypertension following incident pulmonary embolism and the disease monitoring patterns in this population. Methods We conducted a retrospective claims database analysis of incident pulmonary embolism cases (July 1, 2010 to September 30, 2011) and extracted data for 1 year prior to and 2 years post the incident pulmonary embolism event. Data were analyzed for diagnoses and symptoms related to pulmonary hypertension, claims consistent with other heart or lung diseases, diagnostic imaging tests, and time to first diagnostic imaging test post pulmonary embolism. Results Of the 7,068 incident pulmonary embolism patients that met eligibility criteria, 87% had a claim for a pulmonary hypertension–related symptom and 7.6% had a claim for pulmonary hypertension during follow-up. Only 55% of all pulmonary embolism patients had diagnostic procedural claim(s) post pulmonary embolism: echocardiogram, 47%; computed tomographic angiography, 20%; ventilation-perfusion scan, 6%; and right heart catheterization or pulmonary angiography, <1%. The mean time from pulmonary embolism diagnosis to first screening test was 131 days. Conclusions Despite exhibiting pulmonary hypertension–related symptoms, many pulmonary embolism patients did not undergo imaging tests that could diagnose pulmonary hypertension or chronic thromboembolic pulmonary hypertension. This study suggests that physician education regarding the risk of pulmonary hypertension and chronic thromboembolic pulmonary hypertension after pulmonary embolism may need to be improved.
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