2,548 research outputs found
Targeting VIP and PACAP receptor signalling: new therapeutic strategies in multiple sclerosis
MS (multiple sclerosis) is a chronic autoimmune and neurodegenerative pathology of the CNS (central nervous system) affecting approx. 2.5 million people worldwide. Current and emerging DMDs (disease-modifying drugs) predominantly target the immune system. These therapeutic agents slow progression and reduce severity at early stages of MS, but show little activity on the neurodegenerative component of the disease. As the latter determines permanent disability, there is a critical need to pursue alternative modalities. VIP (vasoactive intestinal peptide) and PACAP (pituitary adenylate cyclase-activating peptide) have potent anti-inflammatory and neuroprotective actions, and have shown significant activity in animal inflammatory disease models including the EAE (experimental autoimmune encephalomyelitis) MS model. Thus, their receptors have become candidate targets for inflammatory diseases. Here, we will discuss the immunomodulatory and neuroprotective actions of VIP and PACAP and their signalling pathways, and then extensively review the structureāactivity relationship data and biophysical interaction studies of these peptides with their cognate receptors
Microscopic-observation drug-susceptibility assay for the diagnosis of TB.
BACKGROUND: New diagnostic tools are urgently needed to interrupt the transmission of tuberculosis and multidrug-resistant tuberculosis. Rapid, sensitive detection of tuberculosis and multidrug-resistant tuberculosis in sputum has been demonstrated in proof-of-principle studies of the microscopic-observation drug-susceptibility (MODS) assay, in which broth cultures are examined microscopically to detect characteristic growth. METHODS: In an operational setting in Peru, we investigated the performance of the MODS assay for culture and drug-susceptibility testing in three target groups: unselected patients with suspected tuberculosis, prescreened patients at high risk for tuberculosis or multidrug-resistant tuberculosis, and unselected hospitalized patients infected with the human immunodeficiency virus. We compared the MODS assay head-to-head with two reference methods: automated mycobacterial culture and culture on Lƶwenstein-Jensen medium with the proportion method. RESULTS: Of 3760 sputum samples, 401 (10.7%) yielded cultures positive for Mycobacterium tuberculosis. Sensitivity of detection was 97.8% for MODS culture, 89.0% for automated mycobacterial culture, and 84.0% for Lƶwenstein-Jensen culture (P<0.001); the median time to culture positivity was 7 days, 13 days, and 26 days, respectively (P<0.001), and the median time to the results of susceptibility tests was 7 days, 22 days, and 68 days, respectively. The incremental benefit of a second MODS culture was minimal, particularly in patients at high risk for tuberculosis or multidrug-resistant tuberculosis. Agreement between MODS and the reference standard for susceptibility was 100% for rifampin, 97% for isoniazid, 99% for rifampin and isoniazid (combined results for multidrug resistance), 95% for ethambutol, and 92% for streptomycin (kappa values, 1.0, 0.89, 0.93, 0.71, and 0.72, respectively). CONCLUSIONS: A single MODS culture of a sputum sample offers more rapid and sensitive detection of tuberculosis and multidrug-resistant tuberculosis than the existing gold-standard methods used
Allosteric mechanism of action of the therapeutic anti-IgE antibody omalizumab
Immunoglobulin E and its interactions with receptors FcĻµRI and CD23 play a central role in allergic disease. Omalizumab, a clinically approved therapeutic antibody, inhibits the interaction between IgE and FcĻµRI, preventing mast cell and basophil activation, and blocks IgE binding to CD23 on B cells and antigen-presenting cells. We solved the crystal structure of the complex between an omalizumab-derived Fab and IgE-Fc, with one Fab bound to each CĻµ3 domain. Free IgE-Fc adopts an acutely bent structure, but in the complex it is only partially bent, with large-scale conformational changes in the CĻµ3 domains that inhibit the interaction with FcĻµRI. CD23 binding is inhibited sterically due to overlapping binding sites on each CĻµ3 domain. Studies of omalizumab Fab binding in solution demonstrate the allosteric basis for FcĻµRI inhibition and, together with the structure, reveal how omalizumab may accelerate dissociation of receptor-bound IgE from FcĻµRI, exploiting the intrinsic flexibility and allosteric potential of IgE
Flavour Physics in the Soft Wall Model
We extend the description of flavour that exists in the Randall-Sundrum (RS)
model to the soft wall (SW) model in which the IR brane is removed and the
Higgs is free to propagate in the bulk. It is demonstrated that, like the RS
model, one can generate the hierarchy of fermion masses by localising the
fermions at different locations throughout the space. However, there are two
significant differences. Firstly the possible fermion masses scale down, from
the electroweak scale, less steeply than in the RS model and secondly there now
exists a minimum fermion mass for fermions sitting towards the UV brane. With a
quadratic Higgs VEV, this minimum mass is about fifteen orders of magnitude
lower than the electroweak scale. We derive the gauge propagator and despite
the KK masses scaling as , it is demonstrated that the
coefficients of four fermion operators are not divergent at tree level. FCNC's
amongst kaons and leptons are considered and compared to calculations in the RS
model, with a brane localised Higgs and equivalent levels of tuning. It is
found that since the gauge fermion couplings are slightly more universal and
the SM fermions typically sit slightly further towards the UV brane, the
contributions to observables such as and , from the
exchange of KK gauge fields, are significantly reduced.Comment: 33 pages, 15 figures, 5 tables; v2: references added; v3:
modifications to figures 4,5 and 6. version to appear in JHE
Heavy-meson physics and flavour violation with a single generation
We study flavour-violating processes which involve heavy B- and D-mesons and
are mediated by Kaluza-Klein modes of gauge bosons in a previously suggested
model where three generations of the Standard Model fermions originate from a
single generation in six dimensions. We find the bound on the size R of the
extra spatial dimensions 1/R>3.3 TeV, which arises from the three-body decay
B_s to K mu e. Due to the still too low statistics this bound is much less
stringent than the constraint arising from K to mu e, 1/R>64 TeV, which was
found in a previous work (Frere et al., JHEP, 2003). Nevertheless, we argue
that a clear signature of the model would be an observation of K to mu e and
B_s to K mu e decays without observations of other flavour and lepton number
changing processes at the same precision level.Comment: 15 page
5D UED: Flat and Flavorless
5D UED is not automatically minimally flavor violating. This is due to flavor
asymmetric counter-terms required on the branes. Additionally, there are likely
to be higher dimensional operators which directly contribute to flavor
observables. We document a mostly unsuccessful attempt at utilizing
localization in a flat extra dimension to resolve these flavor constraints
while maintaining KK-parity as a good quantum number. It is unsuccessful
insofar as we seem to be forced to add brane operators in such a way as to
precisely mimic the effects of a double throat warped extra dimension. In the
course of our efforts, we encounter and present solutions to a problem common
to many extra dimensional models in which fields are "doubly localized:"
ultra-light modes. Under scrutiny, this issue seems tied to an intrinsic
tension between maintaining Kaluza-Klein parity and resolving mass hierarchies
via localization.Comment: 27 pages, 6 figure
Violent Crime, Epilepsy, and Traumatic Brain Injury
Jan Volavka discusses new research by Seena Fazel and colleagues that reports increased risk for violent crime among people with traumatic brain injury and epilepsy
Dolutegravir in pregnant mice is associated with increased rates of fetal defects at therapeutic but not at supratherapeutic levels
BACKGROUND: Dolutegravir (DTG) is a preferred regimen for all people with HIV including pregnant women, but its effects on the fetus are not fully understood. Periconceptional exposure to DTG has been associated with increased rates of neural tube defects (NTDs), although it is unknown whether this is a causal relationship. This has led to uncertainty around the use of DTG in women of reproductive potential. METHODS: Pregnant C57BL/6J mice were randomly allocated to control (water), 1x-DTG (2.5Ā mg/kg-peak plasma concentration ~3000Ā ng/ml - therapeutic level), or 5x-DTG (12.5Ā mg/kg-peak plasma concentration ~12,000Ā ng/ml - supratherapeutic level), once daily from gestational day 0.5 until sacrifice. DTG was administered with 50Ā mg/kg tenofovir+33.3Ā mg/kg emtricitabine. Fetal phenotypes were determined, and maternal and fetal folate levels were quantified by mass-spectrometry. FINDINGS: 352 litters (91 control, 150 1x-DTG, 111 5x-DTG) yielding 2776 fetuses (747 control, 1174 1x-DTG, 855 5x-DTG) were assessed. Litter size and viability rates were similar between groups. Fetal and placenta weights were lower in the 1x-DTG vs. control. Placental weight was higher in the 5x-DTG vs. control. Five NTDs were observed, all in the 1x-DTG group. Fetal defects, including microphthalmia, severe edema, and vascular/bleeding defects were more frequent in the 1x-DTG group. In contrast, defect rates in the 5x-DTG were similar to control. Fetal folate levels were similar between control and 1x-DTG, but were significantly higher in the 5x-DTG group. INTERPRETATION: Our findings support a causal relationship of DTG at therapeutic doses with increased risk for fetal defects, including NTDs at a rate that is similar that reported in the Tsepamo study for women exposed to DTG-based ART from conception. The non-monotonic dose-response relationship between DTG and fetal anomalies could explain the previous lack of fetal toxicity findings from pre-clinical DTG studies. The fetal folate levels suggest that DTG is unlikely to be an inhibitor of folate uptake. FUNDING: This project has been funded with Federal funds from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Department of Health and Human Services, under Contract No. HHSN275201800001I
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