Mongersen, an oral SMAD7 antisense oligonucleotide, and crohn's disease

Background Crohn's disease-related inflammation is characterized by reduced activity of the immunosuppressive cytokine transforming growth factor β1 (TGF-β1) due to high levels of SMAD7, an inhibitor of TGF-β1 signaling. Preclinical studies and a phase 1 study have shown that an oral SMAD7 antisense oligonucleotide, mongersen, targets ileal and colonic SMAD7. Methods In a double-blind, placebo-controlled, phase 2 trial, we evaluated the efficacy of mongersen for the treatment of persons with active Crohn's disease. Patients were randomly assigned to receive 10, 40, or 160 mg of mongersen or placebo per day for 2 weeks. The primary outcomes were clinical remission at day 15, defined as a Crohn's Disease Activity Index (CDAI) score of less than 150, with maintenance of remission for at least 2 weeks, and the safety of mongersen treatment. A secondary outcome was clinical response (defined as a reduction of 100 points or more in the CDAI score) at day 28. Results The proportions of patients who reached the primary end point were 55% and 65% for the 40-mg and 160-mg mongersen groups, respectively, as compared with 10% for the placebo group (P<0.001). There was no significant difference in the percentage of participants reaching clinical remission between the 10-mg group (12%) and the placebo group. The rate of clinical response was significantly greater among patients receiving 10 mg (37%), 40 mg (58%), or 160 mg (72%) of mongersen than among those receiving placebo (17%) (P = 0.04, P<0.001, and P<0.001, respectively). Most adverse events were related to complications and symptoms of Crohn's disease. Conclusions We found that study participants with Crohn's disease who received mongersen had significantly higher rates of remission and clinical response than those who received placebo

Age-related changes in global motion coherence: conflicting haemodynamic and perceptual responses

Our aim was to use both behavioural and neuroimaging data to identify indicators of perceptual decline in motion processing. We employed a global motion coherence task and functional Near Infrared Spectroscopy (fNIRS). Healthy adults (n = 72, 18-85) were recruited into the following groups: young (n = 28, mean age = 28), middle-aged (n = 22, mean age = 50), and older adults (n = 23, mean age = 70). Participants were assessed on their motion coherence thresholds at 3 different speeds using a psychophysical design. As expected, we report age group differences in motion processing as demonstrated by higher motion coherence thresholds in older adults. Crucially, we add correlational data showing that global motion perception declines linearly as a function of age. The associated fNIRS recordings provide a clear physiological correlate of global motion perception. The crux of this study lies in the robust linear correlation between age and haemodynamic response for both measures of oxygenation. We hypothesise that there is an increase in neural recruitment, necessitating an increase in metabolic need and blood flow, which presents as a higher oxygenated haemoglobin response. We report age-related changes in motion perception with poorer behavioural performance (high motion coherence thresholds) associated with an increased haemodynamic response

Intravenous apoptotic spleen cell infusion induces a TGF-beta-dependent regulatory T-cell expansion.: Apoptosis and regulatory T cells

International audienceApoptotic leukocytes are endowed with immunomodulatory properties that can be used to enhance hematopoietic engraftment and prevent graft-versus-host disease (GvHD). This apoptotic cell-induced tolerogenic effect is mediated by host macrophages and not recipient dendritic cells or donor phagocytes present in the bone marrow graft as evidenced by selective cell depletion and trafficking experiments. Furthermore, apoptotic cell infusion is associated with TGF-beta-dependent donor CD4+CD25+ T-cell expansion. Such cells have a regulatory phenotype (CD62L(high) and intracellular CTLA-4+), express high levels of forkhead-box transcription factor p3 (Foxp3) mRNA and exert ex vivo suppressive activity through a cell-to-cell contact mechanism. In vivo CD25 depletion after apoptotic cell infusion prevents the apoptotic cell-induced beneficial effects on engraftment and GvHD occurrence. This highlights the role of regulatory T cells in the tolerogenic effect of apoptotic cell infusion. This novel association between apoptosis and regulatory T-cell expansion may also contribute to preventing deleterious autoimmune responses during normal turnover

A Fluorescent Glycolipid-Binding Peptide Probe Traces Cholesterol Dependent Microdomain-Derived Trafficking Pathways

10.1371/journal.pone.0002933PLoS ONE38

Effects of Noise Bandwidth and Amplitude Modulation on Masking in Frog Auditory Midbrain Neurons

Natural auditory scenes such as frog choruses consist of multiple sound sources (i.e., individual vocalizing males) producing sounds that overlap extensively in time and spectrum, often in the presence of other biotic and abiotic background noise. Detection of a signal in such environments is challenging, but it is facilitated when the noise shares common amplitude modulations across a wide frequency range, due to a phenomenon called comodulation masking release (CMR). Here, we examined how properties of the background noise, such as its bandwidth and amplitude modulation, influence the detection threshold of a target sound (pulsed amplitude modulated tones) by single neurons in the frog auditory midbrain. We found that for both modulated and unmodulated masking noise, masking was generally stronger with increasing bandwidth, but it was weakened for the widest bandwidths. Masking was less for modulated noise than for unmodulated noise for all bandwidths. However, responses were heterogeneous, and only for a subpopulation of neurons the detection of the probe was facilitated when the bandwidth of the modulated masker was increased beyond a certain bandwidth – such neurons might contribute to CMR. We observed evidence that suggests that the dips in the noise amplitude are exploited by TS neurons, and observed strong responses to target signals occurring during such dips. However, the interactions between the probe and masker responses were nonlinear, and other mechanisms, e.g., selective suppression of the response to the noise, may also be involved in the masking release

Rapid Dissemination of SIV Follows Multisite Entry after Rectal Inoculation

Receptive ano-rectal intercourse is a major cause of HIV infection in men having sex with men and in heterosexuals. Current knowledge of the mechanisms of entry and dissemination during HIV rectal transmission is scarce and does not allow the development of preventive strategies. We investigated the early steps of rectal infection in rhesus macaques inoculated with the pathogenic isolate SIVmac251 and necropsied four hours to nine days later. All macaques were positive for SIV. Control macaques inoculated with heat-inactivated virus were consistently negative for SIV. SIV DNA was detected in the rectum as early as four hours post infection by nested PCR for gag in many laser-microdissected samples of lymphoid aggregates and lamina propria but never in follicle-associated epithelium. Scarce SIV antigen positive cells were observed by immunohistofluorescence in the rectum, among intraepithelial and lamina propria cells as well as in clusters in lymphoid aggregates, four hours post infection and onwards. These cells were T cells and non-T cells that were not epithelial cells, CD68+ macrophages, DC-SIGN+ cells or fascin+ dendritic cells. DC-SIGN+ cells carried infectious virus. Detection of Env singly spliced mRNA in the mucosa by nested RT-PCR indicated ongoing viral replication. Strikingly, four hours post infection colic lymph nodes were also infected in all macaques as either SIV DNA or infectious virus was recovered. Rapid SIV entry and dissemination is consistent with trans-epithelial transport. Virions appear to cross the follicle-associated epithelium, and also the digestive epithelium. Viral replication could however be more efficient in lymphoid aggregates. The initial sequence of events differs from both vaginal and oral infections, which implies that prevention strategies for rectal transmission will have to be specific. Microbicides will need to protect both digestive and follicle-associated epithelia. Vaccines will need to induce immunity in lymph nodes as well as in the rectum

A Review of Translational Magnetic Resonance Imaging in Human and Rodent Experimental Models of Small Vessel Disease

Cerebral small vessel disease (SVD) is a major health burden, yet the pathophysiology remains poorly understood with no effective treatment. Since much of SVD develops silently and insidiously, non-invasive neuroimaging such as MRI is fundamental to detecting and understanding SVD in humans. Several relevant SVD rodent models are established for which MRI can monitor in vivo changes over time prior to histological examination. Here, we critically review the MRI methods pertaining to salient rodent models and evaluate synergies with human SVD MRI methods. We found few relevant publications, but argue there is considerable scope for greater use of MRI in rodent models, and opportunities for harmonisation of the rodent-human methods to increase the translational potential of models to understand SVD in humans. We summarise current MR techniques used in SVD research, provide recommendations and examples and highlight practicalities for use of MRI SVD imaging protocols in pre-selected, relevant rodent models.</p

A search for rare B → Dμ+μ− decays

A search for rare B→Dμ+μ− decays is performed using proton-proton collision data collected by the LHCb experiment, corresponding to an integrated luminosity of 9 fb−1. No significant signals are observed in the non-resonant μ+μ− modes, and upper limits of B(B0→D ̄ ̄ ̄ ̄0μ+μ−)&lt;5.1×10−8, B(B+→D+sμ+μ−)&lt;3.2×10−8, B(B0s→D ̄ ̄ ̄ ̄0μ+μ−)&lt;1.6×10−7 and fc/fu⋅B(B+c→D+sμ+μ−)&lt;9.6×10−8 are set at the 95\% confidence level, where fc and fu are the fragmentation fractions of a B meson with a c and u quark respectively in proton-proton collisions. Each result is either the first such measurement or an improvement by three orders of magnitude on an existing limit. Separate upper limits are calculated when the muon pair originates from a J/ψ→μ+μ− decay. The branching fraction of B+c→D+sJ/ψ multiplied by the fragmentation-fraction ratio is measured to be fc/fu⋅B(B+c→D+sJ/ψ)=(1.63±0.15±0.13)×10−5, where the first uncertainty is statistical and the second systematic