Anti-Insulin Receptor Autoantibodies Are Not Required for Type 2 Diabetes Pathogenesis in NZL/Lt Mice, a New Zealand Obese (NZO)-Derived Mouse Strain

The New Zealand obese (NZO) mouse strain shares with the related New Zealand black (NZB) strain a number of immunophenotypic traits. Among these is a high proportion of B-1 B lymphocytes, a subset associated with autoantibody production. Approximately 50% of NZO/HlLt males develop a chronic insulin-resistant type 2 diabetes syndrome associated with 2 unusual features: the presence of B lymphocyte–enriched peri-insular infiltrates and the development of anti-insulin receptor autoantibodies (AIRAs). To establish the potential pathogenic contributions ofBlymphocytes and AIRAs in this model, a disrupted immunoglobulin heavy chain gene (Igh-6) congenic on the NZB/BlJ background was backcrossed 4 generations into the NZO/HlLt background and was then intercrossed to produce mice that initially segregated for wild-type versus the mutant Igh-6 allele and thus permitted comparison of syndrome development. A new flow cytometric assay (AIRA binding to transfected Chinese hamster ovary cells stably expressing mouse insulin receptor) showed IgM and IgG subclass AIRAs in serum from Igh-6 intact males, but not in Igh6null male serum. However, the absence of B lymphocytes and antibodies distinguishing mutant from wild-type males failed to significantly affect diabetes-free survival. The Igh6nullmales gained weight less rapidly than wild-type males, probably accounting for a retardation, but not prevention, of hyperglycemia. Thus, AIRA and the Blymphocyte component of the peri-insulitis in chronic diabetics were not essential either to development of insulin resistance or to eventual pancreatic beta cell failure and loss. A new substrain, designated NZL, was generated by inbreeding Igh-6 wild-type segregants. Currently at the F10 generation, NZL mice exhibit the same juvenile-onset obesity as NZO/HlLt males, but develop type 2 diabetes at a higher frequency (> 80%). Also, unlike NZO/HlLt mice that are difficult to breed, the NZL/Lt strain breeds well and thus offers clear advantages to obesity/diabetes researchers

Stimulant Reduction Intervention using Dosed Exercise (STRIDE) - CTN 0037: Study protocol for a randomized controlled trial

<p>Abstract</p> <p>Background</p> <p>There is a need for novel approaches to the treatment of stimulant abuse and dependence. Clinical data examining the use of exercise as a treatment for the abuse of nicotine, alcohol, and other substances suggest that exercise may be a beneficial treatment for stimulant abuse, with direct effects on decreased use and craving. In addition, exercise has the potential to improve other health domains that may be adversely affected by stimulant use or its treatment, such as sleep disturbance, cognitive function, mood, weight gain, quality of life, and anhedonia, since it has been shown to improve many of these domains in a number of other clinical disorders. Furthermore, neurobiological evidence provides plausible mechanisms by which exercise could positively affect treatment outcomes. The current manuscript presents the rationale, design considerations, and study design of the National Institute on Drug Abuse (NIDA) Clinical Trials Network (CTN) CTN-0037 Stimulant Reduction Intervention using Dosed Exercise (STRIDE) study.</p> <p>Methods/Design</p> <p>STRIDE is a multisite randomized clinical trial that compares exercise to health education as potential treatments for stimulant abuse or dependence. This study will evaluate individuals diagnosed with stimulant abuse or dependence who are receiving treatment in a residential setting. Three hundred and thirty eligible and interested participants who provide informed consent will be randomized to one of two treatment arms: Vigorous Intensity High Dose Exercise Augmentation (DEI) or Health Education Intervention Augmentation (HEI). Both groups will receive TAU (i.e., usual care). The treatment arms are structured such that the quantity of visits is similar to allow for equivalent contact between groups. In both arms, participants will begin with supervised sessions 3 times per week during the 12-week acute phase of the study. Supervised sessions will be conducted as one-on-one (i.e., individual) sessions, although other participants may be exercising at the same time. Following the 12-week acute phase, participants will begin a 6-month continuation phase during which time they will attend one weekly supervised DEI or HEI session.</p> <p>Clinical Trials Registry</p> <p>ClinicalTrials.gov, <a href="http://www.clinicaltrials.gov/ct2/show/NCT01141608">NCT01141608</a></p> <p><url>http://clinicaltrials.gov/ct2/show/NCT01141608?term=Stimulant+Reduction+Intervention+using+Dosed+Exercise&rank=1</url></p

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Search for gravitational-lensing signatures in the full third observing run of the LIGO-Virgo network

Gravitational lensing by massive objects along the line of sight to the source causes distortions of gravitational wave-signals; such distortions may reveal information about fundamental physics, cosmology and astrophysics. In this work, we have extended the search for lensing signatures to all binary black hole events from the third observing run of the LIGO--Virgo network. We search for repeated signals from strong lensing by 1) performing targeted searches for subthreshold signals, 2) calculating the degree of overlap amongst the intrinsic parameters and sky location of pairs of signals, 3) comparing the similarities of the spectrograms amongst pairs of signals, and 4) performing dual-signal Bayesian analysis that takes into account selection effects and astrophysical knowledge. We also search for distortions to the gravitational waveform caused by 1) frequency-independent phase shifts in strongly lensed images, and 2) frequency-dependent modulation of the amplitude and phase due to point masses. None of these searches yields significant evidence for lensing. Finally, we use the non-detection of gravitational-wave lensing to constrain the lensing rate based on the latest merger-rate estimates and the fraction of dark matter composed of compact objects

Search for eccentric black hole coalescences during the third observing run of LIGO and Virgo

Despite the growing number of confident binary black hole coalescences observed through gravitational waves so far, the astrophysical origin of these binaries remains uncertain. Orbital eccentricity is one of the clearest tracers of binary formation channels. Identifying binary eccentricity, however, remains challenging due to the limited availability of gravitational waveforms that include effects of eccentricity. Here, we present observational results for a waveform-independent search sensitive to eccentric black hole coalescences, covering the third observing run (O3) of the LIGO and Virgo detectors. We identified no new high-significance candidates beyond those that were already identified with searches focusing on quasi-circular binaries. We determine the sensitivity of our search to high-mass (total mass M&gt;70 M⊙) binaries covering eccentricities up to 0.3 at 15 Hz orbital frequency, and use this to compare model predictions to search results. Assuming all detections are indeed quasi-circular, for our fiducial population model, we place an upper limit for the merger rate density of high-mass binaries with eccentricities 0&lt;e≤0.3 at 0.33 Gpc−3 yr−1 at 90\% confidence level

Ultralight vector dark matter search using data from the KAGRA O3GK run

Among the various candidates for dark matter (DM), ultralight vector DM can be probed by laser interferometric gravitational wave detectors through the measurement of oscillating length changes in the arm cavities. In this context, KAGRA has a unique feature due to differing compositions of its mirrors, enhancing the signal of vector DM in the length change in the auxiliary channels. Here we present the result of a search for U(1)B−L gauge boson DM using the KAGRA data from auxiliary length channels during the first joint observation run together with GEO600. By applying our search pipeline, which takes into account the stochastic nature of ultralight DM, upper bounds on the coupling strength between the U(1)B−L gauge boson and ordinary matter are obtained for a range of DM masses. While our constraints are less stringent than those derived from previous experiments, this study demonstrates the applicability of our method to the lower-mass vector DM search, which is made difficult in this measurement by the short observation time compared to the auto-correlation time scale of DM

Monoterpenoid extract of sage (Salvia lavandulaefolia) with cholinesterase inhibiting properties improves cognitive performance and mood in healthy adults

Extracts of sage (Salvia officinalis/lavandulaefolia) with terpenoid constituents have previously been shown to inhibit cholinesterase and improve cognitive function. The current study combined an in vitro investigation of the cholinesterase inhibitory properties and phytochemical constituents of a S. lavandulaefolia essential oil, with a double-blind, placebo-controlled, balanced crossover study assessing the effects of a single dose on cognitive performance and mood. In this latter investigation 36 healthy participants received capsules containing either 50 µL of the essential oil or placebo on separate occasions, 7 days apart. Cognitive function was assessed using a selection of computerized memory and attention tasks and the Cognitive Demand Battery before the treatment and 1-h and 4-h post-dose. The essential oil was a potent inhibitor of human acetylcholinesterase (AChE) and consisted almost exclusively of monoterpenoids. Oral consumption lead to improved performance of secondary memory and attention tasks, most notably at the 1-h post-dose testing session, and reduced mental fatigue and increased alertness which were more pronounced 4-h post-dose. These results extend previous observations of improved cognitive performance and mood following AChE inhibitory sage extracts and suggest that the ability of well-tolerated terpenoid-containing extracts to beneficially modulate cholinergic function and cognitive performance deserves further attention

Re-evaluating the Na+ conductance of adult rat alveolar type II pneumocytes: evidence for the involvement of cGMP-activated cation channels

Alveolar epithelial type II pneumocytes were isolated and purified from adult rat lung by elastase digestion and differential adhesion, and cultured in serum-free medium for ∼2 days on glass coverslips for subsequent patch-clamp studies employing symmetrical sodium isethionate solutions.Whole-cell Na+ currents exhibited essentially linear current-voltage relationships which were mildly inhibited (by ∼25 %) by 10 μm amiloride. In contrast, 1 mm Zn2+ inhibited the currents by ∼55 % with an IC50 of ∼134 μm and maximal blockade achieved between 5 and 10 mm. The effects of Zn2+ and amiloride were additive, and independent of the order of blocker addition.Gd2+, Zn2+ and La3+ at 10 mm were all effective at rapidly, reversibly and significantly blocking the amiloride-insensitive currents by ∼60 %. In contrast, Ni2+ was a very weak inhibitor (30 % inhibition at 10 mm).Pimozide (10 μm) caused inhibition of whole-cell cation conductance by ∼55 %. The inhibitory effect of pimozide was concentration dependent with an IC50 of ∼1 μm and was maximally effective between 10 and 30 μm. Sequential addition of Zn2+ and pimozide, in either order, revealed no overlapping inhibitory effect on the amiloride-insensitive conductance, and supported the notion that the Zn2+- and pimozide-sensitive currents are identical.The amiloride-insensitive, Zn2+-blockable conductance was characterised by a Na+/K+ permeability ratio (PNa/PK) of 0.73 ± 0.02.8Br-cGMP (100 μm), a membrane-permeable analogue of cGMP, evoked a robust activation of whole-cell cation conductance to 220 % of control. This activation was apparent in either the absence or the presence of 10 μm amiloride, but was completely abolished in the presence of Zn2+.These data support the in vivo and in situ observations of a substantial amiloride-resistant Na+ conductance, demonstrate directly that cyclic nucleotide-gated non-selective cation channels are functionally expressed in alveolar epithelial type II cells, and suggest that these channels may contribute to the fluid-reabsorptive driving force in adult lung