Differences in peripheral noradrenergic function among actively drinking and abstinent alcohol-dependent individuals.

We examined whether excessive alcohol consumption was related to changes in plasma levels of noradrenaline (NA) and whether these changes recover following abstinence. We also explored whether there were differences in NA levels between Type I and Type II alcoholics and controls during active drinking and abstinence. Plasma concentrations of NA were determined in (1) 27 Caucasian men with alcohol dependence who were regularly drinking (active drinkers) within 24 hours of hospitalization, (2) 29 Caucasian alcohol-dependent men who were in remission (abstinent for a minimum of three months), and (3) 28 race- and gender-matched healthy controls. NA concentrations were significantly higher in actively drinking alcohol-dependent subjects compared to those in remission and controls. While Type I and Type II alcoholic individuals differed across clinical measures, NA levels were similar in the two subtypes. Both subtypes showed an elevation in NA levels during active drinking compared to controls, but NA levels did not differ between the two subtypes and controls during remission. The findings indicate that chronic exposure to alcohol may lead to disturbances in NA activity that may manifest in early abstinence. However, the changes in NA activity appears to normalize after a longer period of abstinence. Alterations in NA activity do not seem to be specific for Type I or Type II subtypes of alcoholism

Comprehensive genome analysis of 203 genomes provides structural genomics with new insights into protein family space

We present an analysis of 203 completed genomes in the Gene3D resource (including 17 eukaryotes), which demonstrates that the number of protein families is continually expanding over time and that singleton-sequences appear to be an intrinsic part of the genomes. A significant proportion of the proteomes can be assigned to fewer than 6000 well-characterized domain families with the remaining domain-like regions belonging to a much larger number of small uncharacterized families that are largely species specific. Our comprehensive domain annotation of 203 genomes enables us to provide more accurate estimates of the number of multi-domain proteins found in the three kingdoms of life than previous calculations. We find that 67% of eukaryotic sequences are multi-domain compared with 56% of sequences in prokaryotes. By measuring the domain coverage of genome sequences, we show that the structural genomics initiatives should aim to provide structures for less than a thousand structurally uncharacterized Pfam families to achieve reasonable structural annotation of the genomes. However, in large families, additional structures should be determined as these would reveal more about the evolution of the family and enable a greater understanding of how function evolves

Cavopulmonary assist: Long-term reversal of the Fontan paradox

Objective Fontan circulatory inefficiency can be addressed by replacing the missing subpulmonary power source to reverse the Fontan paradox. An implantable cavopulmonary assist device is described that will simultaneously reduce systemic venous pressure and increase pulmonary arterial pressure, improving preload and cardiac output, in a univentricular Fontan circulation on a long-term basis. Methods A rotary blood pump that was based on the von Karman viscous pump was designed for implantation into the total cavopulmonary connection (TCPC). It will impart modest pressure energy to augment Fontan flow without risk of obstruction. In the event of rotational failure, it is designed to default to a passive flow diverter. Pressure-flow performance was characterized in vitro in a Fontan mock circulatory loop with blood analog. Results The pump performed through the fully specified operating range, augmenting flow in all 4 directions of the TCPC. Pressure rise of 6 to 8 mm Hg was readily achieved, ranging to 14 mm Hg at highest speed (5600 rpm). Performance was consistent across a wide range of cardiac outputs. In stalled condition (0 rpm), there was no discernible pressure loss across the TCPC. Conclusions A blood pump technology is described that can reverse the Fontan paradox and may permit a surgical strategy of long-term biventricular maintenance of a univentricular Fontan circulation. The technology is intended for Fontan failure in which right-sided circulatory inefficiencies predominate and ventricular systolic function is preserved. It may also apply before clinical Fontan failure as health maintenance to preempt the progression of Fontan disease

Starspots and relativity: Applied Doppler imaging for the Gravity Probe B mission

We present Doppler images and surface differential rotation measurements for the primary of the RS CVn binary IM Pegasi, the guide star for the Gravity Probe B experiment. The data used is a subset of that taken during optical support of the mission and was obtained almost nightly over a near three year period from the Automatic Spectroscopic Telescope operated by Tennessee State University. Using the technique of least-squares deconvolution to increase the signal-to-noise ratio of the data, we have reconstructed 31 maximum entropy Doppler images of the star. The images show that the spot features are relatively stable for over a year (and possibly longer) with both a polar spot and lower latitude features. The most intense features are located on the side facing the secondary. In addition, we have incorporated a solar-like differential rotation law into the imaging process to determine the level of surface differential rotation for IM Peg for 22 epochs. A weighted least-squares average of the measurements gives a surface shear of 0.0142 ± 0.0007 rad/d, meaning that the equator takes ∼440 ± 20 days to lap the poles. Although the level of surface differential rotation was shown to vary over the period of the observations, this may indicate an underestimate in the errors of the method rather than any temporal evolution in the differential rotation

The implications of outcome truncation in reproductive medicine RCTs: a simulation platform for trialists and simulation study.

From Europe PMC via Jisc Publications RouterHistory: ppub 2021-08-01, epub 2021-08-06Publication status: PublishedFunder: Wellcome Trust; Grant(s): 204796/Z/16/ZBackgroundRandomised controlled trials in reproductive medicine are often subject to outcome truncation, where the study outcomes are only defined in a subset of the randomised cohort. Examples include birthweight (measurable only in the subgroup of participants who give birth) and miscarriage (which can only occur in participants who become pregnant). These outcomes are typically analysed by making a comparison between treatment arms within the subgroup (for example, comparing birthweights in the subgroup who gave birth or miscarriages in the subgroup who became pregnant). However, this approach does not represent a randomised comparison when treatment influences the probability of being observed (i.e. survival). The practical implications of this for the design and interpretation of reproductive trials are unclear however.MethodsWe developed a simulation platform to investigate the implications of outcome truncation for reproductive medicine trials. We used this to perform a simulation study, in which we considered the bias, type 1 error, coverage, and precision of standard statistical analyses for truncated continuous and binary outcomes. Simulation settings were informed by published assisted reproduction trials.ResultsIncreasing treatment effect on the intermediate variable, strength of confounding between the intermediate and outcome variables, and the presence of an interaction between treatment and confounder were found to adversely affect performance. However, within parameter ranges we would consider to be more realistic, the adverse effects were generally not drastic. For binary outcomes, the study highlighted that outcome truncation could cause separation in smaller studies, where none or all of the participants in a study arm experience the outcome event. This was found to have severe consequences for inferences.ConclusionWe have provided a simulation platform that can be used by researchers in the design and interpretation of reproductive medicine trials subject to outcome truncation and have used this to conduct a simulation study. The study highlights several key factors which trialists in the field should consider carefully to protect against erroneous inferences. Standard analyses of truncated binary outcomes in small studies may be highly biassed, and it remains to identify suitable approaches for analysing data in this context

Gene3D: modelling protein structure, function and evolution

The Gene3D release 4 database and web portal () provide a combined structural, functional and evolutionary view of the protein world. It is focussed on providing structural annotation for protein sequences without structural representatives—including the complete proteome sets of over 240 different species. The protein sequences have also been clustered into whole-chain families so as to aid functional prediction. The structural annotation is generated using HMM models based on the CATH domain families; CATH is a repository for manually deduced protein domains. Amongst the changes from the last publication are: the addition of over 100 genomes and the UniProt sequence database, domain data from Pfam, metabolic pathway and functional data from COGs, KEGG and GO, and protein–protein interaction data from MINT and BIND. The website has been rebuilt to allow more sophisticated querying and the data returned is presented in a clearer format with greater functionality. Furthermore, all data can be downloaded in a simple XML format, allowing users to carry out complex investigations at their own computers

Meta-analysis of drug-related deaths soon after release from prison

Aims The transition from prison back into the community is particularly hazardous for drug-using offenders whose tolerance for heroin has been reduced by imprisonment. Studies have indicated an increased risk of drug-related death soon after release from prison, particularly in the first 2 weeks. For precise, up-to-date understanding of these risks, a meta-analysis was conducted on the risk of drug-related death in weeks 1 + 2 and 3 + 4 compared with later 2-week periods in the first 12 weeks after release from prison. Methods English-language studies were identified that followed up adult prisoners for mortality from time of index release for at least 12 weeks. Six studies from six prison systems met the inclusion criteria and relevant data were extracted independently. Results These studies contributed a total of 69 093 person-years and 1033 deaths in the first 12 weeks after release, of which 612 were drug-related. A three- to eightfold increased risk of drug-related death was found when comparing weeks 1 + 2 with weeks 3–12, with notable heterogeneity between countries: United Kingdom, 7.5 (95% CI: 5.7–9.9); Australia, 4.0 (95% CI: 3.4–4.8); Washington State, USA, 8.4 (95% CI: 5.0–14.2) and New Mexico State, USA, 3.1 (95% CI: 1.3–7.1). Comparing weeks 3 + 4 with weeks 5–12, the pooled relative risk was: 1.7 (95% CI: 1.3–2.2). Conclusions These findings confirm that there is an increased risk of drug-related death during the first 2 weeks after release from prison and that the risk remains elevated up to at least the fourth week

Simulation-Based Design of Bicuspidization of the Aortic Valve

Objective: Severe congenital aortic valve pathology in the growing patient remains a challenging clinical scenario. Bicuspidization of the diseased aortic valve has proven to be a promising repair technique with acceptable durability. However, most understanding of the procedure is empirical and retrospective. This work seeks to design the optimal gross morphology associated with surgical bicuspidization with simulations, based on the hypothesis that modifications to the free edge length cause or relieve stenosis. Methods: Model bicuspid valves were constructed with varying free edge lengths and gross morphology. Fluid-structure interaction simulations were conducted in a single patient-specific model geometry. The models were evaluated for primary targets of stenosis and regurgitation. Secondary targets were assessed and included qualitative hemodynamics, geometric height, effective height, orifice area and prolapse. Results: Stenosis decreased with increasing free edge length and was pronounced with free edge length less than or equal to 1.3 times the annular diameter d. With free edge length 1.5d or greater, no stenosis occurred. All models were free of regurgitation. Substantial prolapse occurred with free edge length greater than or equal to 1.7d. Conclusions: Free edge length greater than or equal to 1.5d was required to avoid aortic stenosis in simulations. Cases with free edge length greater than or equal to 1.7d showed excessive prolapse and other changes in gross morphology. Cases with free edge length 1.5-1.6d have a total free edge length approximately equal to the annular circumference and appeared optimal. These effects should be studied in vitro and in animal studies

The N-terminal ricin propeptide influences the fate of ricin A-chain in tobacco protoplasts.

The plant toxin ricin is synthesized in castor bean seeds as an endoplasmic reticulum (ER)-targeted precursor. Removal of the signal peptide generates proricin in which the mature A- and B-chains are joined by an intervening propeptide and a 9-residue propeptide persists at the N terminus. The two propeptides are ultimately removed in protein storage vacuoles, where ricin accumulates. Here we have demonstrated that the N-terminal propeptide of proricin acts as a nonspecific spacer to ensure efficient ER import and glycosylation. Indeed, when absent from the N terminus of ricin A-chain, the non-imported material remained tethered to the cytosolic face of the ER membrane, presumably by the signal peptide. This species appeared toxic to ribosomes. The propeptide does not, however, influence catalytic activity per se or the vacuolar targeting of proricin or the rate of retrotranslocation/degradation of A-chain in the cytosol. The likely implications of these findings to the survival of the toxin-producing tissue are discussed

Quantization of Nonstandard Hamiltonian Systems

The quantization of classical theories that admit more than one Hamiltonian description is considered. This is done from a geometrical viewpoint, both at the quantization level (geometric quantization) and at the level of the dynamics of the quantum theory. A spin-1/2 system is taken as an example in which all the steps can be completed. It is shown that the geometry of the quantum theory imposes restrictions on the physically allowed nonstandard quantum theories.Comment: Revtex file, 23 pages, no figure