Differential expression of α-synuclein splice variants in the brain of alcohol misusers: Influence of genotype

Background: Chronic alcohol misuse causes damage in the central nervous system that may lead to tolerance, craving and dependence. These behavioural changes are likely the result of cellular adaptations that include changes in gene expression. α-Synuclein is involved in the dopaminergic reward pathway, where it regulates dopamine synthesis and release. Previous studies have found that the gene for α-synuclein, SNCA, is differentially expressed in alcohol misusers. Methods: The present study measured the expression of three α-synuclein variants, SNCA-140, SNCA-112, and SNCA-115 in the prefrontal cortex of controls and alcohol misusers with and without cirrhosis of the liver. In addition, eight SNPs located in the 5'- and 3'-UTRs were genotyped in a Caucasian population of 125 controls and 115 alcohol misusers. Results: The expression of SNCA-140 and SNCA-112 was significantly lower in alcohol misusers with cirrhosis than in controls. However, SNCA-115 expression was significantly greater in alcohol misusers with cirrhosis than in controls. Allele and genotype frequencies differed significantly between alcohol misusers and controls for three SNPs, rs356221, rs356219 and rs2736995. Two SNPs, rs356221 and rs356219, were in high linkage disequilibrium. There was no increased risk of alcoholism associated with specific genotypes or haplotypes. Our results suggest that the rs356219/356221 G-A haplotype may decrease the chance of having an alcohol misuse phenotype. Conclusion: These findings suggest that alcohol misuse may alter the expression of the individual α-synuclein splice variants differently in human brain. There was no evidence of an effect of sequence variation on the expression of α-synuclein splice variants in this population

Neighbourhood prevalence-to-notification ratios for adult bacteriologically-confirmed tuberculosis reveals hotspots of underdiagnosis in Blantyre, Malawi

Funding: This work was supported by two grants from Wellcome Trust (ELC grant number WT200901/Z/16/Z) and (PM grant number 200901/Z/16/Z). JRC was funded by UK Medical Research Council (MRC) programme grant MC_UU_00004/07. PJD was supported by a fellowship from the MRC (MR/P022081/1); this UK funded award was part of the EDCTP2 programme supported by the European Union. RMB was funded by Wellcome Trust (203905/16/Z). KCH was supported by the European Research Council (757699) and UK FCDO (Leaving no-one behind: transforming gendered pathways to health for TB). TC was supported by US NIH R01 R01AI147854.Local information is needed to guide targeted interventions for respiratory infections such as tuberculosis (TB). Case notification rates (CNRs) are readily available, but systematically underestimate true disease burden in neighbourhoods with high diagnostic access barriers. We explored a novel approach, adjusting CNRs for under-notification (P:N ratio) using neighbourhood-level predictors of TB prevalence-to-notification ratios. We analysed data from 1) a citywide routine TB surveillance system including geolocation, confirmatory mycobacteriology, and clinical and demographic characteristics of all registering TB patients in Blantyre, Malawi during 2015–19, and 2) an adult TB prevalence survey done in 2019. In the prevalence survey, consenting adults from randomly selected households in 72 neighbourhoods had symptom-plus-chest X-ray screening, confirmed with sputum smear microscopy, Xpert MTB/Rif and culture. Bayesian multilevel models were used to estimate adjusted neighbourhood prevalence-to-notification ratios, based on summarised posterior draws from fitted adult bacteriologically-confirmed TB CNRs and prevalence. From 2015–19, adult bacteriologically-confirmed CNRs were 131 (479/371,834), 134 (539/415,226), 114 (519/463,707), 56 (283/517,860) and 46 (258/578,377) per 100,000 adults per annum, and 2019 bacteriologically-confirmed prevalence was 215 (29/13,490) per 100,000 adults. Lower educational achievement by household head and neighbourhood distance to TB clinic was negatively associated with CNRs. The mean neighbourhood P:N ratio was 4.49 (95% credible interval [CrI]: 0.98–11.91), consistent with underdiagnosis of TB, and was most pronounced in informal peri-urban neighbourhoods. Here we have demonstrated a method for the identification of neighbourhoods with high levels of under-diagnosis of TB without the requirement for a prevalence survey; this is important since prevalence surveys are expensive and logistically challenging. If confirmed, this approach may support more efficient and effective targeting of intensified TB and HIV case-finding interventions aiming to accelerate elimination of urban TB.Peer reviewe

Refinement of acoustic-tagging protocol for twaite shad Alosa fallax (Lacépède), a species sensitive to handling and sedation

Telemetry investigations to gather essential information about fish migrations are reliant on the behaviour, condition and survival of the animals being unaltered by the tagging procedure. Twaite shad (Alosa fallax Lacépède; 'shad’) is a threatened clupeid fish for which there is a considerable knowledge gap on their anadromous movements. They are also reported to be sensitive to handling and anaesthesia, resulting in practical difficulties in tag implantation; previous investigations externally attached tags without sedation. The aim of this study was to incrementally refine the acoustic-tagging protocol for shad via application of a previously un-tried anaesthetic (i.e. tricaine methanesulphonate (MS-222)) and by surgical implantation of the tag in the peritoneal cavity. All captured shad (n = 25) survived handling, anaesthesia and tagging, and were detected moving upstream after release. Surgically implantation (n = 5) was significantly faster than externally mounting the tag (n = 20) and time to recover was similar. Total upstream movement, total movement, residence time in receiver array and speed of upstream movement were statistically similar for externally and internally tagged fish. Post-spawning, a large proportion (68%) of tagged fish returned to the estuary, downstream of the receiver array. Internal tagging under anaesthesia is recommended for studying anadromous movements of shad, given welfare benefits during surgery and once at liberty, thus increasing the likelihood of tagged fish performing natural behaviours. Further, implantation of tags programmed to last many years enables multiple spawning migrations by the same individuals to be studied, which would lead to substantial advances in ecological knowledge and potentially reduce the number of fish tagged

Quantum Vortex in a Vectorial Bose-Einstein Condensate

Quantum vortices in the multi-component Bose-Einstein condensation (BEC) are investigated theoretically. It is found that three kinds of the vortex configurations are possible and their physical properties are discussed in details, including the density distribution and the spin texture. By using the Bogoliubov theory extended to the three component BEC, the collective modes for these vortices are evaluated. The local vortex stability for these vortices are examined in light of the existence of the negative eigenvalue, yielding a narrow magnetization window for the local intrinsic stable region where the multi-components work together to stabilize a vortex in a self-organized way.Comment: 8 pages, 14 eps figure

Predicting the long-term impact of antiretroviral therapy scale-up on population incidence of tuberculosis.

OBJECTIVE: To investigate the impact of antiretroviral therapy (ART) on long-term population-level tuberculosis disease (TB) incidence in sub-Saharan Africa. METHODS: We used a mathematical model to consider the effect of different assumptions about life expectancy and TB risk during long-term ART under alternative scenarios for trends in population HIV incidence and ART coverage. RESULTS: All the scenarios we explored predicted that the widespread introduction of ART would initially reduce population-level TB incidence. However, many modelled scenarios projected a rebound in population-level TB incidence after around 20 years. This rebound was predicted to exceed the TB incidence present before ART scale-up if decreases in HIV incidence during the same period were not sufficiently rapid or if the protective effect of ART on TB was not sustained. Nevertheless, most scenarios predicted a reduction in the cumulative TB incidence when accompanied by a relative decline in HIV incidence of more than 10% each year. CONCLUSIONS: Despite short-term benefits of ART scale-up on population TB incidence in sub-Saharan Africa, longer-term projections raise the possibility of a rebound in TB incidence. This highlights the importance of sustaining good adherence and immunologic response to ART and, crucially, the need for effective HIV preventive interventions, including early widespread implementation of ART

Quantized circular motion of a trapped Bose-Einstein condensate: coherent rotation and vortices

We study the creation of vortex states in a trapped Bose-Einstein condensate by a rotating force. For a harmonic trapping potential the rotating force induces only a circular motion of the whole condensate around the trap center which does not depend on the interatomic interaction. For the creation of a pure vortex state it is necessary to confine the atoms in an anharmonic trapping potential. The efficiency of the creation can be greatly enhanced by a sinusodial variation of the force's angular velocity. We present analytical and numerical calculations for the case of a quartic trapping potential. The physical mechanism behind the requirement of an anharmonic trapping potential for the creation of pure vortex states is explained. [Changes: new numerical and analytical results are added and the representation is improved.]Comment: 13 Pages, 5 Figures, RevTe

Metabolic strategies for the degradation of the neuromodulator agmatine in mammals

Agmatine (1-amino-4-guanidinobutane), a precursor for polyamine biosynthesis, has been identified as an important neuromodulator with anticonvulsant, antineurotoxic and antidepressant actions in the brain. In this context it has emerged as an important mediator of addiction/satiety pathways associated with alcohol misuse. Consequently, the regulation of the activity of key enzymes in agmatine metabolism is an attractive strategy to combat alcoholism and related addiction disorders. Agmatine results from the decarboxylation of L-arginine in a reaction catalyzed by arginine decarboxylase (ADC), and can be converted to either guanidine butyraldehyde by diamine oxidase (DAO) or putrescine and urea by the enzyme agmatinase (AGM) or the more recently identified AGM-like protein (ALP). In rat brain, agmatine, AGM and ALP are predominantly localised in areas associated with roles in appetitive and craving (drug-reinstatement) behaviors. Thus, inhibitors of AGM or ALP are promising agents for the treatment of addictions. In this review, the properties of DAO, AGM and ALP are discussed with a view to their role in the agmatine metabolism in mammals

The Global Burden of Latent Tuberculosis Infection: A Re-estimation Using Mathematical Modelling.

BACKGROUND: The existing estimate of the global burden of latent TB infection (LTBI) as "one-third" of the world population is nearly 20 y old. Given the importance of controlling LTBI as part of the End TB Strategy for eliminating TB by 2050, changes in demography and scientific understanding, and progress in TB control, it is important to re-assess the global burden of LTBI. METHODS AND FINDINGS: We constructed trends in annual risk in infection (ARI) for countries between 1934 and 2014 using a combination of direct estimates of ARI from LTBI surveys (131 surveys from 1950 to 2011) and indirect estimates of ARI calculated from World Health Organisation (WHO) estimates of smear positive TB prevalence from 1990 to 2014. Gaussian process regression was used to generate ARIs for country-years without data and to represent uncertainty. Estimated ARI time-series were applied to the demography in each country to calculate the number and proportions of individuals infected, recently infected (infected within 2 y), and recently infected with isoniazid (INH)-resistant strains. Resulting estimates were aggregated by WHO region. We estimated the contribution of existing infections to TB incidence in 2035 and 2050. In 2014, the global burden of LTBI was 23.0% (95% uncertainty interval [UI]: 20.4%-26.4%), amounting to approximately 1.7 billion people. WHO South-East Asia, Western-Pacific, and Africa regions had the highest prevalence and accounted for around 80% of those with LTBI. Prevalence of recent infection was 0.8% (95% UI: 0.7%-0.9%) of the global population, amounting to 55.5 (95% UI: 48.2-63.8) million individuals currently at high risk of TB disease, of which 10.9% (95% UI:10.2%-11.8%) was isoniazid-resistant. Current LTBI alone, assuming no additional infections from 2015 onwards, would be expected to generate TB incidences in the region of 16.5 per 100,000 per year in 2035 and 8.3 per 100,000 per year in 2050. Limitations included the quantity and methodological heterogeneity of direct ARI data, and limited evidence to inform on potential clearance of LTBI. CONCLUSIONS: We estimate that approximately 1.7 billion individuals were latently infected with Mycobacterium tuberculosis (M.tb) globally in 2014, just under a quarter of the global population. Investment in new tools to improve diagnosis and treatment of those with LTBI at risk of progressing to disease is urgently needed to address this latent reservoir if the 2050 target of eliminating TB is to be reached