Dopamine Transporter Phosphorylation, Palmitoylation And Membrane Localization And Mobility In Health And Disease

The dopaminergic system is a regulatory system of the brain controlling various motor, cognitive and behavioral activities. Neurotransmitter dopamine (DA) plays an important role in modulating brain circuits controlling functions of this system with dopamine transporter (DAT) maintaining its homeostasis. Abnormalities in this homeostasis and/or nucleotide polymorphisms in the DAT structure leads to its association with a wide range of neurological and neuropsychiatric disorders, with attention-deficit hyperactivity disorder (ADHD) being one of them. Disrupting the normal function of DAT, many psychostimulants such as amphetamine (AMPH) upon being transported via DAT into the pre-synaptic neuron alters DAT properties triggering N-terminal DAT phosphorylation associated DA efflux. Recently identified, ADHD associated human DAT (hDAT) single nucleotide polymorphism (SNP), A559V, displayed anomalous DA efflux (ADE). Our results showed A559V hDAT and its rat homologue, A558V rat DAT (rDAT), displaying AMPH independent increased phosphorylation, including T53 site (human equivalent being S53), a proline directed phosphorylation site specific for rDAT, further unaffected by AMPH, which may support ADE observed for this polymorphism. These SNPs also showed reciprocal decreased palmitoylation status. With these modifications impacting DAT properties, we found phosphorylation driven increased membrane raft localization for A559V hDAT and other palmitoylation deficient mutants. These membrane rafts serve as a site for localization of phosphorylated DAT and a platform for DA efflux. These mutants also showed increased lateral membrane mobility, which was reciprocally decreased for phosphorylation deficient mutants (T53A rDAT, S7A hDAT and S53A hDAT) which have increased palmitoylation. Further, studies confirmed C581 to be a palmitoylation site in humans, with C581A hDAT being a palmitoylation deficient mutant having elevated phosphorylation with membrane microdomain and mobility properties similar to A559V hDAT. For A559V hDAT, the close proximity of Val substitution to the palmitoylation site could cause a structural alteration in DAT transmembrane spanning domain (TMD) 12 helical structure. The bulkier substitution may mechanistically hinder C581 palmitoylation causing its movement away from DAT core region, lose of flexibility, altered DAT membrane localization, mobility and function. We believe other phosphorylation or palmitoylation deficient mutants might show similar unknown mechanisms, reciprocally regulating post-translational modifications. With palmitoylation helping in membrane raft partitioning, stabilization of membrane anchoring and integral membrane protein interaction, we demonstrate palmitoylation to be a factor for DAT membrane mobility. We believe the palmitate group affects DAT’s interaction with binding partners and cholesterol and that its deficiency leads to increased lateral membrane mobility. This palmitoylation status could be the driving force for phosphorylation driven increased localization of phosphorylated DAT in membrane raft microdomains, leading to increased interaction with binding partners, serving as a platform for phosphorylation-dependent DA efflux either by AMPH-stimulation or by polymorphism

Global burden of 288 causes of death and life expectancy decomposition in 204 countries and territories and 811 subnational locations, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

BACKGROUND Regular, detailed reporting on population health by underlying cause of death is fundamental for public health decision making. Cause-specific estimates of mortality and the subsequent effects on life expectancy worldwide are valuable metrics to gauge progress in reducing mortality rates. These estimates are particularly important following large-scale mortality spikes, such as the COVID-19 pandemic. When systematically analysed, mortality rates and life expectancy allow comparisons of the consequences of causes of death globally and over time, providing a nuanced understanding of the effect of these causes on global populations. METHODS The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 cause-of-death analysis estimated mortality and years of life lost (YLLs) from 288 causes of death by age-sex-location-year in 204 countries and territories and 811 subnational locations for each year from 1990 until 2021. The analysis used 56 604 data sources, including data from vital registration and verbal autopsy as well as surveys, censuses, surveillance systems, and cancer registries, among others. As with previous GBD rounds, cause-specific death rates for most causes were estimated using the Cause of Death Ensemble model-a modelling tool developed for GBD to assess the out-of-sample predictive validity of different statistical models and covariate permutations and combine those results to produce cause-specific mortality estimates-with alternative strategies adapted to model causes with insufficient data, substantial changes in reporting over the study period, or unusual epidemiology. YLLs were computed as the product of the number of deaths for each cause-age-sex-location-year and the standard life expectancy at each age. As part of the modelling process, uncertainty intervals (UIs) were generated using the 2·5th and 97·5th percentiles from a 1000-draw distribution for each metric. We decomposed life expectancy by cause of death, location, and year to show cause-specific effects on life expectancy from 1990 to 2021. We also used the coefficient of variation and the fraction of population affected by 90% of deaths to highlight concentrations of mortality. Findings are reported in counts and age-standardised rates. Methodological improvements for cause-of-death estimates in GBD 2021 include the expansion of under-5-years age group to include four new age groups, enhanced methods to account for stochastic variation of sparse data, and the inclusion of COVID-19 and other pandemic-related mortality-which includes excess mortality associated with the pandemic, excluding COVID-19, lower respiratory infections, measles, malaria, and pertussis. For this analysis, 199 new country-years of vital registration cause-of-death data, 5 country-years of surveillance data, 21 country-years of verbal autopsy data, and 94 country-years of other data types were added to those used in previous GBD rounds. FINDINGS The leading causes of age-standardised deaths globally were the same in 2019 as they were in 1990; in descending order, these were, ischaemic heart disease, stroke, chronic obstructive pulmonary disease, and lower respiratory infections. In 2021, however, COVID-19 replaced stroke as the second-leading age-standardised cause of death, with 94·0 deaths (95% UI 89·2-100·0) per 100 000 population. The COVID-19 pandemic shifted the rankings of the leading five causes, lowering stroke to the third-leading and chronic obstructive pulmonary disease to the fourth-leading position. In 2021, the highest age-standardised death rates from COVID-19 occurred in sub-Saharan Africa (271·0 deaths [250·1-290·7] per 100 000 population) and Latin America and the Caribbean (195·4 deaths [182·1-211·4] per 100 000 population). The lowest age-standardised death rates from COVID-19 were in the high-income super-region (48·1 deaths [47·4-48·8] per 100 000 population) and southeast Asia, east Asia, and Oceania (23·2 deaths [16·3-37·2] per 100 000 population). Globally, life expectancy steadily improved between 1990 and 2019 for 18 of the 22 investigated causes. Decomposition of global and regional life expectancy showed the positive effect that reductions in deaths from enteric infections, lower respiratory infections, stroke, and neonatal deaths, among others have contributed to improved survival over the study period. However, a net reduction of 1·6 years occurred in global life expectancy between 2019 and 2021, primarily due to increased death rates from COVID-19 and other pandemic-related mortality. Life expectancy was highly variable between super-regions over the study period, with southeast Asia, east Asia, and Oceania gaining 8·3 years (6·7-9·9) overall, while having the smallest reduction in life expectancy due to COVID-19 (0·4 years). The largest reduction in life expectancy due to COVID-19 occurred in Latin America and the Caribbean (3·6 years). Additionally, 53 of the 288 causes of death were highly concentrated in locations with less than 50% of the global population as of 2021, and these causes of death became progressively more concentrated since 1990, when only 44 causes showed this pattern. The concentration phenomenon is discussed heuristically with respect to enteric and lower respiratory infections, malaria, HIV/AIDS, neonatal disorders, tuberculosis, and measles. INTERPRETATION Long-standing gains in life expectancy and reductions in many of the leading causes of death have been disrupted by the COVID-19 pandemic, the adverse effects of which were spread unevenly among populations. Despite the pandemic, there has been continued progress in combatting several notable causes of death, leading to improved global life expectancy over the study period. Each of the seven GBD super-regions showed an overall improvement from 1990 and 2021, obscuring the negative effect in the years of the pandemic. Additionally, our findings regarding regional variation in causes of death driving increases in life expectancy hold clear policy utility. Analyses of shifting mortality trends reveal that several causes, once widespread globally, are now increasingly concentrated geographically. These changes in mortality concentration, alongside further investigation of changing risks, interventions, and relevant policy, present an important opportunity to deepen our understanding of mortality-reduction strategies. Examining patterns in mortality concentration might reveal areas where successful public health interventions have been implemented. Translating these successes to locations where certain causes of death remain entrenched can inform policies that work to improve life expectancy for people everywhere. FUNDING Bill & Melinda Gates Foundation

Bifid Mandibular Condyle: A rare in plenty

The bifid mandibular condyle has also been termed as Double Headed Condyle or Condylar Duplication. Bifid condyle was first reported by Hrdlicka in 1941. Since then, to the best of our knowledge, about 49 cases of bifid condyle have been reported in medical literature. We present here six cases of bifid mandibular condyle that we encountered during the span of one year. These were incidental findings on panoramic radiographs and were later confirmed with coronal computed tomographs. This article also reviews the relevant literature

Evaluating LDL-C control in Indian acute coronary syndrome (ACS) patients- A retrospective real-world study LDL-C control in ACS

Background: Low-density lipoprotein-cholesterol (LDL-C) is an independent risk factor for atherosclerotic cardiovascular disease (ASCVD) progression. Although lipid lowering therapies remain the cornerstone of secondary ACSVD prevention, there exists residual dyslipidemia. The current study aimed to evaluate the real-world experience related to the treatment patterns and LDL-C control in Indian Acute Coronary Syndrome (ACS) patients. Methods: This was a real-world, descriptive, retrospective, observational, and multicentric study conducted across India. The data was collected for 1 year following the ACS event. The change in the levels of LDL-C from the baseline to the follow-up visits and the control of LDL-C, the change in lipid profile, lipoprotein levels, treatment patterns for lipid-lowering, and tolerability of existing treatments were evaluated. Results: Overall, 575 patients were included from 11 centers across India. The mean age of the patients was 52.92 years, with male predominance (76.35%). Although there was a significant reduction in the mean levels of LDL-C from the baseline [(122.64 ± 42.01 mg/dl to 74.41 ± 26.45 mg/dl (p < 0.001)], it was observed that despite high-intensity statin therapy, only 20.87% patients managed to achieve target LDL-C of <55 mg/dL and 55.65% were unable to reach LDL-C levels of <70 mg/dl one year after the event. Six patients reported adverse events without treatment discontinuation. Conclusion: The majority of the patients received high-intensity statins and did not attain target LDL-C levels, suggesting LDL-C control after an ACS event requires management with novel therapies having better efficacy as recommended by international and national guidelines

Additional file 2: of Integrated genomics approach to identify biologically relevant alterations in fewer samples

Additional Tables S1-S8: Copy number alterations of known genomic locations identified in HNSCC cell lines. Copy number alterations in halmark genes identified in HNSCC cell lines. Gene expression of hallmark genes by RNA sequencing and qPCR. Features of whole exome and transcriptome sequencing. Validation of mutations in hallmark and novel genes. Details of mutations identified by integrated analysis in HNSCC cell lines. Primer sequences used for Sanger sequenicng based validation of mutations. Primers used for copy number and gene expression study using qPCR. (ZIP 249 kb

Prevalence, years lived with disability, and trends in anaemia burden by severity and cause, 1990–2021: findings from the Global Burden of Disease Study 2021

Background: Anaemia is a major health problem worldwide. Global estimates of anaemia burden are crucial for developing appropriate interventions to meet current international targets for disease mitigation. We describe the prevalence, years lived with disability, and trends of anaemia and its underlying causes in 204 countries and territories. Methods: We estimated population-level distributions of haemoglobin concentration by age and sex for each location from 1990 to 2021. We then calculated anaemia burden by severity and associated years lived with disability (YLDs). With data on prevalence of the causes of anaemia and associated cause-specific shifts in haemoglobin concentrations, we modelled the proportion of anaemia attributed to 37 underlying causes for all locations, years, and demographics in the Global Burden of Disease Study 2021. Findings: In 2021, the global prevalence of anaemia across all ages was 24·3% (95% uncertainty interval [UI] 23·9–24·7), corresponding to 1·92 billion (1·89–1·95) prevalent cases, compared with a prevalence of 28·2% (27·8–28·5) and 1·50 billion (1·48–1·52) prevalent cases in 1990. Large variations were observed in anaemia burden by age, sex, and geography, with children younger than 5 years, women, and countries in sub-Saharan Africa and south Asia being particularly affected. Anaemia caused 52·0 million (35·1–75·1) YLDs in 2021, and the YLD rate due to anaemia declined with increasing Socio-demographic Index. The most common causes of anaemia YLDs in 2021 were dietary iron deficiency (cause-specific anaemia YLD rate per 100 000 population: 422·4 [95% UI 286·1–612·9]), haemoglobinopathies and haemolytic anaemias (89·0 [58·2–123·7]), and other neglected tropical diseases (36·3 [24·4–52·8]), collectively accounting for 84·7% (84·1–85·2) of anaemia YLDs. Interpretation: Anaemia remains a substantial global health challenge, with persistent disparities according to age, sex, and geography. Estimates of cause-specific anaemia burden can be used to design locally relevant health interventions aimed at improving anaemia management and prevention. Funding: Bill & Melinda Gates Foundation