The Caenorhabditis elegans Kinesin-3 motor UNC-104/ KIF1A is degraded upon loss of specific binding to cargo

UNC-104/KIF1A is a Kinesin-3 motor that transports synaptic vesicles from the cell body towards the synapse by binding to PI(4,5)P(2) through its PH domain. The fate of the motor upon reaching the synapse is not known. We found that wild-type UNC-104 is degraded at synaptic regions through the ubiquitin pathway and is not retrogradely transported back to the cell body. As a possible means to regulate the motor, we tested the effect of cargo binding on UNC-104 levels. The unc-104(e1265) allele carries a point mutation (D1497N) in the PI(4,5)P(2) binding pocket of the PH domain, resulting in greatly reduced preferential binding to PI(4,5)P(2)in vitro and presence of very few motors on pre-synaptic vesicles in vivo. unc-104(e1265) animals have poor locomotion irrespective of in vivo PI(4,5)P(2) levels due to reduced anterograde transport. Moreover, they show highly reduced levels of UNC-104 in vivo. To confirm that loss of cargo binding specificity reduces motor levels, we isolated two intragenic suppressors with compensatory mutations within the PH domain. These show partial restoration of in vitro preferential PI(4,5)P(2) binding and presence of more motors on pre-synaptic vesicles in vivo. These animals show improved locomotion dependent on in vivo PI(4,5)P(2) levels, increased anterograde transport, and partial restoration of UNC-104 protein levels in vivo. For further proof, we mutated a conserved residue in one suppressor background. The PH domain in this triple mutant lacked in vitro PI(4,5)P(2) binding specificity, and the animals again showed locomotory defects and reduced motor levels. All allelic variants show increased UNC-104 levels upon blocking the ubiquitin pathway. These data show that inability to bind cargo can target motors for degradation. In view of the observed degradation of the motor in synaptic regions, this further suggests that UNC-104 may get degraded at synapses upon release of cargo

Cytotoxicity Evaluation of Zinc Oxide Nanoparticle-Coated Gutta Percha in Zebrafish: Optimal Concentrations for Enhanced Antibacterial Effect and Reduced Toxicity

Background: Microorganisms have frequently been the cause of infections in the periapical tissue and dental pulp. The infected pulp tissue is removed and the root canal space is then prepared, cleaned and filled with a core root filling material. A persistent or secondary root canal system infection may be the cause of endodontic treatment failure. Concerning the issue, it is the need of the hour to look for alternative coating materials for Gutta Percha (GP) cones to increase their antimicrobial and antibiofilm efficacy for a successful outcome of the root canal therapies.Aim: The aim of this study was to assess the cytotoxicity of commercial GP cones modified with thin deposition of zinc oxide nanoparticles.Materials and Methods: Zinc oxide nanoparticles are extracted from zinc acetate and sodium hydroxide. Zinc oxide nanoparticles incorporated in PVA polymer. 1%, 3%, 5% zinc oxide nanoparticles are incorporated in PVA polymer separately. The surface of GP cones were modified by dip coating in PVA polymer. Group A- uncoated GP, Group B - coated GP. Cytotoxicity tests on zebrafish models were performed and 1%, 3%, 5% were compared.Result: 1% Nanostructured zinc oxide coated GP shows less toxicity than 3%, 5% zinc oxide coated GP

Combination of Leucine- Fluoroquinolone in Inhibiting Dental Pathogen Biofilms

Purpose: Leucine, an essential amino acid, has shown potential in modulating bacterial growth, with potential applications in dentistry and oral health. When used in conjunction with fluoroquinolones, which are antibiotics known for their broad-spectrum activity, it is effective against a variety of bacterial pathogens. The principal aim of the study was to assess the combinatorial efficacy of leucine - fluoroquinolone antibiotics in the deterring of biofilm formed by prominent dental pathogens. Materials & Methods: 100 mL of Brain Heart Infusion broth was inoculated with 4-5 colonies of S.mutans and E.faecalis and incubated at 37 degree C overnight in an incubator. Leucine & Leucine - fluoroquinolone was diluted to desired concentrations and added to BHI broth in the wells & was inoculated with 50 mL of broth culture. The Broth was aspirated, washed, & 150 µL of crystal violet was added to each well & allowed to stand for 15-20 minutes. The dye was removed, washed, and then dissolved by adding 150 µL of 30% glacial acetic acid in each well. Reading was taken using ELISA plate reader at 570 nm.Results: The optical density of leucine was comparatively higher than the combination of leucine and ciprofloxacin in case of both Streptococcus mutans and Enterococcus faecalis, demonstrating that proportion of biofilm formation with S.mutans & E.faecalis had decreased when treated with leucine-ciprofloxacin antibiotic combination than with leucine alone.Conclusion: Leucine has potential anti-biofilm activity if used as an adjuvant along with an antibiotic against drug resistant strains of bacteria such as S.mutans & E.faecalis

Prevalence of Class I Caries Among Out Patients with Diabetes Visiting A Private Dental Hospital - A Retrospective Analysis

Diabetes is a metabolic disorder that is common among all ages of people worldwide. Whereas Dental caries is one of the most prevalent and preventable diseases. Both diabetes and caries are associated with carbohydrate intake.Diabetic patients have increased sucrose level and less amount of fluoride content that promotes demineralisation thereby providing the favourable environment for caries progression.However there is still some controversy regarding the relationship between diabetes and caries. Hence the aim of the present study was to assess the prevalence of class 1 dental caries in patients with type 2 diabetes mellitus. We reviewed patient records and analysed the data of 86000 patients between June 2019 and march 2020 from which 600 diabetic patients were included in the study and assessed for age,gender and presence of class 1 caries in each tooth. Collected data was tabulated in excel sheet and imported in SPSS version 17 for statistical analysis. Among 600 diabetic patients, 55.9% showed presence of caries and 44% were without class 1 caries. The result was highly significant (t-test; P<0.001). 40 to 50 years age group patients showed high prevalence of caries(64%) and 20 to 30 age groups showed minimal prevalence(17.6%). Males showed higher prevalence than females with 56.4% and 43.5%. This result was not significant (Chi-square test; P=0.013). Tooth number 37(15.5%) showed high incidence followed by 38(7.1%) and 47(6.8%). Mandibular posteriors(60.3%) showed higher prevalence than maxillary posteriors (30.3%)

Structural Annotation of Mycobacterium tuberculosis Proteome

Of the ∼4000 ORFs identified through the genome sequence of Mycobacterium tuberculosis (TB) H37Rv, experimentally determined structures are available for 312. Since knowledge of protein structures is essential to obtain a high-resolution understanding of the underlying biology, we seek to obtain a structural annotation for the genome, using computational methods. Structural models were obtained and validated for ∼2877 ORFs, covering ∼70% of the genome. Functional annotation of each protein was based on fold-based functional assignments and a novel binding site based ligand association. New algorithms for binding site detection and genome scale binding site comparison at the structural level, recently reported from the laboratory, were utilized. Besides these, the annotation covers detection of various sequence and sub-structural motifs and quaternary structure predictions based on the corresponding templates. The study provides an opportunity to obtain a global perspective of the fold distribution in the genome. The annotation indicates that cellular metabolism can be achieved with only 219 folds. New insights about the folds that predominate in the genome, as well as the fold-combinations that make up multi-domain proteins are also obtained. 1728 binding pockets have been associated with ligands through binding site identification and sub-structure similarity analyses. The resource (http://proline.physics.iisc.ernet.in/Tbstructuralannotation), being one of the first to be based on structure-derived functional annotations at a genome scale, is expected to be useful for better understanding of TB and for application in drug discovery. The reported annotation pipeline is fairly generic and can be applied to other genomes as well

Assessing performance of the Healthcare Access and Quality Index, overall and by select age groups, for 204 countries and territories, 1990-2019: a systematic analysis from the Global Burden of Disease Study 2019

Background: Health-care needs change throughout the life course. It is thus crucial to assess whether health systems provide access to quality health care for all ages. Drawing from the Global Burden of Diseases, Injuries, and Risk Factors Study 2019 (GBD 2019), we measured the Healthcare Access and Quality (HAQ) Index overall and for select age groups in 204 locations from 1990 to 2019. Methods: We distinguished the overall HAQ Index (ages 0–74 years) from scores for select age groups: the young (ages 0–14 years), working (ages 15–64 years), and post-working (ages 65–74 years) groups. For GBD 2019, HAQ Index construction methods were updated to use the arithmetic mean of scaled mortality-to-incidence ratios (MIRs) and risk-standardised death rates (RSDRs) for 32 causes of death that should not occur in the presence of timely, quality health care. Across locations and years, MIRs and RSDRs were scaled from 0 (worst) to 100 (best) separately, putting the HAQ Index on a different relative scale for each age group. We estimated absolute convergence for each group on the basis of whether the HAQ Index grew faster in absolute terms between 1990 and 2019 in countries with lower 1990 HAQ Index scores than countries with higher 1990 HAQ Index scores and by Socio-demographic Index (SDI) quintile. SDI is a summary metric of overall development. Findings: Between 1990 and 2019, the HAQ Index increased overall (by 19·6 points, 95% uncertainty interval 17·9–21·3), as well as among the young (22·5, 19·9–24·7), working (17·2, 15·2–19·1), and post-working (15·1, 13·2–17·0) age groups. Large differences in HAQ Index scores were present across SDI levels in 2019, with the overall index ranging from 30·7 (28·6–33·0) on average in low-SDI countries to 83·4 (82·4–84·3) on average in high-SDI countries. Similarly large ranges between low-SDI and high-SDI countries, respectively, were estimated in the HAQ Index for the young (40·4–89·0), working (33·8–82·8), and post-working (30·4–79·1) groups. Absolute convergence in HAQ Index was estimated in the young group only. In contrast, divergence was estimated among the working and post-working groups, driven by slow progress in low-SDI countries. Interpretation: Although major gaps remain across levels of social and economic development, convergence in the young group is an encouraging sign of reduced disparities in health-care access and quality. However, divergence in the working and post-working groups indicates that health-care access and quality is lagging at lower levels of social and economic development. To meet the needs of ageing populations, health systems need to improve health-care access and quality for working-age adults and older populations while continuing to realise gains among the young. Funding: Bill & Melinda Gates Foundation

The global burden of adolescent and young adult cancer in 2019 : a systematic analysis for the Global Burden of Disease Study 2019

Background In estimating the global burden of cancer, adolescents and young adults with cancer are often overlooked, despite being a distinct subgroup with unique epidemiology, clinical care needs, and societal impact. Comprehensive estimates of the global cancer burden in adolescents and young adults (aged 15-39 years) are lacking. To address this gap, we analysed results from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019, with a focus on the outcome of disability-adjusted life-years (DALYs), to inform global cancer control measures in adolescents and young adults. Methods Using the GBD 2019 methodology, international mortality data were collected from vital registration systems, verbal autopsies, and population-based cancer registry inputs modelled with mortality-to-incidence ratios (MIRs). Incidence was computed with mortality estimates and corresponding MIRs. Prevalence estimates were calculated using modelled survival and multiplied by disability weights to obtain years lived with disability (YLDs). Years of life lost (YLLs) were calculated as age-specific cancer deaths multiplied by the standard life expectancy at the age of death. The main outcome was DALYs (the sum of YLLs and YLDs). Estimates were presented globally and by Socio-demographic Index (SDI) quintiles (countries ranked and divided into five equal SDI groups), and all estimates were presented with corresponding 95% uncertainty intervals (UIs). For this analysis, we used the age range of 15-39 years to define adolescents and young adults. Findings There were 1.19 million (95% UI 1.11-1.28) incident cancer cases and 396 000 (370 000-425 000) deaths due to cancer among people aged 15-39 years worldwide in 2019. The highest age-standardised incidence rates occurred in high SDI (59.6 [54.5-65.7] per 100 000 person-years) and high-middle SDI countries (53.2 [48.8-57.9] per 100 000 person-years), while the highest age-standardised mortality rates were in low-middle SDI (14.2 [12.9-15.6] per 100 000 person-years) and middle SDI (13.6 [12.6-14.8] per 100 000 person-years) countries. In 2019, adolescent and young adult cancers contributed 23.5 million (21.9-25.2) DALYs to the global burden of disease, of which 2.7% (1.9-3.6) came from YLDs and 97.3% (96.4-98.1) from YLLs. Cancer was the fourth leading cause of death and tenth leading cause of DALYs in adolescents and young adults globally. Interpretation Adolescent and young adult cancers contributed substantially to the overall adolescent and young adult disease burden globally in 2019. These results provide new insights into the distribution and magnitude of the adolescent and young adult cancer burden around the world. With notable differences observed across SDI settings, these estimates can inform global and country-level cancer control efforts. Copyright (C) 2021 The Author(s). Published by Elsevier Ltd.Peer reviewe

Global, regional, and national sex-specific burden and control of the HIV epidemic, 1990-2019, for 204 countries and territories: the Global Burden of Diseases Study 2019

Background: The sustainable development goals (SDGs) aim to end HIV/AIDS as a public health threat by 2030. Understanding the current state of the HIV epidemic and its change over time is essential to this effort. This study assesses the current sex-specific HIV burden in 204 countries and territories and measures progress in the control of the epidemic. Methods: To estimate age-specific and sex-specific trends in 48 of 204 countries, we extended the Estimation and Projection Package Age-Sex Model to also implement the spectrum paediatric model. We used this model in cases where age and sex specific HIV-seroprevalence surveys and antenatal care-clinic sentinel surveillance data were available. For the remaining 156 of 204 locations, we developed a cohort-incidence bias adjustment to derive incidence as a function of cause-of-death data from vital registration systems. The incidence was input to a custom Spectrum model. To assess progress, we measured the percentage change in incident cases and deaths between 2010 and 2019 (threshold >75% decline), the ratio of incident cases to number of people living with HIV (incidence-to-prevalence ratio threshold <0·03), and the ratio of incident cases to deaths (incidence-to-mortality ratio threshold <1·0). Findings: In 2019, there were 36·8 million (95% uncertainty interval [UI] 35·1–38·9) people living with HIV worldwide. There were 0·84 males (95% UI 0·78–0·91) per female living with HIV in 2019, 0·99 male infections (0·91–1·10) for every female infection, and 1·02 male deaths (0·95–1·10) per female death. Global progress in incident cases and deaths between 2010 and 2019 was driven by sub-Saharan Africa (with a 28·52% decrease in incident cases, 95% UI 19·58–35·43, and a 39·66% decrease in deaths, 36·49–42·36). Elsewhere, the incidence remained stable or increased, whereas deaths generally decreased. In 2019, the global incidence-to-prevalence ratio was 0·05 (95% UI 0·05–0·06) and the global incidence-to-mortality ratio was 1·94 (1·76–2·12). No regions met suggested thresholds for progress. Interpretation: Sub-Saharan Africa had both the highest HIV burden and the greatest progress between 1990 and 2019. The number of incident cases and deaths in males and females approached parity in 2019, although there remained more females with HIV than males with HIV. Globally, the HIV epidemic is far from the UNAIDS benchmarks on progress metrics. Funding: The Bill & Melinda Gates Foundation, the National Institute of Mental Health of the US National Institutes of Health (NIH), and the National Institute on Aging of the NIH

Cancer Incidence, Mortality, Years of Life Lost, Years Lived With Disability, and Disability-Adjusted Life Years for 29 Cancer Groups From 2010 to 2019: A Systematic Analysis for the Global Burden of Disease Study 2019.

The Global Burden of Diseases, Injuries, and Risk Factors Study 2019 (GBD 2019) provided systematic estimates of incidence, morbidity, and mortality to inform local and international efforts toward reducing cancer burden. To estimate cancer burden and trends globally for 204 countries and territories and by Sociodemographic Index (SDI) quintiles from 2010 to 2019. The GBD 2019 estimation methods were used to describe cancer incidence, mortality, years lived with disability, years of life lost, and disability-adjusted life years (DALYs) in 2019 and over the past decade. Estimates are also provided by quintiles of the SDI, a composite measure of educational attainment, income per capita, and total fertility rate for those younger than 25 years. Estimates include 95% uncertainty intervals (UIs). In 2019, there were an estimated 23.6 million (95% UI, 22.2-24.9 million) new cancer cases (17.2 million when excluding nonmelanoma skin cancer) and 10.0 million (95% UI, 9.36-10.6 million) cancer deaths globally, with an estimated 250 million (235-264 million) DALYs due to cancer. Since 2010, these represented a 26.3% (95% UI, 20.3%-32.3%) increase in new cases, a 20.9% (95% UI, 14.2%-27.6%) increase in deaths, and a 16.0% (95% UI, 9.3%-22.8%) increase in DALYs. Among 22 groups of diseases and injuries in the GBD 2019 study, cancer was second only to cardiovascular diseases for the number of deaths, years of life lost, and DALYs globally in 2019. Cancer burden differed across SDI quintiles. The proportion of years lived with disability that contributed to DALYs increased with SDI, ranging from 1.4% (1.1%-1.8%) in the low SDI quintile to 5.7% (4.2%-7.1%) in the high SDI quintile. While the high SDI quintile had the highest number of new cases in 2019, the middle SDI quintile had the highest number of cancer deaths and DALYs. From 2010 to 2019, the largest percentage increase in the numbers of cases and deaths occurred in the low and low-middle SDI quintiles. The results of this systematic analysis suggest that the global burden of cancer is substantial and growing, with burden differing by SDI. These results provide comprehensive and comparable estimates that can potentially inform efforts toward equitable cancer control around the world.Funding/Support: The Institute for Health Metrics and Evaluation received funding from the Bill & Melinda Gates Foundation and the American Lebanese Syrian Associated Charities. Dr Aljunid acknowledges the Department of Health Policy and Management of Kuwait University and the International Centre for Casemix and Clinical Coding, National University of Malaysia for the approval and support to participate in this research project. Dr Bhaskar acknowledges institutional support from the NSW Ministry of Health and NSW Health Pathology. Dr Bärnighausen was supported by the Alexander von Humboldt Foundation through the Alexander von Humboldt Professor award, which is funded by the German Federal Ministry of Education and Research. Dr Braithwaite acknowledges funding from the National Institutes of Health/ National Cancer Institute. Dr Conde acknowledges financial support from the European Research Council ERC Starting Grant agreement No 848325. Dr Costa acknowledges her grant (SFRH/BHD/110001/2015), received by Portuguese national funds through Fundação para a Ciência e Tecnologia, IP under the Norma Transitória grant DL57/2016/CP1334/CT0006. Dr Ghith acknowledges support from a grant from Novo Nordisk Foundation (NNF16OC0021856). Dr Glasbey is supported by a National Institute of Health Research Doctoral Research Fellowship. Dr Vivek Kumar Gupta acknowledges funding support from National Health and Medical Research Council Australia. Dr Haque thanks Jazan University, Saudi Arabia for providing access to the Saudi Digital Library for this research study. Drs Herteliu, Pana, and Ausloos are partially supported by a grant of the Romanian National Authority for Scientific Research and Innovation, CNDS-UEFISCDI, project number PN-III-P4-ID-PCCF-2016-0084. Dr Hugo received support from the Higher Education Improvement Coordination of the Brazilian Ministry of Education for a sabbatical period at the Institute for Health Metrics and Evaluation, between September 2019 and August 2020. Dr Sheikh Mohammed Shariful Islam acknowledges funding by a National Heart Foundation of Australia Fellowship and National Health and Medical Research Council Emerging Leadership Fellowship. Dr Jakovljevic acknowledges support through grant OI 175014 of the Ministry of Education Science and Technological Development of the Republic of Serbia. Dr Katikireddi acknowledges funding from a NHS Research Scotland Senior Clinical Fellowship (SCAF/15/02), the Medical Research Council (MC_UU_00022/2), and the Scottish Government Chief Scientist Office (SPHSU17). Dr Md Nuruzzaman Khan acknowledges the support of Jatiya Kabi Kazi Nazrul Islam University, Bangladesh. Dr Yun Jin Kim was supported by the Research Management Centre, Xiamen University Malaysia (XMUMRF/2020-C6/ITCM/0004). Dr Koulmane Laxminarayana acknowledges institutional support from Manipal Academy of Higher Education. Dr Landires is a member of the Sistema Nacional de Investigación, which is supported by Panama’s Secretaría Nacional de Ciencia, Tecnología e Innovación. Dr Loureiro was supported by national funds through Fundação para a Ciência e Tecnologia under the Scientific Employment Stimulus–Institutional Call (CEECINST/00049/2018). Dr Molokhia is supported by the National Institute for Health Research Biomedical Research Center at Guy’s and St Thomas’ National Health Service Foundation Trust and King’s College London. Dr Moosavi appreciates NIGEB's support. Dr Pati acknowledges support from the SIAN Institute, Association for Biodiversity Conservation & Research. Dr Rakovac acknowledges a grant from the government of the Russian Federation in the context of World Health Organization Noncommunicable Diseases Office. Dr Samy was supported by a fellowship from the Egyptian Fulbright Mission Program. Dr Sheikh acknowledges support from Health Data Research UK. Drs Adithi Shetty and Unnikrishnan acknowledge support given by Kasturba Medical College, Mangalore, Manipal Academy of Higher Education. Dr Pavanchand H. Shetty acknowledges Manipal Academy of Higher Education for their research support. Dr Diego Augusto Santos Silva was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - Brasil Finance Code 001 and is supported in part by CNPq (302028/2018-8). Dr Zhu acknowledges the Cancer Prevention and Research Institute of Texas grant RP210042