Dietary supplementation of clinically utilized PI3K p110α inhibitor extends the lifespan of male and female mice.

Diminished insulin and insulin-like growth factor-1 signaling extends the lifespan of invertebrates1-4; however, whether it is a feasible longevity target in mammals is less clear5-12. Clinically utilized therapeutics that target this pathway, such as small-molecule inhibitors of phosphoinositide 3-kinase p110α (PI3Ki), provide a translatable approach to studying the impact of these pathways on aging. Here, we provide evidence that dietary supplementation with the PI3Ki alpelisib from middle age extends the median and maximal lifespan of mice, an effect that was more pronounced in females. While long-term PI3Ki treatment was well tolerated and led to greater strength and balance, negative impacts on common human aging markers, including reductions in bone mass and mild hyperglycemia, were also evident. These results suggest that while pharmacological suppression of insulin receptor (IR)/insulin-like growth factor receptor (IGFR) targets could represent a promising approach to delaying some aspects of aging, caution should be taken in translation to humans.

Pre-exposure prophylaxis awareness, acceptability and potential stigma among medical and non-medical clinic staff in methadone treatment settings in northern New Jersey: The key role of non-medical staff in enhancing HIV prevention.

BACKGROUND: HIV prevention is needed among people who use drugs (PWUD) due to mixing sex and drugs, selling/trading sex, and/or injecting drugs. Pre-exposure prophylaxis (PrEP) is an extremely effective biomedical HIV prevention strategy, but uptake remains low among communities most in need of HIV prevention, including PWUD. Previous studies have found that providers are less willing to prescribe PrEP to PWUD, yet PWUD express high levels of PrEP acceptance. More research is needed to understand how people who provide substance use treatment services think about PrEP to maximize this biomedical prevention strategy. METHODS: The study conducted semistructured interviews with 29 staff members in two methadone clinic settings in urban northern New Jersey. Staff members included medical providers, methadone counselors, intake coordinators, front desk staff, lab technicians, security guards, and administrative/leadership personnel. RESULTS: All staff recognized the need for HIV prevention among their patient populations, but most were either unaware of PrEP or unfamiliar with its purpose and how it works. Medical providers were more likely to have some PrEP knowledge in comparison to counselors and other staff, but the former largely did not have in-depth knowledge. Among those familiar with PrEP, many confused PrEP with HIV medication, as Truvada was the only FDA-approved PrEP at the time of the study. About half of participants expressed clear support for PrEP, while the other half expressed mixed or negative attitudes related to HIV, sexual behavior, and mistrust of the medication. Both the positive and negative perceptions entailed stigmatizing elements. RECOMMENDATIONS: Due to patients' frequent interactions with non-medical staff (e.g., front desk staff, lab technicians, etc.), all staff, not only medical personnel, should be aware of PrEP and comfortable discussing it to foster well-informed, nonjudgmental conversations about HIV prevention with patients. PrEP education should specifically address HIV and sexual-related stigma, as even positive perceptions of PrEP may entail stigmatizing elements.

Correlates of PrEP Uptake Among Young Sexual Minority Men and Transgender Women in New York City: The Need to Reframe "Risk" Messaging and Normalize Preventative Health.

Pre-exposure prophylaxis (PrEP) is an effective form of HIV prevention, but young sexual minority men face myriad barriers to PrEP uptake. Participants (n = 202) completed a survey on healthcare experiences and beliefs about HIV and PrEP. While 98% of the sample knew about PrEP, only 23.2% reported currently taking PrEP. Participants were more likely to be taking PrEP if they received PrEP information from a healthcare provider and endorsed STI-related risk compensation. Conversely, PrEP uptake was less likely among those with concerns about medication use and adherence. While there were no racial/ethnic differences in PrEP uptake, there were differences in correlates of PrEP use for White participants and participants of color. To facilitate PrEP uptake, clinicians should provide PrEP education and screen all patients for PrEP candidacy. Additionally, public health messaging must reframe HIV "risk", highlight benefits of STI testing, and emphasize the importance of preventive healthcare for SMM.

"Worn out": Coping strategies for managing antiretroviral treatment fatigue among urban people of color living with HIV who were recently disengaged from outpatient HIV care.

Antiretroviral-related treatment fatigue is inconsistently defined in the literature on barriers to ART adherence. Research suggests that treatment fatigue is a salient challenge for people struggling with antiretroviral therapy adherence, but little is known about how people living with HIV attempt to manage this fatigue. Twenty-seven semi-structured interviews were conducted with low-income people of color living with HIV in NYC that were currently, or recently, disengaged from HIV care. The findings from this exploratory study suggest that treatment fatigue was common and that participants devised personal strategies to overcome it. These strategies included using reminder programs, requesting weekly rather than monthly pill quantities, and taking "pill holidays". The varied nature- and varying levels of effectiveness- of these strategies highlight the need for specific programming to provide tailored support. Future research should examine treatment fatigue as a specific subtype of adherence challenge, and aim to define pill fatigue clearly.

Resilience and Beliefs in the Effectiveness of Current Antiretroviral Therapies Among Recently Disengaged Low-Income People of Color Living with HIV.

Consistent antiretroviral adherence is key to viral suppression, but many low-income people of color living with HIV are not optimally adherent due to a wide variety of interrelated social and structural factors. Previous studies have found that HIV medication beliefs are an important facet of adherence. In contrast to the AZT era , currently available antiretroviral therapies are significantly safer and more effective, but research suggests that negative beliefs may persist among racial and ethnic minority people. Twenty-seven semi-structured interviews were conducted with low-income Black and Latinx people living with HIV in New York City that were currently, or had been recently, disengaged from outpatient HIV medical care. This research suggests that socially and economically marginalized people living with HIV, many long-term survivors who lived through the AZT era, recognized that current treatments are very effective in making HIV a chronic, manageable illness and a significant improvement compared to the therapies early in the epidemic. Most importantly, the data suggests that people demonstrate great resilience despite their experiences of social and economic exclusion. Both clinical practice and public health interventions can benefit from these findings. HIV care providers should speak with patients about their beliefs related to HIV medication, and public health interventions should specifically address HIV medication-related beliefs in order to enhance adherence. In order to avoid reifying people's marginalization, public health should endeavor to recognize and support people's resilience.

Mining of Indian wheat germplasm collection for adult plant resistance to leaf rust.

Leaf rust (Puccinia triticina Eriks.) is a fungal disease of wheat (Triticum spp.), which causes considerable yield loss. Adult plant resistance (APR) is one of the most sustainable approaches to control leaf rust. In this study, field-testing was carried out across ten different locations, followed by molecular screening, to detect the presence of APR genes, Lr34+, Lr46+, Lr67+ and Lr68 in Indian wheat germplasm. In field screening, 190 wheat accessions were selected from 6,319 accessions based on leaf tip necrosis (LTN), disease severity and the average coefficient of infection. Molecular screening revealed that 73% of the accessions possessed known APR genes either as single or as a combination of two or three genes. The occurrence of increased LTN intensity, decreased leaf rust severity and greater expression of APR genes were more in relatively cooler locations. In 52 lines, although the presence of the APR genes was not detected, it still displayed high levels of resistance. Furthermore, 49 accessions possessing either two or three APR genes were evaluated for stability across locations for grain yield. It emerged that eight accessions had wider adaptability. Resistance based on APR genes, in the background of high yielding cultivars, is expected to provide a high level of race non-specific resistance, which is durable.

Identification and characterization of finger millet OPAQUE2 transcription factor gene under different nitrogen inputs for understanding their role during accumulation of prolamin seed storage protein.

In this study, we report the isolation and characterization of the mRNA encoding OPAQUE2 (O2) like TF of finger millet (FM) (Eleusine coracana) (EcO2). Full-length EcO2 mRNA was isolated using conserved primers designed by aligning O2 mRNAs of different cereals followed by 3' and 5' RACE (Rapid Amplification of cDNA Ends). The assembled full-length EcO2 mRNA was found to contain an ORF of 1248-nt coding the 416 amino acids O2 protein. Domain analysis revealed the presence of the BLZ and bZIP-C domains which is a characteristic feature of O2 proteins. Phylogenetic analysis of EcO2 protein with other bZIP proteins identified using finger millet transcriptome data and O2 proteins of other cereals showed that EcO2 shared high sequence similarity with barley BLZ1 protein. Transcripts of EcO2 were detected in root, stem, leaves, and seed development stages. Furthermore, to investigate nitrogen responsiveness and the role of EcO2 in regulating seed storage protein gene expression, the expression profiles of EcO2 along with an α-prolamin gene were studied during the seed development stages of two FM genotypes (GE-3885 and GE-1437) differing in grain protein content (13.8 and 6.2%, respectively) grown under increasing nitrogen inputs. Compared to GE-1437, the EcO2 was relatively highly expressed during the S2 stage of seed development which further increased as nitrogen input was increased. The Ecα-prolamin gene was strongly induced in the high protein genotype (GE-3885) at all nitrogen inputs. These results indicate the presence of nitrogen responsiveness regulatory elements which might play an important role in accumulating protein in FM genotypes through modulating EcO2 expression by sensing plant nitrogen status.

Conspiracy Beliefs Are Not Necessarily a Barrier to Engagement in HIV Care Among Urban, Low-Income People of Color Living with HIV.

BACKGROUND: HIV-related "conspiracy beliefs" include ideas about the genocidal origin of HIV to target minority people, and the notion that a cure for HIV is being deliberately withheld. Previous literature suggests that these beliefs may negatively affect engagement in HIV care and ART adherence, but little is known about how people who are disengaged from care may think about these ideas. METHODS: Twenty-seven semi-structured interviews were conducted with low-income Black and Latinx people living with HIV in NYC who were currently disengaged from, or recently re-engaged in, HIV care. FINDINGS: The data suggest that HIV-related "conspiracy beliefs" are not necessarily a barrier to care. Regardless of whether or not people endorsed these ideas, participants were largely dismissive, and prioritized focusing on managing their HIV and overall health and life challenges. RECOMMENDATIONS: Interventions aiming to improve ART adherence and retention in HIV care should focus on building trust between clinicians and populations that have experienced historical, as well as ongoing, marginalization. HIV care providers should ask patients open-ended questions specifically about their beliefs about HIV and ART in order to address potential suspicion. Moving away from the phrase "conspiracy beliefs" in favor of more neutral language, such as "HIV-related beliefs," can enable us to better understand these ideas in the context of people's daily lives. CONCLUSIONS: Further research is needed to better understand how structural inequality may shape how people experience mistrust, and how mistrust may factor into the constellation of barriers to consistent engagement in HIV care.

Applicability of different mixed dentition analysis in Lucknow population.

AIMS: The aim of this study was to test the reliability of Moyer's and Tanaka-Johnston method of mixed dentition analysis among Lucknow population and also derive a linear regression equation that would predict sum of mesiodistal widths of upper and lower canines and premolars for both sexes. SETTING AND DESIGN: Moyer's and Tanaka-Johnston mixed dentition space analysis were developed from a sample of North European descent children. Hence, it becomes questionable when applied to individuals with different ethnic origin. MATERIALS AND METHODS: Actual mesiodistal widths of permanent upper and lower incisors, canines, and premolars were recorded on 100 dental casts for both sexes using digital Vernier caliper nearest of 0.02 mm. Predicted values of mesiodistal widths of permanent upper and lower canines and premolars were obtained using Moyer's probability analysis at the 75th percentile and Tanaka-Johnston method. Both actual and predicted values for both sexes were put to statistical evaluation using student "t" test and unpaired "t" test. RESULTS: Differences between the actual and predicted values of upper and lower permanent canines and premolars were statistically significant in both sexes (P < 0.05) for both Moyer's and Tanaka-Johnston mixed dentition analysis. Four linear regression, equations were developed for both sexes to predict mesiodistal widths of erupting upper and lower permanent canines and premolars using the lower incisors. No significant difference was observed when the regression equations were applied. CONCLUSION: Predictions from linear regression equations matched well with the data obtained from the samples of the present study for both males and females of Lucknow population.

Genotyping-by-Sequencing Analysis for Determining Population Structure of Finger Millet Germplasm of Diverse Origins.

Finger millet [ (L.) Gaertn.] is grown mainly by subsistence farmers in arid and semiarid regions of the world. To broaden its genetic base and to boost its production, it is of paramount importance to characterize and genotype the diverse gene pool of this important food and nutritional security crop. However, as a result of nonavailability of the genome sequence of finger millet, the progress could not be made in realizing the molecular basis of unique qualities of the crop. In the present investigation, attempts have been made to characterize the genetically diverse collection of 113 finger millet accessions through whole-genome genotyping-by-sequencing (GBS), which resulted in a genome-wide set of 23,000 single-nucleotide polymorphisms (SNPs) segregating across the entire collection and several thousand SNPs segregating within every accession. A model-based population structure analysis reveals the presence of three subpopulations among the finger millet accessions, which are in parallel with the results of phylogenetic analysis. The observed population structure is consistent with the hypothesis that finger millet was domesticated first in Africa, and from there it was introduced to India some 3000 yr ago. A total of 1128 gene ontology (GO) terms were assigned to SNP-carrying genes for three main categories: biological process, cellular component, and molecular function. Facilitated access to high-throughput genotyping and sequencing technologies are likely to improve the breeding process in developing countries, and as such, this data will be very useful to breeders who are working for the genetic improvement of finger millet.

Injured astrocytes are repaired by Synaptotagmin XI-regulated lysosome exocytosis.

Astrocytes are known to facilitate repair following brain injury; however, little is known about how injured astrocytes repair themselves. Repair of cell membrane injury requires Ca(2+)-triggered vesicle exocytosis. In astrocytes, lysosomes are the main Ca(2+)-regulated exocytic vesicles. Here we show that astrocyte cell membrane injury results in a large and rapid calcium increase. This triggers robust lysosome exocytosis where the fusing lysosomes release all luminal contents and merge fully with the plasma membrane. In contrast to this, receptor stimulation produces a small sustained calcium increase, which is associated with partial release of the lysosomal luminal content, and the lysosome membrane does not merge into the plasma membrane. In most cells, lysosomes express the synaptotagmin (Syt) isoform Syt VII; however, this isoform is not present on astrocyte lysosomes and exogenous expression of Syt VII on lysosome inhibits their exocytosis. Deletion of one of the most abundant Syt isoform in astrocyte--Syt XI--suppresses astrocyte lysosome exocytosis. This identifies lysosome as Syt XI-regulated exocytic vesicle in astrocytes. Further, inhibition of lysosome exocytosis (by Syt XI depletion or Syt VII expression) prevents repair of injured astrocytes. These results identify the lysosomes and Syt XI as the sub-cellular and molecular regulators, respectively of astrocyte cell membrane repair.

Recent vs Conventional Methods of Caries Removal: A Comparative in vivo Study in Pediatric Patients.

AIMS: To compare the three different methods of caries removal, conventional method using Airotor and chemomechanical method using Carisolv and Papacarie. SETTINGS AND DESIGN: The patients with multiple carious teeth were selected either in the deciduous dentition or mixed dentition. Ninety primary molars were selected from 30 children (10 males and 20 females) between the age group 6 and 9 years. MATERIALS AND METHODS: After caries excavation, cavities were evaluated for caries removal or clinical efficacy by the tactile and visual criteria, microbiological efficacy, time taken for the procedure. Patient acceptability toward the treatment was also checked with the help of a visual analog scale (VAS). The observations thus obtained were subjected to statistical analysis using analysis of variance (ANOVA), Mann-Whitney U-test and Kruskal-Wallis test. RESULTS: The clinical efficacy of caries removal was highest with Airotor while the microbiological efficacy of caries removal was almost comparable with Airotor, Carisolv and Papacarie caries removal methods. The time taken to remove caries by Airotor method was observed to be least while the patient acceptance was found to be highest with Papacarie method. How to cite this article: Chowdhry S, Saha S, Samadi F, Jaiswal JN, Garg A, Chowdhry P. Recent vs Conventional Methods of Caries Removal: A Comparative in vivo Study in Pediatric Patients. Int J Clin Pediatr Dent 2015;8(1):6-11.

Alteration of Genetic Make-up in Karnal Bunt Pathogen (Tilletia indica) of Wheat in Presence of Host Determinants.

Alteration of genetic make-up of the isolates and monosporidial strains of Tilletia indica causing Karnal bunt (KB) disease in wheat was analyzed using DNA markers and SDS-PAGE. The generation of new variation with different growth characteristics is not a generalized feature and is not only dependant on the original genetic make up of the base isolate/monosporidial strains but also on interaction with host. Host determinant(s) plays a significant role in the generation of variability and the effect is much pronounced in monosporidial strains with narrow genetic base as compared to broad genetic base. The most plausible explanation of genetic variation in presence of host determinant(s) are the recombination of genetic material from two different mycelial/sporidia through sexual mating as well as through para-sexual means. The morphological and development dependent variability further suggests that the variation in T. indica strains predominantly derived through the genetic rearrangements.

Dysferlin regulates cell membrane repair by facilitating injury-triggered acid sphingomyelinase secretion.

Dysferlin deficiency compromises the repair of injured muscle, but the underlying cellular mechanism remains elusive. To study this phenomenon, we have developed mouse and human myoblast models for dysferlinopathy. These dysferlinopathic myoblasts undergo normal differentiation but have a deficit in their ability to repair focal injury to their cell membrane. Imaging cells undergoing repair showed that dysferlin-deficit decreased the number of lysosomes present at the cell membrane, resulting in a delay and reduction in injury-triggered lysosomal exocytosis. We find repair of injured cells does not involve formation of intracellular membrane patch through lysosome-lysosome fusion; instead, individual lysosomes fuse with the injured cell membrane, releasing acid sphingomyelinase (ASM). ASM secretion was reduced in injured dysferlinopathic cells, and acute treatment with sphingomyelinase restored the repair ability of dysferlinopathic myoblasts and myofibers. Our results provide the mechanism for dysferlin-mediated repair of skeletal muscle sarcolemma and identify ASM as a potential therapy for dysferlinopathy.

Association mapping of agro-morphological characters among the global collection of finger millet genotypes using genomic SSR markers.

Identification of alleles responsible for various agro-morphological characters is a major concern to further improve the finger millet germplasm. Forty-six genomic SSRs were used for genetic analysis and population structure analysis of a global collection of 190 finger millet genotypes and fifteen agro-morphological characters were evaluated. The overall results showed that Asian genotypes were smaller in height, smaller flag leaf length, less basal tiller number, early flowering and early maturity nature, small ear head length, and smaller in length of longest finger. The 46 SSRs yielded 90 scorable alleles and the polymorphism information content values varied from 0.292 to 0.703 at an average of 0.442. The gene diversity was in the range of 0.355 to 0.750 with an average value of 0.528. The 46 genomic SSR loci grouped the 190 finger millet genotypes into two major clusters based on their geographical origin by the both phylogenetic clustering and population structure analysis by STRUCTURE software. Association mapping of QTLs for 15 agro-morphological characters with 46 genomic SSRs resulted in identification of five markers were linked to QTLs of four traits at a significant threshold (P) level of ≤ 0.01 and ≤ 0.001. The QTL for basal tiller number was strongly associated with the locus UGEP81 at a P value of 0.001 by explaining the phenotypic variance (R (2)) of 10.8%. The QTL for days to 50% flowering was linked by two SSR loci UGEP77 and UGEP90, explained 10 and 8.7% of R (2) respectively at a P value of 0.01. The SSR marker, FM9 found to have strong association to two agro-morphological traits, flag leaf width (P-0.001, R(2)-14.1 %) and plant height (P-0.001, R(2)-11.2%). The markers linked to the QTLs for above agro-morphological characters found in the present study can be further used for cloning of the full length gene, fine mapping and their further use in the marker assisted breeding programmes for introgression of alleles into locally well adapted germplasm.

'Metal to resin': a comparative evaluation of conventional band and loop space maintainer with the fiber reinforced composite resin space maintainer in children.

AIMS: To compare the clinical efficacy of two space maintainers namely, conventional band and loop and Fiber Reinforced Composite Resin (FRCR) space maintainers. SUBJECTS AND METHODS: Thirty healthy children, aged 5 to 8 years were selected having at least two deciduous molars in different quadrants indicated for extraction or lost previously. FRCR space maintainer was placed in one quadrant and in the other quadrant band and loop space maintainer was cemented. All the patients were recalled at 1 st, 3 rd, and 6 th months for evaluation of both types of space maintainer. Patient acceptability, time taken, and clinical efficacy was recorded. STATISTICAL ANALYSIS USED: The observations thus obtained were subjected to statistical analysis using Chi- square test and Mann-Whitney U test. RESULTS: Patient acceptability was greater in Group I (FRCR) in comparison to Group II (band and loop space maintainer). The time taken by Group I was significantly lower as compared to that of Group II. In Group I, debonding of enamel, composite was the most common complication leading to failure followed by debonding of fiber composite. In Group II, cement loss was the most common complication leading to failure followed by slippage of band and fracture of loop. The success rates of Groups I and Group II weares 63.3% and 36.7%, respectively. CONCLUSION: The study concluded that FRCRFiber Reinforced Composite Resin (Ribbond) space maintainers can be considered as viable alternative to the conventional band and loop space maintainers.

Cloning and characterization of cold, salt and drought inducible C-repeat binding factor gene from a highly cold adapted ecotype of Lepidium latifolium L.

The dehydration-responsive element-binding (DREB) protein/C-Repeat Binding Factors (CBFs) belongs to APETALA2 (AP2) family transcription factors that binds to DRE/CRT cis-element in cold-responsive (COR) genes and induce COR genes. CBFs have been isolated and characterized from evolutionarily diverse plant species. CBF pathway is conserved by CBF regulon and the size or the number and kind of target genes vary among freezing sensitive and tolerant plants. Hence, cloning of CBFs from highly freezing tolerant plants such as Lepidium latifolium L. will be useful in understanding the freezing tolerance of this species. In this study, LlCBF, a CBF1 family gene from L. Latifolium L., was cloned using RT-PCR and RACE-PCR. The full length mRNA of LlCBF is 948 bp with an open reading frame of 642 bp, encoding a protein of 213 amino acids with a molecular weight of 23.92 kDa and a theoretical isoelectric point of 4.80. Amino acid sequence analysis showed that LlCBF has an AP2 DNA binding domain, a potential CBF type nuclear localization signal (NLS) and C-terminal acidic domain. Semi-quantitative RT-PCR analysis of LlCBF revealed that this gene is up-regulated by high salt, dehydration and low temperature stresses. The investigation is therefore successful in cloning of a gene having strong homology with CBF transcription factors and responsive to low temperature, high salt and dehydration conditions.

DREB1/CBF transcription factors: their structure, function and role in abiotic stress tolerance in plants.

Drought, high salinity and low temperature are major abiotic stresses that influence survival, productivity and geographical distribution of many important crops across the globe. Plants respond to these environmental challenges via physiological, cellular and molecular processes, which results in adjusted metabolic and structural alterations. The dehydration-responsiveelement-binding (DREB) protein / C-repeat binding factors (CBFs) belong to APETALA2 (AP2) family transcription factors that bind to DRE/CRT cis-element and regulate the expression of stress-responsive genes. DREB1/CBF genes, therefore, play an important role in increasing stress tolerance in plants and their deployment using transgenic technology seems to be a potential alternative in management of abiotic stresses in crop plants. This review is mainly focussed on the structural characteristics as well as transcriptional regulation of gene expression in response to various abiotic stresses, with particular emphasis on the role of DREB1/CBF regulon in stress-responsive gene expression. The recent progress related to genetic engineering of DREB1/CBF transcription factors in various crops and model plants is also summarized.

Oral pemphigus vulgaris in a pediatric patient.

Pemphigus vulgaris is a chronic autoimmune mucocutaneous disease that initially manifests in the form of intraoral lesions, which spread to other mucous membranes and the skin. The etiology of pemphigus vulgaris is still unknown, although the disease has attracted considerable interest. The pemphigus group of diseases is characterized by the production of autoantibody against intercellular substances and is thus classified as autoimmune diseases. A case of oral pemphigus vulgaris is presented with special emphasis on diagnostic modalities.