Recombinant Mitochondrial Transcription Factor A with N-terminal Mitochondrial Transduction Domain Increases Respiration and Mitochondrial Gene Expression in G11778A Leber's Hereditary Optic Neuropathy Cybrid Cells

Diseases involving mitochondrial defects usually manifest themselves in high-energy, post-mitotic tissues such as brain, retina, skeletal and cardiac muscle and frequently cause deficiencies in mitochondrial bioenergetics. We have developed a scalable procedure to produce recombinant human mitochondrial transcription factor A (TFAM) modified with an N-terminal protein transduction domain (PTD) and mitochondrial localization signal (MLS) that allow it to cross membranes and enter mitochondria through its "mitochondrial transduction domain" (MTD,=PTD+MLS). _In vitro_ studies in a classic mitochondrial disease cell model demonstrated that Alexa488-labeled MTD-TFAM rapidly entered the mitochondrial compartment. MTD-TFAM treatment of these cell lines reversibly increased oxygen consumption (respiration) rates 3-fold, levels of respiratory proteins and mitochondrial gene expression. _In vivo_ results demonstrated that respiration increased to lesser degrees in mitochondria from tissues of mice injected with MTD-TFAM. MTD-TFAM can alter mitochondrial bioenergetics and holds promise for treatment of mitochondrial diseases involving deficiencies of energy production

PRIVACY AUDITING AND DEDUPLICATING DATA WITH SECCLOUD IN CLOUD COMPUTING

As the cloud computing technology develops during the last decade, outsourcing data to cloud service for storage becomes an attractive trend, which benefits in sparing efforts on heavy data maintenance and management. Nevertheless, since the outsourced cloud storage is not fully trustworthy, it raises security concerns on how to realize data deduplication in cloud while achieving integrity auditing. In this work, we study the problem of integrity auditing and secure deduplication on cloud data. Specifically, aiming at achieving both data integrity and deduplication in cloud, we propose two secure systems, namely SecCloud and SecCloud+. SecCloud introduces an auditing entity with a maintenance of a MapReduce cloud, which helps clients generate data tags before uploading as well as audit the integrity of data having been stored in cloud. Compared with previous work, the computation by user in SecCloud is greatly reduced during the file uploading and auditing phases. SecCloud+ is designed motivated by the fact that customers always want to encrypt their data before uploading, and enables integrity auditing and secure deduplication on encrypted data

Some subordination theorems associated with a new operator

In this paper we introduce a linear operator and obtain certain differential subordination properties associated with this linear operator. Some relevant consequences of the main results including new variations of earlier known results are also pointed out

DEVELOPMENT AND CHARACTERIZATION OF GASTRO RETENTIVE MUCOADHESIVE MICROBEADS CONTAINING SIMVASTATIN WITH DIFFERENT CROSS LINKING AGENTS

Objective: The aim of the present work was to prepare and examine drug release of the oral controlled release microbeads using different curing agents by emulsification internal ionic gelation technique. Methods: Cross-linked alginate microbeads were prepared with different cross linking agents by using mucoadhesive properties. The formation and compatibility of microbeads were confirmed by compatibility studies. Prepared microbeads evaluated for encapsulated efficiency, micromeritic properties, drug loading, in vitro wash off studies, in vitro dissolution studies, drug release kinetics and stability studies Results: The in vitro drug release was influenced by both type of curing agents and type of polymers and no significant changes in characterization parameters was observed after 3 mo stability studies. The sustained release profile of optimized batch was found to be 99.66±0.18% in comparison to pure drug profile of 28.64±0.02% at 12 h release study. Results of both wash-off and in vitro studies suggests that batch (SF2) prepared with aluminium chloride has shown better mucoadhesive property. Drug release of optimized batch follows zero order with non fickian mechanism according to Korsmeyer-Peppas equation. Conclusion: The data suggest the use of simvastatin mucoadhesive cross linked microbeads to offer the potential for oral controlled drug delivery with improved gastric retention and capable to provide sustained drug release by using cross linking agents

Mitochondrial DNA Copy Numbers in Pyramidal Neurons are Decreased and Mitochondrial Biogenesis Transcriptome Signaling is Disrupted in Alzheimer’s Disease Hippocampi

Alzheimer\u27s disease (AD) is the major cause of adult-onset dementia and is characterized in its pre-diagnostic stage by reduced cerebral cortical glucose metabolism and in later stages by reduced cortical oxygen uptake, implying reduced mitochondrial respiration. Using quantitative PCR we determined the mitochondrial DNA (mtDNA) gene copy numbers from multiple groups of 15 or 20 pyramidal neurons, GFAP(+) astrocytes and dentate granule neurons isolated using laser capture microdissection, and the relative expression of mitochondrial biogenesis (mitobiogenesis) genes in hippocampi from 10 AD and 9 control (CTL) cases. AD pyramidal but not dentate granule neurons had significantly reduced mtDNA copy numbers compared to CTL neurons. Pyramidal neuron mtDNA copy numbers in CTL, but not AD, positively correlated with cDNA levels of multiple mitobiogenesis genes. In CTL, but not in AD, hippocampal cDNA levels of PGC1α were positively correlated with multiple downstream mitobiogenesis factors. Mitochondrial DNA copy numbers in pyramidal neurons did not correlate with hippocampal Aβ1-42 levels. After 48 h exposure of H9 human neural stem cells to the neurotoxic fragment Aβ25-35, mtDNA copy numbers were not significantly altered. In summary, AD postmortem hippocampal pyramidal neurons have reduced mtDNA copy numbers. Mitochondrial biogenesis pathway signaling relationships are disrupted in AD, but are mostly preserved in CTL. Our findings implicate complex alterations of mitochondria-host cell relationships in AD

Contribution of germline BRCA1 and BRCA2 sequence alterations to breast cancer in Northern India

BACKGROUND: A large number of distinct mutations in the BRCA1 and BRCA2 genes have been reported worldwide, but little is known regarding the role of these inherited susceptibility genes in breast cancer risk among Indian women. We investigated the distribution and the nature of BRCA1 and BRCA2 germline mutations and polymorphisms in a cohort of 204 Indian breast cancer patients and 140 age-matched controls. METHOD: Cases were selected with regard to early onset disease (≤40 years) and family history of breast and ovarian cancer. Two hundred four breast cancer cases along with 140 age-matched controls were analyzed for mutations. All coding regions and exon-intron boundaries of the BRCA1 and BRCA2 genes were screened by heteroduplex analysis followed by direct sequencing of detected variants. RESULTS: In total, 18 genetic alterations were identified. Three deleterious frame-shift mutations (185delAG in exon 2; 4184del4 and 3596del4 in exon 11) were identified in BRCA1, along with one missense mutation (K1667R), one 5'UTR alteration (22C>G), three intronic variants (IVS10-12delG, IVS13+2T>C, IVS7+38T>C) and one silent substitution (5154C>T). Similarly three pathogenic protein-truncating mutations (6376insAA in exon 11, 8576insC in exon19, and 9999delA in exon 27) along with one missense mutation (A2951T), four intronic alterations (IVS2+90T>A, IVS7+75A>T, IVS8+56C>T, IVS25+58insG) and one silent substitution (1593A>G) were identified in BRCA2. Four previously reported polymorphisms (K1183R, S1613G, and M1652I in BRCA1, and 7470A>G in BRCA2) were detected in both controls and breast cancer patients. Rare BRCA1/2 sequence alterations were observed in 15 out of 105 (14.2%) early-onset cases without family history and 11.7% (4/34) breast cancer cases with family history. Of these, six were pathogenic protein truncating mutations. In addition, several variants of uncertain clinical significance were identified. Among these are two missense variants, one alteration of a consensus splice donor sequence, and a variant that potentially disrupts translational initiation. CONCLUSION: BRCA1 and BRCA2 mutations appear to account for a lower proportion of breast cancer patients at increased risk of harboring such mutations in Northern India (6/204, 2.9%) than has been reported in other populations. However, given the limited extent of reported family history among these patients, the observed mutation frequency is not dissimilar from that reported in other cohorts of early onset breast cancer patients. Several of the identified mutations are unique and novel to Indian patients

Outcomes and long-term follow-up with the use of ureteral access sheath for pediatric ureteroscopy and stone treatment: Results from a tertiary endourology center

PURPOSE: The aim of this study was to retrospectively analyze outcomes of flexible ureteroscopy and laser fragmentation (FURSL) of renal stones with the use of ureteral access sheath (UAS) in the pediatric population.MATERIALS AND METHODS: We retrospectively collected data between January 2011 and January 2018 for patient demographics, stone characteristics, and outcomes in 21 children who underwent FURSL with the use of UAS.RESULTS: Twenty-one patients (10 boys and 11 girls) with a mean age of 11.8 years (range: 2-16 years) underwent FURSL using an access sheath. The stone location was in the lower pole in 13 patients (62%) with 12 patients (57%) having multiple stones. A 9.5F (35 cm) Cook Flexor UAS was used in all cases. The mean and overall stone size was 12 mm (range: 5-30 mm) and 15.4 mm (range: 5-35 mm), respectively. Preoperative stent was present in 8(38%) patients, and a postoperative stent or overnight ureteric catheter was inserted in 14 patients (67%). Thirty-one procedures (average: 1.5/patient) were needed to achieve a stone-free rate of 95%. There were no procedural or long-term complications noted over a mean follow-up of 26 months (4-37 months).CONCLUSION: The use of UAS in the treatment of pediatric renal stones is safe and feasible with good outcomes and without any long-term sequelae.</p

Stereoselective total synthesis of (+)-mueggelone, a novel inhibitor of fish development

An efficient stereoselective total synthesis of (+)-mueggelone, a novel inhibitor of fish development, is described. Highlights of the strategy include the utilization of Sharpless asymmetric epoxidation, Yamaguchi lactonization and an olefin cross-metathesis as the key steps

Effect of Kayyonyadi churna in the management of Pandu roga (Anaemia)

Pandu roga is one of the diseases mentioned in Ayurveda characterized by the whitish discolouration of the skin due to the loss of blood. The disease is comparable with Anaemia in the modern medical literature. The incidence of the problem is high in school going children, adolescents and pregnant women. So to find a cost effective remedy for the management of anaemia, Kayyonyadi churna is taken for the study which contains most of the commonly available plants and Mandura bhasma. Both of them act to reduce the Anaemia by virtue of their properties and acts as a supplement of Iron. An open end clinical trial was taken up for the study on 30 patients and 1-2 gms of the churna is given twice daily along with Takra for 30 days. It was observed from the study that the drug showed marked reduction in the clinical symptoms (p value &lt;0.0001) and improvement in the Hb% (p value &lt;0.0001)

First concise total synthesis of 5-epi-prelactone B

First short total synthesis of 5-epi-prelactone B has been achieved involving Sharpless asymmetric epoxidation and intramolecular hydride transfer reaction for formation of the aldol product by nonaldol chemistry as the key steps