Acetylation Profiles of Histone and Non-Histone Proteins in Breast Cancer

This study evaluates the impact of protein acetylation on breast cancer gene expression and the regulation of metabolism. Acetylation is the second abundant post-translational modification after phosphorylation, regulating protein activity and function. The alterations in acetylation of both histone and non-histone proteins is known to be related to many human diseases, including cancer. Acetylation and deacetylation of histones is closely associated with the regulation of gene expression, while acetylation of non-histone proteins may have a broad effect on major cellular processes, such as proliferation, metabolism, cell cycle and apoptosis, imbalanced regulation of which is essential for cancer development. Therefore, it’s critical to explore the role of this post-translational modification in cancer in a systematic manner. Here, utilizing a unique acetylome dataset for 120 patients with breast cancer, as well as genomic and proteomic data, I showed the impact of acetylation on gene expression and metabolic enzymes. More specifically, the association between histone H2B acetylation level and expression of FOXA1 and GATA3 transcription factors has been established. In addition, acetylation of metabolic enzymes has been demonstrated to reveal additional information on metabolism regulation in breast cancer

Кількісне визначення оксациліну методами кінетико-спектрофотометрії та окисно-відновного титрування

The search for new analytical reactions and finding out the optimal conditions for their course, which can be used as the basis for quantitative analytical determinations of penicillins, is a very urgent task.Aim. To develop methods for the quantitative determination of Oxacillin.Materials and methods. The study object was Oxacillin sodium salt powder in vials for preparing a solution for injections(0.5 g). Peroxomonosulfate acid as triple potassium salt 2КНSO5∙КНSO4∙K2SO4 (Oxone®) of “extra pure” grade was used as an oxidant. The methods of kinetic spectriphotometry and redox titration were used.Results and discussion. A simple procedure for the quantitative determination of the Oxacillin pure substance by the kinetic spectrophotometry and redox titration methods using potassium hydrogen peroxomonosulfate (KHSO5) has been developed. The results of the drug analysis obtained by newly developed and current methods are in good agreement with each other; δ (correctness) = (0.45 – 0.86) %.Conclusions. Using the methods of kinetic spectrophotometric and redox titration, two independent procedures for thequantitative determination of oxacillin in the substance and the drug product have been developed using potassium hydrogen peroxomonosulfate as an analytical reagent (KHSO5). A relative standard deviation RSD = (1.24 – 2.17) %.Мета. Пошук нових аналітичних реакцій та з’ясування оптимальних умов їх перебігу, які можуть бути покладені в основу кількісних аналітичних визначень пеніцилінів, є вельми актуальним завданням. Метою цієї роботи було розробити методики кількісного визначення оксациліну.Матеріали та методи. Обʼєктом дослідження був Оксацилін – порошок натрій оксациліну у флаконах для приготування розчину для ін’єкцій (0,5 г). Як окисник використовували потрійну калієву сіль 2КНSO5∙КНSO4∙K2SO4 кваліфікації “extra pure” (Oxone®). У дослідженні було задіяно методи кінетико-спектрофотометрії та окисно-відновного титрування.Результати та їх обговорення. Розроблено процедуру кількісного визначення оксациліну методами кінетико-спектрофотометрії та йодометричного титрування з використанням калій гідрогенпероксомоносульфату. Результати аналізу препарату, одержані за новоопрацьованими та чинними методиками, добре узгоджуються між собою; δ (правильність) = (0.45 – 0.86) %.Висновки. За допомогою методів кінетико-спектрофотометрії та йодометричного титрування розроблено дві незалежні методики кількісного визначення оксациліну в субстанції та лікарському препараті з використанням калій гідрогенпероксомоносульфату як аналітичного реагенту (KHSO5). Відносне стандартне відхилення RSD (1,24 – 2,17) %

Toward the neural implementation of structure learning

Despite significant advances in neuroscience, the neural bases of intelligence remain poorly understood. Arguably the most elusive aspect of intelligence is the ability to make robust inferences that go far beyond one's experience. Animals categorize objects, learn to vocalize and may even estimate causal relationships -all in the face of data that is often ambiguous and sparse. Such inductive leaps are thought to result from the brain's ability to infer latent structure that governs the environment. However, we know little about the neural computations that underlie this ability. Recent advances in developing computational frameworks that can support efficient structure learning and inductive inference may provide insight into the underlying component processes and help pave the path for uncovering their neural implementation

Proteogenomic characterization of endometrial carcinoma

We undertook a comprehensive proteogenomic characterization of 95 prospectively collected endometrial carcinomas, comprising 83 endometrioid and 12 serous tumors. This analysis revealed possible new consequences of perturbations to the p53 and Wnt/β-catenin pathways, identified a potential role for circRNAs in the epithelial-mesenchymal transition, and provided new information about proteomic markers of clinical and genomic tumor subgroups, including relationships to known druggable pathways. An extensive genome-wide acetylation survey yielded insights into regulatory mechanisms linking Wnt signaling and histone acetylation. We also characterized aspects of the tumor immune landscape, including immunogenic alterations, neoantigens, common cancer/testis antigens, and the immune microenvironment, all of which can inform immunotherapy decisions. Collectively, our multi-omic analyses provide a valuable resource for researchers and clinicians, identify new molecular associations of potential mechanistic significance in the development of endometrial cancers, and suggest novel approaches for identifying potential therapeutic targets

Imaging cortical dynamics in GCaMP transgenic rats with a head-mounted widefield macroscope

Widefield imaging of calcium dynamics is an emerging method for mapping regional neural activity but is currently limited to restrained animals. Here we describe cScope, a head- mounted widefield macroscope developed to image large-scale cortical dynamics in rats during natural behavior. cScope provides a 7.8 by 4 mm field of view, dual illumination paths for both fluorescence and hemodynamic correction, and can be fabricated at low cost using readily attainable components. We also report the development of Thy-1 transgenic rat strains with widespread neuronal expression of the calcium indicator GCaMP6f. We combined these two technologies to image large-scale calcium dynamics in the dorsal neocortex during a visual evidence accumulation task. Quantitative analysis of task-related dynamics revealed multiple regions having neural signals that encode behavioral choice and sensory evidence. Our results provide a new transgenic resource for calcium imaging in rats and extend the domain of headmounted microscopes to larger-scale cortical dynamics.Accepted manuscrip

Genome-Wide Mycobacterium tuberculosis Variation (GMTV) Database: A New Tool for Integrating Sequence Variations and Epidemiology

Background Tuberculosis (TB) poses a worldwide threat due to advancing multidrug-resistant strains and deadly co-infections with Human immunodeficiency virus. Today large amounts of Mycobacterium tuberculosis whole genome sequencing data are being assessed broadly and yet there exists no comprehensive online resource that connects M. tuberculosis genome variants with geographic origin, with drug resistance or with clinical outcome. Description Here we describe a broadly inclusive unifying Genome-wide Mycobacterium tuberculosis Variation (GMTV) database, (http://mtb.dobzhanskycenter.org) that catalogues genome variations of M. tuberculosis strains collected across Russia. GMTV contains a broad spectrum of data derived from different sources and related to M. tuberculosis molecular biology, epidemiology, TB clinical outcome, year and place of isolation, drug resistance profiles and displays the variants across the genome using a dedicated genome browser. GMTV database, which includes 1084 genomes and over 69,000 SNP or Indel variants, can be queried about M. tuberculosis genome variation and putative associations with drug resistance, geographical origin, and clinical stages and outcomes. Conclusions Implementation of GMTV tracks the pattern of changes of M. tuberculosis strains in different geographical areas, facilitates disease gene discoveries associated with drug resistance or different clinical sequelae, and automates comparative genomic analyses among M. tuberculosis strains

Epigenetic regulation during cancer transitions across 11 tumour types

Chromatin accessibility is essential in regulating gene expression and cellular identity, and alterations in accessibility have been implicated in driving cancer initiation, progression and metastasi

Atrasentan and renal events in patients with type 2 diabetes and chronic kidney disease (SONAR): a double-blind, randomised, placebo-controlled trial

Background: Short-term treatment for people with type 2 diabetes using a low dose of the selective endothelin A receptor antagonist atrasentan reduces albuminuria without causing significant sodium retention. We report the long-term effects of treatment with atrasentan on major renal outcomes. Methods: We did this double-blind, randomised, placebo-controlled trial at 689 sites in 41 countries. We enrolled adults aged 18–85 years with type 2 diabetes, estimated glomerular filtration rate (eGFR)25–75 mL/min per 1·73 m 2 of body surface area, and a urine albumin-to-creatinine ratio (UACR)of 300–5000 mg/g who had received maximum labelled or tolerated renin–angiotensin system inhibition for at least 4 weeks. Participants were given atrasentan 0·75 mg orally daily during an enrichment period before random group assignment. Those with a UACR decrease of at least 30% with no substantial fluid retention during the enrichment period (responders)were included in the double-blind treatment period. Responders were randomly assigned to receive either atrasentan 0·75 mg orally daily or placebo. All patients and investigators were masked to treatment assignment. The primary endpoint was a composite of doubling of serum creatinine (sustained for ≥30 days)or end-stage kidney disease (eGFR <15 mL/min per 1·73 m 2 sustained for ≥90 days, chronic dialysis for ≥90 days, kidney transplantation, or death from kidney failure)in the intention-to-treat population of all responders. Safety was assessed in all patients who received at least one dose of their assigned study treatment. The study is registered with ClinicalTrials.gov, number NCT01858532. Findings: Between May 17, 2013, and July 13, 2017, 11 087 patients were screened; 5117 entered the enrichment period, and 4711 completed the enrichment period. Of these, 2648 patients were responders and were randomly assigned to the atrasentan group (n=1325)or placebo group (n=1323). Median follow-up was 2·2 years (IQR 1·4–2·9). 79 (6·0%)of 1325 patients in the atrasentan group and 105 (7·9%)of 1323 in the placebo group had a primary composite renal endpoint event (hazard ratio [HR]0·65 [95% CI 0·49–0·88]; p=0·0047). Fluid retention and anaemia adverse events, which have been previously attributed to endothelin receptor antagonists, were more frequent in the atrasentan group than in the placebo group. Hospital admission for heart failure occurred in 47 (3·5%)of 1325 patients in the atrasentan group and 34 (2·6%)of 1323 patients in the placebo group (HR 1·33 [95% CI 0·85–2·07]; p=0·208). 58 (4·4%)patients in the atrasentan group and 52 (3·9%)in the placebo group died (HR 1·09 [95% CI 0·75–1·59]; p=0·65). Interpretation: Atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease who were selected to optimise efficacy and safety. These data support a potential role for selective endothelin receptor antagonists in protecting renal function in patients with type 2 diabetes at high risk of developing end-stage kidney disease. Funding: AbbVie