Functional characterization of BRCC3 mutations in acute myeloid leukemia with t(8;21)(q22;q22.1)

BRCA1/BRCA2-containing complex 3 (BRCC3) is a Lysine 63-specific deubiquitinating enzyme (DUB) involved in inflammasome activity, interferon signaling, and DNA damage repair. Recurrent mutations in BRCC3 have been reported in myelodysplastic syndromes (MDS) but not in de novo AML. In one of our recent studies, we found BRCC3 mutations selectively in 9/191 (4.7%) cases with t(8;21)(q22;q22.1) AML but not in 160 cases of inv(16)(p13.1q22) AML. Clinically, AML patients with BRCC3 mutations had an excellent outcome with an event-free survival of 100%. Inactivation of BRCC3 by CRISPR/Cas9 resulted in improved proliferation in t(8;21)(q22;q22.1) positive AML cell lines and together with expression of AML1-ETO induced unlimited self-renewal in mouse hematopoietic progenitor cells in vitro. Mutations in BRCC3 abrogated its deubiquitinating activity on IFNAR1 resulting in an impaired interferon response and led to diminished inflammasome activity. In addition, BRCC3 inactivation increased release of several cytokines including G-CSF which enhanced proliferation of AML cell lines with t(8;21)(q22;q22.1). Cell lines and primary mouse cells with inactivation of BRCC3 had a higher sensitivity to doxorubicin due to an impaired DNA damage response providing a possible explanation for the favorable outcome of BRCC3 mutated AML patients

Modulation of Working Memory Using Transcranial Electrical Stimulation: A Direct Comparison Between TACS and TDCS

Transcranial electrical stimulation (TES) has been considered a promising tool for improving working memory (WM) performance. Recent studies have demonstrated modulation of networks underpinning WM processing through application of transcranial alternating current (TACS) as well as direct current (TDCS) stimulation. Differences between study designs have limited direct comparison of the efficacy of these approaches, however. Here we directly compared the effects of theta TACS (6 Hz) and anodal TDCS on WM, applying TACS to the frontal-parietal loop and TDCS to the dorsolateral prefrontal cortex (DLPFC). WM was evaluated using a visual 2-back WM task. A within-subject, crossover design was applied (N = 30) in three separate sessions. TACS, TDCS, and sham stimulation were administered in a counterbalanced order, and the WM task was performed before, during, and after stimulation. Neither reaction times for hits (RT-hit) nor accuracy differed according to stimulation type with this study design. A marked practice effect was noted, however, with improvement in RT-hit irrespective of stimulation type, which peaked at the end of the second session. Pre-stimulation RT-hits in session three returned to the level observed pre-stimulation in session two, irrespective of stimulation type. The participants who received sham stimulation in session one and had therefore improved their performance due to practice alone, had thus reached a plateau by session two, enabling us to pool RT-hits from sessions two and three for these participants. The pooling allowed implementation of a within-subject crossover study design, with a direct comparison of the effects of TACS and TDCS in a subgroup of participants (N = 10), each of whom received both stimulation types, in a counterbalanced order, with pre-stimulation performance the same for both sessions. TACS resulted in a greater improvement in RT-hits than TDCS (F(2,18) = 4.31 p = 0.03). Our findings suggest that future work optimizing the application of TACS has the potential to facilitate WM performance

Comprehensive CRISPR-Cas9 screens identify genetic determinants of drug responsiveness in multiple myeloma

The introduction of new drugs in the past years has substantially improved outcome in multiple myeloma (MM). However, the majority of patients eventually relapse and become resistant to one or multiple drugs. While the genetic landscape of relapsed/ resistant multiple myeloma has been elucidated, the causal relationship between relapse-specific gene mutations and the sensitivity to a given drug in MM has not systematically been evaluated. To determine the functional impact of gene mutations, we performed combined whole-exome sequencing (WES) of longitudinal patient samples with CRISPR-Cas9 drug resistance screens for lenalidomide, bortezomib, dexamethasone, and melphalan. WES of longitudinal samples from 16 MM patients identified a large number of mutations in each patient that were newly acquired or evolved from a small subclone (median 9, range 1-55), including recurrent mutations in TP53, DNAH5, and WSCD2. Focused CRISPR-Cas9 resistance screens against 170 relapse-specific mutations functionally linked 15 of them to drug resistance. These included cereblon E3 ligase complex members for lenalidomide, structural genes PCDHA5 and ANKMY2 for dexamethasone, RB1 and CDK2NC for bortezomib, and TP53 for melphalan. In contrast, inactivation of genes involved in the DNA damage repair pathway, including ATM, FANCA, RAD54B, and BRCC3, enhanced susceptibility to cytotoxic chemotherapy. Resistance patterns were highly drug specific with low overlap and highly correlated with the treatment-dependent clonal evolution in patients. The functional association of specific genetic alterations with drug sensitivity will help to personalize treatment of MM in the future

Trends of credit service market development in Ukraine

Актуальність обраної теми підтверджується тим, що в Україні сформована банкоцентрична модель функціонування національного господарства, існує об’єктивна необхідність пошуку нових напрямків забезпечення стійкості банківської системи та зниження ймовірності прояву системних ризиків на основі диверсифікації напрямів діяльності банківських установ. Розширення спектра банківських послуг, що надаються клієнтам, дозволяє перерозподілити фінансові ризики, знижуючи рівень їх негативного впливу на ефективність роботи банку, сформувати нові канали надходження доходів. У результаті проведеного аналізу тенденцій розвитку банківської системи України виявлено, що з кожним роком кількість комерційних банків, які мають банківську ліцензію постійно зменшується, що в основному було спричинено важкою фінансово-економічною ситуацією в державі, кризовими явищами, веденням тимчасової адміністрації в банках та їх ліквідацією. Враховуючи високу ризиковість банківської діяльності, багато власників комерційних банків, особливо невеликих, можуть у майбутньому самоліквідуватись. У такому процесі актуалізуються питання підвищення обсягів надання кредитних послуг в Україні та зростання питомої ваги комісійних надходжень у загальній структурі доходів банківських установ. У статті проаналізовано сучасний стан розвитку ринку кредитних послуг в Україні, визначено особливості його функціонування. Оцінювання сучасного стану ринку кредитних послуг було проведено за допомогою аналізу класичних показників діяльності банківських установ в Україні, що дозволило визначити її базові особливості функціонування. Також були виявлені й труднощі проведення ґрунтовних досліджень їх надання клієнтам. Запропоновано методи впливу на ефективність процесу диверсифікації кредитних банківських послуг (визначення зовнішніх й внутрішніх умов диверсифікації кредитних банківських послуг і їх проектування на продуктову політику банку; типізація клієнтів та визначення перспективних цільових ринкових сегментів; визначення технологічних аспектів реалізації диверсифікації кредитних послуг комерційного банку; побудова прогнозних моделей продажів трансформованих продуктів та послуг комерційних банків; оцінка ефективності витрат на диверсифікацію кредитних банківських послуг).The importance of the chosen issue is confirmed by the fact that a bank-centered model of national economy functioning is formed in Ukraine, there is an objective need to find new directions for ensuring the stability of the banking system and reduce the probability of systemic risks manifestation on the basis of diversification of the banking institutions activity. Expansion of the banking services range provided to the customers makes it possible to redistribute financial risks, reducing the level of their negative impact on the bank operating efficiency, to form new revenue streams. Analysis of the trends of banking system development in Ukraine shows that every year the number of commercial banks having banking license is steadily decreasing, mainly as the result of difficult financial and economic situation in the country, crisis phenomena, temporary bank administration introduction and its dissolution. Taking into account high riskiness of banking activities, many commercial bank owners, especially small ones, can self-dissolve in the future. In such process, the problems of credit services volume increase in Ukraine and the growth of commission share in general income structure of banking institutions become actual. The current state of credit services market development in Ukraine is analyzed, the peculiarities of its functioning are identified in this paper. The evalution of the current state of credit services market is carried out due to the analysis of classical indicators of banking institutions activities in Ukraine making it possible to determine its basic functioning features. However, the difficulties of carrying out the profound research of their provision to the customers are also identified. Based on this, the methods of influence on the efficiency of credit banking services diversification process (definition of external and internal conditions of credit banking services diversification and their design on the bank product policy; customers typification and determination of promising target market segments; determination of technological aspects for implementation the commercial bank credit services diversification; construction of forecasting models for sales of commercial banks transformed products and services; estimation of cost effectiveness for credit banking services diversification) are proposed

BMP-2 Dependent Increase of Soft Tissue Density in Arthrofibrotic TKA

Arthrofibrosis after total knee arthroplasty (TKA) is difficult to treat, as its aetiology remains unclear. In a previous study, we established a connection between the BMP-2 concentration in the synovial fluid and arthrofibrosis after TKA. The hypothesis of the present study was, therefore, that the limited range of motion in arthrofibrosis is caused by BMP-2 induced heterotopic ossifications, the quantity of which is dependent on the BMP-2 concentration in the synovial fluid

Search for neutral charmless B decays at LEP

A search for rare charmless decays of \Bd and \Bs mesons has been performed in the exclusive channels \Bd_{(\mathrm s)}\ra\eta\eta, \Bd_{(\mathrm s)}\ra\eta\pio and \Bd_{(\mathrm s)}\ra\pio\pio. The data sample consisted of three million hadronic \Zo decays collected by the L3 experiment at LEP from 1991 through 1994. No candidate event has been observed and the following upper limits at 90\% confidence level on the branching ratios have been set \begin{displaymath} \mathrm{Br}(\Bd\ra\eta\eta)<4.1\times 10^{-4},\,\, \mathrm{Br}(\Bs\ra\eta\eta)<1.5\times 10^{-3},\,\, \end{displaymath} \begin{displaymath} \mathrm{Br}(\Bd\ra\eta\pio)<2.5\times 10^{-4},\,\, \mathrm{Br}(\Bs\ra\eta\pio)<1.0\times 10^{-3},\,\, \end{displaymath} \begin{displaymath} \mathrm{Br}(\Bd\ra\pio\pio)<6.0\times 10^{-5},\,\, \mathrm{Br}(\Bs\ra\pio\pio)<2.1\times 10^{-4}. \end{displaymath} These are the first experimental limits on \Bd\ra\eta\eta and on the \Bs neutral charmless modes

Модернизация ректификационной колонны разделения пропан-пропиленовой фракции

Объектом проектирования является ректификационная колонна непрерывного действия для разделения пропан пропиленовой фракции, а также конденсатора-холодильника для конденсации пропилена. Целью работы является расчет ректификационной колонны и конденсатора-холодильника. В ходе расчета колонны был составлен материальный баланс колонны, рассчитано оптимальное флегмовое число и оптимальное значение числа теоретических тарелок. Так же был выполнен конструктивно-механический расчет. Входе которого определили исполнительную марку стали ректификационной колонны, условия прочности и устойчивости, найдены значения толщины стенки цилиндрической обечайки, эллиптических днища и крышки. Произведен расчет штуцеров и фланцев. В технологическом расчете теплообменника был составлен тепловой баланс. РассчитаныThe design object is a continuous distillation column for the separation of propane propylene fraction, as well as a condenser-cooler for condensation of propylene. The aim of the work is to calculate the distillation column and condenser-refrigerator. During the calculation of the column, the material balance of the column was compiled, the optimal reflux ratio and the optimal value of the number of theoretical plates were calculated. A structural and mechanical calculation was also performed. The inlet of which the executive grade of the distillation column was determined, the strength and stability conditions, the wall thickness of the cylindrical shell, elliptical bottom and cover were found. Calculation of fittings and flanges. In the technological calculation of the heat exchanger,