Inova Design Solutions (United Kingdom)

В работе рассматриваются математические и компьютерные модели и методы изучения образцов пород с включениями псевдофрактальной структуры и перспективы применения компьютерного моделирования для изучения их строения. Подобные структуры имеют место, например, в трещиноватых горных массивах. Они, в свою очередь, могут являться коллекторами углеводородов, изучение и исследование свойств которых обусловливает актуальность исследования. В статье предложен способ компьютерного моделирования анизотропных по упругим параметрам псевдофрактальных включений в образцах горных пород в виде параллелепипедов и эллипсоидальных луночек. Для математической модели распространения звуковой волны в геологическом образце породы, насыщенной анизотропными фрактальными включениями (микроанизотропия), применяется способ расчета на основе объемных интегральных представлений и интегральных уравнений поля в частотной области. В статье представлены результаты проведенных вычислительных экспериментов по комплексному исследованию трещиноватых коллекторов, с возможностью расширения исследуемой области и моделированием распространения в ней разных видов полей. Материалы статьи представляют практическую ценность для исследования трещиноватых горных пород на больших глубинах с помощью применения полученного алгоритма генерации анизотропных псевдофрактальных включений и расчета в их присутствии сейсмических полей. This paper examines mathematical and computer models and methods for studying rock samples containing pseudo-fractal inclusions and the potential for using computer modeling to investigate their structure. Such structures are found, for example, in fractured rock massifs. These structures, in turn, can serve as hydrocarbon reservoirs, and the study and investigation of their properties makes this research relevant. The article proposes a method for computer modeling pseudo-fractal inclusions in rock samples in the form of parallelepipeds and ellipsoidal dimples, with anisotropic elastic parameters. A calculation method based on volumetric integral representations and integral field equations in the frequency domain is used to mathematically model sound wave propagation in a geological rock sample saturated with anisotropic fractal inclusions (microanisotropy). The article presents the results of computational experiments on a comprehensive study of fractured reservoirs, with the possibility of expanding the study area and modeling the propagation of various types of fields within it. The materials of the article are of practical value for the study of fractured rocks at great depths by applying the obtained algorithm for generating anisotropic pseudofractal inclusions and calculating seismic fields in their presence.

Lignin is the largest component of biomass and the second most abundant natural polymer. Lignin-based products are commonly applied as binders, and are utilized for polymer applications. The purpose of this study is to use lignin as an admixture in mortar. The lignin dissolved in 1M NaOH solution, and the ratio was 1:5 by weight. The lignin contents utilised in this study were 1%, 2%, 3% by weight of cement and a cement water rasio of 0.4. Lignin as an admixture in mortar increased the flowability value. The flowability value increased as the lignin content rose. the highest compressive strength and flexural strength occured at 1% lignin content. They were 35.71 MPa and it was 5.49 MPa, at the age of 28 days. The longest setting time was obtained at 3% lignin content for initial setting time of 285 minutes, and final setting time of 540 minutes. Based on the results of the setting time test, it has been determined that the more lignin was mixed in, the longer the setting time will be. Therefore lignin as an admixture to the mortar makes changes its characteristics.

Abstract Background SCD is the most common inherited blood disorder caused by a mutation in the β - globin (HBB) gene, resulting in dysfunctional hemoglobin S (HbS) that polymerizes under hypoxic conditions with consequent characteristic and pathogenic dysmorphic erythrocytes. Increased expression of fetal hemoglobin (HbF) can counteract this process, ameliorating clinical manifestations and symptoms of SCD and reducing morbidity and mortality. Pociredir, a novel, oral HbF inducer in development for the treatment of SCD, targets the embryonic ectoderm development subunit of polycomb repressive complex 2, inhibiting trimethylation of lysine 27 on histone H3, decreasing BCL11A expression and increasing HbF. We report on an ongoing phase 1b, open-label, multicenter, international study evaluating the safety, PK, and PD of oral pociredir in patients with SCD (PIONEER; ClinicalTrials.gov ID: NCT05169580). Methods The study was approved by regulatory authorities and ethics committees of participating sites. All participants provided written informed consent prior to their inclusion. PIONEER will enroll up to 70 patients 18-65 years of age with SCD (genotypes: S/S, S/β0, S/β+, and S/C). Current key inclusion criteria are poor response or intolerance of hydroxy urea (HU) and severe sickle cell disease. Exclusion criteria include prior hematopoietic stem cell transplant, or gene therapies; receiving scheduled transfusions; having known chromosomal abnormality or genetic mutation that may put the patient at increased risk of myelodysplastic syndrome or acute myeloid leukemia. Pociredir will be administered orally once daily for 12 weeks. Patients will be followed post dosing for 4 weeks. Primary endpoints are safety and tolerability and PK of pociredir. Secondary endpoints are changes from baseline in HbF and other SCD relevant biomarkers. Before a significant study amendment, patients enrolled across 3 cohorts. Cohort 1 enrolled 10 adults who received pociredir at a dose of 6 mg once daily (QD) for 4 weeks, with an option to continue for 8 more weeks. Cohorts 2 and 3 enrolled 2 adults (2 mg QD for 12 weeks) and 4 adults (12 mg QD), respectively. Concurrent hydroxyurea (HU) was allowed for patients included in the analysis. Results As of data cut off, 16 patients with HbSS genotype have been included in the analysis. Their mean age was 30.3 years (range, 21-48), and most participants were female (69%). Baseline mean HbF was 9.3% (range, 3.2-19.9%) and 5 patients were on HU. Ten patients had 23 adverse events (AEs), with 8 AEs deemed possibly related to pociredir, including headache (n = 2), lip numbness, diarrhea, tinnitus, fatigue, drowsiness, and nausea. All related AEs were mild, nonserious, resolved quickly, and did not lead to drug discontinuation. Four AEs were vaso-occlusive crises (VOCs); 1 was a serious AE involving ACS, unrelated to the drug, in a nonadherent patient. Other VOCs were mild to moderate and managed as outpatients. No laboratory-related AEs, deaths, or discontinuations occurred. Maximum HbF increase from baseline was 9.8% points at 12 weeks (Cohort 1) and 10.0% points at 6 weeks (Cohort 3). Most patients showed improved hemolysis biomarkers. Conclusions Preliminary safety, PK, and efficacy results demonstrate a favorable safety profile, a dose-dependent increase in HbF, and a reduction in hemolysis, supporting further investigation. PIONEER is currently enrolling in Nigeria, South Africa, and the United States.

<div class="section abstract"><div class="htmlview paragraph">In this study, an initial approach using deep reinforcement learning to replicate the complex behaviors of motorcycle riders was presented. Three learning examples were demonstrated: following a target velocity, maintaining stability at low speeds, and following a target trajectory. These examples serve as a starting point for further research. Additionally, the proficiency of the constructed models was examined using rider proficiency evaluation methods developed in previous studies. Initial results indicated that the models have the potential to mimic real rider behaviors; however, challenges such as differences between the model’s output and what humans can produce were also identified for future work.</div></div>

Non-factor therapies are changing the treatment paradigm in hemophilia A, which was previously dominated by replacement-therapy using factor VIII (FVIII) concentrates. However, the FVIII equivalence of these new therapies has remained unclear, since in vitro assays generate variable responses. Here we used four different in vivo bleeding models to compare FVIII to emicizumab and to a sequence-identical analog of the tissue factor pathway inhibitor-targeting antibody marstacimab (SIA-marstacimab). The severity of these models was variable, each requiring different doses of FVIII to reduce blood loss to levels of wild-type mice. For example, a dose of 2.5 IU/kg FVIII was needed for full correction in the tail vein transection (TVT) model, whereas 25 IU/kg was needed in the saphenous vein puncture (SVP) model. Intermediate doses were required in the tail artery transection (TAT) model (5 IU/kg) and tail clip model (7.5 IU/kg). Importantly, FVIII treatment produced stable clots, without spontaneous rebleeds being observed. Both emicizumab and SIA-marstacimab (used at therapeutic doses of 55 μg/mL and 16 μg/mL, respectively) displayed a variable, model-dependent FVIII equivalence. For example, emicizumab proved equivalent to 5 IU/kg FVIII in the tail clip model, and to 10 IU/kg in the SVP model. Strikingly, both emicizumab and SIA-marstacimab treatment resulted in spontaneous rebleeds in the TVT, TAT and tail clip models, further distinguishing them from FVIII treatment. Our data suggest that there is unlikely to be a single FVIII equivalence for emicizumab, SIA-marstacimab, and similar molecules, because their activity is dependent on local conditions and severity of the injury.

Why does a normal cell possibly harboring genetic mutations in oncogene or tumor suppressor genes becomes malignant and develops a tumor is a subject of intense debate. Various theories have been proposed but their experimental test has been hampered by the unpredictable and improbable malignant transformation of single cells. Here, using an optogenetic approach we permanently turn on an oncogene (KRASG12V) in a single cell of a zebrafish brain that, only in synergy with the transient co-activation of a reprogramming factor (VENTX/NANOG/OCT4), undergoes a deterministic malignant transition and robustly and reproducibly develops within 6 days into a full-blown tumor. The controlled way in which a single cell can thus be manipulated to give rise to cancer lends support to the ‘ground state theory of cancer initiation’ through ‘short-range dispersal’ of the first malignant cells preceding tumor growth.

ABSTRACT LMNA cardiomyopathy, caused by mutations in the LMNA gene, is a severe form of dilated cardiomyopathy characterized by arrhythmias, contractile dysfunction, and increased myocardial fibrosis, which impairs left ventricular function and predisposes to heart failure. While the disease has been well characterized, a lack of insight into the pathogenesis impeded the development of therapies. We here used patient-derived LMNA p.H222P cardiomyocytes (hiPSC-CMs) and their isogenic controls and a Lmna H222P/H222P mouse model to dissect abnormal cardiac mechanisms leading to the development of the disease. We showed that LMNA p.H222P hiPSC-CMs exhibit elevated diastolic calcium levels and hypocontractility. They displayed nuclear shape abnormalities, a hallmark of LMNA cardiomyopathy, associated with altered chromosome spatial organization and gene expression profiles. Using transcriptomic analysis, we further revealed that genes related to cardiac extracellular matrix (ECM) remodeling, deposition, and components are dysregulated in both LMNA p.H222P hiPSC-CMs and mutated mice, suggesting a conserved pathogenic mechanism across species. Conversely, molecular inhibition of Loxl2, a key component of the ECM establishment, preserved the cardiac function in vivo . Taken together, our findings suggest that targeting Loxl2 could be a promising therapeutic strategy to maintain cardiac function in LMNA cardiomyopathy.