Length-dependent changes in contractile dynamics are blunted due to cardiac myosin binding protein-C ablation

Enhanced cardiac contractile function with increased sarcomere length (SL) is, in part, mediated by a decrease in the radial distance between myosin heads and actin. The radial disposition of myosin heads relative to actin is modulated by cardiac myosin binding protein-C (cMyBP-C), suggesting that cMyBP-C contributes to the length-dependent activation (LDA) in the myocardium. However, the precise roles of cMyBP-C in modulating cardiac LDA are unclear. To determine the impact of cMyBP-C on LDA, we measured isometric force, myofilament Ca2+-sensitivity (pCa50) and length-dependent changes in kinetic parameters of cross-bridge (XB) relaxation (krel), and recruitment (kdf) due to rapid stretch, as well as the rate of force redevelopment (ktr) in response to a large slack-restretch maneuver in skinned ventricular multicellular preparations isolated from the hearts of wild-type (WT) and cMyBP-C knockout (KO) mice, at SL’s 1.9µm or 2.1µm. Our results show that maximal force was not significantly different between KO and WT preparations but length-dependent increase in pCa50 was attenuated in the KO preparations. pCa50 was not significantly different between WT and KO preparations at long SL (5.82±0.02 in WT vs. 5.87±0.02 in KO), whereas pCa50 was significantly different between WT and KO preparations at short SL (5.71±0.02 in WT vs. 5.80±0.01 in KO; p<0.05). The ktr, measured at half-maximal Ca2+-activation, was significantly accelerated at short SL in WT preparations (8.74±0.56s-1at 1.9µm vs. 5.71±0.40s-1at 2.1µm, p<0.05). Furthermore, krel and kdf were accelerated by 32% and 50%, respectively at short SL in WT preparations. In contrast, ktr was not altered by changes in SL in KO preparations (8.03±0.54s-1at 1.9µm vs. 8.90±0.37s-1at 2.1µm). Similarly, KO preparations did not exhibit length-dependent changes in krel and kdf. Collectively, our data implicate cMyBP-C is an important regulator of LDA via its impact on dynamic XB behavior due to changes in SL

Stage 3 N2 lung cancer: A multidisciplinary therapeutic conundrum

The treatment of stage III N2 non-small cell lung cancer (NSCLC) remains debated. There is an absence of a universally agreed definition of resectability for this heterogeneous group and a lack of trial data. We reviewed and compared current international guidelines and evidence surrounding management of stage III N2 NSCLC. The Irish and Australian guidelines advise subcategorising N2 disease into N2a (may be resectable) and N2b (never resectable). On the contrary, American and British guidelines avoid subcategorising N2 disease, emphasising importance of local MDT decisions. It is suggested that evidence for resection of stage III tumours is relatively weak, but that stage IIIA should generally be considered for resection, and stage IIIB is not recommended for resection. For resectable disease, surgery may be combined with neoadjuvant chemoimmunotherapy, or adjuvant chemotherapy followed by immunotherapy and radiotherapy in selected patients. There is some evidence that technically resectable disease can be treated solely with radiotherapy with similar outcomes to resection. In the event of unresectable disease, chemoradiotherapy has been the traditional management option. However, recent studies with chemoradiotherapy alongside immunotherapy appear promising. There are many factors that influence the treatment pathway offered to patients with stage III N2 NSCLC, including patient factors, team expertise, and local resources. Therefore, the role of MDTs in defining resectability and formulating an individualised treatment plan is crucial. [Abstract copyright: © 2024. Crown.

Clinical study of multiple myeloma and treatment responses in a tertiary care centre

Background: Multiple myeloma (MM) evolves from Monoclonal gammopathy of unknown significance (MGUS), a premalignant clinical condition. Second to non-Hodgkin’s lymphoma, MM is the most common haematological malignancy. The aim of the study was to review the clinical profile and response of individuals treated for MM from this part of country.Methods: We evaluated data of patients with MM managed between 2013 and 2019 at a tertiary care cancer hospital in Rajamahenderi, India. Data regarding demographic variables, clinical features, disease characteristics and treatment details were collected and analysed.Results: Total of 54 patients with MM were managed. Mean age was 59.4 years. Males accounted for 63%. Bone pain (90%) was the most common symptom. Elevated serum creatinine was noted in 16.7% and M band in 42 (77.8%). X-ray of skull showed lytic lesions in 41 (75.9%). Mean haemoglobin value was 8.8±1.9 g/dl and serum calcium was 9.12 mg/dl. Majority of subjects, 44 (81.48%) belong to stage IIIA, 9 (16.67%) to stage IIIB, and 1.85% to stage IIA of Durie Salmon staging system. No response was noted in 17 (31.5%), 4 (7.4%) subjects had a progressive disease even on treatment, and 8 (14.8%) subjects had a very good partial response. Median survival of subjects belonging to DSS stage II was 17 months, IIIA was 11.037 months and stage IIIB was 17.463 months.Conclusions: MM has an early onset in India. Though MM is an incurable disease, many promising treatment options are there which lead to increase in survival. Early treatment helps in improving mortality rates, better quality of life and decreases disease burden

On the performance of GPU accelerated q-LSKUM based meshfree solvers in Fortran, C++, Python, and Julia

This report presents a comprehensive analysis of the performance of GPU accelerated meshfree CFD solvers for two-dimensional compressible flows in Fortran, C++, Python, and Julia. The programming model CUDA is used to develop the GPU codes. The meshfree solver is based on the least squares kinetic upwind method with entropy variables (q-LSKUM). To assess the computational efficiency of the GPU solvers and to compare their relative performance, benchmark calculations are performed on seven levels of point distribution. To analyse the difference in their run-times, the computationally intensive kernel is profiled. Various performance metrics are investigated from the profiled data to determine the cause of observed variation in run-times. To address some of the performance related issues, various optimisation strategies are employed. The optimised GPU codes are compared with the naive codes, and conclusions are drawn from their performance.Comment: 42 pages, 3 figure

An intelligent energy management system for educational buildings

There is a wide variation in the energy consumption between different educational institutions due to the adoption of different management strategies and different levels of occupants’ environmental understanding. The presence of large amounts of information and communication technology (ICT) equipment and heating, ventilation, and air conditioning (HVAC) system causes a major consumption of energy in higher education institution (HEI) buildings. The main objective of this research is to investigate the use of ICT to optimize the energy consumption in HEI buildings and reduce carbon dioxide (CO 2 ) emission. The first phase of the system has been implemented at King Saud University to measure energy consumption through sensors that read energy consumption of electrical appliances and devices every 10 seconds. The analysis of collected data allows us to develop and employ energy saving strategies that lead to a reduction in total energy consumption. Our preliminary results show that up to 17% of energy consumption can be reduced by simply dealing with standby energy loss of labs’ computers. The novelty of this research comes from the use of a functional database approach to deal with high volume of data and query performance and the incorporation of a timetabling system in energy management system

The master developmental regulator Jab1/Cops5/Csn5 is essential for proper bone growth and survival in mice

Jab1, also known as Csn5/Cops5, is a key subunit of the COP9 Signalosome, a highly conserved macromolecular complex. We previously reported that the conditional knockout of Jab1 in mouse limb buds and chondrocytes results in severely shortened limbs and neonatal lethal chondrodysplasia, respectively. In this study, we further investigated the specific role of Jab1 in osteoblast differentiation and postnatal bone growth by characterizing a novel mouse model, the Osx-cre; Jab1flox/flox conditional knockout (Jab1 cKO) mouse, in which Jab1 is deleted in osteoblast precursor cells. Jab1 cKO mutant mice appeared normal at birth, but developed progressive dwarfism. Inevitably, all mutant mice died prior to weaning age. The histological and micro-computed tomography analysis of mutant long bones revealed severely altered bone microarchitecture, with a significant reduction in trabecular thickness. Moreover, Jab1 cKO mouse tibiae had a drastic decrease in mineralization near the epiphyseal growth plates, and Jab1 cKO mice also developed spontaneous fractures near the tibiofibular junction. Additionally, our cell culture studies demonstrated that Jab1 deletion in osteoblast precursors led to decreased mineralization and a reduced response to TGFβ and BMP signaling. Moreover, an unbiased reporter screen also identified decreased TGFβ activity in Jab1-knockdown osteoblasts. Thus, Jab1 is necessary for proper osteoblast differentiation and postnatal bone growth, likely in part through its positive regulation of the TGFβ and BMP signaling pathways in osteoblast progenitor cells

FCRL1 immunoregulation in B cell development and malignancy

Immunotherapeutic targeting of surface regulatory proteins and pharmacologic inhibition of critical signaling pathways has dramatically shifted our approach to the care of individuals with B cell malignancies. This evolution in therapy reflects the central role of the B cell receptor (BCR) signaling complex and its co-receptors in the pathogenesis of B lineage leukemias and lymphomas. Members of the Fc receptor-like gene family (FCRL1-6) encode cell surface receptors with complex tyrosine-based regulation that are preferentially expressed by B cells. Among them, FCRL1 expression peaks on naïve and memory B cells and is unique in terms of its intracellular co-activation potential. Recent studies in human and mouse models indicate that FCRL1 contributes to the formation of the BCR signalosome, modulates B cell signaling, and promotes humoral responses. Progress in understanding its regulatory properties, along with evidence for its over-expression by mature B cell leukemias and lymphomas, collectively imply important yet unmet opportunities for FCRL1 in B cell development and transformation. Here we review recent advances in FCRL1 biology and highlight its emerging significance as a promising biomarker and therapeutic target in B cell lymphoproliferative disorders

Computer vision and machine learning for robust phenotyping in genome-wide studies

Traditional evaluation of crop biotic and abiotic stresses are time-consuming and labor-intensive limiting the ability to dissect the genetic basis of quantitative traits. A machine learning (ML)-enabled image-phenotyping pipeline for the genetic studies of abiotic stress iron deficiency chlorosis (IDC) of soybean is reported. IDC classification and severity for an association panel of 461 diverse plant-introduction accessions was evaluated using an end-to-end phenotyping workflow. The workflow consisted of a multi-stage procedure including: (1) optimized protocols for consistent image capture across plant canopies, (2) canopy identification and registration from cluttered backgrounds, (3) extraction of domain expert informed features from the processed images to accurately represent IDC expression, and (4) supervised ML-based classifiers that linked the automatically extracted features with expert-rating equivalent IDC scores. ML-generated phenotypic data were subsequently utilized for the genome-wide association study and genomic prediction. The results illustrate the reliability and advantage of ML-enabled image-phenotyping pipeline by identifying previously reported locus and a novel locus harboring a gene homolog involved in iron acquisition. This study demonstrates a promising path for integrating the phenotyping pipeline into genomic prediction, and provides a systematic framework enabling robust and quicker phenotyping through ground-based systems