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Dual-action kinase inhibitors influence p38α MAP kinase dephosphorylation

Reversible protein phosphorylation directs essential cellular processes including cell division, cell growth, cell death, inflammation, and differentiation. Because protein phosphorylation drives diverse diseases, kinases and phosphatases have been targets for drug discovery, with some achieving remarkable clinical success. Most protein kinases are activated by phosphorylation of their activation loops, which shifts the conformational equilibrium of the kinase toward the active state. To turn off the kinase, protein phosphatases dephosphorylate these sites, but how the conformation of the dynamic activation loop contributes to dephosphorylation was not known. To answer this, we modulated the activation loop conformational equilibrium of human p38α ΜΑP kinase with existing kinase inhibitors that bind and stabilize specific inactive activation loop conformations. From this, we identified three inhibitors that increase the rate of dephosphorylation of the activation loop phospho-threonine by the PPM serine/threonine phosphatase WIP1. Hence, these compounds are “dual-action” inhibitors that simultaneously block the active site and promote p38α dephosphorylation. Our X-ray crystal structures of phosphorylated p38α bound to the dual-action inhibitors reveal a shared flipped conformation of the activation loop with a fully accessible phospho-threonine. In contrast, our X-ray crystal structure of phosphorylated apo human p38α reveals a different activation loop conformation with an inaccessible phospho-threonine, thereby explaining the increased rate of dephosphorylation upon inhibitor binding. These findings reveal a conformational preference of phosphatases for their targets and suggest a unique approach to achieving improved potency and specificity for therapeutic kinase inhibitors.

Length of stay in the pediatrics emergency department and associated factors among pediatrics patients in Eastern Ethiopia public hospital, Ethiopia 2022

Introduction Patient length of stay is a crucial measure of the emergency department, and it is a vital indicator of health services to evaluate its efficacy, patient care, organizational management, and health care system. Despite this, there are a few studies conducted on pediatric emergency length of stay in developing countries. Therefore, this study serves as input for evidence of pediatric emergency length of stay and associated factors in public hospitals. Methods An institution-based cross-sectional study was conducted among children who attended in pediatric emergency department of Eastern Ethiopia public hospital from May 01 to Jun 31, 2022. A total of 761 children were selected by systematic sampling technique and interview using structured questionnaires. After data is collected and cleaned, entered using Epi data version 4.6 and then exported to Stata version 14.1 for analysis. Finally, an AOR with a 95% CI was computed, and variables with a P-value < 0.05 in the multivariable analysis were taken as significant factors for prolonged length of stay. Result The prevalence of prolonged length of stay in the emergency ward was 214 (72%). Living in a rural residence ([AOR = 1.65, 95% CI (1.10–2.48)], having a duration of pain > = 12 ([AOR = 1.92, 95% CI (1.13–3.25)], waiting time > = 5 minute ([AOR = 2.24, 95% CI (1.1–4.248541)], having comorbid illness ([AOR = 1.92, 95%CI, 1.13–3.25)], and higher acuity level and absence of medication in the hospital were ([AOR = 2.26, 95%CI (1.02–2.46]) were significantly associated factors for prolonged length of stay. Conclusion and recommendation This study revealed that more than two-thirds of children admitted to pediatric emergency had prolonged lengths of stay. This result indicated that higher proportion of the length of stay in pediatric emergency in Eastern Ethiopian public hospitals compare to national. Hence, it is better to give priority to strengthening the focused evaluation of important variables and manage accordingly.

A comprehensive guide to selecting suitable wavelet decomposition level and functions in discrete wavelet transform for fault detection in distribution networks

AbstractThe paper presents a comprehensive analysis of the IEEE-16 bus system under different operating conditions. It discusses the selection of suitable decomposition level and wavelet function for analyzing non-stationary signals to enhance power distribution network fault detection. MATLAB/Simulink is used to simulate the system, and transient fault current signals are processed with the MATLAB Wavelet Toolbox. The optimal decomposition level is determined by energy concentration, with the highest energy found in scales D9 (b4), D8 (b5), and D7 (b6), and D8 having the most concentration. Using MATLAB classifier learner, the article evaluates seven common mother wavelets with 53 wavelet functions, and sym3 is found to be the most efficient wavelet function in terms of training time, prediction speed, and accuracy of SVM classifiers. All fault types both symmetrical/unsymmetrical types, and various normal transient conditions such as load/capacitor/DG switching are detected/discriminated with nearly 100% accuracy at the midpoint of line 6–7 with various fault conditions, inception angles (0, 30, 45, 60, 90 and 120°) and a fault resistance of (5,10, 15, and 20 ohms). Additionally, 9 MW wind Farm is integrated at busbar 10, and various fault scenarios are simulated to assess system performance with 100% Accuracy.

Structural and functional dynamics of human cone cGMP-phosphodiesterase important for photopic vision

Cone cGMP-phosphodiesterase (PDE6) is the key effector enzyme for daylight vision, and its properties are critical for shaping distinct physiology of cone photoreceptors. We determined the structures of human cone PDE6C in various liganded states by single-particle cryo-EM that reveal essential functional dynamics and adaptations of the enzyme. Our analysis exposed the dynamic nature of PDE6C association with its regulatory γ-subunit (Pγ) which allows openings of the catalytic pocket in the absence of phototransduction signaling, thereby controlling photoreceptor noise and sensitivity. We demonstrate evolutionarily recent adaptations of PDE6C stemming from residue substitutions in the Pγ subunit and the noncatalytic cGMP binding site and influencing the Pγ dynamics in holoPDE6C. Thus, our structural analysis sheds light on the previously unrecognized molecular evolution of the effector enzyme in cones that advances adaptation for photopic vision.

Association of varicose veins with the risk of heart failure: A nationwide cohort study

Background Research investigating the association between varicose veins (VV) and heart failure has been limited. Here, we examine this association within a nationwide longitudinal cohort, hypothesizing an increased risk of heart failure associated with the presence of VV. Methods Our study included 390,436 participants based on health screening results conducted from 2005 to 2010 in the South Korean health screening cohort database. Presence of VV was defined as having at least two claims based on International Classification of Diseases, Tenth Revision (ICD-10) codes I830-832, I839, or I868. Propensity score matching (PSM) at a ratio of 1:5 was employed to categorize the participants into two groups based on the presence of VV. The primary outcome, heart failure incidence, was defined as two or more claims with ICD-10 code I50 during follow-up. Results Among the participants, presence of VV was noted in 5,008 (1.28%) individuals. Over a median follow-up period of 13.33 years (interquartile range 10.4–16.26), 55,023 cases of heart failure (14.0%) occurred. In the multivariable analysis, the group with VV consistently showed an increased incidence risk of heart failure compared to the group without VV, both before (hazard ratios [HR], 1.174; 95% confidence interval [CI], 1.089–1.265) and after PSM (HR, 1.171; 95% CI, 1.070–1.283). Landmark analysis also found a consistent relationship between the presence of VV and the incidence risk of heart failure before (HR, 1.190; 95% CI, 1.103–1.285) and after PSM (HR, 1.144; 95% CI, 1.044–1.254). Conclusions This study revealed a significant increase in the risk of heart failure among patients with VV in the general population of South Korea. Given that the presence of VV is likely associated with an increased risk of heart failure in the general population, the potential for future heart failure should be taken into consideration when VV are present.

Damage analysis and grading control technology of surrounding rock in high geo-stress roadway

Reply to Caruso Bavisotto et al.: Toward exploring the potential of muscle-secreting exosomes in the muscle–brain axis

Geology and climate drive alpine plant compositional variation among peaks in the Cascade Range of Washington

Alpine areas are host to diverse plant communities that support ecosystems through structural and floral resources and persist through specialized adaptations to harsh high-elevation conditions. An ongoing question in these plant communities is whether composition is shaped by stochastic processes (e.g., dispersal limitations) or by deterministic processes (e.g., climate, geology), and if those processes select for common phylogenetic clades across space. This study evaluates the drivers of dissimilarity in alpine vascular plant communities across 32 peaks in the Cascade Mountain Range of Washington State and examines the effects of incorporating phylogenetic relatedness to these conclusions. We documented an average of 54 species per peak and used our overall inventory of 307 taxa to construct a phylogenetic tree for the entire mountain range plant community sampled. We used multivariate techniques to quantify the phylogenetic and taxonomic differences between alpine plant communities and to relate those differences to each peak’s climate, geology, and topography. Our models indicate that the age of each peak’s parent material formation, precipitation, latitude, and temperature had the largest role in shaping alpine plant communities relative to the baseline effects of distance between peaks and time of sampling. A unique result was a distinct plant community in peaks with ultramafic geologic parent material formed in the Paleozoic Era, which has an extreme geochemistry that we found to form evolutionarily distinct lineages compared to all other peaks. With changing climate conditions and disturbance regimes, understanding facets of alpine plant communities like species turnover, geologic endemism, and responses to precipitation changes are vital to conserving these ecosystems.

The number of available sample observations modulates gambler’s fallacy in betting behaviors

Structure-guided design and synthesis of C22- and C32-modified FK520 analogs with enhanced activity against human pathogenic fungi

Invasive fungal infections are a leading cause of death worldwide. Translating molecular insights into clinical benefits is challenging because fungal pathogens and their hosts share similar eukaryotic physiology. Consequently, current antifungal treatments have limited efficacy, may be poorly fungicidal in the host, can exhibit toxicity, and are increasingly compromised by emerging resistance. We have established that the phosphatase calcineurin (CaN) is required for invasive fungal disease and an attractive target for antifungal drug development. CaN is a druggable target, and there is vast clinical experience with the CaN inhibitors FK506 and cyclosporin A (CsA). However, while FK506 and its natural analog FK520 exhibit antifungal activity, they are also immunosuppressive in the host and thus not fungal-selective. We leverage our pathogenic fungal CaN-FK506-FKBP12 complex X-ray structures and biophysical data to support structure-based ligand design as well as structure–activity relationship analyses of broad-spectrum FK506/FK520 derivatives with potent antifungal activity and reduced immunosuppressive activity. Here, we apply molecular docking studies to develop antifungal C22- or C32-modified FK520 derivatives with improved therapeutic index scores. Among them, the C32-modified FK520 derivative JH-FK-44 ( 7 ) demonstrates a significantly improved therapeutic index compared to JH-FK-08, our lead compound to date. NMR binding studies with C32-derivatives are consistent with our hypothesis that C32 modifications disrupt the hydrogen bonding network in the human complex while introducing favorable electrostatic and cation–π interactions with the fungal FKBP12 R86 residue. These findings further reinforce calcineurin inhibition as a promising strategy for antifungal therapy.

Link prediction of heterogeneous complex networks based on an improved embedding learning algorithm

Link prediction in heterogeneous networks is an active research topic in the field of complex network science. Recognizing the limitations of existing methods, which often overlook the varying contributions of different local structures within these networks, this study introduces a novel algorithm named SW-Metapath2vec. This algorithm enhances the embedding learning process by assigning weights to meta-path traces generated through random walks and translates the potential connections between nodes into the cosine similarity of embedded vectors. The study was conducted using multiple real-world and synthetic datasets to validate the proposed algorithm’s performance. The results indicate that SW-Metapath2vec significantly outperforms benchmark algorithms. Notably, the algorithm maintains high predictive performance even when a substantial proportion of network nodes are removed, demonstrating its resilience and potential for practical application in analyzing large-scale heterogeneous networks. These findings contribute to the advancement of link prediction techniques and offer valuable insights and tools for related research areas.

Relationship between major depressive disorder and myalgic encephalomyelitis/chronic fatigue syndrome: a two-sample mendelian randomization study analysis

An animal model recapitulates human hepatic diseases associated with <i>GATA6</i> mutations

Heterozygotic GATA6 mutations are responsible for various congenital diseases in the heart, pancreas, liver, and other organs in humans. However, there is lack of an animal that can comprehensively model these diseases since GATA6 is essential for early embryogenesis. Here, we report the establishment of a gata6 knockout zebrafish which recapitulates most of the symptoms in patients with GATA6 mutations, including cardiac outflow tract defects, pancreatic hypoplasia/agenesis, gallbladder agenesis, and various liver diseases. Particularly in the liver, the zebrafish gata6 model exhibits the paucity of intrahepatic bile ducts, disrupted bile canaliculi, cholestasis, resembling the liver diseases associated with GATA6 mutations. Moreover, an unreported phenotype, hepatic cysts, has been also revealed in the model. Mechanistically, Gata6 interacts with Hhex and binds lrh-1 promoter to synergistically activate its expression, thereby enhancing the Lrh-1-mediated β-catenin signaling which is essential for liver development. This transcriptional activation of lrh-1 is tightly controlled by the negative feedback, in which Lrh1 interacts with Gata6 to weaken its transactivation ability. Moreover, Gata6 level is regulated by Hhex-mediated proteasomal degradation. The orchestration by these three transcription factors precisely modulates Gata6 activity, ensuring β-catenin signaling output and proper liver development in zebrafish. Importantly, the molecular mechanism identified in zebrafish is conserved in human cells. GATA6 mutant variants associated with hepatobiliary malformations in humans interact aberrantly with HHEX, resulting in subsequent impairments of LRH-1 activation. Conclusively, the disease model established here provides both phenotypic and mechanism insights into the human hepatic diseases associated with GATA6 mutations.

Screening of serum biomarkers in patients with PCOS through lipid omics and ensemble machine learning

Polycystic ovary syndrome (PCOS) is a primary endocrine disorder affecting premenopausal women involving metabolic dysregulation. We aimed to screen serum biomarkers in PCOS patients using untargeted lipidomics and ensemble machine learning. Serum from PCOS patients and non-PCOS subjects were collected for untargeted lipidomics analysis. Through analyzing the classification of differential lipid metabolites and the association between differential lipid metabolites and clinical indexes, ensemble machine learning, data preprocessing, statistical test pre-screening, ensemble learning method secondary screening, biomarkers verification and evaluation, and diagnostic panel model construction and verification were performed on the data of untargeted lipidomics. Results indicated that different lipid metabolites not only differ between groups but also have close effects on different corresponding clinical indexes. PI (18:0/20:3)-H and PE (18:1p/22:6)-H were identified as candidate biomarkers. Three machine learning models, logistic regression, random forest, and support vector machine, showed that screened biomarkers had better classification ability and effect. In addition, the correlation of candidate biomarkers was low, indicating that the overlap between the selected biomarkers was low, and the combination of panels was more optimized. When the AUC value of the test set of the constructed diagnostic panel model was 0.815, the model’s accuracy in the test set was 0.74, specificity was 0.88, and sensitivity was 0.7. This study demonstrated the applicability and robustness of machine learning algorithms to analyze lipid metabolism data for efficient and reliable biomarker screening. PI (18:0/20:3)-H and PE (18:1p/22:6)-H showed great potential in diagnosing PCOS.

Worse survival of hepatocellular cancer patients with membranous insulin receptor overexpression

AbstractHepatocellular cancer (HCC) therapy is in need for an ideal companion diagnostic. Preclinical experimental studies have identified the insulin receptor (IR) and its synergistic counterpart, the IGF1 receptor (IGF1R), as relevant in HCC development, and the ligands IGF1 and IGF2 have been found to be elevated in HCC. This study aimed to bridge the gap to the clinical setting and explore whether the IR or the IGF1R would be of prognostic significance and would be associated with clinicopathologic parameters in HCC patients. In our retrospective cohort study located at the University Hospital Schleswig-Holstein, Campus Kiel, Germany, HCC samples of 139 patients were examined for IR and IGF1R expression by immunohistochemistry. A HistoScore was correlated with clinicopathological characteristics and survival. IR overexpression was frequently observed and was associated with clinicopathological parameters and survival. Membranous IR expression was associated with worse tumor specific survival (p = 0.043). Intriguingly, membranous IR expression was associated with worse tumor specific survival (p = 0.017) in the subgroup of patients undergoing sorafenib therapy. IGF1R expression was not associated with survival. In conclusion, our results suggest that membranous IR expression plays a role in HCC prognosis and treatment resistance, inspiring future validation as a potential companion diagnostic in HCC.

Reconciling heterogeneous dengue virus infection risk estimates from different study designs

Uncovering rates at which susceptible individuals become infected with a pathogen, i.e., the force of infection (FOI), is essential for assessing transmission risk and reconstructing distribution of immunity in a population. For dengue, reconstructing exposure and susceptibility statuses from the measured FOI is of particular significance as prior exposure is a strong risk factor for severe disease. FOI can be measured via many study designs. Longitudinal serology is considered gold standard measurements, as they directly track the transition of seronegative individuals to seropositive due to incident infections (seroincidence). Cross-sectional serology can provide estimates of FOI by contrasting seroprevalence across ages. Age of reported cases can also be used to infer FOI. Agreement of these measurements, however, has not been assessed. Using 26 y of data from cohort studies and hospital-attended cases from Kamphaeng Phet province, Thailand, we found FOI estimates from the three sources to be highly inconsistent. Annual FOI estimates from seroincidence were 1.75 to 4.05 times higher than case-derived FOI. Seroprevalence-derived was moderately correlated with case-derived FOI (correlation coefficient = 0.47) with slightly lower estimates. Through extensive simulations and theoretical analysis, we show that incongruences between methods can result from failing to account for dengue antibody kinetics, assay noise, and heterogeneity in FOI across ages. Extending standard inference models to include these processes reconciled the FOI and susceptibility estimates. Our results highlight the importance of comparing inferences across multiple data types to uncover additional insights not attainable through a single data type/analysis.

Biomechanical effects of saddle height changes in leisure cycling with unilateral transtibial prostheses: A simulated study

Cycling is a beneficial physical activity for rehabilitating individuals with lower-limb amputations and serves as a feasible leisure sport. However, the optimal bicycle configuration for cycling with a unilateral transtibial prosthesis at leisure levels has not been investigated. For saddle height at professional cycling levels, existing literature suggests utilizing the same configuration as that used by intact cyclists, where the knee reaches 25–35° at maximum extension. However, leisure cyclists tend to select lower saddle heights, and cycling with a unilateral transtibial prosthesis infers altered biomechanics during cycling practice. This study aimed to investigate the effects of cycling at different saddle heights with a simulated unilateral prosthesis. Ten able-bodied participants wore orthoses to simulate prosthetic conditions. The experimental task was performed on an ergometer at 40 W resistance, 60 rpm to simulate leisure cycling. Standard saddle height was defined as maximum knee extension of 45°. This height was used as the control condition and its trials were performed without orthoses. The variable heights were set as height percentage variations (-7%, -3.5%, 0, +3.5%, and +7%). Muscle activity, joint movement, force application to the pedals, perceived exertion, and comfort were evaluated. The -3.5% and -7% saddle heights resulted in joint movement and muscle activity levels closer to those in the control conditions, which also showed improved power symmetry between the affected and non-affected legs. In addition, the -3.5% height increased comfort level in participants. In conclusion, selecting lower saddle heights may be beneficial for unilateral transtibial amputees during leisure cycling. The optimal saddle height for this population may maintain maximum knee extension within the 37–45° range, dynamically measured on the affected side.

Digital-twin driven alignment control method for marine shafting with air spring vibration isolation system

AbstractShafting alignment is crucial for marine propulsion systems and may affect the safety and stability of ship operations. Air spring vibration isolation systems (ASVISs) for marine shafting can help control the shafting alignment state by actively adjusting air spring pressures while effectively reducing the mechanical noise. However, how to accurately control the alignment state of marine shafting with air spring vibration isolation system remains a challenge. To address this issue, a digital twin (DT)-driven alignment control method is proposed in this paper. First, we design a digital twin prediction model based on the neural network to describe the data mapping relationship between the air spring pressures and shafting alignment state. Then, based on the prediction model, we transform the shafting alignment control problem into a non-linear optimization problem in which our objective is to minimize the alignment error while balancing the load on different air springs. To obtain the optimal air spring pressures, the genetic algorithm is introduced to solve the optimization problem, fully exploiting its global search capacity. Moreover, in order to achieve the optimized pressures, a soft-constrained controller based on proportional-integral-derivative (PID) algorithm is developed to accurately generate specific control policies based on the monitoring data. Finally, the feasibility and the effectiveness of the proposed alignment control method is verified with a real ASVIS.

Tamsulosin ameliorates bone loss by inhibiting the release of Cl ⁻ through wedging into an allosteric site of TMEM16A

TMEM16A, a key calcium-activated chloride channel, is crucial for many physiological and pathological processes such as cancer, hypertension, and osteoporosis, etc. However, the regulatory mechanism of TMEM16A is poorly understood, limiting the discovery of effective modulators. Here, we unveil an allosteric gating mechanism by presenting a high-resolution cryo-EM structure of TMEM16A in complex with a channel inhibitor that we identified, Tamsulosin, which is resolved at 2.93 Å. Tamsulosin wedges itself into a pocket within the extracellular domain of TMEM16A, surrounded by α1-α2, α5-α6, and α9-α10 loops. This binding stabilizes a transient preopen conformation of TMEM16A, which is activated by Ca 2+ ions while still preserving a closed pore to prevent Cl − permeation. Validation of this binding site through computational, electrophysiological, and functional experiments, along with site-directed mutagenesis, confirmed the pivotal roles of the pocket-lining residues R605 and E624 on α5-α6 loop in modulating Tamsulosin binding and pore activity. Tamsulosin induces significant positional shifts in extracellular loops, particularly the α5-α6 loop, which moves toward the extracellular exit of the pore, leading to noticeable structural rearrangements in pore-lining helices. The hinges induced by P595 in α5 and G711 in α7 introduce flexibility to the transmembrane helices, orienting Y593 to collaborate with I641 in effectively gating the preopening pore. Notably, Tamsulosin demonstrates significant antiosteoporotic effects by inhibiting TMEM16A, suggesting potential for its repurposing in new therapeutic indications. Our study not only enhances our understanding of the gating mechanism of TMEM16A inhibition but also facilitates structure-based drug design targeting TMEM16A.

Supervised pulmonary tele-rehabilitation and individualized home-based pulmonary rehabilitation for patients with COPD, unable to participate in center-based programs. The protocol for a multicenter randomized controlled trial - the REPORT study

Introduction Chronic obstructive pulmonary disease (COPD) costs EURO 1.4 billion annually in healthcare costs. Pulmonary rehabilitation (PR) is a vital aspect of care for patients with COPD, but despite the compelling evidence, it is delivered to less than 30%. Frequent transport to the center-based program is regularly reported as reasons for non-attendance. The effectiveness and feasibility of pulmonary tele-rehabilitation (PTR) and home-based pulmonary rehabilitation (HPR) have never been investigated in patients with COPD who are unable to attend conventional outpatient PR. Materials and methods This study is a multicenter randomized controlled trial consisting of three parallel groups; PTR, HPR and a control group. 180 patients with moderate to very severe COPD, who are unable to attend in center-based PR programs will be included. The PTR group receives group-based resistance- and endurance training and patient education 60 min. twice a week for 10-weeks. HPR comprises an individual self-initiated home-based PR program with online motivational and professional counseling. The goal is to achieve at least 20 min. of muscle-endurance based exercises three days weekly for 10-weeks. The PTR and HPR group use a tablet with a conference system. The control group receives usual care (no PR). After completion of the intervention, the PTR and HPR groups are offered 65-weeks groupbased maintance program supervised once a week online via tablet. The primary outcome is change in respiratory symptoms measured with the COPD Assessment Test after 10-weeks (primary endpoint). Discussion The study aims to test a possible equivalence between PTR and HPR and their superiority to controls on respiratory symptoms. The study will provide valuable insights into the effectiveness of new rehabilitation models and maintenance programs for patients with COPD. If the two new delivery models can reduce respiratory symptoms, patients with moderate to very severe COPD can participate in both home- or centerbased PR. Trial registration The trial is registrered and approved by the Ethics Committee of The Capital Region of Denmark (H-22015777; 29.08.2022) and the Danish Data Protection Agency (P-2022-245-13101, 25.05.2022). The trial is registrered at ClinicalTrials.gov, identifier: NCT05664945 (23.12.2022).