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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 <sup>−</sup> 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).
Expert evaluation of large language models for clinical dialogue summarization
Nucleation mechanism of multiple-order parameter ferroelectric domain wall motion in hafnia
Ferroelectric hafnia exhibits promising robust polarization and silicon compatibility for ferroelectric devices. Unfortunately, it suffers from difficult polarization switching. Methods to enable easier polarization switching are needed, and the underlying reason for this switching difficulty is not understood. Here, we investigated the 180 ° domain walls of hafnia and their motion through nucleation. We found that the domains of multiple-order parameter hafnia possess complicated three-dimensional dipole patterns and lead to domain walls of different symmetry. The most common domain wall type is a complex domain wall involving reversal of both polarization and tetragonality order parameters. This domain wall symmetry ensures a good matching of the dipoles perpendicular to the domain wall, which leads to low domain wall energy. However, this ensures a sharp, high-energy, charged domain wall on the edges of nuclei that results in difficult nucleation. Thus, this domain wall is too stable to move, which explains the switching difficulty of hafnia. By contrast, another simple domain wall, involving only polarization reversal, has a poor matching of dipoles perpendicular to the domain wall. This leads to higher domain wall energy and ensures a diffusive and low-energy charged domain wall that enables easier nucleation. This simple domain wall is thus not too stable and easier to move. Our theory advances domain wall nucleation theory from the field of conventional single-order parameter to multiple-order parameters. We propose controlling the populations of different domain wall types in hafnia as a way to enable fast polarization switching and lower coercive fields.
Practices and preferences in the use of magnification among endodontists and restorative dentists: A multicentre study
Background and objectives Aim of the current study was to assess the perception, preference, and practice of endodontists and restorative dentists at different locations around the world about dental magnification instruments. Materials and methods A multicenter, cross-sectional study was ethically approved from the local committee of bioethics. After thorough literature search, a questionnaire was designed and validated. Later, the questionnaire was distributed to 10% (53 participants) of the total planned participants to conduct a pilot study. Based on the feedback from these participants, any ambiguities or discrepancies observed in the items and content of the questionnaire was modified. The questionnaire was assessed for its internal consistency as part of validating the items with Cronbach’s alpha of 0.80. The completed questionnaire with an informed consent form for the participant was administered to the endodontists and restorative dentists in three different geographical regions namely MENA (Middle East and Northern Africa), British-Isles, and Indian Sub-continent using WhatsApp through the snowball convenience sampling technique. Results Majority of the participants were male (56.5%) and in the age group of 25–35 years (30.3%). About 68.9% were from Indian sub-continent, followed by the British-Isles (16.5%) and the least (14.6%) were from the MENA region. By large, the participants of the present study, strongly agreed that dental magnification devices improved ergonomics, quality of work, and should be considered as standard of care in modern endodontic. Flip-up magnifiers (51.1%) and medium (8x-16x) magnification were preferred by majority of the participants. About 46.3% of specialist reported that they always used devices for all operative and endodontic procedures, especially while locating hidden and canals and negotiating calcified canals. Participants practicing in British-Isles have 2.42 times (P<0.05) higher adequate perception with reference participants in Indian sub-continent. Additionally, participants with fellowship have 2.77 times more (P<0.01) adequate perception with reference to their counterparts with a master’s degree. Conclusions Most of the participants believe that dental magnification devices enhance the prognosis and quality of treatment of possibly all operative and endodontics procedures. Thus, emphasized on the inclusion of devices in the postgraduate curriculum and signifies the role of continuing dental education for specialist and dental assistant handling devices. However, multicenter studies with larger sample is required for generalizing the results.
Spatio-temporal analysis of litterfall load in the lower reaches of Qarqan and Tarim rivers using BP neural networks
Structures of methane and ammonia monooxygenases in native membranes
Methane- and ammonia-oxidizing bacteria play key roles in the global carbon and nitrogen cycles, respectively. These bacteria use homologous copper membrane monooxygenases to accomplish the defining chemical transformations of their metabolisms: the oxidations of methane to methanol by particulate methane monooxygenase (pMMO) and ammonia to hydroxylamine by ammonia monooxygenase (AMO), enzymes of prime interest for applications in mitigating climate change. However, investigations of these enzymes have been hindered by the need for disruptive detergent solubilization prior to structure determination, confounding studies of pMMO and precluding studies of AMO. Here, we overcome these challenges by using cryoEM to visualize pMMO and AMO directly in their native membrane arrays at 2.4 to 2.8 Å resolution. These structures reveal details of the copper centers, numerous bound lipids, and previously unobserved components, including identifiable and distinct supernumerary helices interacting with pMMO and AMO, suggesting a widespread role for these helices in copper membrane monooxygenases. Comparisons between these structures, their metallocofactors, and their unexpected protein–protein interactions highlight features that may govern activity or the formation of higher-order arrays in native membranes. The ability to obtain molecular insights within the native membrane will enable further understanding of these environmentally important enzymes.
Research protocol for a systematic review and meta-analysis of the effects of music on anxiety and physiological outcomes in patients undergoing bronchoscopy
Introduction Bronchoscopy is a routine clinical examination that can cause discomfort and anxiety in patients. This paper presents a protocol for a systematic review and meta-analysis aiming to assess the effect of music on anxiety and physiological outcomes in patients undergoing bronchoscopy. Methods The protocol adhere to Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols guidelines and has been registered in PROSPERO (CRD42024567398). Our documentary research strategy will involve four databases: PubMed, Google Scholar, Scopus, and the Cochrane Library. In addition, manual searches will be conducted through related articles and references. We will include randomized controlled trials that evaluate the effect of music on patients undergoing bronchoscopy. The primary outcome will be the anxiety level and the secondary outcome will include physiological outcomes. Study selection, data extraction, and quality assessment will be carried out independently by two reviewers. Any discrepancies will be resolved through consultation with a third reviewer. The quality and the risk of bias in the studies will be evaluated using The Joanna Briggs Institute critical appraisal tool. The results of this systematic review will be synthesized to provide an overview on the effectiveness of music on anxiety and physiological parameters in patients during bronchoscopy. If the results are considered acceptable and sufficiently homogeneous, a meta-analysis will be performed to synthesize the findings. Conclusion The systematic review produced from this protocol will provide evidence on the effectiveness of music for patients undergoing bronchoscopy and will contribute to strengthening the existing body of knowledge on non-pharmacological interventions for anxiety management during medical procedures.