bluuebunny/crossref_metadata_2025 huggingface dataset:
Neural network emulation of the human ventricular cardiomyocyte action potential for more efficient computations in pharmacological studies
Authors: Grandits Thomas , Augustin Christoph M , Haase Gundolf , Jost Norbert , Mirams Gary R , Niederer Steven A , Plank Gernot , Varró András , Virág László , Jung Alexander
Published: December 2023

Computer models of the human ventricular cardiomyocyte action potential (AP) have reached a level of detail and maturity that has led to an increasing number of applications in the pharmaceutical sector. However, interfacing the models with experimental data can become a significant computational burden. To mitigate the computational burden, the present study introduces a neural network (NN) that emulates the AP for given maximum conductances of selected ion channels, pumps, and exchangers. Its applicability in pharmacological studies was tested on synthetic and experimental data. The NN emulator potentially enables massive speed-ups compared to regular simulations and the forward problem (find drugged AP for pharmacological parameters defined as scaling factors of control maximum conductances) on synthetic data could be solved with average root-mean-square errors (RMSE) of 0.47 mV in normal APs and of 14.5 mV in abnormal APs exhibiting early afterdepolarizations (72.5% of the emulated APs were alining with the abnormality, and the substantial majority of the remaining APs demonstrated pronounced proximity). This demonstrates not only very fast and mostly very accurate AP emulations but also the capability of accounting for discontinuities, a major advantage over existing emulation strategies. Furthermore, the inverse problem (find pharmacological parameters for control and drugged APs through optimization) on synthetic data could be solved with high accuracy shown by a maximum RMSE of 0.22 in the estimated pharmacological parameters. However, notable mismatches were observed between pharmacological parameters estimated from experimental data and distributions obtained from the Comprehensive in vitro Proarrhythmia Assay initiative. This reveals larger inaccuracies which can be attributed particularly to the fact that small tissue preparations were studied while the emulator was trained on single cardiomyocyte data. Overall, our study highlights the potential of NN emulators as powerful tool for an increased efficiency in future quantitative systems pharmacology studies.
Divergent downstream biosynthetic pathways are supported by L-cysteine synthases of Mycobacterium tuberculosis
Authors: Khan Mehak Zahoor , Hunt Debbie M , Singha Biplab , Kapoor Yogita , Singh Nitesh Kumar , Prasad D V Sai , Dharmarajan Sriram , Sowpati Divya Tej , de Carvalho Luiz Pedro S , Nandicoori Vinay Kumar
Published: December 2023

Mycobacterium tuberculosis’s (Mtb) autarkic lifestyle within the host involves rewiring its transcriptional networks to combat host-induced stresses. With the help of RNA sequencing performed under various stress conditions, we identified that genes belonging to Mtb sulfur metabolism pathways are significantly upregulated during oxidative stress. Using an integrated approach of microbial genetics, transcriptomics, metabolomics, animal experiments, chemical inhibition, and rescue studies, we investigated the biological role of non-canonical L-cysteine synthases, CysM and CysK2. While transcriptome signatures of RvΔcysM and RvΔcysK2 appear similar under regular growth conditions, we observed unique transcriptional signatures when subjected to oxidative stress. We followed pool size and labelling (34S) of key downstream metabolites, viz. mycothiol and ergothioneine, to monitor L-cysteine biosynthesis and utilization. This revealed the significant role of distinct L-cysteine biosynthetic routes on redox stress and homeostasis. CysM and CysK2 independently facilitate Mtb survival by alleviating host-induced redox stress, suggesting they are not fully redundant during infection. With the help of genetic mutants and chemical inhibitors, we show that CysM and CysK2 serve as unique, attractive targets for adjunct therapy to combat mycobacterial infection.
Cryptic diversity and phylogeographic patterns ofDeto echinata(Isopoda: Detonidae) in southern Africa
Authors: Santamaria Carlos A. , Griffiths Charles L.
Published: December 2023

Recent phylogeographic studies of poorly-dispersing coastal invertebrates in highly biodiverse regions have led to the discovery of high levels of cryptic diversity and complex phylogeographic patterns that suggest isolation, geological, and ecological processes have shaped their biodiversity. Studies of southern African coastal invertebrates have uncovered cryptic diversity for various taxa and phylogeographic patterns that, although sharing some similarities across taxa, do differ. These findings underscore the need for additional studies to better understand the biodiversity levels, distributional patterns, and processes responsible for producing coastal biodiversity in that region. The coastal isopodDeto echinatais of particular interest, as its complex taxonomic history, poor dispersal capabilities, and broad geographic distribution suggest the potential for cryptic diversity. We use mitochondrial and nuclear sequences to characterizeD. echinataindividuals from localities ranging from northern Namibia to Glentana, about 2,500 km along the coastline on the south coast of South Africa. These are used to assess whetherD. echinataharbors cryptic genetic diversity and whether phylogeographic distributional patterns correlate with those previously documented for other coastal isopods in the region. Analysis of mitochondrial and nuclear sequences revealed two deeply-divergent lineages that exhibit a distributional break in the Cape Peninsula region. These findings suggestD. echinatais a cryptic species complex in need of taxonomic revision and highlight the need for further taxonomic and phylogeographic studies of similarly poorly-dispersing coastal invertebrates in southern Africa.
Prácticas de liderazgo instruccional en colaboración con líder intermedio para desarrollar habilidades de lenguaje verbal en estudiantes de NT1, en una Escuela de la Región Metropolitana
Authors:   , Burgos Arce Jasmine Jesús
Published: December 2023

Este estudio, se basa en la implementación de cinco prácticas de liderazgo instruccional (Volante y Müller, 2017), con el objetivo de promover el desarrollo del lenguaje verbal en estudiantes de educación parvularia. Para ello, se realizó una investigación de tipo profesional, involucrando a una coordinadora de ciclo, tres educadoras de párvulos y estudiantes de dos niveles de NT1. A través de su implementación, se identificaron avances en el lenguaje verbal de estudiantes, con mejoras en la expresión y en la incorporación de nuevas palabras, experimentando aumentos del 43% y 50% en ambos niveles respectivamente. La intervención también incluyó ciclos de observación y retroalimentación docente, que resaltaron un aumento del 124% en las observaciones de nivel 4, donde se evidencian los tres elementos del triángulo instruccional de Cohen (2003): desempeño del profesor, actividad del estudiantes y contenidos, articulados de manera efectiva. Con relación a las modalidades de observación, se observó un aumento del 124% en las modalidades de nivel 7, las cuales abarcan descripciones con interpretación y evaluación en un solo registro. Finalmente, se implementaron estrategias para la desprivatización de la práctica profesional observando mejoras en las prácticas de enseñanza, por medio la incorporación de estrategias didácticas que potenciaron la participación de los estudiantes en sus procesos de enseñanza aprendizaje.
Lawsuits Over the Price of Insulin—State Efforts for Insulin Access
Authors: Aaron Daniel G. , Cohen I. Glenn , Adashi Eli Y.
Published: December 2023

This Viewpoint discusses the litigation strategy of state-initiated lawsuits alleging illegal and immoral conduct regarding the pricing of insulin by pharmaceutical companies and pharmacy benefit managers.
Consequences of a Health System Not Knowing Which Patients Are Deceased
Authors: Wenger Neil S. , Sanz Vidorreta Fernando Javier , Dudley Michael T. , Walling Anne M. , Hogarth Michael
Published: December 2023

This quality improvement study in a California health system investigates the proportion of active patients who were deceased but not noted as such in the electronic health record (EHR), as well as encounters after death.
Maternal Prenatal Depressive Symptoms and Fetal Growth During the Critical Rapid Growth Stage
Authors: Zhang Lu , Li Ping , Ge Qiaoyue , Sun Zeyuan , Cai Jiarui , Xiao Chenghan , Yu Chuan , Nosarti Chiara , Liao Jiaqiang , Liu Zhenmi
Published: December 2023

Importance

Fetal growth in the critical rapid growth stage (CRGS) before delivery, approximately between 30 to 37 gestational weeks, carries significant implications for subsequent overweight, obesity, and arterial health. Previous evidence has demonstrated the association between maternal depressive symptoms and fetal growth trajectories from early to late pregnancy, but there remains limited understanding of the association of these symptoms with the longitudinal fetal growth change within the CRGS.

Objective

To investigate the association between maternal depressive symptoms and fetal growth during the CRGS before delivery.

Design, Setting, and Participants

This prospective birth cohort study was conducted from January 2018 to December 2020. Volunteer pregnant women were enrolled in their first trimester of prenatal visits. Women with severe disease before pregnancy and multiple births, fetuses with congenital anomalies, and preterm or postterm births were excluded. This multicenter study was based in 13 hospitals covering 81 counties across 12 cities in Sichuan Province, China. Follow-up visits were performed at the second trimester, the third trimester, and 24 hours after delivery. The analysis was conducted from January to May 2023.

Exposures

Maternal depressive symptoms, as a continuous variable, measured by the Edinburgh Postpartum Depression Scale (EPDS) at a median gestational week of 24 (range, 14 to 27) weeks of gestation. A higher score on the EPDS indicates worse depressive symptoms.

Main Outcomes and Measures

The main outcomes included ultrasonography-measured biparietal diameter (BPD), femur length (FL), and abdominal circumference (AC), along with calculated estimated fetal weight (EFW). These parameters were evaluated longitudinally at a median gestational week of 30 (range, 28 to 32) and 37 (range, 35 to 39) weeks. Linear mixed models were used to estimate the associations between maternal depressive symptoms and fetal growth parameters.

Results

A total of 2676 mother-offspring dyads were included, in which the mean (SD) age of mothers was 28.0 (4.4) years, and 1294 (48.4%) of the offspring were female. The median (IQR) maternal EPDS score was 5.0 (4.0 to 9.0). After adjustment for confounders, a significant correlation was found between a higher score of depressive symptoms in mothers and a slower rate of fetal growth across FL (β = −0.40; 95% CI, −0.58 to −0.22), AC (β = −1.97; 95% CI, −2.90 to −1.03), and EFW (β = −50.11; 95% CI, −68.46 to −31.75). These associations were stronger in female fetuses or those with better family socioeconomic conditions.

Conclusions and Relevance

In this prospective cohort study, maternal depressive symptoms were associated with slower fetal growth rate in the CRGS before delivery. Early screening for depressive disorders in pregnant women appears to be essential for fetal growth and later health.
Two novel phosphoramide derivatives moiety as corrosion inhibitor for mild steel: Experimental and theoretical study
Authors: Gholivand Khodayar , Barzegari Azam , Kashani Hadi Mazruee , Fallah Nasrin
Published: December 2023

Two novel phosphoramide containing thiazole derivatives with the name of bis(5‐amino‐1,3,4‐thiadiazol‐2‐yl) phenylphosphonotrithioate (C1) and O, O‐diethyl (5‐((diethoxyphosphorothioyl) thio)‐1,3,4‐thiadiazol‐2yl) phosphoramidothioate (C2) as corrosion inhibition were synthesized and identified by 1H NMR, 13C NMR, 31P NMR, IR, and mass spectroscopies. The electrochemical behavior of mild steel (MS) in hydrochloric acid 1‐M (HCl) solution was perused in the absence and presence of C1 and C2. To determine corrosion inhibition of phosphoramide compounds, scanning electron microscopy (SEM), potentiodynamic polarization (PDP), and electrochemical impedance spectroscopy (EIS) were used. The EIS results show that the charge transfer resistance increases with the addition of inhibitors to the hydrochloric acid solution. The most inhibitor efficiency was 89%, which demonstrated the appropriate anti‐corrosion property of C1. EIS results show better charge transfer resistance on the surface of MS at increased inhibitor concentrations. The PDP analysis showed that C1 and C2 are mixed‐type inhibitors. The PDP examination appeared that C1 and C2 are mixed‐type inhibitors. To way better get the comes about of corrosion inhibition and structure of target compounds, the highest occupied molecular orbital (HOMO) and least unoccupied molecular orbital (LUMO) energies, hardness, dipole moment, and electrophilicity index of synthesized compounds were explored computationally using the density functional theory (DFT) strategy. The hypothetical comes about in great understanding with the exploratory information.
Effects of tartary buckwheat in enhancing bioactive compounds and sensory properties of traditional fruit kombucha beverage
Authors: Xiao Sha , Pan Yuting , Li Xinyi , Xu Min , Tang Yiwen , Cao Yang , Zhou Yihan , Zou Liang , Zhao Jianglin , Wang Aili
Published: December 2023

Background and Objectives

Tartary buckwheat (TB) has high nutritional value, is gluten‐free, and has adaptability to cold climates, which makes it a valuable crop for agriculture. Few high‐value‐added products are made using TB.

Findings

Addition of TB significantly increased (p < .05) the contents of total phenolic and flavonoid in pineapple kombucha (PK) beverage, especially the amount of rutin. In addition, TB contributed abundant organic acids to kombucha beverage, especially acetic acid, citric acid, and malic acid. Although addition of TB increased the sourness and astringency of the beverage, it also contributed toward a unique buckwheat aroma by increasing the abundance of volatile compounds such as esters. In addition, there was no significant difference (p > .05) in the sweetness, bitterness, and pineapple flavor between TBPK and PK beverages.

Conclusion

The developed kombucha beverage using TBPK infusion is advantageous over traditional fruit kombucha in terms of providing abundant nutrients as well as a pleasant flavor and has the potential to be used to develop a functional beverage with multiple health benefits.

Significance and Novelty

In this study, TB with high nutritional value was used for the first time as a fermentation substrate to enhance bioactive compounds and sensory properties in traditional kombucha beverages.
Multifunctional flame‐retardant co‐based interlayer for improving lithium−sulphur batteries performance
Authors: Yang Shihan , Cao Yongan , Zhu Tianjiao , Chen Yuchao , Wang Wenju , Meng Shaoliang , Wu Delin
Published: December 2023

Lithium–sulphur batteries (LSBs) have elicited great interest due to their remarkably high energy density. However, challenges such as the dissolution of lithium polysulfides (LiPSs), low reaction kinetics, and safety concerns associated with LSBs impede large‐scale application. In this work, a multifunctional Co‐HP‐GC interlayer was prepared using evaporation, refluxing, and impregnation procedures. Notably, after ignition, this interlayer retained its structural integrity, indicative of excellent flame retardancy and thermal stability. Furthermore, the addition of cobalt atoms augmented the cyclic performance of the batteries by expediting the redox kinetics of LiPSs transformation and electron transfer at the interface. The electrodeposition capacity of Li2S cathode with Co‐HP‐GC interlayer reached up to 199.2 mAh g−1, higher than the 155.7 mAh g−1 achieved with a graphene oxide/carbonized fibre paper (G‐CCP) interlayer. This, in turn, curtails the shuttle effect whilst improving sulphur utilization. LSBs possessing a Co‐HP‐GC interlayer demonstrated superior cyclic and rate performance. At 0.5 C, the initial specific capacity of the battery fitted with a Co‐HP‐GC interlayer was 915.8 mAh g−1, with the rate of attenuation reduced by approximately half. The strategy integrates the multifunctional flame‐retardant interlayer into various battery systems, demonstrating wide‐ranging potential applicability within the realm of LSBs.
Mapping the avian visual tectofugal pathway using 3D reconstruction
Authors: Straight Parker J. , Gignac Paul M. , Kuenzel Wayne J.
Published: December 2023

Image processing in amniotes is usually accomplished by the thalamofugal and/or tectofugal visual systems. In laterally eyed birds, the tectofugal system dominates with functions such as color and motion processing, spatial orientation, stimulus identification, and localization. This makes it a critical system for complex avian behavior. Here, the brains of chicks, Gallus gallus, were used to produce serial brain sections in either coronal, sagittal, or horizontal planes and stained with either Nissl and Gallyas silver myelin or Luxol fast blue stain and cresyl echt violet (CEV). The emerging techniques of diffusible iodine‐based contrast‐enhanced computed tomography (diceCT) coupled with serial histochemistry in three planes were used to generate a comprehensive three‐dimensional (3D) model of the avian tectofugal visual system. This enabled the 3D reconstruction of tectofugal circuits, including the three primary neuronal projections. Specifically, major components of the system included four regions of the retina, layers of the optic tectum, subdivisions of the nucleus rotundus in the thalamus, the entopallium in the forebrain, and supplementary components connecting into or out of this major avian visual sensory system. The resulting 3D model enabled a better understanding of the structural components and connectivity of this complex system by providing a complete spatial organization that occupied several distinct brain regions. We demonstrate how pairing diceCT with traditional histochemistry is an effective means to improve the understanding of, and thereby should generate insights into, anatomical and functional properties of complicated neural pathways, and we recommend this approach to clarify enigmatic properties of these pathways.
Design and analysis of a coupling coil structure for high‐efficiency wireless charging system for consumer electronics
Authors: Zheng Zonghua , Fang Xin , Zhang Yiming
Published: December 2023

This paper introduces a novel type of coupling coil structure that can be used for wireless charging of consumer electronics. The coupling loop configuration includes an eight‐shaped transceiver coil and dual rectangular coils integrated on the printed circuit board (PCB). Moreover, when numerous transmitting coils of this structure are staged in parallel, it can sustain a consistent mutual inductance even when the receiver coil is not aligned, which can efficiently stabilize output power during charging. The article first models three different coil structures based on circuit theory and simulates their electromagnetic fields in commercial software and then performs a comparison among the three types of coils. Finally, it verifies the anti‐offset capability of the modified structure through a 25 W wireless power transmission experimental platform. The experimental outcomes are in accordance with the simulation and theoretical analysis, and compared with traditional dual‐transmitting coil structures, better overall power transmission efficiency has been achieved.
Transformer‐less drive and operation stability analysis of dielectric barrier discharge using a double resonance circuit
Authors: Tamida Taichiro , Nagata Ryota , Itani Taiga
Published: December 2023

A dielectric barrier discharge load (DBD) with a maintenance voltage of 1.5 kV has been successfully driven stably from a 48 V inverter only by resonance voltage boost and no transformer. The proposed circuit consists of a two‐stage resonant circuit. The circuit operation is investigated using both prototyping measurement and circuit simulation, which shows that despite the high Q value, the design margin and operating stability of the circuit are extremely wide. It is found that this operational stability can be explained by considering the impedance characteristics of DBD. We believe that the circuit is suitable for driving discharge loads such as DBD in practical applications.
Modal analysis of earthquake records for dams using stochastic subspace based on error analysis
Authors: Pourgholi Mehran , Ghannadi Mahin , Gavgani Saba Sadeghi
Published: December 2023

System identification based on seismic data is crucial for updating numerical analyses and implementing health monitoring strategies for critical structures such as dams. However, most system identification methods have been developed with the assumption of white noise and stationarity of excitations, which is inconsistent with the nature of seismic data. As a result, the systems estimated from such methods are often associated with high uncertainties, making obtaining accurate and reliable results challenging. In this study, a new figure of merit (FOM) is proposed for tracking the ill‐conditioning of systems by analyzing the errors in stochastic subspace identification (SSI) through the inversion process. Unlike the condition number, which measures the ratio between the largest and smallest singular values, this FOM uses all singular values to assess the system's ill‐conditioning comprehensively. A semi‐automatic identification method based on SSI has been developed using the proposed FOM. The optimal dimensions of the Hankel matrix are obtained so that none of the system error components dominate. Frequency/damping clustering is used to overcome the identified system's over‐determination and remove outliers. Finally, the complexity of the modal shapes resulting from clustering is examined to validate the structural modal characteristics. The procedure was validated using seismic data from the Finite Element Model of Koyna Dam. It identified the first four modal frequencies of the structure with less than 2% error rate. The average error in estimating damping ratios was below 20%. The algorithm was then used to analyze the seismic monitoring data of Pacoima Dam for the Chino Hill 2008 and Granada Hills 2020 earthquakes. Despite the closely spaced Pacoima Dam modes, the study demonstrated excellent accuracy and robust methodology performance. By distinguishing the structural modes related to the dam body from other modes of the “dam‐foundation‐reservoir” system, the proposed method helps to determine the existing model's nonlinearity.
Temporal evolution of the extreme excursions of multivariate k$$ k $$th order Markov processes with application to oceanographic data
Authors: Tendijck Stan , Jonathan Philip , Randell David , Tawn Jonathan
Published: December 2023

We develop two models for the temporal evolution of extreme events of multivariate th order Markov processes. The foundation of our methodology lies in the conditional extremes model of Heffernan and Tawn (Journal of the Royal Statistical Society: Series B (Methodology), 2014, 66, 497–546), and it naturally extends the work of Winter and Tawn (Journal of the Royal Statistical Society: Series C (Applied Statistics), 2016, 65, 345–365; Extremes, 2017, 20, 393–415) and Tendijck et al. (Environmetrics 2019, 30, e2541) to include multivariate random variables. We use cross‐validation‐type techniques to develop a model order selection procedure, and we test our models on two‐dimensional meteorological‐oceanographic data with directional covariates for a location in the northern North Sea. We conclude that the newly‐developed models perform better than the widely used historical matching methodology for these data.
Implementation of an all‐age eating disorders service in the National health service in England: The Dorset experience
Authors: Newell Ciarán
Published: December 2023

This article provides a commentary on the development of an integrated all‐age eating disorders service in the Eating disorders service within the NHS in Dorset. Previously separate services existed for those under the age of 18 and those age 18 and over. The change from traditional age based services to the all age service was prompted by the observed problems with transitions for patients, their families and the service such as discontinuities in care, and distress to patients and families. In addition the literature on transitions although limited in eating disorders showed that patient and carer perspectives were mostly negative about transitions. The aim was to create an all‐age service working with patients of different ages, through developing the competencies of the team to appropriately meet the needs of the all age population. This paper describes the context and rationale for this change, its implementation using the organisational change policy approach to service transformation, including addressing the concerns of the stakeholders (patients, carers, staff, and mental health service commissioners), as well as observed changes in the service and its development. Since the all‐age service started in 2016, new research has become available on both the improvement of the transition experience and the potential advantages of all‐age services and relevant aspects are discussed.
From nature to cancer therapy: Evaluating the Streptomyces clavuligerus secondary metabolites for potential protein kinase inhibitors
Authors: Saini Ravi , Kumari Sonali , Singh Amit , Mishra Abha
Published: December 2023

The study aimed to evaluate the antioxidant, protein kinase inhibitory (PKIs) potential, cytotoxicity activity of Streptomyces clavuligerus extract. DPPH assay revealed a robust free radical scavenging capacity (IC50 28.90 ± 0.24 µg/mL) of organic extract with a maximum inhibition percentage of 61 ± 1.04%. PKIs assay revealed the formation of a whitish bald zone by S. clavuligerus extracts which indicates the presence of PKIs. The cytotoxicity activity of organic fraction of extract through Sulforhodamine B assay on MCF‐7, Hop‐62, SiHa, and PC‐3 cell lines demonstrated the lowest GI50 value against the MCF‐7 cell line followed by the PC‐3 cell line, showing potent growth inhibitory potential against human breast cancer and human prostate cancer cell line. HR‐LCMS analysis identified multiple secondary metabolites from the organic and aqueous extracts of S. clavuligerus when incubated at 30°C under 200 rpm for 3 days. All the secondary metabolites were elucidated for their potential to inhibit RTKs by molecular docking, molecular dynamic simulation, MM/GBSA calculations, and free energy approach. It revealed the superior inhibitory potential of epirubicin (Epi) and dodecaprenyl phosphate‐galacturonic acid (DPGA) against fibroblast growth factors receptor (FGFR). Epi also exhibited excellent inhibitory activity against the platelet‐derived growth factor receptor (PDGFR), while DPGA effectively inhibited the vascular endothelial growth factor receptor. Additionally, the presence Epi in S. clavuligerus extract was validated through the HPLC technique. Thus, our findings highlight a superior inhibitory potential of Epi against FGFR and PDGFR RTKs than the FDA‐approved drug.
In silico and structure‐based evaluation of deleterious mutations identified in human Chk1, Chk2, and Wee1 protein kinase
Authors: Colaco Venessa , Goswami Nabajyoti , Goel Vijay Kumar , Srivastava Sunil Kumar , Lalrohlua Pachuau , Senthil Kumar Nachimuthu , Borah Probodh , Baruah Reshita , Varma Ashok K.
Published: December 2023

Checkpoint kinases Chk1, Chk2, Wee1 are playing a key role in DNA damage response and genomic integrity. Cancer‐associated mutations identified in human Chk1, Chk2, and Wee1 were retrieved to understand the function associated with the mutation and also alterations in the folding pattern. Therefore, an attempt has been made to identify deleterious effect of variants using in silico and structure‐based approach. Variants of uncertain significance for Chk1, Chk2, and Wee1 were retrieved from different databases and four prediction servers were employed to predict pathogenicity of mutations. Further, Interpro, I‐Mutant 3.0, Consurf, TM‐align, and have (y)our protein explained were used for comprehensive study of the deleterious effects of variants. The sequences of Chk1, Chk2, and Wee1 were analyzed using Clustal Omega, and the three‐dimensional structures of the proteins were aligned using TM‐align. The molecular dynamics simulations were performed to explore the differences in folding pattern between Chk1, Chk2, Wee1 wild‐type, and mutant protein and also to evaluate the structural integrity. Thirty‐six variants in Chk1, 250 Variants in Chk2, and 29 in Wee1 were categorized as pathogenic using in silico prediction tools. Furthermore, 25 mutations in Chk1, 189 in Chk2, and 14 in Wee1 were highly conserved, possessing deleterious effect and also influencing the protein structure and function. These identified mutations may provide underlying genetic intricacies to serve as potential targets for therapeutic inventions and clinical management.
SARS‐CoV‐2 nucleocapsid protein enhances the level of mitochondrial reactive oxygen species
Authors: Yu Haiyun , Yang Lu , Han Zhennan , Zhou Xiaoyu , Zhang Zihan , Sun Tianli , Zheng Fang , Yang Jingzhi , Guan Fei , Xie Jungang , Liu Chaohong
Published: December 2023

Coronavirus disease 2019 (COVID‐19) pathogenesis is influenced by reactive oxygen species (ROS). Nevertheless, the precise mechanisms implicated remain poorly understood. The nucleocapsid (N) protein of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), the main driver for this condition, is a structural protein indispensable for viral replication and assembly, and its role in ROS production has not been reported. This study shows that SARS‐CoV‐2 N protein expression enhances mitochondrial ROS level. Bulk RNA‐sequencing suggests of aberrant redox state of the electron transport chain. Accordingly, this protein hinders ATP production but simultaneously augments the activity of complexes I and III, and most mitochondrially encoded complex I and III proteins are upregulated by it. Mechanistically, N protein of SARS‐CoV‐2 shows significant mitochondrial localization. It interacts with mitochondrial transcription components and stabilizes them. Moreover, it also impairs the activity of antioxidant enzymes with or without detectable interaction.
Network meta analysis to predict the efficacy of an approved treatment in a new indication
Authors: Proper Jennifer L. , Chu Haitao , Prajapati Purvi , Sonksen Michael D. , Murray Thomas A.
Published: December 2023

Drug repurposing refers to the process of discovering new therapeutic uses for existing medicines. Compared to traditional drug discovery, drug repurposing is attractive for its speed, cost, and reduced risk of failure. However, existing approaches for drug repurposing involve complex, computationally‐intensive analytical methods that are not widely used in practice. Instead, repurposing decisions are often based on subjective judgments from limited empirical evidence. In this article, we develop a novel Bayesian network meta‐analysis (NMA) framework that can predict the efficacy of an approved treatment in a new indication and thereby identify candidate treatments for repurposing. We obtain predictions using two main steps: first, we use standard NMA modeling to estimate average relative effects from a network comprised of treatments studied in both indications in addition to one treatment studied in only one indication. Then, we model the correlation between relative effects using various strategies that differ in how they model treatments across indications and within the same drug class. We evaluate the predictive performance of each model using a simulation study and find that the model minimizing root mean squared error of the posterior median for the candidate treatment depends on the amount of available data, the level of correlation between indications, and whether treatment effects differ, on average, by drug class. We conclude by discussing an illustrative example in psoriasis and psoriatic arthritis and find that the candidate treatment has a high probability of success in a future trial.
Radial compressed sensing imaging improves the velocity detection limit of single cell tracking time‐lapse MRI
Authors: Wilken Enrica , Havlas Asli , Masthoff Max , Moussavi Amir , Boretius Susann , Faber Cornelius
Published: December 2023

Purpose

Time‐lapse MRI enables tracking of single iron‐labeled cells. Yet, due to temporal blurring, only slowly moving cells can be resolved. To study faster cells for example during inflammatory processes, accelerated acquisition is needed.

Methods

A rotating phantom system was developed to quantitatively measure the current maximum detectable speed of cells in time‐lapse MRI. For accelerated cell tracking, an interleaved radial acquisition scheme was applied to phantom and murine brain in vivo time‐lapse MRI experiments at 9.4 T. Detection of iron‐labeled cells was evaluated in fully sampled and undersampled reconstructions with and without compressed sensing.

Results

The rotating phantom system enabled ultra‐slow rotation of phantoms and a velocity detection limit of full‐brain Cartesian time‐lapse MRI of up to 172 μm/min was determined. Both phantom and in vivo measurements showed that single cells can be followed dynamically using radial time‐lapse MRI. Higher temporal resolution of undersampled reconstructions reduced geometric distortion, the velocity detection limit was increased to 1.1 mm/min in vitro, and previously hidden fast‐moving cells were recovered. In the mouse brain after in vivo labeling, a total of 42 ± 4 cells were counted in fully sampled, but only 7 ± 1 in undersampled images due to streaking artifacts. Using compressed sensing 33 ± 4 cells were detected.

Conclusion

Interleaved radial time‐lapse MRI permits retrospective reconstruction of both fully sampled and accelerated images, enables single cell tracking at higher temporal resolution and recovers cells hidden before due to blurring. The velocity detection limit as determined with the rotating phantom system increased two‐ to three‐fold compared to previous results.
Velocity selective spin labeling using parallel transmission
Authors: Wu Chia‐Yin , Jin Jin , Dixon Carl , Maillet Donald , Barth Markus , Cloos Martijn A.
Published: December 2023

Purpose

Ultra‐high field (UHF) provides improved SNR which greatly benefits SNR starved imaging techniques such as perfusion imaging. However, transmit field (B1+) inhomogeneities commonly observed at UHF hinders the excitation uniformity. Here we show how replacing standard excitation pulses with parallel transmit pulses can improve efficiency of velocity selective labeling.

Methods

The standard tip‐down and tip‐up excitation pulses found in a velocity selective preparation module were replaced with tailored non‐selective kT‐points pulse solutions. Bloch simulations and experimental validation on a custom‐built flow phantom and in vivo was performed to evaluate different pulse configurations in circularly polarized mode (CP‐mode) and parallel transmit (pTx) mode.

Results

Tailored pTx pulses significantly improved velocity selective labeling fidelity and signal uniformity. The transverse magnetization normalized RMS error was reduced from 0.489 to 0.047 when compared to standard rectangular pulses played in CP‐mode. Simulations showed that manipulation of time symmetry in the tailored pTx pulses is vital in minimizing residual magnetization. In addition, in vivo experiments achieved a 44% lower RF power output and a shorter pulse duration when compared to using adiabatic pulses in CP‐mode.

Conclusion

Using tailored pTx pulses for excitation within a velocity selective labeling preparation mitigated transmit field artifacts and improved SNR and contrast fidelity. The improvement in labeling efficiency highlights the potential of using pTx to improve robustness and accessibility of flow‐based sequences such as velocity selective spin labeling at ultra‐high field.
Co‐development and evaluation of the Musculoskeletal Telehealth Toolkit for physiotherapists
Authors: Ezzat Allison M. , King Matthew G. , De Oliveira Silva Danilo , Pazzinatto Marcella F. , Caneiro J. P. , Gourd Stephanie , McGlasson Rhona , Malliaras Peter , Dennett Amy , Russell Trevor , Kemp Joanne L. , Barton Christian J.
Published: December 2023

Introduction

In‐person physiotherapy services are not readily available to all individuals with musculoskeletal conditions, especially those in rural regions or with time‐intensive responsibilities. The COVID‐19 pandemic highlighted that telehealth may facilitate access to, and continuity of care, yet many physiotherapists lack telehealth confidence and training. This project co‐developed and evaluated a web‐based professional development toolkit supporting physiotherapists to provide telehealth services for musculoskeletal conditions.

Methods

A mixed‐methods exploratory sequential design applied modified experience‐based co‐design methods (physiotherapists [n = 13], clinic administrators [n = 2], and people with musculoskeletal conditions [n = 7]) to develop an evidence‐informed toolkit. Semi‐structured workshops were conducted, recorded, transcribed, and thematically analysed, refining the toolkit prototype. Subsequently, the toolkit was promoted via webinars and social media. The usability of the toolkit was examined with pre‐post surveys examining changes in confidence, knowledge, and perceived telehealth competence (19 statements modelled from the theoretical domains framework) between toolkit users (>30 min) and non‐users (0 min) using chi‐squared tests for independence. Website analytics were summarised.

Results

Twenty‐two participants engaged in co‐design workshops. Feedback led to the inclusion of more patient‐facing resources, increased assessment‐related visual content, streamlined toolkit organisation, and simplified, downloadable infographics. Three hundred and twenty‐nine physiotherapists from 21 countries completed the baseline survey, with 172 (52%) completing the 3‐month survey. Toolkit users had greater improvement in knowledge, confidence, and competence than non‐users in 42% of statements. Seventy‐two percentage of toolkit users said it changed their practice, and 95% would recommend the toolkit to colleagues. During the evaluation period, the toolkit received 5486 total views.

Discussion

The co‐designed web‐based Musculoskeletal Telehealth Toolkit is a professional development resource that may increase physiotherapist's confidence, knowledge, and competence in telehealth.
Topological Properties of a Non‐Hermitian Quasi‐1D Chain with a Flat Band
Authors: Martínez‐Strasser C. , Herrera M. A. J. , García‐Etxarri A. , Palumbo G. , Kunst F. K. , Bercioux D.
Published: December 2023

The spectral properties of a non‐Hermitian quasi‐1D lattice in two of the possible dimerization configurations are investigated. Specifically, it focuses on a non‐Hermitian diamond chain that presents a zero‐energy flat band. The flat band originates from wave interference and results in eigenstates with a finite contribution only on two sites of the unit cell. To achieve the non‐Hermitian characteristics, the system under study presents non‐reciprocal hopping terms in the chain. This leads to the accumulation of eigenstates on the boundary of the system, known as the non‐Hermitian skin effect. Despite this accumulation of eigenstates, for one of the two considered configurations, it is possible to characterize the presence of non‐trivial edge states at zero energy by a real‐space topological invariant known as the biorthogonal polarization. This work shows that this invariant, evaluated using the destructive interference method, characterizes the non‐trivial phase of the non‐Hermitian diamond chain. For the second non‐Hermitian configuration, there is a finite quantum metric associated with the flat band. Additionally, the system presents the skin effect despite the system having a purely real or imaginary spectrum. The two non‐Hermitian diamond chains can be mapped into two models of the Su‐Schrieffer‐Heeger chains, either non‐Hermitian, and Hermitian, both in the presence of a flat band. This mapping allows to draw valuable insights into the behavior and properties of these systems.
The progression and mechanisms of mental illness symptoms in university student‐athletes during the COVID‐19 pandemic
Authors: Labossière Sophie , Couture Sophie , Laurier Catherine , Lemieux Annie , Boudreault Véronique
Published: December 2023

A few studies have examined mental illness symptoms in university student‐athletes during the COVID‐19 pandemic, but the limited use of longitudinal design limits the understanding of the progression of these symptoms and the mechanisms by which they developed. The present research aims to describe the trajectory of variation of mental illness symptoms (anxiety, depression, alcohol consumption disorders, and eating disorders) throughout the pandemic, to test causality between perceived stress and symptoms, and to identify individual characteristics (sociodemographic, perceived stress, and social support) influencing the trajectories of mental illness symptoms. On three occasions during the pandemic, 211 university student‐athletes were surveyed. Latent growth models and random intercept crossed‐lagged panel models were performed. Results indicate that anxiety and depressive symptoms significantly decreased throughout the COVID‐19 pandemic while alcohol consumption disorder symptoms significantly increased and eating disorder symptoms did not change significantly. Second, perceived stress was a significant cause of anxiety and depressive symptoms during this pandemic. Conversely, eating disorder symptoms significantly predicted perceived stress. Finally, average perceived stress and average social support availability throughout the COVID‐19 pandemic, and identifying as a visible minority, significantly predicted the trajectory of depressive symptoms, allowing for the identification of a sub‐population at higher risk. Based on these findings, teaching stress management strategies should be an essential component of programs to prevent mental illness symptoms in university student‐athletes. Reducing environmental stressors and their consequences among this population should also be prioritised.
An Ellagic Acid Coordinated Copper‐Based Nanoplatform for Efficiently Overcoming Cancer Chemoresistance by Cuproptosis and Synergistic Inhibition of Cancer Cell Stemness
Authors: Lu Shuaijun , Tian Hailong , Li Bowen , Li Lei , Jiang Hao , Gao Yajie , Zheng Lin , Huang Canhua , Zhou Yuping , Du Zhongyan , Xu Jia
Published: December 2023

Drug resistance is one of the leading causes of treatment failure in current cancer chemotherapy. In addition to the classical drug efflux transporter‐mediated chemoresistance, cancer cells with stemness features play a crucial role in escaping the maximum impact of chemotherapy. To sensitize cancer chemotherapy, in a novel approach, the hedgehog pathway inhibitor ellagic acid (EA) is coordinated with Cu2+ to develop nanoscale metal–organic frameworks (EA‐Cu), which are then loaded with doxorubicin (DOX) and modified with targeted chondroitin sulfate (CS) to form the CS/E‐C@DOX nanoplatform (CS/NPs). Notably, EA inhibits stemness maintenance by suppressing the hedgehog pathway, while Cu2+ further decreases stemness features of tumor cells by disrupting mitochondrial metabolism, effectively enhancing DOX‐mediated chemotherapy. Meanwhile, EA can act synergistically with Cu2+ to cause mitochondrial dysfunction and cuproptosis, which effectively decreases ATP levels and subsequently suppresses the activity of P‐glycoprotein (P‐gp), thus reducing drug efflux and sensitizing DOX‐mediated chemotherapy. Additionally, the attached CS endows CS/NPs with specific tumor targeting properties, whereas EA‐Cu endows this nanoplatform with pH/glutathione (GSH) dual‐responsive release behavior. Taken together, CS/NPs exhibited excellent antitumor effects by inducing cuproptosis and significantly inhibiting cancer cell stemness, which has great potential for overcoming cancer chemoresistance.
Phylogenomics resolves the rediscovered Himalayan endemic Brachymeniopsis gymnostoma (Bryophyta, Funariaceae), as a species of Entosthodon, prompting also the transfer of Clavitheca poeltii
Authors: Zhang Li , Zuo Qin , Ma Wen‐Zhang , Shevock James R. , Patel Nikisha , Johnson Matthew , Medina Rafael , Wilding Nicholas , Goffinet Bernard
Published: December 2023

Traits of the spore‐bearing generation have historically provided the basis for systematic concepts across the phylogenetic spectrum and depth of mosses. Whether taxa characterized by a simple sporophytic architecture are closely related or emerged from independent reduction is often ambiguous. Phylogenomic inferences in the Funariaceae, which hold the model taxon Physcomitrium patens, revealed that several such shifts in sporophyte complexity occurred, and mostly within the Entosthodon‐Physcomitrium complex. Here, we report the rediscovery of the monospecific, Himalayan endemic genera Brachymeniopsis and Clavitheca, after nearly 100 years and 40 years since their respective descriptions. The genera are characterized by, among other traits, their short sporophytes lacking the sporangial peristome teeth controlling spore dispersal. Phylogenomic inferences reveal that Brachymeniopsis gymnostoma arose within the clade of Entosthodon s.str., a genus with typically long‐exserted capsules. We therefore propose to transfer B. gymnostoma to the genus Entosthodon, as E. gymnostomus comb. nov. Furthermore, Clavitheca poeltii, the sole species of the genus, is morphologically highly similar to E. gymnostomus, and should also be transferred to Entosthodon, but is retained as a distinct taxon, E. poeltii comb. nov., until additional populations allow for testing the robustness of the observed divergence in costa and seta length between the Nepalese and Chinese populations.