bluuebunny/crossref_metadata_2025 huggingface dataset:
Brahma‐Related Gene 1 Inhibition Prevents Liver Fibrosis and Cholangiocarcinoma by Attenuating Progenitor Expansion
Authors: Zhou Yongjie , Chen Yuwei , Zhang Xiaoyun , Xu Qing , Wu Zhenru , Cao Xiaoyue , Shao Mingyang , Shu Yuke , Lv Tao , Lu Changli , Xie Mingjun , Wen Tianfu , Yang Jiayin , Shi Yujun , Bu Hong
Published: March 2021

Background and Aims

Intrahepatic cholangiocarcinoma (iCCA) is closely correlated with hepatic progenitor cell (HPC) expansion and liver fibrosis. Brahma‐related gene 1 (Brg1), an enzymatic subunit of the switch/sucrose nonfermentable complex that is critical in stem cell maintenance and tumor promotion, is prominently up‐regulated in both HPCs and iCCA; however, its role in this correlation remains undefined.

Approach and Results

A retrospective cohort study indicated that high Brg1 expression suggests poor prognosis in patients with iCCA. In chronically injured livers induced by a 0.1% 3,5‐diethoxycarbonyl‐1,4‐dihydrocollidine diet or bile duct ligation surgery, HPCs were dramatically activated, as indicated by their enhanced expression of Brg1 and a subset of stem cell markers; however, Brg1 ablation in HPCs strongly suppressed HPC expansion and liver fibrosis. Furthermore, in a chemically induced iCCA model, inhibition of Brg1 by a specific inhibitor or inducible gene ablation markedly improved histology and suppressed iCCA growth. Mechanistically, in addition to transcriptionally promoting both Wnt receptor genes and target genes, Brg1 was found to bind to the β‐catenin/transcription factor 4 transcription complex, suggesting a possible approach for regulation of Wnt/β‐catenin signaling.

Conclusions

We have demonstrated the function of Brg1 in promoting HPC expansion, liver cirrhosis, and, ultimately, iCCA development in chronically injured livers, which is largely dependent on Wnt/β‐catenin signaling. Our data suggest that therapies targeting Brg1‐expressing HPCs are promising for the treatment of liver cirrhosis and iCCA.
Rural Chinese youth during the transition into adulthood: Family dynamics and psychological adjustment
Authors: Zhang Xinwei , Kong Peggy A.
Published: March 2021

Rural youth in China experience numerous challenges during their transition into adulthood. Yet, research on this transition and its relevant influential factors is rare. Through the lens of family systems theory, this study examined the impacts of family dynamics (i.e., interparental and parent–adolescent interactions) in adolescence on the psychological adjustment of youth as they transition into adulthood. Participants were 1330 youth and their mothers in rural Gansu. In 2004, mothers completed questionnaires of interparental and parent–adolescent interactions when youth were adolescents (Mage = 15.03, SD = 1.15). In 2009, youth completed questionnaires of depression and self‐esteem when they were emerging adults (Mage = 20.03, SD = 1.15). Results of structural equation modelling suggested that while interparental interactions in adolescence were not associated with the psychological adjustment of youth in emerging adulthood, positive parent–adolescent interactions in adolescence predicted better psychological adjustment of youth in emerging adulthood. Furthermore, mediation analysis showed that although interparental interactions did not directly affect the psychological adjustment of youth, they were positively associated with parent–adolescent interactions, which in turn contributed to the psychological adjustment of youth. The results reveal an enduring influence of family dynamics on psychological adjustment among rural Chinese youth during the transition into adulthood.
Intercellular Interactions of an Adipogenic CXCL12-Expressing Stromal Cell Subset in Murine Bone Marrow
Authors: Matsushita Yuki , Chu Angel Ka Yan , Ono Wanida , Welch Joshua D , Ono Noriaki
Published: March 2021

Bone marrow houses a multifunctional stromal cell population expressing C-X-C motif chemokine ligand 12 (CXCL12), termed CXCL12-abundant reticular (CAR) cells, that regulates osteogenesis and adipogenesis. The quiescent pre-adipocyte-like subset of CXCL12+ stromal cells (“Adipo-CAR” cells) is localized to sinusoidal surfaces and particularly enriched for hematopoiesis-supporting cytokines. However, detailed characteristics of these CXCL12+ pre-adipocyte-like stromal cells and how they contribute to marrow adipogenesis remain largely unknown. Here we highlight CXCL12-dependent physical coupling with hematopoietic cells as a potential mechanism regulating the adipogenic potential of CXCL12+ stromal cells. Single-cell computational analyses of RNA velocity and cell signaling reveal that Adipo-CAR cells exuberantly communicate with hematopoietic cells through CXCL12-CXCR4 ligand-receptor interactions but do not interconvert with Osteo-CAR cells. Consistent with this computational prediction, a substantial fraction of Cxcl12-creER+ pre-adipocyte-like cells intertwines with hematopoietic cells in vivo and in single-cell preparation in a protease-sensitive manner. Deletion of CXCL12 in these cells using Col2a1-cre leads to a reduction of stromal-hematopoietic coupling and extensive marrow adipogenesis in adult bone marrow, which appears to involve direct conversion of CXCL12+ cells to lipid-laden marrow adipocytes without altering mesenchymal progenitor cell fates. Therefore, these findings suggest that CXCL12+ pre-adipocyte-like marrow stromal cells prevent their premature differentiation by maintaining physical coupling with hematopoietic cells in a CXCL12-dependent manner, highlighting a possible cell-non-autonomous mechanism that regulates marrow adipogenesis. © 2021 American Society for Bone and Mineral Research (ASBMR).
Stem cell in neurodegenerative disorders; an emerging strategy
Authors: Ahani‐Nahayati Milad , Shariati Ali , Mahmoodi Mahnaz , Olegovna Zekiy Angelina , Javidi Kamran , Shamlou Somayeh , Mousakhani Akbar , Zamani Majid , Hassanzadeh Ali
Published: March 2021

Neurodegenerative disorders are a diversity of disorders, surrounding Alzheimer's (AD), Parkinson's (PD), Huntington's diseases (HD), and amyotrophic lateral sclerosis (ALS) accompanied by some other less common diseases generally characterized by either developed deterioration of central or peripheral nervous system structurally or functionally. Today, with the viewpoint of an increasingly aging society, the number of patients with neurodegenerative diseases and sociomedical burdens will spread intensely. During the last decade, stem cell technology has attracted great attention for treating neurodegenerative diseases worldwide because of its unique attributes. As acknowledged, there are several categories of stem cells being able to proliferate and differentiate into various cellular lineages, highlighting their significance in the context of regenerative medicine. In preclinical models, stem cell therapy using mesenchymal stem/stromal cells (MSCs), hematopoietic stem cells (HSCs), and neural progenitor or stem cells (NPCs or NSCs) along with pluripotent stem cells (PSCs)‐derived neuronal cells could elicit desired therapeutic effects, enabling functional deficit rescue partially. Regardless of the noteworthy progress in our scientific awareness and understanding of stem cell biology, there still exist various challenges to defeat. In the present review, we provide a summary of the therapeutic potential of stem cells and discuss the current status and prospect of stem cell strategy in neurodegenerative diseases, in particular, AD, PD, ALS, and HD.
Evaluating stability of a Raman spectrometer for long‐time experiments
Authors: Raj Ankit , Witek Henryk A. , Hamaguchi Hiro‐o
Published: March 2021

Raman spectroscopic measurements spanning several hours to days are increasingly common and important. The stability of a Raman spectrometer becomes crucial when comparing spectra recorded at different occasions in such time‐intensive experiments. In this work, series of Raman spectra of benzene and emission spectra of neon were acquired using a standard Raman spectrometer operating in a typical air‐conditioned laboratory, with synchronized measurements of ambient parameters (pressure, temperature, humidity, etc.) subject to continuous unsystematic environmental drifts. The time‐dependent fluctuations of positions and intensities of selected bands in the series of spectra recorded over tens of hours displayed variations of up to ±0.3 cm−1 in the band positions and up to 2% in the associated Raman intensities, with experiments over longer time periods prone to more pronounced fluctuations. After accounting for change in the laser power fluctuations, the intensity variations were reduced to about 1%. Both the variations in the band positions and intensities showed practically no correlation with either of the ambient parameters or the refractive index of air. Tiny drifts in the laser wavenumber (on the order of 0.01 cm−1), attributed to the change in the refractive index of the laser cavity associated with the variations in the ambient pressure, were too small to account for the observed fluctuations in the band positions.
Preclinical models of vertebral osteomyelitis and associated infections: Current models and recommendations for study design
Authors: Joyce Kieran , Sakai Daisuke , Pandit Abhay
Published: March 2021

Spine‐related infections, such as vertebral osteomyelitis, discitis, or spondylitis, are rare diseases that mostly affect adults, and are usually of hematogenous origin. The incidence of this condition has gradually risen in recent years because of increases in spine‐related surgery and hospital‐acquired infections, an aging population, and intravenous (IV) drug use. Spine infections are most commonly caused byStaphylococcus aureus, while other systemic infections such as tuberculosis and brucellosis can also cause spondylitis. Various animal models of vertebral osteomyelitis and associated infections have been investigated in mouse, rat, chicken, rabbit, dog, and sheep models by hematogenous and direct inoculation in surgery, each with their strengths and limitations. This review is the first of its kind to concisely analyze the various existing animal models used to reproduce clinically relevant models of infection. Spine‐related infection models must address the unique anatomy of the spine, the avascular nature of its structures and tissues and the consequences of tissue destruction such as spinal cord compression. Further investigation is necessary to elucidate the specific mechanisms of host‐microbe response to inform antimicrobial therapy and administration techniques in a technically demanding body cavity. Small‐animal models are not suitable for large instrumentation, and difficult IV access thwarts antibiotic administration. In contrast, large‐animal models can be implanted with clinically relevant instrumentation and are resilient to repeat procedures to study postoperative infection. A canine model of infection offers a unique opportunity to design and investigate antimicrobial treatments through recruitment a rich population of canine patients, presenting with a natural disease that is suitable for randomized trials.
Isothermal modelling of protein adsorption to thermo‐responsive polymer grafted Sepharose Fast Flow sorbents
Authors: Tan Sinuo , Saito Kei , Hearn Milton T. W.
Published: March 2021

In this study, five adsorption isotherm models, that is, the Langmuir, Freundlich, Langmuir–Freundlich, Temkin and Brunauer–Emmett–Teller isotherms, were utilized for the analysis of the experimental adsorption data for six classes of poly(N‐isopropylacrylamide)‐based thermo‐responsive copolymer‐grafted Sepharose Fast Flow sorbents of different copolymer compositions with two structurally related proteins, namely bovine holo‐lactoferrin and bovine holo‐transferrin at 20 and 50°C. The experimental data for bovine holo‐lactoferrin could be mathematically fitted to the Freundlich and Temkin isotherms when the protein feed concentrations were in the range of 1–40 mg/mL at both 20 and 50°C. Similar analysis of the binding of the homologous protein, bovine holo‐transferrin, to the same thermo‐responsive copolymer‐grafted sorbents revealed that the experimental data could be fitted to the Langmuir, Freundlich and Temkin isotherms with coefficients of determination value over 0.90.
hnRNP L is essential for myogenic differentiation and modulates myotonic dystrophy pathologies
Authors: Alexander Matthew S. , Hightower Rylie M. , Reid Andrea L. , Bennett Alexis H. , Iyer Lakshmanan , Slonim Donna K. , Saha Madhurima , Kawahara Genri , Kunkel Louis M. , Kopin Alan S. , Gupta Vandana A. , Kang Peter B. , Draper Isabelle
Published: March 2021

Introduction

RNA‐binding proteins (RBPs) play an important role in skeletal muscle development and disease by regulating RNA splicing. In myotonic dystrophy type 1 (DM1), the RBP MBNL1 (muscleblind‐like) is sequestered by toxic CUG repeats, leading to missplicing of MBNL1 targets. Mounting evidence from the literature has implicated other factors in the pathogenesis of DM1. Herein we sought to evaluate the functional role of the splicing factor hnRNP L in normal and DM1 muscle cells.

Methods

Co‐immunoprecipitation assays using hnRNPL and MBNL1 expression constructs and splicing profiling in normal and DM1 muscle cell lines were performed. Zebrafish morpholinos targeting hnrpl and hnrnpl2 were injected into one‐cell zebrafish for developmental and muscle analysis. In human myoblasts downregulation of hnRNP L was achieved with shRNAi. Ascochlorin administration to DM1 myoblasts was performed and expression of the CUG repeats, DM1 splicing biomarkers, and hnRNP L expression levels were evaluated.

Results

Using DM1 patient myoblast cell lines we observed the formation of abnormal hnRNP L nuclear foci within and outside the expanded CUG repeats, suggesting a role for this factor in DM1 pathology. We showed that the antiviral and antitumorigenic isoprenoid compound ascochlorin increased MBNL1 and hnRNP L expression levels. Drug treatment of DM1 muscle cells with ascochlorin partially rescued missplicing of established early biomarkers of DM1 and improved the defective myotube formation displayed by DM1 muscle cells.

Discussion

Together, these studies revealed that hnRNP L can modulate DM1 pathologies and is a potential therapeutic target.
Seismic refraction and electrical resistivity tomographies for geotechnical site characterization of two water reservoirs (El Hierro, Spain)
Authors: Fernández‐Baniela Fabiola , Arias Daniel , Rubio‐Ordóñez Álvaro
Published: March 2021

On El Hierro (Canary Islands, Spain), the company Gorona del Viento El Hierro S.A. carried out the construction of a Wind‐Pumped Hydro Power Station in order to achieve the energy autonomy on the island through 100% renewable energy. The station consists of two man‐made water reservoirs, whose design was adapted to the island topography and emplaced in a valley and an inactive crater. In order to study the subsurface of both reservoirs, the characteristic heterogeneity of volcanic materials was taken into account. Therefore, a research campaign combining different methods was proposed; mechanical investigations traditionally applied in engineering (rotary boreholes, dynamic probing super heavy tests and pits) and geophysical methods (seismic refraction tomography and electrical resistivity tomography) were both utilized. The aims were to determine the geological structure of each site, detect possible anomalies or structures (i.e., faults, volcanic cavities, etc.), identify the different lithologies, determine the soil thickness and depth to bedrock, predict the excavatability of the materials, and obtain data about the physical properties and mechanical behaviour of the ground in an effort to carry out a geotechnical site characterization of both sites. At the site of the upper reservoir, electrical resistivity tomography recorded a high thickness of low resistivity soils, which were subsequently investigated by deep boreholes in order to sample and test them properly, since they could generate high settlements during the construction of the reservoir. At the site of the lower reservoir, the existing palaeorelief in the basaltic bedrock was detected by seismic refraction tomography, which allowed for the selection of the appropriate excavation machinery for the planned earthworks. The geological interpretation of the P‐wave velocity models and electrical resistivity models are shown in this paper, as well as a correlation between geotechnical parameters and geophysical properties of volcanic materials and recent deposits, which will be useful for other civil projects which may be carried out in the future at sites with similar geological conditions.
Self‐management interventions in systemic sclerosis: A systematic review
Authors: Wojeck Robyn K. , Bailey Donald E. , Somers Tamara J. , Knisely Mitchell R.
Published: March 2021

Systemic sclerosis is a rare and incurable autoimmune disease in which patients are challenged with self‐managing their disease. Systematic evaluation of the essential self‐management intervention components and self‐management outcomes is necessary to assess the state of the science of self‐management for patients with systemic sclerosis. As such, the purpose of this systematic review was to identify and describe self‐management interventions and their impact on self‐management outcomes in adults with systemic sclerosis. Studies were included if they contained a self‐management intervention, incorporated at least one self‐management outcome identified as a common data element by the National Institute of Nursing Research (i.e., patient activation, self‐efficacy, self‐regulation, global health), and were conducted in adults with systemic sclerosis. Using the Preferred Reporting Items for Systematic Reviews and Meta‐Analysis guidelines, PubMed, Cumulative Index of Nursing and Allied Health Literature, and Embase were searched from the inception of each database to March 2020, yielding a total of 215 studies. Of these reports, 16 met the inclusion criteria for this review. There was notable variability in the types of self‐management interventions and their effects on key self‐management outcomes. Self‐management interventions focused on improving physical function through rehabilitation programs were the most common interventions (n = 7). The poor methodological quality of the studies included in this systematic review, however, limited the synthesis of and recommendations for self‐management interventions in adults with systemic sclerosis. Future research in systemic sclerosis should include key self‐management outcomes in larger, more rigorously designed studies to allow for comparisons across studies and to advance the science of self‐management.
Three machine learning algorithms and their utility in exploring risk factors associated with primary cesarean section in low‐risk women: A methods paper
Authors: Clark Rebecca R. S. , Hou Jintong
Published: March 2021

Machine learning, a branch of artificial intelligence, is increasingly used in health research, including nursing and maternal outcomes research. Machine learning algorithms are complex and involve statistics and terminology that are not common in health research. The purpose of this methods paper is to describe three machine learning algorithms in detail and provide an example of their use in maternal outcomes research. The three algorithms, classification and regression trees, least absolute shrinkage and selection operator, and random forest, may be used to understand risk groups, select variables for a model, and rank variables' contribution to an outcome, respectively. While machine learning has plenty to contribute to health research, it also has some drawbacks, and these are discussed as well. To provide an example of the different algorithms' function, they were used on a completed cross‐sectional study examining the association of oxytocin total dose exposure with primary cesarean section. The results of the algorithms are compared to what was done or found using more traditional methods.
Temporal Trends and Predictors in the Use of Stereotactic Body Radiotherapy for Treatment of Metastatic Renal Cell Carcinoma in the U.S
Authors: Paciotti Marco , Schmidt Andrew L. , Ravi Praful , McKay Rana R. , Trinh Quoc-Dien , Choueiri Toni K.
Published: March 2021

This letter to the editor outlines the use of stereotactic body radiotherapy for metastatic renal cell carcinoma in the U.S., identifying clinical predictors of utilization using the National Cancer Database.
Use of Molecular Assays and Circulating Tumor DNA in Early-Stage Colorectal Cancer: A Roundtable Discussion of the Gastrointestinal Cancer Therapy Expert Group
Authors: Loaiza-Bonilla Arturo , Benson Al B. , Grothey Axel , Karimi Misagh , Klempner Samuel J. , Lin Daniel , Mahtani Reshma , Soares Heloisa P.
Published: March 2021

The use of genomic testing is rapidly emerging as an important clinical tool both for cancer diagnosis and for guiding treatment decisions in a wide range of malignancies, including gastrointestinal (GI) cancers such as colorectal cancer (CRC). Advances in technologies such as polymerase chain reaction and next-generation sequencing methods have made it possible to noninvasively screen for CRC through, for example, the use of blood- or stool-based testing, with high specificity. Tests are also available that can provide prognostic information beyond traditional clinicopathologic factors such as tumor size, grade, and nodal status, which can enable clinicians to more accurately risk stratify patients for recurrence. Lastly, in the setting of resected CRC, tests are now available that can detect circulating tumor DNA as a means for noninvasive minimal/molecular residual disease monitoring, thereby potentially guiding the use of adjuvant chemotherapy and/or escalating or de-escalating therapy. The Gastrointestinal Cancer Therapy Expert Group (GICTEG) recently convened a virtual meeting to discuss current issues related to genomic testing in GI cancer, with the goal of providing guidance on the use of these tests for the practicing community oncologist, for whom GI cancer may be only one of many tumor types encountered. This article provides a summary of the discussion and highlights the key opinions of the GICTEG on this topic.

Implications for Practice

The Gastrointestinal Cancer Therapy Expert Group seeks to provide practical guidance and opinion on the treatment of gastrointestinal malignancies, including colorectal cancer (CRC), for the practicing community oncologist in situations for which guidelines from established bodies, such as the National Comprehensive Cancer Network and the American Society of Clinical Oncology, may be less clear. In the present report, clinical guidance on the use of molecular assays for a range of clinical indications in CRC is presented, including the use of circulating tumor DNA to detect minimal/molecular residual disease in patients with successfully resected early-stage CRC.
Drug hapten‐specific T‐cell activation: Current status and unanswered questions
Authors: Adair Kareena , Meng Xiaoli , Naisbitt Dean J.
Published: March 2021

Drug haptens are formed from the irreversible, covalent binding of drugs to nucleophilic moieties on proteins, which can warrant adverse reactions in the body including severe delayed‐type, T‐cell mediated, drug hypersensitivity reactions (DHRs). While three main pathways exist for the activation of T‐cells in DHRs, namely the hapten model, the pharmacological interaction model and the altered peptide repertoire model, the exact antigenic determinants responsible have not yet been defined. In recent years, progress has been made using advanced mass spectrometry‐based proteomic methods to identify protein carriers and characterise the structure of drug‐haptenated proteins. Since genome‐wide association studies discovered a link between human leukocyte antigens (HLA) and an individual's susceptibility to DHRs, much effort has been made to define the drug‐associated HLA ligands driving T‐cell activation, including the elution of natural HLA peptides from HLA molecules and the generation of HLA‐binding peptides. In this review, we discuss our current methodology used to design and synthesise drug‐modified HLA ligands to investigate their immunogenicity using T‐cell models, and thus their implication in drug hypersensitivity.
Oxidant‐Accelerated Polydopamine Modification Process for the Fast Fabrication of PDA on HMX with Improved Mechanical Stability
Authors: Duan Shuyi , Wang Dehai , Jiang Quanping , Xiao Chun , Liu Huihui , Guo Ya , Li Shangbin , Zhu Qing
Published: March 2021

Polydopamine surface coating shows the capability to improve the adhesive properties as well as mechanical stabilities of energetic materials, which is highly desired for the development of insensitive munitions. However, the slow polymerization process of dopamine makes the coating process time‐consuming and uneconomic. Herein, an oxidant‐accelerated strategy was demonstrated to obtain fast polymerization kinetics of dopamine for the surface modification of HMX crystals. Upon the addition of oxidant, PDA was able to form surface layer of HMX particles within 5 min without changing the shape and polymorph of HMX crystals. The PDA coating showed the ability to improve the wettability of HMX, contributing to its abundant active groups. Moreover, the mechanical stability of PDA on HMX (HMX@PDA) samples was improved accompany with the increasing coating time, and the friction explosion probability and drop height of 300 s treated sample were 40 % and 64 cm, respectively. The detonation velocity was also measured, which showed that the effect of PDA coating on the detonation velocity of HMX was not significant. More importantly, our protocol showed the capability to fabricate HMX@PDA with different particle sizes on a large scale, satisfying the application demands of insensitive high explosives.
Increasing the value and efficiency of herbicide resistance surveys
Authors: Squires Caleb C , Coleman Guy RY , Broster John C , Preston Christopher , Boutsalis Peter , Owen Mechelle J , Jalaludin Adam , Walsh Michael J
Published: March 2021

The scale of herbicide resistance within a cropping region can be estimated and monitored using surveys of weed populations. The current approach to herbicide resistance surveys is time‐consuming, logistically challenging and costly. Here we review past and current approaches used in herbicide resistance surveys with the aims of (i) defining effective survey methodologies, (ii) highlighting opportunities for improving efficiencies through the use of new technologies and (iii) identifying the value of repeated region‐wide herbicide resistance surveys. One of the most extensively surveyed areas of the world's cropping regions is the Australian grain production region, with >2900 fields randomly surveyed in each of three surveys conducted over the past 15 years. Consequently, recommended methodologies are based on what has been learned from the Australian experience. Traditional seedling‐based herbicide screening assays remain the most reliable and widely applicable method for characterizing resistance in weed populations. The use of satellite or aerial imagery to plan collections and image analysis to rapidly quantify screening results could complement traditional resistance assays by increasing survey efficiency and sampling accuracy. Global management of herbicide‐resistant weeds would benefit from repeated and standardized surveys that track herbicide resistance evolution within and across cropping regions. © 2021 Society of Chemical Industry.
Insights into the Hydrogen‐Related Mechanism behind Defect Formation during Light‐ and Elevated‐Temperature‐Induced Degradation
Authors: Hammann Benjamin , Rachdi Lazhar , Kwapil Wolfram , Schindler Florian , Schubert Martin C.
Published: March 2021

By investigating the formation of light‐ and elevated‐temperature‐induced degradation (LeTID) defects under dark annealing conditions alongside the formation of the boron–hydrogen complex, it is found that both formations are limited by presumably the same reaction. Starting with this observation, two possible mechanisms of LeTID defect formation, a hydrogen‐related association and dissociation process, are discussed. Including the current knowledge on hydrogen in silicon as well as on the reverse reaction to the defect formation, the dissociation mechanism seems to be more likely: the LeTID precursor is composed of hydrogen being bound to another complex. During dark annealing, the hydrogen dissociates and binds to its sink, which herein is boron. The remaining complex is recombination active and leads thus to the observed degradation.
Gaussian accelerated molecular dynamics: Principles and applications
Authors: Wang Jinan , Arantes Pablo R. , Bhattarai Apurba , Hsu Rohaine V. , Pawnikar Shristi , Huang Yu‐ming M. , Palermo Giulia , Miao Yinglong
Published: March 2021

Gaussian accelerated molecular dynamics (GaMD) is a robust computational method for simultaneous unconstrained enhanced sampling and free energy calculations of biomolecules. It works by adding a harmonic boost potential to smooth biomolecular potential energy surface and reduce energy barriers. GaMD greatly accelerates biomolecular simulations by orders of magnitude. Without the need to set predefined reaction coordinates or collective variables, GaMD provides unconstrained enhanced sampling and is advantageous for simulating complex biological processes. The GaMD boost potential exhibits a Gaussian distribution, thereby allowing for energetic reweighting via cumulant expansion to the second order (i.e., “Gaussian approximation”). This leads to accurate reconstruction of free energy landscapes of biomolecules. Hybrid schemes with other enhanced sampling methods, such as the replica‐exchange GaMD (rex‐GaMD) and replica‐exchange umbrella sampling GaMD (GaREUS), have also been introduced, further improving sampling and free energy calculations. Recently, new “selective GaMD” algorithms including the Ligand GaMD (LiGaMD) and Peptide GaMD (Pep‐GaMD) enabled microsecond simulations to capture repetitive dissociation and binding of small‐molecule ligands and highly flexible peptides. The simulations then allowed highly efficient quantitative characterization of the ligand/peptide binding thermodynamics and kinetics. Taken together, GaMD and its innovative variants are applicable to simulate a wide variety of biomolecular dynamics, including protein folding, conformational changes and allostery, ligand binding, peptide binding, protein–protein/nucleic acid/carbohydrate interactions, and carbohydrate/nucleic acid interactions. In this review, we present principles of the GaMD algorithms and recent applications in biomolecular simulations and drug design.

This article is categorized under:

Structure and Mechanism > Computational Biochemistry and Biophysics

Molecular and Statistical Mechanics > Molecular Dynamics and Monte‐Carlo Methods

Molecular and Statistical Mechanics > Free Energy Methods
Speech aging: Production and perception
Authors: Tucker Benjamin V. , Ford Catherine , Hedges Stephanie
Published: March 2021

In this overview we describe literature on how speech production and speech perception change in healthy or normal aging across the adult lifespan. In the production section we review acoustic characteristics that have been investigated as potentially distinguishing younger and older adults. In the speech perception section studies concerning speaker age estimation and those investigating older listeners' perception are addressed. Our discussion focuses on major themes and other fruitful areas for future research.

This article is categorized under:

Linguistics > Language in Mind and Brain

Linguistics > Linguistic Theory

Psychology > Development and Aging
On the Certificate Revocation Problem in the Maritime Sector
Authors: Bour Guillaume , Bernsmed Karin , Borgaonkar Ravishankar , Meland Per Håkon
Published: March 2021

Maritime shipping is currently undergoing rapid digitalization, but with increasing exposure to cyber threats, there is a need to improve the security of the ship communication technology used during operations across international waters, as well as close to local shores and in ports. To this aid, there are ongoing standardization efforts for an international maritime Public Key Infrastructure, but the inherent properties of limited connectivity and bandwidth make certificate revocation a problematic affair compared to traditional Internet systems. The main contribution of this paper is an analysis of certificate revocation techniques based on how they fulfil fundamental maritime requirements and simulated usage over time. Our results identify CRLs (with Delta CRLs) and CRLite as the two most promising candidates. Finally, we outline the pros and cons with these two different solutions.
Understanding Civility
Authors: Bonotti Matteo , Zech Steven T.
Published: March 2021

This chapter introduces the concept of civility and identifies its two main dimensions. The first, politeness, is related to norms of etiquette and good manners. Politeness involves both structural and agential components, and presents two important functional aspects: it can be used to signal respect and consideration for others, and it can help facilitate social cooperation. The second dimension of civility, public-mindedness, involves treating others as free and equal members of society. Civility as public-mindedness presents two sub-dimensions. The first, moral civility, demands that we respect other people’s fundamental rights, liberties, and equal civic standing, for example by avoiding racist and discriminatory speech and behaviour. The second, justificatory civility, requires that we refrain from justifying political rules based on self-interested or sectarian reasons.
Civility as Politeness During COVID-19
Authors: Bonotti Matteo , Zech Steven T.
Published: March 2021

This chapter examines new challenges to the politeness dimension of civility presented by COVID-19. First, the pandemic has made it more difficult for people to identify norms of politeness and behave appropriately in circumstances that were previously less contested and problematic. Furthermore, signalling respect and consideration towards others via polite speech or behaviour is more likely to go awry during COVID-19. Additionally, the lack of clarity surrounding norms of politeness may prevent polite acts from helping to mitigate conflict and facilitate cooperative social exchange. Finally, citizens and politicians can exploit disruptions around politeness norms to engage in behaviour that under normal circumstances would be considered impolite. The chapter also identifies potential solutions that governments, businesses, and citizens can adopt to respond to these challenges.
Non-standard interactions in SMEFT confronted with terrestrial neutrino experiments
Authors: Du Yong , Li Hao-Lin , Tang Jian , Vihonen Sampsa , Yu Jiang-Hao
Published: March 2021

Abstract

The Standard Model Effective Field Theory (SMEFT) provides a systematic and model-independent framework to study neutrino non-standard interactions (NSIs). We study the constraining power of the on-going neutrino oscillation experiments T2K, NOνA, Daya Bay, Double Chooz and RENO in the SMEFT framework. A full consideration of matching is provided between different effective field theories and the renormalization group running at different scales, filling the gap between the low-energy neutrino oscillation experiments and SMEFT at the UV scale. We first illustrate our method with a top- down approach in a simplified scalar leptoquark model, showing more stringent constraints from the neutrino oscillation experiments compared to collider studies. We then provide a bottom-up study on individual dimension-6 SMEFT operators and find NSIs in neutrino experiments already sensitive to new physics at ∼20 TeV when the Wilson coefficients are fixed at unity. We also investigate the correlation among multiple operators at the UV scale and find it could change the constraints on SMEFT operators by several orders of magnitude compared with when only one operator is considered. Furthermore, we find that accelerator and reactor neutrino experiments are sensitive to different SMEFT operators, which highlights the complementarity of the two experiment types.
On p-form gauge theories and their conformal limits
Authors: Bandos Igor , Lechner Kurt , Sorokin Dmitri , Townsend Paul K.
Published: March 2021

Abstract

Relations between the various formulations of nonlinear p-form electrodynamics with conformal-invariant weak-field and strong-field limits are clarified, with a focus on duality invariant (2n − 1)-form electrodynamics and chiral 2n-form electrodynamics in Minkowski spacetime of dimension D = 4n and D = 4n + 2, respectively. We exhibit a new family of chiral 2-form electrodynamics in D = 6 for which these limits exhaust the possibilities for conformal invariance; the weak-field limit is related by dimensional reduction to the recently discovered ModMax generalisation of Maxwell’s equations. For n > 1 we show that the chiral ‘strong-field’ 2n-form electrodynamics is related by dimensional reduction to a new Sl(2; ℝ)-duality invariant theory of (2n − 1)-form electrodynamics.
Regional specification and complementation with non-neuroectodermal cells in human brain organoids
Authors: Tanaka Yoshiaki , Park In-Hyun
Published: March 2021

Along with emergence of the organoids, their application in biomedical research has been currently one of the most fascinating themes. For the past few years, scientists have made significant contributions to deriving organoids representing the whole brain and specific brain regions. Coupled with somatic cell reprogramming and CRISPR/Cas9 editing, the organoid technologies were applied for disease modeling and drug screening. The methods to develop organoids further improved for rapid and efficient generation of cerebral organoids. Additionally, refining the methods to develop the regionally specified brain organoids enabled the investigation of development and interaction of the specific brain regions. Recent studies started resolving the issue in the lack of non-neuroectodermal cells in brain organoids, including vascular endothelial cells and microglia, which play fundamental roles in neurodevelopment and are involved in the pathophysiology of acute and chronic neural disorders. In this review, we highlight recent advances of neuronal organoid technologies, focusing on the region-specific brain organoids and complementation with endothelial cells and microglia, and discuss their potential applications to neuronal diseases.
Selbstuntersuchung von Hoden und Brust – eine retrospektive Kohortenstudie an Medizinstudierenden
Authors: Jahnen Matthias , Dichtl Lorenz , Stirenberg Nora , Dinkel Andreas , Schiele Stefan , Schulwitz Helga , Gschwend Jürgen E. , Herkommer Kathleen
Published: March 2021

Hintergrund

Durch eine regelmäßige Selbstuntersuchung kann ein Malignom der Hoden oder Brust gegebenenfalls frühzeitig erkannt und kurativ behandelt werden. Ziel dieser Arbeit war es, das Selbstuntersuchungsverhalten von Medizinstudierenden zu untersuchen und Faktoren, die eine regelmäßige Selbstuntersuchung beeinflussen, zu identifizieren.

Methodik

Medizinstudierende wurden mittels Fragebogen bezüglich ihres Gesundheits- und Sexualverhaltens befragt. 98,8 % der Studierenden nahmen teil (n = 473). Die erhobenen Daten wurden mittels univariater und multivariater logistischer Regression analysiert.

Ergebnisse

Es gaben 64,2 % der männlichen Studierenden (n = 177) an, regelmäßig ihre Hoden zu untersuchen und 72,2 % der weiblichen Studierenden (n = 296) gaben an, regelmäßig ihre Brust abzutasten. Studierende, die nicht mit ihrer/ihrem PartnerIn bzw. mit ihren FreundInnen über ihre Sexualität sprechen, führten seltener eine Selbstuntersuchung durch (p < 0,05). Männliche Studierende, die in den letzten 4 Wochen vor Befragung keinen Geschlechtsverkehr hatten und weibliche Studierende, die im gleichen Zeitraum nicht masturbierten, führten seltener eine Selbstuntersuchung durch (p < 0,05).

Diskussion

Der Anteil an Medizinstudierenden, der eine regelmäßige Selbstuntersuchung durchführt, ist im Vergleich zu weniger medizinisch gebildeten jungen Erwachsenen hoch. Wissen über die Relevanz von Hoden- bzw. Brustkrebs scheint grundlegend für eine regelmäßige Selbstuntersuchung zu sein. Ein belastetes Sexualleben schränkt solch ein Gesundheitsverhalten möglicherweise ein. Eine Verbesserung der Aufklärung über Hodenkrebs und die urologische Anbindung von Jungen/junger Männer bieten daher die Möglichkeit, die Bereitschaft zur Selbstuntersuchung innerhalb dieser Altersgruppe zu steigern.
A sharp interface method using enriched finite elements for elliptic interface problems
Authors: Höllbacher Susanne , Wittum Gabriel
Published: March 2021

We present an immersed boundary method for the solution of elliptic interface problems with discontinuous coefficients which provides a second-order approximation of the solution. The proposed method can be categorised as an extended or enriched finite element method. In contrast to other extended FEM approaches, the new shape functions get projected in order to satisfy the Kronecker-delta property with respect to the interface. The resulting combination of projection and restriction was already derived in Höllbacher and Wittum (TBA, 2019a) for application to particulate flows. The crucial benefits are the preservation of the symmetry and positive definiteness of the continuous bilinear operator. Besides, no additional stabilisation terms are necessary. Furthermore, since our enrichment can be interpreted as adaptive mesh refinement, the standard integration schemes can be applied on the cut elements. Finally, small cut elements do not impair the condition of the scheme and we propose a simple procedure to ensure good conditioning independent of the location of the interface. The stability and convergence of the solution will be proven and the numerical tests demonstrate optimal order of convergence.
Meningioma MRI radiomics and machine learning: systematic review, quality score assessment, and meta-analysis
Authors: Ugga Lorenzo , Perillo Teresa , Cuocolo Renato , Stanzione Arnaldo , Romeo Valeria , Green Roberta , Cantoni Valeria , Brunetti Arturo
Published: March 2021

Purpose

To systematically review and evaluate the methodological quality of studies using radiomics for diagnostic and predictive purposes in patients with intracranial meningioma. To perform a meta-analysis of machine learning studies for the prediction of intracranial meningioma grading from pre-operative brain MRI.

Methods

Articles published from the year 2000 on radiomics and machine learning applications in brain imaging of meningioma patients were included. Their methodological quality was assessed by three readers with the radiomics quality score, using the intra-class correlation coefficient (ICC) to evaluate inter-reader reproducibility. A meta-analysis of machine learning studies for the preoperative evaluation of meningioma grading was performed and their risk of bias was assessed with the Quality Assessment of Diagnostic Accuracy Studies tool.

Results

In all, 23 studies were included in the systematic review, 8 of which were suitable for the meta-analysis. Total (possible range, −8 to 36) and percentage radiomics quality scores were respectively 6.96 ± 4.86 and 19 ± 13% with a moderate to good inter-reader reproducibility (ICC = 0.75, 95% confidence intervals, 95%CI = 0.54–0.88). The meta-analysis showed an overall AUC of 0.88 (95%CI = 0.84–0.93) with a standard error of 0.02.

Conclusions

Machine learning and radiomics have been proposed for multiple applications in the imaging of meningiomas, with promising results for preoperative lesion grading. However, future studies with adequate standardization and higher methodological quality are required prior to their introduction in clinical practice.
Are psychological symptoms a risk factor for musculoskeletal pain in adolescents?
Authors: Andreucci Alessandro , Campbell Paul , Dunn Kate M.
Published: March 2021

Adolescent musculoskeletal pain is common and is associated with musculoskeletal pain in adulthood. Psychological symptoms, also common in adolescence, have been shown to be associated with musculoskeletal pain, but the current evidence is mixed and may be dependent on effect modifiers. This study investigated whether adolescents with psychological symptoms (internalizing and externalizing constructs) at age 13 years were at higher odds for musculoskeletal pain at age 17 years and whether the associations were modified by pubertal status and sex. A prospective cohort design examined data on 3865 adolescents from the Avon Longitudinal Study of Parents and Children (ALSPAC). Associations between baseline (aged 13 years) internalizing and externalizing symptoms and musculoskeletal pain at follow-up (aged 17 years) were investigated using logistic regression producing odds ratios (OR) and 95% confidence intervals (95% CI). In total 43.1% of adolescents reported musculoskeletal pain at follow-up. Externalizing symptoms at baseline increased the odds of musculoskeletal pain (OR 1.68, 95% CI 1.28, 2.20), and internalizing symptoms demonstrated a non-significant increase (OR 1.26, 95% CI 0.98, 1.62). Effect modification analysis showed an increased effect dependent on pubertal status.

Conclusion: Adolescents with externalizing symptoms, and to some extent internalizing symptoms, are at increased odds of later musculoskeletal pain. Future research is now required to understand the reasons for these associations.

What is Known:• Current evidence regarding the association between internalizing symptoms and externalizing symptoms and future musculoskeletal pain in adolescents is mixed.

What is New:• This study found that adolescents with externalizing symptoms, and to some extent internalizing symptoms, are at increased odds for musculoskeletal pain, with an increased influence dependent on pubertal status.• These results are of interest for the development of timely preventative interventions designed to reduce the risk of musculoskeletal pain.
Whole-body arginine dimethylation is associated with all-cause mortality in adult renal transplant recipients
Authors: Post Adrian , Bollenbach Alexander , Bakker Stephan J. L. , Tsikas Dimitrios
Published: March 2021

Arginine residues in proteins can be singly or doubly methylated post-translationally. Proteolysis of arginine-methylated proteins provides monomethyl arginine, asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA). ADMA and SDMA are considered cardiovascular risk factors, with the underlying mechanisms being not yet fully understood. SDMA lacks appreciable metabolism and is almost completely eliminated by the kidney, whereas ADMA is extensively metabolized to dimethylamine (DMA), with a minor ADMA fraction of about 10% being excreted unchanged in the urine. Urinary DMA and ADMA are useful measures of whole-body asymmetric arginine-dimethylation, while urinary SDMA serves as a whole-body measure of symmetric arginine-dimethylation. In renal transplant recipients (RTR), we previously found that higher plasma ADMA concentrations and lower urinary ADMA and SDMA concentrations were associated with a higher risk of all-cause mortality. Yet, in this RTR collective, no data were available for urinary DMA. For the present study, we additionally measured the excretion rate of DMA in 24-h collected urine samples of the RTR and of healthy kidney donors in the cohort, with the aim to quantitate whole-body asymmetric (ADMA, DMA) and symmetric (SDMA) arginine-dimethylation. We found that lower DMA excretion rates were associated with higher all-cause mortality, yet not with cardiovascular mortality. In the healthy donors, kidney donation was associated with considerable decreases in ADMA (by − 39%, P < 0.0001) and SDMA (by − 21%, P < 0.0001) excretion rates, yet there was no significant change in DMA (by − 9%, P = 0.226) excretion rate. Our results suggest that protein-arginine dimethylation is altered in RTR compared to healthy kidney donors and that it is pronouncedly shifted from symmetric to asymmetric arginine-dimethylation, with whole-body protein-arginine dimethylation being almost unaffected.