bluuebunny/crossref_metadata_2025 huggingface dataset:
A transcriptomics-guided drug target discovery strategy identifies receptor ligands for lung regeneration
Authors: Wu Xinhui , Bos I. Sophie T. , Conlon Thomas M. , Ansari Meshal , Verschut Vicky , van der Koog Luke , Verkleij Lars A. , D’Ambrosi Angela , Matveyenko Aleksey , Schiller Herbert B. , Königshoff Melanie , Schmidt Martina , Kistemaker Loes E. M. , Yildirim Ali Önder , Gosens Reinoud
Published: March 2022

Currently, there is no pharmacological treatment targeting defective tissue repair in chronic disease. Here, we used a transcriptomics-guided drug target discovery strategy using gene signatures of smoking-associated chronic obstructive pulmonary disease (COPD) and from mice chronically exposed to cigarette smoke, identifying druggable targets expressed in alveolar epithelial progenitors, of which we screened the function in lung organoids. We found several drug targets with regenerative potential, of which EP and IP prostanoid receptor ligands had the most profound therapeutic potential in restoring cigarette smoke–induced defects in alveolar epithelial progenitors in vitro and in vivo. Mechanistically, we found, using single-cell RNA sequencing analysis, that circadian clock and cell cycle/apoptosis signaling pathways were differentially expressed in alveolar epithelial progenitor cells in patients with COPD and in a relevant model of COPD, which was prevented by prostaglandin E2 or prostacyclin mimetics. We conclude that specific targeting of EP and IP receptors offers therapeutic potential for injury to repair in COPD.
Temporal control of the integrated stress response by a stochastic molecular switch
Authors: Klein Philipp , Kallenberger Stefan M. , Roth Hanna , Roth Karsten , Ly-Hartig Thi Bach Nga , Magg Vera , Aleš Janez , Talemi Soheil Rastgou , Qiang Yu , Wolf Steffen , Oleksiuk Olga , Kurilov Roma , Di Ventura Barbara , Bartenschlager Ralf , Eils Roland , Rohr Karl , Hamprecht Fred A. , Höfer Thomas , Fackler Oliver T. , Stoecklin Georg , Ruggieri Alessia
Published: March 2022

Stress granules (SGs) are formed in the cytosol as an acute response to environmental cues and activation of the integrated stress response (ISR), a central signaling pathway controlling protein synthesis. Using chronic virus infection as stress model, we previously uncovered a unique temporal control of the ISR resulting in recurrent phases of SG assembly and disassembly. Here, we elucidate the molecular network generating this fluctuating stress response by integrating quantitative experiments with mathematical modeling and find that the ISR operates as a stochastic switch. Key elements controlling this switch are the cooperative activation of the stress-sensing kinase PKR, the ultrasensitive response of SG formation to the phosphorylation of the translation initiation factor eIF2α, and negative feedback via GADD34, a stress-induced subunit of protein phosphatase 1. We identify GADD34 messenger RNA levels as the molecular memory of the ISR that plays a central role in cell adaptation to acute and chronic stress.
Exploring far-from-equilibrium ultrafast polarization control in ferroelectric oxides with excited-state neural network quantum molecular dynamics
Authors: Linker Thomas , Nomura Ken-ichi , Aditya Anikeya , Fukshima Shogo , Kalia Rajiv K. , Krishnamoorthy Aravind , Nakano Aiichiro , Rajak Pankaj , Shimmura Kohei , Shimojo Fuyuki , Vashishta Priya
Published: March 2022

Ferroelectric materials exhibit a rich range of complex polar topologies, but their study under far-from-equilibrium optical excitation has been largely unexplored because of the difficulty in modeling the multiple spatiotemporal scales involved quantum-mechanically. To study optical excitation at spatiotemporal scales where these topologies emerge, we have performed multiscale excited-state neural network quantum molecular dynamics simulations that integrate quantum-mechanical description of electronic excitation and billion-atom machine learning molecular dynamics to describe ultrafast polarization control in an archetypal ferroelectric oxide, lead titanate. Far-from-equilibrium quantum simulations reveal a marked photo-induced change in the electronic energy landscape and resulting cross-over from ferroelectric to octahedral tilting topological dynamics within picoseconds. The coupling and frustration of these dynamics, in turn, create topological defects in the form of polar strings. The demonstrated nexus of multiscale quantum simulation and machine learning will boost not only the emerging field of ferroelectric topotronics but also broader optoelectronic applications.
Small RNAs couple embryonic developmental programs to gut microbes
Authors: Ohno Hayao , Bao Zhirong
Published: March 2022

Embryogenesis has long been known for its robustness to environmental factors. Although developmental tuning of embryogenesis to the environment experienced by the parent may be beneficial, little is understood on whether and how developmental patterns proactively change. Here, we show that
Caenorhabditis elegans
undergoes alternative embryogenesis in response to maternal gut microbes. Harmful microbes result in altered endodermal cell divisions; morphological changes, including left-right asymmetric development; double association between intestinal and primordial germ cells; and partial rescue of fecundity. The miR-35 microRNA family, which is controlled by systemic endogenous RNA interference and targets the β-transducin repeat-containing protein/cell division cycle 25 (CDC25) pathway, transmits intergenerational information to regulate cell divisions and reproduction. Our findings challenge the widespread assumption that
C. elegans
has an invariant cell lineage that consists of a fixed cell number and provide insights into how organisms optimize embryogenesis to adapt to environmental changes through epigenetic control.
NUAK1 promotes organ fibrosis via YAP and TGF-β/SMAD signaling
Authors: Zhang Tianzhou , He Xiaolin , Caldwell Lauren , Goru Santosh Kumar , Ulloa Severino Luisa , Tolosa Monica F. , Misra Paraish S. , McEvoy Caitríona M. , Christova Tania , Liu Yong , Atin Cassandra , Zhang Johnny , Hu Catherine , Vukosa Noah , Chen Xiaolan , Krizova Adriana , Kirpalani Anish , Gregorieff Alex , Ni Ruoyu , Chan Kin , Gill Mandeep K. , Attisano Liliana , Wrana Jeffrey L. , Yuen Darren A.
Published: March 2022

Fibrosis is a central pathway that drives progression of multiple chronic diseases, yet few safe and effective clinical antifibrotic therapies exist. In most fibrotic disorders, transforming growth factor–β (TGF-β)–driven scarring is an important pathologic feature and a key contributor to disease progression. Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) are two closely related transcription cofactors that are important for coordinating fibrogenesis after organ injury, but how they are activated in response to tissue injury has, so far, remained unclear. Here, we describe NUAK family kinase 1 (NUAK1) as a TGF-β–inducible profibrotic kinase that is up-regulated in multiple fibrotic organs in mice and humans. Mechanistically, we show that TGF-β induces a rapid increase in NUAK1 in fibroblasts. NUAK1, in turn, can promote profibrotic YAP and TGF-β/SMAD signaling, ultimately leading to organ scarring. Moreover, activated YAP and TAZ can induce further NUAK1 expression, creating a profibrotic positive feedback loop that enables persistent fibrosis. Using mouse models of kidney, lung, and liver fibrosis, we demonstrate that this fibrogenic signaling loop can be interrupted via fibroblast-specific loss of NUAK1 expression, leading to marked attenuation of fibrosis. Pharmacologic NUAK1 inhibition also reduced scarring, either when initiated immediately after injury or when initiated after fibrosis was already established. Together, our data suggest that NUAK1 plays a critical, previously unrecognized role in fibrogenesis and represents an attractive target for strategies that aim to slow fibrotic disease progression.
Evaluation of the Hologic Aptima Combo 2 Assay for Detection of Neisseria gonorrhoeae from Joint Fluid Specimens
Authors: Alexander David C. , Taylor Robert M. , Martin Irene , Adam Heather , Lagacé-Wiens Philippe , Pieroni Peter , Karlowsky James A. , Van Caeseele Paul
Published: March 2022

Gonorrhea is a sexually transmitted bacterial infection caused by
Neisseria gonorrhoeae
. Nucleic acid amplification testing is the preferred method for routine diagnosis of gonorrhea from urogenital specimens, but culture is commonly used for diagnosis of disseminated infections, including gonococcal arthritis.
Student Anxiety and Engagement with Online Instruction across Two Semesters of COVID-19 Disruptions
Authors: Pennino Eric , Ishikawa Catherine , Ghosh Hajra Sayonita , Singh Navneet , McDonald Kelly
Published: March 2022

The sudden shift to online learning due to the COVID-19 pandemic left many instructors wondering how to minimize anxiety while keeping students engaged in their virtual courses. In this study, we explored (i) specific online instructional tasks that caused students to experience anxiety, (ii) factors that hindered student engagement with online instruction, and (iii) changes in student anxiety and engagement between spring 2020 and fall 2020.
Reverse Genetics System for Heartland Bandavirus: NSs Protein Contributes to Heartland Bandavirus Virulence
Authors: Taniguchi Satoshi , Inagaki Takuya , Tajima Shigeru , Suzuki Tadaki , Yoshikawa Tomoki , Fukushi Shuetsu , Park Eun-Sil , Fujii Hikaru , Morikawa Shigeru , Tani Hideki , Nakayama Eri , Maeki Takahiro , Shimojima Masayuki , Lim Chang-Kweng , Saijo Masayuki
Published: March 2022

Heartland bandavirus (HRTV) is a tick-borne virus identified in the United States in 2009. HRTV causes fever, fatigue, decreased appetite, headache, nausea, diarrhea, and muscle or joint pain in humans.
High Seroprevalence of SARS-CoV-2 in White-Tailed Deer (Odocoileus virginianus) at One of Three Captive Cervid Facilities in Texas
Authors: Roundy Christopher M. , Nunez Chase M. , Thomas Logan F. , Auckland Lisa D. , Tang Wendy , Richison Jack J. , Green Breanna R. , Hilton Clayton D. , Cherry Michael J. , Pauvolid-Corrêa Alex , Hamer Gabriel L. , Cook Walter E. , Hamer Sarah A.
Published: March 2022

As SARS-CoV-2 vaccine coverage of the human population increases and variants of concern continue to emerge, identification of the epidemiologic importance of animal virus reservoirs is critical. We found that nearly all (94.4%) of the captive white-tailed deer at a cervid facility in central Texas had neutralizing antibodies for SARS-CoV-2.
PM10 and Other Climatic Variables Are Important Predictors of Seasonal Variability of Coccidioidomycosis in Arizona
Authors: Kollath Daniel R. , Mihaljevic Joseph R. , Barker Bridget M.
Published: March 2022

The inhalation of environmental infectious propagules from the fungal pathogens
Coccidioides immitis
and
Coccidioides posadasii
by susceptible mammals can result in coccidioidomycosis (Valley fever). Arizona is known to be a region where the pathogen is hyperendemic, and reported cases are increasing throughout the western United States.
Coccidioides
spp. are naturally occurring fungi in arid soils.
Suprasellar paraganglioma in a clinical setting of von Hippel-Lindau syndrome
Authors: Ghaisas Shamika , Rao Kavitha Shekar , Preethi Archana , Rani Padmaja Kumari
Published: March 2022

A man in his 20s presented to the neurosurgery department 2 years ago with headache and blurred vision. He was diagnosed to have a suprasellar mass on neuroimaging. Best-corrected visual acuity in the right eye was 6/36 and that in the left eye was 6/60. Automated visual fields showed a temporal hemianopia in the right eye and an advanced field defect in the left eye. His hormonal profile was normal, and he underwent partial excision of suprasellar tumour, which was a histopathologically proven paraganglioma (PGL). Subsequently, the patient underwent radiotherapy and his vision and visual fields showed improvement. Follow-up examination 3 years later showed a left retinal capillary hemangioblastoma (RCH), which was treated with green laser photocoagulation, resulting in complete sclerosis. This case is unique because of the extremely rare coexistence of a sellar PGL and RCH, which to our knowledge has not been reported so far.
Severe diffuse proliferative bronchiolitis complicating culture-proven disseminated BCG infection after intravesical instillation for bladder cancer
Authors: Notghi Alp Aslan Andrew , Hosseini Faroakh , Tsogas Nickolaos
Published: March 2022

A man in his 70s was admitted to hospital following several months of dyspnoea, night sweats, weight loss and, latterly, fevers. His symptoms correlated with a second maintenance cycle of intravesical BCG instillation for superficial bladder cancer. Blood tests showed raised C-reactive protein, alkaline phosphatase and gamma-GT, although extensive further investigations did not reveal any specific cause. Treatment for a presumed diagnosis of disseminated BCG infection was started, following which his fevers ceased. Later available results of liver biopsy taken prior to treatment supported this diagnosis, and mycobacterial blood and urine cultures grewMycobacterium bovis. Recovery was complicated by a severe diffuse proliferative bronchiolitis which responded to corticosteroids. This case highlights an important dichotomy in the pathophysiology of disseminated BCG infection. It demonstrates how morbidity can be caused by both a direct dissemination of the organism and an immune hypersensitivity response in the same patient.
Developing an interprofessional learning and working culture to improve person-centred care in nursing homes: a realist action research protocol
Authors: Verbeek Frank H O , Lovink Marleen H , Laurant Miranda G H , van Vught Anneke J A H
Published: March 2022

Introduction

Healthcare is changing due to the ageing of the general population, complex care demands and growing attention to person-centred care. To deal with these changes and provide the best possible person-centred care, the different professionals in nursing homes should all collaborate intensively. However, most professionals work within the field of their own expertise and share very little knowledge, experiences and insights. A lack of an interprofessional learning and working culture also prevents professionals with different expertise from working and learning intensively together to achieve high-quality person-centred care. There is a gap of knowledge about how to develop such a culture. Our aim is to provide insights into what actions, in what context and to what extent can contribute to an impactful development of an interprofessional learning and working culture.

Methods and analysis

The realist action research design will be applied. It consists of three iterative steps: plan, act and observe, and reflect. First, we will formulate the theory about interprofessional learning and working culture and measure this culture by means of interviews, focus groups and questionnaires. Second, we will apply the nine principles of Practice Development to coach professionals from six Dutch nursing homes to improve their interprofessional learning and working culture. Finally, we will evaluate the impact of the changed attitudes and skills on healthcare practice.

Ethics and dissemination

Approval for the project was given by the Hogeschool van Arnhem en Nijmegen (HAN) Research Ethics Committee, the Netherlands, registration number EACO 164.12/19. All organisations, professionals and residents/family members will be informed verbally and by letter about the study and asked for informed consent. The results will be presented in peer-reviewed scientific journals, professional journals and at symposia and conferences. The findings will be transferred to an online toolbox and e-learning modules for graduated professionals and students.
Changing epidemiology of firearm injury: a cohort study of non-fatal firearm victimisation before and during the COVID-19 pandemic, Indianapolis, Indiana
Authors: Magee Lauren A , Lucas Bailee , Fortenberry James Dennis
Published: March 2022

Objective

To examine victimisation rates, geographic patterns and neighbourhood characteristics associated with non-fatal firearm injury rates before and during the COVID-19 pandemic.

Design

A retrospective cohort study.

Setting

City of Indianapolis, Indiana, USA, 1 January 2017–30 June 2021.

Participants

Intentional non-fatal firearm injury victims from Indianapolis Metropolitan Police Department records. The study included information on 2578 non-fatal firearm injury victims between ages 0 and 77 years. Of these victims, 82.5% were male and 77.4% were black.

Primary and secondary outcome measures

Rates of non-fatal firearm injuries per 100 000 population by victim age, race, sex and incident motive. Prepandemic and peripandemic non-fatal firearm injury rates.

Results

Non-fatal shooting rates increased 8.60%, from 57.0 per 100 000 person-years in prepandemic years to 65.6 per 100 000 person-years during the pandemic (p<0.001). Rates of female victims (15.2 vs 23.8 per 100,000; p<0.001) and older victims (91.3 vs 120.4 per 100,000; p<0.001) increased significantly during the pandemic compared with the prepandemic period. Neighbourhoods with higher levels of structural disadvantage (IRR: 1.157, 95% CI 1.012 to 1.324) and prepandemic firearm injury rates (IRR: 1.001, 95% CI 1.001 to 1.002) was positively associated with higher rates of non-fatal firearm injuries during the pandemic, adjusting for neighbourhood characteristics.

Conclusions

Non-fatal firearm injuries increased significantly during the COVID-19 pandemic, particularly among female and older victims. Efforts are needed to expand and rethink current firearm prevention efforts that both address the diversification of victimisation and the larger societal trauma of firearm violence.
Can routine screening for alcohol consumption in pregnancy be ethically and legally justified?
Authors: Bennett Rebecca , Bowden Catherine
Published: March 2022

In the UK, it has been proposed that alongside the current advice to abstain from alcohol completely in pregnancy, there should be increased screening of pregnant women for alcohol consumption in order to prevent instances of fetal alcohol spectrum disorder. The Scottish Intercollegiate Guidelines Network published guidelines in 2019 recommending that standardised screening questionnaires and associated use of biomarkers should be considered to identify alcohol exposure in pregnancy. This was followed in 2020 by the National Institute for Health and Care Excellence Draft Quality Standard, which recommended that pregnant women should have information on their alcohol consumption recorded throughout their pregnancy and this information transferred to the child’s health records. Most recently, Public Health England has stated that the alcohol intake of all women should be recorded throughout pregnancy, not just at the initial booking appointment and that tools such as blood biomarkers and meconium testing should be researched in order to determine true prevalence rates of alcohol in pregnancy. We argue that this proposed enhanced screening undermines women’s autonomy and their legal right to be sufficiently informed to consent to screening. We argue that there is no evidence that this kind of screening will result in a reduction of fetal harm and there is a danger that undermining the autonomy of women and the trust relationship between women and healthcare professionals may even increase harm to future children.
Industrial Experience of Finding Cryptographic Vulnerabilities in Large-scale Codebases
Authors: Xiao Ya , Zhao Yang , Allen Nicholas , Keynes Nathan , Yao Danfeng (Daphne) , Cifuentes Cristina
Published: March 2022

Enterprise environment often screens large-scale (millions of lines of code) codebases with static analysis tools to find bugs and vulnerabilities. Parfait is a static code analysis tool used in Oracle to find security vulnerabilities in industrial codebases. Recently, many studies show that there are complicated cryptographic vulnerabilities caused by misusing cryptographic APIs in Java
TM

1

In this paper, we describe how we realize a precise and scalable detection of these complicated cryptographic vulnerabilities based on Parfait framework. The key challenge in the detection of cryptographic vulnerabilities is the high false alarm rate caused by pseudo-influences. Pseudo-influences happen if security-irrelevant constants are used in constructing security-critical values. Static analysis is usually unable to distinguish them from hard-coded constants that expose sensitive information. We tackle this problem by specializing the backward dataflow analysis used in Parfait with refinement insights, an idea from the tool CryptoGuard [
20
]. We evaluate our analyzer on a comprehensive Java cryptographic vulnerability benchmark and eleven large real-world applications. The results show that the Parfait-based cryptographic vulnerability detector can find real-world cryptographic vulnerabilities in large-scale codebases with high true-positive rates and low runtime cost.
Driving E3 Ligase Substrate Specificity for Targeted Protein Degradation: Lessons from Nature and the Laboratory
Authors: Cowan Angus D. , Ciulli Alessio
Published: March 2022

Methods to direct the degradation of protein targets with proximity-inducing molecules that coopt the cellular degradation machinery are advancing in leaps and bounds, and diverse modalities are emerging. The most used and well-studied approach is to hijack E3 ligases of the ubiquitin–proteasome system. E3 ligases use specific molecular recognition to determine which proteins in the cell are ubiquitinated and degraded. This review focuses on the structural determinants of E3 ligase recruitment of natural substrates and neo-substrates obtained through monovalent molecular glues and bivalent proteolysis-targeting chimeras. We use structures to illustrate the different types of substrate recognition and assess the basis for neo-protein–protein interactions in ternary complex structures. The emerging structural and mechanistic complexity is reflective of the diverse physiological roles of protein ubiquitination. This molecular insight is also guiding the application of structure-based design approaches to the development of new and existing degraders as chemical tools and therapeutics.
The Purinosome: A Case Study for a Mammalian Metabolon
Authors: Pedley Anthony M. , Pareek Vidhi , Benkovic Stephen J.
Published: March 2022

Over the past fifteen years, we have unveiled a new mechanism by which cells achieve greater efficiency in de novo purine biosynthesis. This mechanism relies on the compartmentalization of de novo purine biosynthetic enzymes into a dynamic complex called the purinosome. In this review, we highlight our current understanding of the purinosome with emphasis on its biophysical properties and function and on the cellular mechanisms that regulate its assembly. We propose a model for functional purinosomes in which they consist of at least ten enzymes that localize near mitochondria and carry out de novo purine biosynthesis by metabolic channeling. We conclude by discussing challenges and opportunities associated with studying the purinosome and analogous metabolons.
Better, Faster, Cheaper: Recent Advances in Cryo–Electron Microscopy
Authors: Chua Eugene Y.D. , Mendez Joshua H. , Rapp Micah , Ilca Serban L. , Tan Yong Zi , Maruthi Kashyap , Kuang Huihui , Zimanyi Christina M. , Cheng Anchi , Eng Edward T. , Noble Alex J. , Potter Clinton S. , Carragher Bridget
Published: March 2022

Cryo–electron microscopy (cryo-EM) continues its remarkable growth as a method for visualizing biological objects, which has been driven by advances across the entire pipeline. Developments in both single-particle analysis and in situ tomography have enabled more structures to be imaged and determined to better resolutions, at faster speeds, and with more scientists having improved access. This review highlights recent advances at each stageof the cryo-EM pipeline and provides examples of how these techniques have been used to investigate real-world problems, including antibody development against the SARS-CoV-2 spike during the recent COVID-19 pandemic.
Advances in Manufacturing Cardiomyocytes from Human Pluripotent Stem Cells
Authors: Floy Martha E. , Shabnam Fathima , Simmons Aaron D. , Bhute Vijesh J. , Jin Gyuhyung , Friedrich Will A. , Steinberg Alexandra B. , Palecek Sean P.
Published: March 2022

The emergence of human pluripotent stem cell (hPSC) technology over the past two decades has provided a source of normal and diseased human cells for a wide variety of in vitro and in vivo applications. Notably, hPSC-derived cardiomyocytes (hPSC-CMs) are widely used to model human heart development and disease and are in clinical trials for treating heart disease. The success of hPSC-CMs in these applications requires robust, scalable approaches to manufacture large numbers of safe and potent cells. Although significant advances have been made over the past decade in improving the purity and yield of hPSC-CMs and scaling the differentiation process from 2D to 3D, efforts to induce maturation phenotypes during manufacturing have been slow. Process monitoring and closed-loop manufacturing strategies are just being developed. We discuss recent advances in hPSC-CM manufacturing, including differentiation process development and scaling and downstream processes as well as separation and stabilization.
Milk exosomes in nutrition and drug delivery
Authors: Ngu Alice , Wang Shu , Wang Haichuan , Khanam Afsana , Zempleni Janos
Published: March 2022

Exosomes are natural nanoparticles that originate in the endocytic system. Exosomes play an important role in cell-to-cell communication by transferring RNAs, lipids, and proteins from donor cells to recipient cells or by binding to receptors on the recipient cell surface. The concentration of exosomes and the diversity of cargos are high in milk. Exosomes and their cargos resist degradation in the gastrointestinal tract and during processing of milk in dairy plants. They are absorbed and accumulate in tissues following oral administrations, cross the blood-brain barrier, and dietary depletion and supplementation elicit phenotypes. These features have sparked the interest of the nutrition and pharmacology communities for exploring milk exosomes as novel bioactive food compounds and for delivering drugs to diseased tissues. This review discusses the current knowledgebase, uncertainties, and controversies in these lines of scholarly endeavor and health research.
IL-17A contributes to skeletal muscle atrophy in lung cancer-induced cachexia via JAK2/STAT3 pathway
Authors: Ying Lin , Yao Yinan , Lv Handi , Lu Guohua , Zhang Qin , Yang Yunmei , Zhou Jianying
Published: March 2022

Cachexia is a complex metabolic syndrome that occurs in approximately 50% of patients with cancer. Skeletal muscle atrophy is the primary clinical feature. Interleukin (IL)-17A, a proinflammatory factor, plays an important role in many chronic inflammatory diseases. Here, we describe a novel signaling pathway through which IL-17A induced muscle atrophy. We conducted a retrospective clinical study to investigate the relationship between IL-17A and the skeletal muscle index in patients with lung adenocarcinoma. We also investigated the involvement of JAK2/STAT3 signaling pathway regarding the main features of cachexia by injecting Lewis lung carcinoma (LLC) cells into C57BL/6 mice as a model to replicate cancer-induced cachexia. In vitro, C2C12 myotubes were treated with recombinant IL-17A, anti-IL-17A monoclonal antibody, STAT3 inhibitor AG490, and LLC-conditioned medium. Cell viability and aging were also evaluated. We found that in cancer conditions, increased serum levels of IL-17A were related to muscle wasting. JAK2/STAT3 phosphorylation was observed in the muscle of LLC tumor-bearing mice, accompanied by decreased MHC/Myog levels and increased MuRF1/Atrogin-1 levels. Administration of anti-IL-17A monoclonal antibody and AG490 slowed muscle atrophy development. Consistent with the in vivo findings, C2C12 myotubes treated with IL-17A and LLC-conditioned medium demonstrated phosphorylated JAK2/STAT3 signaling, resulting in MHC loss and myotube atrophy. IL-17A also inhibited C2C12 cell proliferation, cell cycle breaking, and cellular senescence. Our results identify that phosphorylation of IL-17A/JAK2/STAT3 signaling pathway appears to be an important component in the pathogenesis of LLC tumor-induced cachexia. Targeted therapy of IL-17A may be a promising approach to reduce skeletal muscle loss in patients with cancer.
Adult enteric Dclk1-positive glial and neuronal cells reveal distinct responses to acute intestinal injury
Authors: Middelhoff Moritz , Valenti Giovanni , Tomassoni Lorenzo , Ochiai Yosuke , Belin Bryana , Takahashi Ryota , Malagola Ermanno , Nienhüser Henrik , Finlayson Michael , Hayakawa Yoku , Zamechek Leah B. , Renz Bernhard W. , Westphalen C. Benedikt , Quante Michael , Margolis Kara G. , Sims Peter A. , Laise Pasquale , Califano Andrea , Rao Meenakshi , Gershon Michael D. , Wang Timothy C.
Published: March 2022

The kinase DCLK1 identifies glial-like and neuronal cell types in adult murine enteric ganglia, which resist acute injury-mediated cell death yet differ in their cellular response to injury. Interestingly, Dclk1-labeled glial-like cells show prominent transcriptional changes in response to injury and harbor features reminiscent of previously described enteric neural precursor cells. Our data thus add to recently emerging evidence of reserve cellular plasticity in the adult enteric nervous system.
Cytokine signature clusters as a tool to compare changes associated with tobacco product use in upper and lower airway samples
Authors: Payton Alexis D. , Perryman Alexia N. , Hoffman Jessica R. , Avula Vennela , Wells Heather , Robinette Carole , Alexis Neil E. , Jaspers Ilona , Rager Julia E. , Rebuli Meghan E.
Published: March 2022

Inhalation exposure to cigarette smoke and e-cigarette aerosol is known to alter the respiratory immune system, particularly cytokine signaling. In assessments of health impacts of tobacco product use, cytokines are often measured using a variety of sample types, from serum to airway mucosa. However, it is currently unclear whether and how well cytokine levels from different sample types and the airway locations they represent are correlated, making comparing studies that utilize differing sample types challenging. To address this challenge, we compared baseline cytokine signatures in upper and lower airways and systemic samples and evaluated how groups of coexpressed cytokines change with tobacco product use. Matched nasal lavage fluid (NLF), nasal epithelial lining fluid (NELF), sputum, and circulating serum samples were collected from 14 nonsmokers, 13 cigarette smokers, and 17 e-cigarette users and analyzed for levels of 22 cytokines. Individual cytokine signatures were first compared across each sample type, followed by identification of cytokine clusters within each sample type. Identified clusters were then evaluated for potential alterations following tobacco product use using eigenvector analyses. Individual cytokine signatures in the respiratory tract were significantly correlated (NLF, NELF, and sputum) compared with randomly permutated signatures, whereas serum was not significantly different from random permutations. Cytokine clusters that were similar across airway sample types were modified by tobacco product use, particularly e-cigarettes, indicating a degree of uniformity in terms of how cytokine host defense and immune cell recruitment responses cooperate in the upper and lower airways. Overall, cluster-based analyses were found to be especially useful in small cohort assessments, providing higher sensitivity than individual signatures to detect biologically meaningful differences between tobacco use groups. This novel cluster analysis approach revealed that eigencytokine patterns in noninvasive upper airway samples simulate cytokine patterns in lower airways.
Reviewing the suitability of mitochondrial transplantation as therapeutic approach for pulmonary hypertension in the era of personalized medicine
Authors: Maarman Gerald J.
Published: March 2022

Pulmonary hypertension (PH) is a fatal disease, defined as a mean pulmonary artery pressure ≥25 mmHg. It is caused, in part, by mitochondrial dysfunction. Among the various biological therapies proposed to rescue mitochondrial dysfunction, evidence going back as far as 2009 suggests that mitochondrial transplantation is an alternative. Although scant, recent PH findings and other literature support a role for mitochondrial transplantation as a therapeutic approach in the context of PH. In experimental models of PH, it confers beneficial effects that include reduced pulmonary vasoconstriction, reduced pulmonary vascular remodeling, and improved right ventricular function. It also reduces the proliferation of pulmonary artery smooth muscle cells. However, first, we must understand that more research is needed before mitochondrial transplantation can be considered an effective therapy in the clinical setting, as many of the mechanisms or potential long-term risks are still unknown. Second, the current challenges of mitochondrial transplantation are surmountable and should not deter researchers from further investigating its effectiveness and trying to overcome these challenges in creative ways.
Subthalamic deep brain stimulation of an anatomically detailed model of the human hyperdirect pathway
Authors: Bingham Clayton S. , McIntyre Cameron C.
Published: March 2022

We used biophysical models to study pathway recruitment and conduction latencies of the hyperdirect pathway (HDP) in response to subthalamic deep brain stimulation (DBS). The model system allowed us to assess the influence of increased anatomical realism on pathway activity and the possibility of identifying HDP activity in evoked potentials (EPs) recorded in either the subthalamic nucleus (STN) or cortex. The model predicts that HDP activation is accentuated by complex axonal branching in the STN.
Changes in error-correction behavior according to visuomotor maps in goal-directed projection tasks
Authors: Kusafuka Ayane , Onagawa Ryoji , Kimura Arata , Kudo Kazutoshi
Published: March 2022

We found that participants changed their error-correction behaviors according to the conditions and could ignore visual perturbations. This suggests that humans can be implicitly aware of differences in visuomotor maps and adapt accordingly to visual errors. These findings provide suggestions for how to notice and adapt our movements to the environment and our own dynamically changing conditions, to perform accurate movements consistently.
Moving Target Defense-Based Denial-of-Service Mitigation in Cloud Environments: A Survey
Authors: Nguyen Minh , Debroy Saptarshi
Published: March 2022

With the increased frequency and intensity of denial-of-service (DoS) attacks on critical cloud-hosted services, resource adaptation schemes adopted by the cloud service providers (CSPs) need to be intelligent. Specifically, they need to be adaptable to attack behavior and be dynamic to curb resource over-utilization. The concept of moving target defense (MTD) has recently emerged as an effective and agile defense mechanism against DoS attacks that particularly target cloud-hosted applications. However, the existing surveys that seek to explore this space either focus more on MTD for generic cyberattack mitigation or on DoS attack defense on cloud systems. In this survey, we particularly provide an in-depth analysis on how MTD can help recover critical cloud assets in the face of DoS attacks and how emerging programmable technologies such as software-defined networking (SDN) can be leveraged to achieve that goal. Unlike existing surveys, we categorize DoS attacks on cloud platforms based on their working mechanism. We also discuss the non-MTD-based DoS defense strategies for both cloud and non-cloud infrastructures in order to highlight the pros and cons of MTD-based strategies. We introduce MTD working mechanisms and present how existing research is envisioning MTD’s application in mitigating DoS attacks, both with and without SDN. We also take an in-depth look at the testbed implementations and resilience and performance evaluations of MTD approaches. Finally, we articulate the existing challenges in MTD for DoS mitigation in cloud systems and how these challenges are shaping the future research in this domain.
Pervasive Refusal Syndrome: Three Case Reports—Autism as a Predisposing Factor and Gentle Coercion to Shorten Duration of Disorder?
Authors: Jarbin Håkan , Saldeen Ann-Sofie , Forslund Carl-Magnus
Published: March 2022

Background. Pervasive refusal syndrome (PRS) is a severe child psychiatric syndrome not yet included in the international classification and mostly affecting girls aged 7-15 years. Hospital admission and severe loss of function extend for many months and years but most recover. Autism has been suggested as a predisposing factor but largely lacks support for typical cases of PRS. Treatment is not evidence-based and described as requiring a lengthy inpatient stay with a very gradual and sensitive rehabilitation program. Case Presentations. Three cases of pervasive refusal syndrome (PRS) in girls aged 9–16 years are presented to report autism as a predisposing factor and to discuss gentle coercion as part of the management strategy to speed up the lengthy recovery. The cases, which met the proposed criteria and typical background characteristics, were noted with the addition of undiagnosed autism in two cases. The duration of inpatient admission was 8–14 months. Disease duration was 15-36 months. An adequate but negative lorazepam trial to rule out catatonia was carried out. Treatment was in one case successfully expedited with gentle coercion within a transparent management plan. Rehabilitation was slower in PRS with comorbid autism; additionally, accommodations to school and living support needed to be put in place. Conclusions. PRS is a useful clinical entity and best perceived as a primitive reaction to overwhelming stress rather than as catatonia. Autism might be another predisposing factor and needs to be assessed. A psychoeducational approach and a clear management plan support rehabilitation. A gentle coercion might hasten recovery.
Research on the Prediction of the Operational Risk Field of Intelligent Vehicles Based on Dual Multiline LiDAR
Authors: Zhang Ruibin , Guo Yingshi , Wang Chang , Zhou Yang , Long Yunze
Published: March 2022

To effectively evaluate the risk situation between intelligent vehicles and surrounding traffic participants in complex scenes, a complex traffic environment perception technology based on dual multiline light detection and ranging (LiDAR) is proposed in this work. The vehicle motion state is predicted by fusing the multiview characteristics of point cloud timing and multitarget interaction information, and the risk assessment model is constructed via artificial potential field theory. The real-time point cloud information is used to obtain the time-sequence bird’s-eye view and range image. The improved VGG19 network model is used to extract the time-sequence high-level abstract combined features in the multiview scene. The constructed time-sequence feature vector is used as the input data of the attention mechanism, and the attention-bidirectional long short-term memory (Attention-BiLSTM) model is used for training to form the desired input-output mapping relationship. The motion state of the target vehicle can therefore be updated, and the static and dynamic risk fields of traffic participants surrounding the vehicle can be established based on artificial potential field theory, thereby allowing for the evaluation of the operational risk of the intelligent vehicle. The results of experiments demonstrate that the prediction effect of the target vehicle state parameters via the use of the proposed model is better than that of other compared models, and the prediction effect of the risk field of intelligent vehicle operation based on the multiview point cloud features and vehicle interaction information is good.
Injection Molding Simulation of Polyoxymethylene Using Crystallization Kinetics Data and Comparison with the Experimental Process
Authors: Schrank Theresia , Berer Michael , Haar Bernd , Ramoa Bruno , Lucyshyn Thomas , Feuchter Michael , Pinter Gerald , Speranza Vito , Pantani Roberto
Published: March 2022

It is well known that the processing conditions in polymer processing have a high impact on the resulting material morphology and consequently the component’s mechanical behavior. However, especially for semicrystalline polymers, the tools available for predicting the final morphology of injection molding parts still have significant limitations. In order to investigate the potential of injection molding simulation for the prediction of the morphology, POM homopolymer specimens were injection molded. The crystallization kinetics data were measured, and simulations in 3D and 2.5D with and without crystallization analysis were conducted in Autodesk Moldflow. The simulations are found to be good accordance with the experiments. Predicted spherulite size and crystalline orientation factor reveal a good qualitative correlation with optical micrographs. Also, the evolution of these parameters along the flow path is plausible. The simulation is found to be a powerful tool for morphology prediction in polymeric parts. Its applicability, however, is still limited to 2.5D models in Autodesk Moldflow, which, of course, is insufficient for complex, thick-walled 3-dimensional parts.
Rhein Ameliorates Cognitive Impairment in an APP/PS1 Transgenic Mouse Model of Alzheimer’s Disease by Relieving Oxidative Stress through Activating the SIRT1/PGC-1α Pathway
Authors: Yin Zhihui , Gao Demin , Du Ke , Han Chen , Liu Yuhan , Wang Ying , Gao Xiaoyan
Published: March 2022

Mitochondrial oxidative stress plays an important role in the pathogenesis of Alzheimer’s disease (AD). Recently, antioxidant therapy has been considered an effective strategy for the treatment of AD. Our previous work discovered that rhein relieved mitochondrial oxidative stress in β-amyloid (Aβ) oligomer-induced primary neurons by improving the sirtuin 1 (SIRT1)/peroxisome proliferator-activated receptor gamma coactivator 1-alpha- (PGC-1α-) regulated mitochondrial biogenesis. While encouraging results have been provided, mechanisms underlying the beneficial effect of rhein on AD are yet to be elucidated in vivo. In this study, we evaluated the therapeutic effect of rhein on an APP/PS1 transgenic (APP/PS1) mouse model of AD and explored its antioxidant mechanisms. As a result, rhein significantly reduced Aβ burden and neuroinflammation and eventually ameliorated cognitive impairment in APP/PS1 mice. Moreover, rhein reversed oxidative stress in the brain of APP/PS1 mice and protected neurons from oxidative stress-associated apoptosis. Further study revealed that rhein promoted mitochondrial biogenesis against oxidative stress by upregulating SIRT1 and its downstream PGC-1α as well as nuclear respiratory factor 1. Improved mitochondrial biogenesis not only increased the activity of superoxide dismutase to scavenge excess reactive oxygen species (ROS) but also repaired mitochondria by mitochondrial fusion to inhibit the production of ROS from the electron transport chain. Notably, the exposure of rhein in the brain analyzed by tissue distribution study indicated that rhein could permeate into the brain to exert its therapeutic effects. In conclusion, these findings drive rhein to serve as a promising therapeutic antioxidant for the treatment of AD. Our research highlights the therapeutic efficacy for AD through regulating mitochondrial biogenesis via the SIRT1/PGC-1α pathway.
An Insight into Pathway and Health Risk Assessment of Toxic Metals in Herbal Medicine
Authors: Zamir Rausan , Islam Nazmul , Kudrat-E-Zahan  , Asraf Ali , Zakaria Choudhury M.
Published: March 2022

Introduction. Along with and in competition with orthodox medicines, herbal medicines have converted into a popular form of cure. While cumulative investigation reports on adverse effects by herbal drug uptake are few, systematic review along with deep insight into other relevant topics (carcinogenic and noncarcinogenic risk assessment, mechanism of toxicity, and entering toxic metal from source to herbal drug) is sporadic. Methods. Therefore, existing research and their published outputs pointing safety assessment of herbal medicines in terms of toxic metals have been reviewed systematically and information synthesized thematically while suggesting mechanism of toxicity, consequence of prolong exposure, and pathway of toxic metal from source to herbal drugs. Result and Discussion. Our study suggests that most of the herbal medicines were unsafe to consume although claimed harmless. Possible pathways regarding migration of toxic metals into herbal medicine are discussed. Conclusion. There should have appropriate screening from herb collection, and manufacturing to selling of finished herbal medicine by authority concerned is backed.
Biochemical Characterization of Seed Oil of Tunisian Sunflower (Helianthus annuus L.) Accessions with Special Reference to Its Fatty Acid Composition and Oil Content
Authors: Hosni Taoufik , Abbes Zouhaier , Abaza Leila , Medimagh Sana , Ben Salah Hamadi , Kharrat Mohamed
Published: March 2022

Sunflower (Helianthus annuus) is a major oilseed crop, cultivated throughout the world, and the nutritional quality of its edible oil ranks among the best vegetable oils in agricultural product. In Tunisia, there is a lack of study on biochemical characterization of sunflower germplasm oil. The present study was conducted to analyze oil content and fatty acid composition of 22 local and introduced sunflower accessions. Results revealed significant variation among studied accessions for all measured biochemical traits. The average oil content of the H. annuus accessions was 53.2%, ranging from 35.33% to 59.67%. The results of this study also indicated that unsaturated acids, particularly oleic acid and linoleic acid, were the most abundant fatty acids in oils. Fatty acid compositions of sunflower oils showed diversity depending on the accession. The first two components of the principal component analysis (PCA) contributed 45.7% of the total variability. Cluster analysis based on PCA separated the accessions into four clear groups, which were not grouped according to their geographical origin. Moreover, the classification of the evaluated sunflower accessions using clustering by Euclidean distance revealed four main groups. Linoleic acid had significant and negative correlations with some saturated acids (palmitic, stearic, and arachidic acids). These data can be useful for selecting sunflower accessions and the development of varieties with improved oil quality.
The Impacts of Reducing the Infection Rate and Infection Source on the Transmission of Emerging Infectious Diseases
Authors: Li Jia-Tong
Published: March 2022

There are many prevention and control measures for emerging infectious diseases. This paper divides the effects of these measures into two categories. One is to reduce the infection rate. The other is to use diagnosis rate to reflect the decreases of the infection source. The impacts of measures intensity, diagnosis rate, and the start time of taking measures on emerging infectious diseases with infectious capacity during the incubation period are considered comprehensively by using a differential equation model. Results show that for each diagnosis rate, the number of infections and deaths has a phase change structure with respect to the measures intensity. If the measures intensity is less than the value of the phase change point, the epidemic will break out whenever measures are taken. If the measures intensity is greater than the value of the phase change point, the epidemic can be controlled when the measures are taken timely. But if measures are not taken in time, epidemic will also break out. The location of the phase change point is related to the diagnosis rate. For the different measures intensity and the diagnosis rate, this paper gives a method to judge whether the spread of the corresponding epidemic can be controlled.