bluuebunny/crossref_metadata_2025 huggingface dataset:
A New Projected Active Set Conjugate Gradient Approach for Taylor-Type Model Predictive Control: Application to Lower Limb Rehabilitation Robots With Passive and Active Rehabilitation
Authors: Shi Tian , Tian Yantao , Sun Zhongbo , Zhang Bangcheng , Pang Zaixiang , Yu Junzhi , Zhang Xin
Published: December 2020

In this paper, a three-order Taylor-type numerical differentiation formula is firstly utilized to linearize and discretize constrained conditions of model predictive control (MPC), which can be generalized from lower limb rehabilitation robots. Meanwhile, a new numerical approach that projected an active set conjugate gradient approach is proposed, analyzed, and investigated to solve MPC. This numerical approach not only incorporates both the active set and conjugate gradient approach but also utilizes a projective operator, which can guarantee that the equality constraints are always satisfied. Furthermore, rigorous proof of feasibility and global convergence also shows that the proposed approach can effectively solve MPC with equality and bound constraints. Finally, an echo state network (ESN) is established in simulations to realize intention recognition for human–machine interactive control and active rehabilitation training of lower-limb rehabilitation robots; simulation results are also reported and analyzed to substantiate that ESN can accurately identify motion intention, and the projected active set conjugate gradient approach is feasible and effective for lower-limb rehabilitation robot of MPC with passive and active rehabilitation training. This approach also ensures computational when disturbed by uncertainties in system.
Sevoflurane Exposure Induces Neuronal Cell Parthanatos Initiated by DNA Damage in the Developing Brain via an Increase of Intracellular Reactive Oxygen Species
Authors: Piao Meihua , Wang Yingying , Liu Nan , Wang Xuedong , Chen Rui , Qin Jing , Ge Pengfei , Feng Chunsheng
Published: December 2020

The safety of volatile anesthetics in infants and young children has been drawing increasing concern due to its potential neurotoxicity in the developing brain. Neuronal death is considered a major factor associated with developmental neurotoxicity after exposure to volatile anesthetics sevoflurane, but its mechanism remains elusive. Parthanatos, a new type of programmed cell death, resulting from poly (ADP-ribose) polymerase 1 (PARP-1) hyperactivation in response to DNA damage, was found to account for the pathogenesis of multiple neurological disorders. However, the role of Parthanatos in sevoflurane-induced neonatal neuronal cell death has not been investigated. To test it, neuronal cells treated with 2, 4, and 8% sevoflurane for 6, 12, and 24 h and postnatal day 7 rats exposed to 2.5% sevoflurane for 6 h were used in the present study. Our results found sevoflurane exposure induced neuronal cell death, which was accompanied by PARP-1 hyperactivation, cytoplasmic polymerized ADP-ribose (PAR) accumulation, mitochondrial depolarization, and apoptosis-inducing factor (AIF) nuclear translocation in the neuronal cells and hippocampi of rats. Pharmacological or genetic inhibition of PAPR-1 significantly alleviated sevoflurane-induced neuronal cell death and accumulation of PAR polymer and AIF nuclear translocation, which were consistent with the features of Parthanatos. We observed in vitro and in vivo that sevoflurane exposure resulted in DNA damage, given that 8-hydroxydeoxyguanosine (8-OHdG) and phosphorylation of histone variant H2AX (γH2AX) were improved. Moreover, we detected that sevoflurane exposure was associated with an overproduction of intracellular reactive oxygen species (ROS). Inhibition of ROS with antioxidant NAC markedly alleviated DNA damage caused by sevoflurane, indicating that ROS participated in the regulation of sevoflurane-induced DNA damage. Additionally, sevoflurane exposure resulted in upregulation of Parthanatos-related proteins and neuronal cell death, which were significantly attenuated by pretreatment with NAC. Therefore, these results suggest that sevoflurane exposure induces neuronal cell Parthanatos initiated by DNA damage in the developing brain via the increase of intracellular ROS.
Development and Validation of a Five-Gene Signature to Predict Relapse-Free Survival in Multiple Sclerosis
Authors: Ye Fei , Liang Jie , Li Jiaoxing , Li Haiyan , Sheng Wenli
Published: December 2020

Background: Multiple sclerosis (MS) is an inflammatory and demyelinating disease of the central nervous system with a variable natural history of relapse and remission. Previous studies have found many differentially expressed genes (DEGs) in the peripheral blood of MS patients and healthy controls, but the value of these genes for predicting the risk of relapse remains elusive. Here we develop and validate an effective and noninvasive gene signature for predicting relapse-free survival (RFS) in MS patients.

Methods: Gene expression matrices were downloaded from Gene Expression Omnibus and ArrayExpress. DEGs in MS patients and healthy controls were screened in an integrated analysis of seven data sets. Candidate genes from a combination of protein–protein interaction and weighted correlation network analysis were used to identify key genes related to RFS. An independent data set (GSE15245) was randomized into training and test groups. Univariate and least absolute shrinkage and selection operator–Cox regression analyses were used in the training group to develop a gene signature. A nomogram incorporating independent risk factors was developed via multivariate Cox regression analyses. Kaplan–Meier methods, receiver-operating characteristic (ROC) curves, and Harrell's concordance index (C-index) were used to estimate the performance of the gene signature and nomogram. The test group was used for external validation.

Results: A five-gene signature comprising FTH1, GBP2, MYL6, NCOA4, and SRP9 was used to calculate risk scores to predict individual RFS. The risk score was an independent risk factor, and a nomogram incorporating clinical parameters was established. ROC curves and C-indices demonstrated great performance of these predictive tools in both the training and test groups.

Conclusions: The five-gene signature may be a reliable tool for assisting physicians in predicting RFS in clinical practice. We anticipate that these findings could not only facilitate personalized treatment for MS patients but also provide insight into the complex molecular mechanism of this disease.
Remote Assessment of Post-Stroke Elbow Function Using Internet-Based Telerobotics: A Proof-of-Concept Study
Authors: Kim Jonghyun , Sin Minki , Kim Won-Seok , Min Yu-Sun , Kim Woojin , Park Daegeun , Paik Nam-Jong , Cho Kyujin , Park Hyung-Soon
Published: December 2020

Purpose: Upper limb hemiparesis is the most common impairment in stroke survivors, and adequate assessment is crucial for setting the rehabilitation strategy and monitoring the effect of treatment. However, adequate timely assessments are difficult due to the limited accessibility to clinics for stroke survivors. We designed this study to investigate whether teleassessments for motor impairments of the spastic elbow (i.e., passive range of motion (PROM), muscle strength, and spasticity) are feasible in stroke survivors.

Methods: To implement a telerobotic system for remote assessment with physical interaction, we constructed a system with a master robot interacting with a doctor (assessor) and a slave robot interacting with the elbow of a subject with stroke. The master robot is operated by the doctor, where the torque and the speed are transferred to the slave robot via the Internet, and the reaction of the patient's elbow to the slave robot's movement is measured with a torque sensor, then finally transferred back to the master robot. An intercontinental remote assessment, which is considered one of the worst possible scenarios, was used as a clinical test to strictly check the feasibility. For the clinical tests, the examiner for the teleassessment was located at a lab in the National Institutes of Health (NIH, Bethesda, MD, USA) while the stroke patients were located at Seoul National University Bundang Hospital (Bundang, Kyeonggido, South Korea).

Results: In total, 12 stroke patients' elbows (age range, 28–74; M:F = 6:6) were tested. For the PROM, the absolute difference between two assessments (in-person vs. remote) was 5.98 ± 3.51° on average (range, 0–11.2). The agreements for the strength and the spasticity of elbow flexor between in-person and remote assessments were substantial (k = 0.643) and fair (k = 0.308), respectively. No adverse events were observed during or immediately after the telerobotic assessment.

Conclusions: Internet-based telerobotic remote assessment for motor impairment of spastic elbow in stroke using our system is feasible even in the worst setting, with too long of a distance and a delayed communication network.
A Comparison of Children Born Preterm and Full-Term on the Autism Spectrum in a Prospective Community Sample
Authors: Luu Jenny , Jellett Rachel , Yaari Maya , Gilbert Melissa , Barbaro Josephine
Published: December 2020

Introduction: Previous research suggests children diagnosed with autism spectrum disorder (ASD or “autism”) born extremely and very preterm face substantially delayed development than their peers born full-term. Further, children born preterm are proposed to show a unique behavioral phenotype, which may overlap with characteristics of autism, making it difficult to disentangle their clinical presentation. To clarify the presentation of autism in children born preterm, this study examined differences in key indicators of child development (expressive language, receptive language, fine motor, and visual reception) and characteristics of autism (social affect and repetitive, restricted behaviors).

Materials and Methods: One fifty-eight children (136 full-term, twenty-two preterm) diagnosed with autism, aged 22–34 months, were identified prospectively using the Social Attention and Communication Surveillance tools during community-based, developmental surveillance checks in the second year of life. Those identified at “high likelihood” of an autism diagnosis were administered the Mullen Scales of Early Learning and the Autism Diagnostic Observation Schedule.

Results: The children born preterm and full-term did not differ significantly in their fine motor, visual reception, expressive language, or receptive language skills. No significant differences in social affect and repetitive and restrictive behavior traits were found.

Discussion: The findings of this study differs from previous research where children diagnosed with autism born very or extremely preterm were developmentally delayed and had greater autistic traits than their term-born peers. These null findings may relate to the large proportion of children born moderate to late preterm in this sample. This study was unique in its use of a community-based, prospectively identified sample of children diagnosed with autism at an early age. It may be that children in these groups differ from clinic- and hospital-based samples, that potential differences emerge later in development, or that within the autism spectrum, children born preterm and full-term develop similarly. It was concluded that within the current sample, at 2 years of age, children diagnosed with autism born preterm are similar to their peers born full-term. Thus, when clinicians identify characteristics of autism in children born preterm, it is important to refer the child for a diagnostic assessment for autism.
Advancing Brain-Computer Interface Applications for Severely Disabled Children Through a Multidisciplinary National Network: Summary of the Inaugural Pediatric BCI Canada Meeting
Authors: Kinney-Lang Eli , Kelly Dion , Floreani Erica D. , Jadavji Zeanna , Rowley Danette , Zewdie Ephrem Takele , Anaraki Javad R. , Bahari Hosein , Beckers Kim , Castelane Karen , Crawford Lindsey , House Sarah , Rauh Chelsea A. , Michaud Amber , Mussi Matheus , Silver Jessica , Tuck Corinne , Adams Kim , Andersen John , Chau Tom , Kirton Adam
Published: December 2020

Thousands of youth suffering from acquired brain injury or other early-life neurological disease live, mature, and learn with only limited communication and interaction with their world. Such cognitively capable children are ideal candidates for brain-computer interfaces (BCI). While BCI systems are rapidly evolving, a fundamental gap exists between technological innovators and the patients and families who stand to benefit. Forays into translating BCI systems to children in recent years have revealed that kids can learn to operate simple BCI with proficiency akin to adults. BCI could bring significant boons to the lives of many children with severe physical impairment, supporting their complex physical and social needs. However, children have been neglected in BCI research and a collaborative BCI research community is required to unite and push pediatric BCI development forward. To this end, the pediatric BCI Canada collaborative network (BCI-CAN) was formed, under a unified goal to cooperatively drive forward pediatric BCI innovation and impact. This article reflects on the topics and discussions raised in the foundational BCI-CAN meeting held in Toronto, ON, Canada in November 2019 and suggests the next steps required to see BCI impact the lives of children with severe neurological disease and their families.
Physiological Synchrony in EEG, Electrodermal Activity and Heart Rate Detects Attentionally Relevant Events in Time
Authors: Stuldreher Ivo V. , Thammasan Nattapong , van Erp Jan B. F. , Brouwer Anne-Marie
Published: December 2020

Interpersonal physiological synchrony (PS), or the similarity of physiological signals between individuals over time, may be used to detect attentionally engaging moments in time. We here investigated whether PS in the electroencephalogram (EEG), electrodermal activity (EDA), heart rate and a multimodal metric signals the occurrence of attentionally relevant events in time in two groups of participants. Both groups were presented with the same auditory stimulus, but were instructed to attend either to the narrative of an audiobook (audiobook-attending: AA group) or to interspersed emotional sounds and beeps (stimulus-attending: SA group). We hypothesized that emotional sounds could be detected in both groups as they are expected to draw attention involuntarily, in a bottom-up fashion. Indeed, we found this to be the case for PS in EDA or the multimodal metric. Beeps, that are expected to be only relevant due to specific “top-down” attentional instructions, could indeed only be detected using PS among SA participants, for EDA, EEG and the multimodal metric. We further hypothesized that moments in the audiobook accompanied by high PS in either EEG, EDA, heart rate or the multimodal metric for AA participants would be rated as more engaging by an independent group of participants compared to moments corresponding to low PS. This hypothesis was not supported. Our results show that PS can support the detection of attentionally engaging events over time. Currently, the relation between PS and engagement is only established for well-defined, interspersed stimuli, whereas the relation between PS and a more abstract self-reported metric of engagement over time has not been established. As the relation between PS and engagement is dependent on event type and physiological measure, we suggest to choose a measure matching with the stimulus of interest. When the stimulus type is unknown, a multimodal metric is most robust.
Neurogenetic and Neuroepigenetic Mechanisms in Cognitive Health and Disease
Authors: Coda Davide Martino , Gräff Johannes
Published: December 2020

Over the last two decades, the explosion of experimental, computational, and high-throughput technologies has led to critical insights into how the brain functions in health and disease. It has become increasingly clear that the vast majority of brain activities result from the complex entanglement of genetic factors, epigenetic changes, and environmental stimuli, which, when altered, can lead to neurodegenerative and neuropsychiatric disorders. Nevertheless, a complete understanding of the molecular mechanisms underlying neuronal activities and higher-order cognitive processes continues to elude neuroscientists. Here, we provide a concise overview of how the interaction between the environment and genetic as well as epigenetic mechanisms shapes complex neuronal processes such as learning, memory, and synaptic plasticity. We then consider how this interaction contributes to the development of neurodegenerative and psychiatric disorders, and how it can be modeled to predict phenotypic variability and disease risk. Finally, we outline new frontiers in neurogenetic and neuroepigenetic research and highlight the challenges these fields will face in their quest to decipher the molecular mechanisms governing brain functioning.
The Neuromuscular Junction in Health and Disease: Molecular Mechanisms Governing Synaptic Formation and Homeostasis
Authors: Rodríguez Cruz Pedro M. , Cossins Judith , Beeson David , Vincent Angela
Published: December 2020

The neuromuscular junction (NMJ) is a highly specialized synapse between a motor neuron nerve terminal and its muscle fiber that are responsible for converting electrical impulses generated by the motor neuron into electrical activity in the muscle fibers. On arrival of the motor nerve action potential, calcium enters the presynaptic terminal, which leads to the release of the neurotransmitter acetylcholine (ACh). ACh crosses the synaptic gap and binds to ACh receptors (AChRs) tightly clustered on the surface of the muscle fiber; this leads to the endplate potential which initiates the muscle action potential that results in muscle contraction. This is a simplified version of the events in neuromuscular transmission that take place within milliseconds, and are dependent on a tiny but highly structured NMJ. Much of this review is devoted to describing in more detail the development, maturation, maintenance and regeneration of the NMJ, but first we describe briefly the most important molecules involved and the conditions that affect their numbers and function. Most important clinically worldwide, are myasthenia gravis (MG), the Lambert-Eaton myasthenic syndrome (LEMS) and congenital myasthenic syndromes (CMS), each of which causes specific molecular defects. In addition, we mention the neurotoxins from bacteria, snakes and many other species that interfere with neuromuscular transmission and cause potentially fatal diseases, but have also provided useful probes for investigating neuromuscular transmission. There are also changes in NMJ structure and function in motor neuron disease, spinal muscle atrophy and sarcopenia that are likely to be secondary but might provide treatment targets. The NMJ is one of the best studied and most disease-prone synapses in the nervous system and it is amenable to in vivo and ex vivo investigation and to systemic therapies that can help restore normal function.
The α5 Nicotinic Acetylcholine Receptor Subunit Differentially Modulates α4β2* and α3β4* Receptors
Authors: Scholze Petra , Huck Sigismund
Published: December 2020

Nicotine, the principal reinforcing compound in tobacco, acts in the brain by activating neuronal nicotinic acetylcholine receptors (nAChRs). This review summarizes our current knowledge regarding how the α5 accessory nAChR subunit, encoded by the CHRNA5 gene, differentially modulates α4β2* and α3β4* receptors at the cellular level. Genome-wide association studies have linked a gene cluster in chromosomal region 15q25 to increased susceptibility to nicotine addiction, lung cancer, chronic obstructive pulmonary disease, and peripheral arterial disease. Interestingly, this gene cluster contains a non-synonymous single-nucleotide polymorphism (SNP) in the human CHRNA5 gene, causing an aspartic acid (D) to asparagine (N) substitution at amino acid position 398 in the α5 nAChR subunit. Although other SNPs have been associated with tobacco smoking behavior, efforts have focused predominantly on the D398 and N398 variants in the α5 subunit. In recent years, significant progress has been made toward understanding the role that the α5 nAChR subunit—and the role of the D398 and N398 variants—plays on nAChR function at the cellular level. These insights stem primarily from a wide range of experimental models, including receptors expressed heterologously in Xenopus oocytes, various cell lines, and neurons derived from human induced pluripotent stem cells (iPSCs), as well as endogenous receptors in genetically engineered mice and—more recently—rats. Despite providing a wealth of available data, however, these studies have yielded conflicting results, and our understanding of the modulatory role that the α5 subunit plays remains incomplete. Here, we review these reports and the various techniques used for expression and analysis in order to examine how the α5 subunit modulates key functions in α4β2* and α3β4* receptors, including receptor trafficking, sensitivity, efficacy, and desensitization. In addition, we highlight the strikingly different role that the α5 subunit plays in Ca2+ signaling between α4β2* and α3β4* receptors, and we discuss whether the N398 α5 subunit variant can partially replace the D398 variant.
Redefining Criteria to Ensure Adequate Sentinel Lymph Node Biopsy With Dual Tracer for Breast Cancer
Authors: Xu Li , Yang Jiqiao , Du Zhenggui , Liang Faqing , Xie Yanyan , Long Quanyi , Chen Jie , Zeng Helin , Lv Qing
Published: December 2020

Background

For sentinel lymph node biopsy (SLNB) in patients with breast cancer, the dual tracer of blue dye and radioisotope with the 10% rule that all nodes with radioactive count of 10% or more of the hottest node ex vivo should be removed is widely accepted. However, the cut-off point of radioactivity is being questioned for possibly excessive removal of negative nodes.

Methods

To compare different percentile rules and optimize the criteria for identifying SLNs, we established a database which prospectively collected the radioactivity, status of blue dye and the pathological results of each SLN in breast cancer patients who successfully underwent SLNB with a combination of methylene blue and radioisotope.

Results

A total of 2,529 SLNs from 1,039 patients were identified from August 2010 to August 2019. 16.4% (414/2,529) positive nodes were removed at a cost of 83.6% (2115/2,529) negative nodes removed excessively. Up to 17.9% (375/2,115) negative nodes were removed as radioactively hot nodes without blue staining. By gradually increasing the threshold by each 10%, the number of negative nodes identified reduced by 18.2% (385/2,115) with only three node-positive patients (1.0%) missed to be identified using the “40% + blue” rule. In patients with ≥ 2 SLNs removed, 12.3% (238/1,942) negative nodes avoided unnecessary removal with only 0.8% (2/239) positive patients missed with the “hottest two + blue” rule.

Conclusions

Our data indicated that the “40% + blue” rule or the “hottest two + blue” rule for SLNB with the dual tracer of blue dye and radioisotope may be considered as a potential alternative rule to minimize extra nodes resected. Nonetheless, it should be validated by prospective trials with long-term follow-up.
The Role of TIM-3 in Hepatocellular Carcinoma: A Promising Target for Immunotherapy?
Authors: Ganjalikhani Hakemi Mazdak , Jafarinia Morteza , Azizi Mahdieh , Rezaeepoor Mahsa , Isayev Orkhan , Bazhin Alexandr V.
Published: December 2020

One of the most common tumors in the world is hepatocellular carcinoma (HCC), and its mortality rates are still on the rise, so addressing it is considered an important challenge for universal health. Despite the various treatments that have been developed over the past decades, the prognosis for advanced liver cancer is still poor. Recently, tumor immunotherapy has opened new opportunities for suppression of tumor progression, recurrence, and metastasis. Besides this, investigation into this malignancy due to high immune checkpoint expression and the change of immunometabolic programming in immune cells and tumor cells is highly considered. Because anti-cytotoxic T lymphocyte–associated protein (CTLA)-4 antibodies and anti-programmed cell death protein (PD)-1 antibodies have shown therapeutic effects in various cancers, studies have shown that T cell immunoglobulin mucin-3 (TIM-3), a new immune checkpoint molecule, plays an important role in the development of HCC. In this review, we summarize the recent findings on signal transduction events of TIM-3, its role as a checkpoint target for HCC therapy, and the immunometabolic situation in the progression of HCC.
Asphyxiated Female and Male Newborn Piglets Have Similar Outcomes With Different Cardiopulmonary Resuscitation Interventions
Authors: Kim Seung Yeon , Shim Gyu-Hong , O'Reilly Megan , Cheung Po-Yin , Lee Tze-Fun , Schmölzer Georg M.
Published: December 2020

Background: Male newborns have a greater risk of poor cardiovascular and respiratory outcomes compared to females. The mechanisms associated with the “male disadvantage” remains unclear. We have previously shown no difference between male and female newborn piglets during hypoxia, asphyxia, resuscitation, and post-resuscitation recovery. However, it is unknown if there are differences in resuscitation outcomes between males and females during different cardiopulmonary resuscitation techniques.

Intervention and Measurements: Secondary analysis of 184 term newborn mixed breed duroc piglets (1–3 days of age, weighing 2.0 (0.2) kg) from seven different studies, which were exposed to 30–50 min of normocapnic hypoxia followed by asphyxia until asystole. This was followed by cardiopulmonary resuscitation. For the analysis, piglets were divided into male and female groups, as well as resuscitation technique groups (sustained inflation, 3:1 compression-to-ventilation ratio, or asynchronous ventilations during chest compressions). Cardiac function, carotid blood flow, and cerebral oxygenation were continuously recorded throughout the experiment.

Main results: Regardless of resuscitation technique, there was no significant difference between males and females in the number achieving return of spontaneous circulation (ROSC) [95/123 (77%) vs. 48/61 (79%)], the time to achieve ROSC [112 (80–185) s vs. 110 (77–186) s], and the 4-h survival rate [81/95 (85%) vs. 40/48 (83%)]. Levels of the injury markers interleukin (IL)−1ß, IL-6, IL-8, and tumor necrosis factor-α in frontoparietal cortex tissue homogenates were similar between males and females.

Conclusions: Regardless of resuscitation technique, there was no significant effect of sex on resuscitation outcome, survival, and hemodynamic recovery in asphyxiated newborn piglets.
Serum Ferritin Predicts Neither Organ Dysfunction Nor Mortality in Pediatric Sepsis Due to Tropical Infections
Authors: Williams Vijai , Menon Nisha , Bhatia Prateek , Biswal Manisha , Sreedharanunni Sreejesh , Rawat Amit , Jayashree Muralidharan , Nallasamy Karthi
Published: December 2020

Objective: To evaluate serial ferritin levels measured in the initial 72 h of admission as a biomarker for new and progressive multi organ dysfunction syndrome (NPMODS) and mortality (unfavorable outcomes) in critically ill children with sepsis due to tropical infections.

Material and Methods: In this prospective observational study from a tertiary care teaching hospital in India, children 3 month to 12 years with a diagnosis of acute febrile illness and any two features suggesting tropical infections [cytopenia (platelet count <1,00,000/cu.mm, total leucocyte count <4,000/cu.mm), hepatomegaly and/or splenomegaly, lymphadenopathy, systemic signs (rash, edema), respiratory distress, and encephalopathy not accounted by localized infection] were eligible for inclusion. Children with known or suspected disorder of iron metabolism were excluded. Primary outcome was to determine the association of serial ferritin levels with mortality and NPMODS. Secondary outcomes included estimation of the prevalence of hyperferritinemia and comparison of risk prediction scores with serial ferritin measurement in predicting unfavorable outcomes.

Measurements and Main Results: In the 202 children enrolled, diagnosis could be established in 133 (65.8%) children. Scrub typhus and dengue were the most common infections. Median (IQR) ferritin measured at admission (n = 183) and on day 3 (n = 120) of hospital stay were 798 (378, 3,205) μg/L and 429 (213,680) μg/L, respectively. Majority (n = 180, 89.1%) had MODS at admission defined as per International pediatric sepsis consensus conference. NPMODS occurred in 47 (23.3%) children of whom 37 (18.3%) died. Children with three or less organ dysfunctions had lower mortality. Neither admission ferritin values nor the percentage change over 72 h was different between children with favorable and unfavorable outcomes. Pediatric Risk of Mortality (PRISM-III) and daily Pediatric Logistic Organ Dysfunction score (dPELOD2 score) were significantly different in those with unfavorable outcomes. Admission ferritin levels and percentage change in 72 h had poor discriminatory power for mortality with AUC of 0.53 (0.53, 0.67) and 0.50 (0.50, 0.64), respectively. dPELOD2 had the best discriminatory power for mortality with AUC of 0.89 (0.89, 0.95).

Conclusions: Serial ferritin estimation predicted neither organ dysfunction nor mortality in pediatric sepsis with tropical infections. dPELOD-2 and PRISM-III predicted unfavorable outcomes better than ferritin. The current diagnostic criteria for MODS overestimated organ dysfunctions in tropical infections and hence may need modification with further validation in this epidemiological cohort.
Perspectives in Peptide-Based Vaccination Strategies for Syndrome Coronavirus 2 Pandemic
Authors: Di Natale Concetta , La Manna Sara , De Benedictis Ilaria , Brandi Paola , Marasco Daniela
Published: December 2020

At the end of December 2019, an epidemic form of respiratory tract infection now named COVID-19 emerged in Wuhan, China. It is caused by a newly identified viral pathogen, the severe acute respiratory syndrome coronavirus (SARS-CoV-2), which can cause severe pneumonia and acute respiratory distress syndrome. On January 30, 2020, due to the rapid spread of infection, COVID-19 was declared as a global health emergency by the World Health Organization. Coronaviruses are enveloped RNA viruses belonging to the family of Coronaviridae, which are able to infect birds, humans and other mammals. The majority of human coronavirus infections are mild although already in 2003 and in 2012, the epidemics of SARS-CoV and Middle East Respiratory Syndrome coronavirus (MERS-CoV), respectively, were characterized by a high mortality rate. In this regard, many efforts have been made to develop therapeutic strategies against human CoV infections but, unfortunately, drug candidates have shown efficacy only intoin vitrostudies, limiting their use against COVID-19 infection. Actually, no treatment has been approved in humans against SARS-CoV-2, and therefore there is an urgent need of a suitable vaccine to tackle this health issue. However, the puzzled scenario of biological features of the virus and its interaction with human immune response, represent a challenge for vaccine development. As expected, in hundreds of research laboratories there is a running out of breath to explore different strategies to obtain a safe and quickly spreadable vaccine; and among others, the peptide-based approach represents a turning point as peptides have demonstrated unique features of selectivity and specificity toward specific targets. Peptide-based vaccines imply the identification of different epitopes both on human cells and virus capsid and the design of peptide/peptidomimetics able to counteract the primary host-pathogen interaction, in order to induce a specific host immune response. SARS-CoV-2 immunogenic regions are mainly distributed, as well as for other coronaviruses, across structural areas such as spike, envelope, membrane or nucleocapsid proteins. Herein, we aim to highlight the molecular basis of the infection and recent peptide-based vaccines strategies to fight the COVID-19 pandemic including their delivery systems.
Considerations for the Analysis of Small Extracellular Vesicles in Physical Exercise
Authors: Brahmer Alexandra , Neuberger Elmo W. I. , Simon Perikles , Krämer-Albers Eva-Maria
Published: December 2020

Physical exercise induces acute physiological changes leading to enhanced tissue cross-talk and a liberation of extracellular vesicles (EVs) into the circulation. EVs are cell-derived membranous entities which carry bioactive material, such as proteins and RNA species, and are important mediators of cell-cell-communication. Different types of physical exercise interventions trigger the release of diverse EV subpopulations, which are hypothesized to be involved in physiological adaptation processes leading to health benefits and longevity. Large EVs (“microvesicles” and “microparticles”) are studied frequently in the context of physical exercise using straight forward flow cytometry approaches. However, the analysis of small EVs (sEVs) including exosomes is hampered by the complex composition of blood, confounding the methodology of EV isolation and characterization. This mini review presents a concise overview of the current state of research on sEVs released upon physical exercise (ExerVs), highlighting the technical limits of ExerV analysis. The purity of EV preparations is highly influenced by the co-isolation of non-EV structures in the size range or density of EVs, such as lipoproteins and protein aggregates. Technical constraints associated with EV purification challenge the quantification of distinct ExerV populations, the identification of their cargo, and the investigation of their biological functions. Here, we offer recommendations for the isolation and characterization of ExerVs to minimize the effects of these drawbacks. Technological advances in the ExerV research field will improve understanding of the inter-cellular cross-talk induced by physical exercise leading to health benefits.
Ficus carica L. Attenuates Denervated Skeletal Muscle Atrophy via PPARα/NF-κB Pathway
Authors: Dai Junxi , Xiang Yaoxian , Fu Da , Xu Lei , Jiang Junjian , Xu Jianguang
Published: December 2020

Treatment options for denervated skeletal muscle atrophy are limited, in part because the underlying molecular mechanisms are not well understood. Unlike previous transcriptomics studies conducted in rodent models of peripheral nerve injury, in the present study, we performed high-throughput sequencing with denervated atrophic biceps muscle and normal (non-denervated) sternocleidomastoid muscle samples obtained from four brachial plexus injury (BPI) patients. We also investigated whether Ficus carica L. (FCL.) extract can suppress denervated muscle atrophy in a mouse model, along with the mechanism of action. We identified 1471 genes that were differentially expressed between clinical specimens of atrophic and normal muscle, including 771 that were downregulated and 700 that were upregulated. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses revealed that the differentially expressed genes were mainly enriched in the GO terms “structural constituent of muscle,” “Z disc,” “M band,” and “striated muscle contraction,” as well as “Cell adhesion molecules,” “Glycolysis/Gluconeogenesis,” “Peroxisome proliferator-activated receptor alpha (PPARα) signaling pathway,” and “P53 signaling pathway.” In experiments using mice, the reduction in wet weight and myofiber diameter in denervated muscle was improved by FCL. extract compared to saline administration, which was accompanied by downregulation of the proinflammatory cytokines interleukin (IL)-1β and IL-6. Moreover, although both denervated groups showed increased nuclear factor (NF)-κB activation and PPARα expression, the degree of NF-κB activation was lower while PPARα and inhibitor of NF-κB IκBα expression was higher in FCL. extract-treated mice. Thus, FCL. extract suppresses denervation-induced inflammation and attenuates muscle atrophy by enhancing PPARα expression and inhibiting NF-κB activation. These findings suggest that FCL. extract has therapeutic potential for preventing denervation-induced muscle atrophy caused by peripheral nerve injury or disease.
COVID-19: A Challenge to Physiology of Aging
Authors: Golubev Aleksei G.
Published: December 2020

The death toll of the current COVID-19 pandemic is strongly biased toward the elderly. COVID-19 case fatality rate (CFR) increases with age exponentially, its doubling time being about 7 years, irrespective of countries and epidemic stages. The same age-dependent mortality pattern known as the Gompertz law is featured by the total mortality and its main constituents attributed to cardiovascular, metabolic, neurological, and oncological diseases. Among patients dying of COVID-19, most have at least one of these conditions, whereas none is found in most of those who pass it successfully. Thus, gerontology is indispensable in dealing with the pandemic, which becomes a benchmark for validating the gerontological concepts and advances. The two basic alternative gerontological concepts imply that either aging results from the accumulation of stochastic damage, or is programmed. Based on these different grounds, several putative anti-aging drugs have been proposed as adjuvant means for COVID-19 prevention and/or treatment. These proposals are reviewed in the context of attributing the molecular targets of these drugs to the signaling pathways between the sensors of resource availability and the molecular mechanisms that allocate resources to storage, growth and reproduction or to self-maintenance and repair. Each of the drugs appears to reproduce only a part of the physiological responses to reduced resource availability caused by either dietary calories restriction or physical activity promotion, which are the most robust means of mitigating the adverse manifestations of aging. In the pathophysiological terms, the conditions of the endothelium, which worsen as age increases and may be significantly improved by the physical activity, is a common limiting factor for the abilities to withstand both physical stresses and challenges imposed by COVID-19. However, the current anti-epidemic measures promote sedentary indoor lifestyles, at odds with the most efficient behavioral interventions known to decrease the vulnerability to both the severe forms of COVID-19 and the prevalent aging-associated diseases. To achieve a proper balance in public health approaches to COVID-19, gerontologists should be involved in crosstalk between virologists, therapists, epidemiologists, and policy makers. The present publication suggests a conceptual background for that.
Enhanced Skeletal Muscle Oxidative Capacity and Capillary-to-Fiber Ratio Following Moderately Increased Testosterone Exposure in Young Healthy Women
Authors: Cardinale Daniele A. , Horwath Oscar , Elings-Knutsson Jona , Helge Torbjörn , Godhe Manne , Bermon Stéphane , Moberg Marcus , Flockhart Mikael , Larsen Filip J. , Hirschberg Angelica Lindén , Ekblom Björn
Published: December 2020

Background:Recently, it was shown that exogenously administered testosterone enhances endurance capacity in women. In this study, our understanding on the effects of exogenous testosterone on key determinants of oxygen transport and utilization in skeletal muscle is expanded.

Methods:In a double-blinded, randomized, placebo-controlled trial, 48 healthy active women were randomized to 10 weeks of daily application of 10 mg of testosterone cream or placebo. Before and after the intervention, VO2max, body composition, total hemoglobin (Hb) mass and blood volumes were assessed. Biopsies from thevastus lateralismuscle were obtained before and after the intervention to assess mitochondrial protein abundance, capillary density, capillary-to-fiber (C/F) ratio, and skeletal muscle oxidative capacity.

Results:Maximal oxygen consumption per muscle mass, Hb mass, blood, plasma and red blood cell volumes, capillary density, and the abundance of mitochondrial protein levels (i.e., citrate synthase, complexes I, II, III, IV-subunit 2, IV-subunit 4, and V) were unchanged by the intervention. However, the C/F ratio, specific mitochondrial respiratory flux activating complex I and linked complex I and II, uncoupled respiration and electron transport system capacity, but not leak respiration or fat respiration, were significantly increased following testosterone administration compared to placebo.

Conclusion:This study provides novel insights into physiological actions of increased testosterone exposure on key determinants of oxygen diffusion and utilization in skeletal muscle of women. Our findings show that higher skeletal muscle oxidative capacity coupled to higher C/F ratio could be major contributing factors that improve endurance performance following moderately increased testosterone exposure.
Fetal Membrane Epigenetics
Authors: Zakar Tamas , Paul Jonathan W.
Published: December 2020

The characteristics of fetal membrane cells and their phenotypic adaptations to support pregnancy or promote parturition are defined by global patterns of gene expression controlled by chromatin structure. Heritable epigenetic chromatin modifications that include DNA methylation and covalent histone modifications establish chromatin regions permissive or exclusive of regulatory interactions defining the cell-specific scope and potential of gene activity. Non-coding RNAs acting at the transcriptional and post-transcriptional levels complement the system by robustly stabilizing gene expression patterns and contributing to ordered phenotype transitions. Here we review currently available information about epigenetic gene regulation in the amnion and the chorion laeve. In addition, we provide an overview of epigenetic phenomena in the decidua, which is the maternal tissue fused to the chorion membrane forming the anatomical and functional unit called choriodecidua. The relationship of gene expression with DNA (CpG) methylation, histone acetylation and methylation, micro RNAs, long non-coding RNAs and chromatin accessibility is discussed in the context of normal pregnancy, parturition and pregnancy complications. Data generated using clinical samples and cell culture models strongly suggests that epigenetic events are associated with the phenotypic transitions of fetal membrane cells during the establishment, maintenance and termination of pregnancy potentially driving and consolidating the changes as pregnancy progresses. Disease conditions and environmental factors may produce epigenetic footprints that indicate exposures and mediate adverse pregnancy outcomes. Although knowledge is expanding rapidly, fetal membrane epigenetics is still in an early stage of development necessitating further research to realize its remarkable basic and translational potential.
Distinct Roles of Smooth Muscle and Non-muscle Myosin Light Chain-Mediated Smooth Muscle Contraction
Authors: Sun Jie , Qiao Yan-Ning , Tao Tao , Zhao Wei , Wei Li-Sha , Li Ye-Qiong , Wang Wei , Wang Ye , Zhou Yu-Wei , Zheng Yan-Yan , Chen Xin , Pan Hong-Chun , Zhang Xue-Na , Zhu Min-Sheng
Published: December 2020

Both smooth muscle (SM) and non-muscle (NM) myosin II are expressed in hollow organs such as the bladder and uterus, but their respective roles in contraction and corresponding physiological functions remain to be determined. In this report, we assessed their roles by analyzing mice deficient ofMyl9, a gene encoding the SM myosin regulatory light chain (SM RLC). We find that globalMyl9-deficient bladders contracted with an apparent sustained phase, despite no initial phase. This sustained contraction was mediated by NM myosin RLC (NM RLC) phosphorylation by myosin light chain kinase (MLCK). NM myosin II was expressed abundantly in the uterus and young mice bladders, of which the force was accordingly sensitive to NM myosin inhibition. Our findings reveal distinct roles of SM RLC and NM RLC in SM contraction.
Structural and Functional Plasticity in the Regenerating Olfactory System of the Migratory Locust
Authors: Bicker Gerd , Stern Michael
Published: December 2020

Regeneration after injury is accompanied by transient and lasting changes in the neuroarchitecture of the nervous system and, thus, a form of structural plasticity. In this review, we introduce the olfactory pathway of a particular insect as a convenient model to visualize neural regeneration at an anatomical level and study functional recovery at an electrophysiological level. The olfactory pathway of the locust (Locusta migratoria) is characterized by a multiglomerular innervation of the antennal lobe by olfactory receptor neurons. These olfactory afferents were axotomized by crushing the base of the antenna. The resulting degeneration and regeneration in the antennal lobe could be quantified by size measurements, dye labeling, and immunofluorescence staining of cell surface proteins implicated in axonal guidance during development. Within 3 days post lesion, the antennal lobe volume was reduced by 30% and from then onward regained size back to normal by 2 weeks post injury. The majority of regenerating olfactory receptor axons reinnervated the glomeruli of the antennal lobe. A few regenerating axons project erroneously into the mushroom body on a pathway that is normally chosen by second-order projection neurons. Based on intracellular responses of antennal lobe output neurons to odor stimulation, regenerated fibers establish functional synapses again. Following complete absence after nerve crush, responses to odor stimuli return to control level within 10–14 days. On average, regeneration of afferents, and re-established synaptic connections appear faster in younger fifth instar nymphs than in adults. The initial degeneration of olfactory receptor axons has a trans-synaptic effect on a second order brain center, leading to a transient size reduction of the mushroom body calyx. Odor-evoked oscillating field potentials, absent after nerve crush, were restored in the calyx, indicative of regenerative processes in the network architecture. We conclude that axonal regeneration in the locust olfactory system appears to be possible, precise, and fast, opening an avenue for future mechanistic studies. As a perspective of biomedical importance, the current evidence for nitric oxide/cGMP signaling as positive regulator of axon regeneration in connectives of the ventral nerve cord is considered in light of particular regeneration studies in vertebrate central nervous systems.