bluuebunny/crossref_metadata_2025 huggingface dataset:
Structural Characterization of a Neutralizing Nanobody With Broad Activity Against SARS-CoV-2 Variants
Authors: Li Tingting , Zhou Bingjie , Luo Zhipu , Lai Yanling , Huang Suqiong , Zhou Yuanze , Li Yaning , Gautam Anupriya , Bourgeau Salome , Wang Shurui , Bao Juan , Tan Jingquan , Lavillette Dimitri , Li Dianfan
Published: June 2022

SARS-CoV-2 and its variants, such as the Omicron continue to threaten public health. The virus recognizes the host cell by attaching its Spike (S) receptor-binding domain (RBD) to the host receptor, ACE2. Therefore, RBD is a primary target for neutralizing antibodies and vaccines. Here, we report the isolation and biological and structural characterization of a single-chain antibody (nanobody) from RBD-immunized alpaca. The nanobody, named DL28, binds to RBD tightly with a KD of 1.56 nM and neutralizes the original SARS-CoV-2 strain with an IC50 of 0.41 μg mL−1. Neutralization assays with a panel of variants of concern (VOCs) reveal its wide-spectrum activity with IC50 values ranging from 0.35 to 1.66 μg mL−1 for the Alpha/Beta/Gamma/Delta and an IC50 of 0.66 μg mL−1 for the currently prevalent Omicron. Competition binding assays show that DL28 blocks ACE2-binding. However, structural characterizations and mutagenesis suggest that unlike most antibodies, the blockage by DL28 does not involve direct competition or steric hindrance. Rather, DL28 may use a “conformation competition” mechanism where it excludes ACE2 by keeping an RBD loop in a conformation incompatible with ACE2-binding.
Characteristics of 24 SARS-CoV-2-Sequenced Reinfection Cases in a Tertiary Hospital in Spain
Authors: Borras-Bermejo Blanca , Piñana Maria , Andrés Cristina , Zules Ricardo , González-Sánchez Alejandra , Esperalba Juliana , Parés-Badell Oleguer , García-Cehic Damir , Rando Ariadna , Campos Carolina , Codina Maria Gema , Martín Maria Carmen , Castillo Carla , García-Comuñas Karen , Vásquez-Mercado Rodrigo , Martins-Martins Reginald , Colomer-Castell Sergi , Pumarola Tomàs , Campins Magda , Quer Josep , Antón Andrés
Published: June 2022

Background

Since the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the main concern is whether reinfections are possible, and which are the associated risk factors. This study aims to describe the clinical and molecular characteristics of 24 sequence-confirmed reinfection SARS-CoV-2 cases over 1 year in Barcelona (Catalonia, Spain).

Methods

Patients with > 45 days between two positive PCR tests regardless of symptoms and negative tests between episodes were initially considered as suspected reinfection cases from November 2020 to May 2021. Whole-genome sequencing (WGS) was performed to confirm genetic differences between consensus sequences and for phylogenetic studies based on PANGOLIN nomenclature. Reinfections were confirmed by the number of mutations, change in lineage, or epidemiological criteria.

Results

From 39 reported suspected reinfection cases, complete viral genomes could be sequenced from both episodes of 24 patients, all were confirmed as true reinfections. With a median age of 44 years (interquartile range [IQR] 32–65), 66% were women and 58% were healthcare workers (HCWs). The median days between episodes were 122 (IQR 72–199), occurring one-third within 3 months. Reinfection episodes were frequently asymptomatic and less severe than primary infections. The absence of seroconversion was associated with symptomatic reinfections. Only one case was reinfected with a variant of concern (VOC).

Conclusion

Severe acute respiratory syndrome coronavirus 2 reinfections can occur in a shorter time than previously reported and are mainly found in immunocompetent patients. Surveillance through WGS is useful to identify viral mutations associated with immune evasion.
Roles of Secretory Immunoglobulin A in Host-Microbiota Interactions in the Gut Ecosystem
Authors: León E. Daniel , Francino M. Pilar
Published: June 2022

In the gastrointestinal tract (GIT), the immune system interacts with a variety of microorganisms, including pathogens as well as beneficial symbionts that perform important physiological functions for the host and are crucial to sustain intestinal homeostasis. In normal conditions, secretory immunoglobulin A (SIgA) is the principal antibody produced by B cells in the GIT mucosa. Polyreactivity provides certain SIgA molecules with the ability of binding different antigens in the bacterial surface, such as O-antigens and teichoic acids, while cross-species reactivity allows them to recognize and interact with different types of bacteria. These functions may be crucial in allowing SIgA to modulate the complex gut microbiota in an efficient manner. Several studies suggest that SIgA can help with the retention and proliferation of helpful members of the gut microbiota. Gut microbiota alterations in people with IgA deficiency include the lack of some species that are known to be normally coated by SIgA. Here, we discuss the different ways in which SIgA behaves in relation to pathogens and beneficial bacteria of the gut microbiota and how the immune system might protect and facilitate the establishment and maintenance of certain gut symbionts.
A Tale of Three Recent Pandemics: Influenza, HIV and SARS-CoV-2
Authors: Miranda Mafalda N. S. , Pingarilho Marta , Pimentel Victor , Torneri Andrea , Seabra Sofia G. , Libin Pieter J. K. , Abecasis Ana B.
Published: June 2022

Emerging infectious diseases are one of the main threats to public health, with the potential to cause a pandemic when the infectious agent manages to spread globally. The first major pandemic to appear in the 20th century was the influenza pandemic of 1918, caused by the influenza A H1N1 strain that is characterized by a high fatality rate. Another major pandemic was caused by the human immunodeficiency virus (HIV), that started early in the 20th century and remained undetected until 1981. The ongoing HIV pandemic demonstrated a high mortality and morbidity rate, with discrepant impacts in different regions around the globe. The most recent major pandemic event, is the ongoing pandemic of COVID-19, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which has caused over 5.7 million deaths since its emergence, 2 years ago. The aim of this work is to highlight the main determinants of the emergence, epidemic response and available countermeasures of these three pandemics, as we argue that such knowledge is paramount to prepare for the next pandemic. We analyse these pandemics’ historical and epidemiological contexts and the determinants of their emergence. Furthermore, we compare pharmaceutical and non-pharmaceutical interventions that have been used to slow down these three pandemics and zoom in on the technological advances that were made in the progress. Finally, we discuss the evolution of epidemiological modelling, that has become an essential tool to support public health policy making and discuss it in the context of these three pandemics. While these pandemics are caused by distinct viruses, that ignited in different time periods and in different regions of the globe, our work shows that many of the determinants of their emergence and countermeasures used to halt transmission were common. Therefore, it is important to further improve and optimize such approaches and adapt it to future threatening emerging infectious diseases.
Isolation, Screening, and Active Metabolites Identification of Anti-Vibrio Fungal Strains Derived From the Beibu Gulf Coral
Authors: Huang Bingyao , Peng Shuai , Liu Shifang , Zhang Yanting , Wei Yuxiao , Xu Xinya , Gao Chenghai , Liu Yonghong , Luo Xiaowei
Published: June 2022

The Beibu Gulf harbors abundant underexplored marine microbial resources, which are rich in diversified secondary metabolites. The genera Vibrio is a well-known pathogenic bacterium of aquatic animals. In this study, 22 fungal strains were isolated and identified from the Beibu Gulf coral via the serial dilution method and internal transcribed spacer (ITS) sequence analysis, which were further divided into three branches by phylogenetic tree analysis. The crude extracts of them via small-scale fermentation were selected for the screening of inhibitory activity against Vibrio alginalyticus, Vibrio coralliilyticus, Vibrio harveyi, Vibrio parahaemolyticus, Vibrio owensii, and Vibrio shilonii. The results showed that eight fungal extracts displayed anti-Vibrio activity via the filter paper disk assay. Several of them showed strong inhibitory effects. Then, two tetramic acid alkaloids, equisetin (1) and 5′-epiequisetin (2), were identified from Fusarium equiseti BBG10 by bioassay-guided isolation, both of which inhibited the growth of Vibrio spp. with the MIC values of 86–132 μg/ml. The scanning electron microscope results showed that cell membranes of Vibrio became corrugated, distorted or ruptured after treatment with 1 and 2. Taken together, this study provided eight fungal isolates with anti-Vibrio potentials, and two alkaloid-type antibiotics were found with anti-Vibrio effects from the bioactive strain F. equiseti BBG10. Our findings highlight the importance of exploring promising microbes from the Beibu Gulf for the identification of anti-Vibrio for future antibiotic development.
N-Lobe of TXNIP Is Critical in the Allosteric Regulation of NLRP3 via TXNIP Binding
Authors: Cheng Fengyu , Wang Nan
Published: June 2022

Inflammasomes are cytoplasmic complexes that form in response to exogenous microbial invasions and endogenous damage signals. Among the known inflammasomes, the activation of the NACHT (NAIP, CIITA, HET-E, and TP1 domain), leucine-rich repeat, and pyrin domain containing protein 3 (NLRP3) inflammasome is also primarily related to neuroinflammation and nerve cell damage. Previous studies reported that under the stimulation of dangerous signals like reactive oxygen species (ROS), the overexpression and interaction of thioredoxin-interacting protein (TXNIP) with NLRP3 may trigger the inflammatory response through the ROS/TXNIP/NLRP3 signaling pathway. This inflammatory response is the pathophysiological basis of some neurological and neurodegenerative diseases. The activation of inflammasome and apoptosis caused by TXNIP are widespread in brain diseases. Previous report has suggested the TXNIP/NLRP3 interaction interface. However, the comprehensive model of the TXNIP/NLRP3 interaction is still unclear. In this study, molecular docking experiments based on the existing crystal model of NLRP3 were performed to investigate the binding of TXNIP and NLRP3. Three in silico models of the TXNIP/NLRP3 complex were selected, and molecular dynamics simulations evaluated the binding stability of the possible interaction between the two proteins. The results revealed that the E690, E693, and D745 residues in NLRP3 and the K212 and R238 residues in TXNIP play a critical role in the TXNIP/NLRP3 interaction. N-terminal of TXNIP is essential in promoting the conformational changes of NLRP3, although it does not directly bind to NLRP3. Our findings reveal the possible binding mechanism between TXNIP and NLRP3 and the associated allosteric regulation of NLRP3. The constructed models may also be useful for inhibitor development targeting the TXNIP/NLRP3 interaction during inflammasome activation via the ROS/TXNIP/NLRP3 pathway.
The Cycling Brain in the Workplace: Does Workload Modulate the Menstrual Cycle Effect on Cognition?
Authors: Xu Min , Chen Dandan , Li Hai , Wang Hongzhi , Yang Li-Zhuang
Published: June 2022

Recent decades have witnessed increased research efforts to clarify how the menstrual cycle influence females’ cognitive and emotional functions. Despite noticeable progress, the research field faces the challenges of inconsistency and low generalizability of research findings. Females of reproductive ages are a heterogeneous population. Generalizing the results of female undergraduates to women in the workplace might be problematic. Furthermore, the critical cognitive processes for daily life and work deserve additional research efforts for improved ecological validity. Thus, this study investigates cognitive performance across the menstrual cycle using a sample of young nurses with similar duties. We developed a mini-computerized cognitive battery to assess four mental skills critical for nursing work: cognitive flexibility, divided attention, response inhibition, and working memory. Participants completed the cognitive battery at menses, late-follicular, and mid-luteal phases. In addition, they were classified into low- and high workload groups according to their subjective workload ratings. Our results demonstrate a general mid-luteal cognitive advantage. Besides, this study reveals preliminary evidence that workload modulates the menstrual cycle effect on cognition. Only females of low workload manifest the mid-luteal cognitive advantage on divided attention and response inhibition, implying that a suitable workload threshold might be necessary for regular neuro-steroid interactions. Thus, this study advocates the significance of research focusing on the cycling brain under workloads.
Recent Machine Learning Progress in Lower Limb Running Biomechanics With Wearable Technology: A Systematic Review
Authors: Xiang Liangliang , Wang Alan , Gu Yaodong , Zhao Liang , Shim Vickie , Fernandez Justin
Published: June 2022

With the emergence of wearable technology and machine learning approaches, gait monitoring in real-time is attracting interest from the sports biomechanics community. This study presents a systematic review of machine learning approaches in running biomechanics using wearable sensors. Electronic databases were retrieved in PubMed, Web of Science, SPORTDiscus, Scopus, IEEE Xplore, and ScienceDirect. A total of 4,068 articles were identified via electronic databases. Twenty-four articles that met the eligibility criteria after article screening were included in this systematic review. The range of quality scores of the included studies is from 0.78 to 1.00, with 40% of articles recruiting participant numbers between 20 and 50. The number of inertial measurement unit (IMU) placed on the lower limbs varied from 1 to 5, mainly in the pelvis, thigh, distal tibia, and foot. Deep learning algorithms occupied 57% of total machine learning approaches. Convolutional neural networks (CNN) were the most frequently used deep learning algorithm. However, the validation process for machine learning models was lacking in some studies and should be given more attention in future research. The deep learning model combining multiple CNN and recurrent neural networks (RNN) was observed to extract different running features from the wearable sensors and presents a growing trend in running biomechanics.
Clinical Manifestations and Molecular Backgrounds of Parkinson's Disease Regarding Genes Identified From Familial and Population Studies
Authors: Nishioka Kenya , Imai Yuzuru , Yoshino Hiroyo , Li Yuanzhe , Funayama Manabu , Hattori Nobutaka
Published: June 2022

Over the past 20 years, numerous robust analyses have identified over 20 genes related to familial Parkinson's disease (PD), thereby uncovering its molecular underpinnings and giving rise to more sophisticated approaches to investigate its pathogenesis. α-Synuclein is a major component of Lewy bodies (LBs) and behaves in a prion-like manner. The discovery of α-Synuclein enables an in-depth understanding of the pathology behind the generation of LBs and dopaminergic neuronal loss. Understanding the pathophysiological roles of genes identified from PD families is uncovering the molecular mechanisms, such as defects in dopamine biosynthesis and metabolism, excessive oxidative stress, dysfunction of mitochondrial maintenance, and abnormalities in the autophagy–lysosome pathway, involved in PD pathogenesis. This review summarizes the current knowledge on familial PD genes detected by both single-gene analyses obeying the Mendelian inheritance and meta-analyses of genome-wide association studies (GWAS) from genome libraries of PD. Studying the functional role of these genes might potentially elucidate the pathological mechanisms underlying familial PD and sporadic PD and stimulate future investigations to decipher the common pathways between the diseases.
Projection of Damaged Visual and Language Regions on Low Trail Making Test Part-B Performance in Stroke Patients
Authors: Nishimura Ayako , Sutoko Stephanie , Kiguchi Masashi , Atsumori Hirokazu , Obata Akiko , Funane Tsukasa , Kandori Akihiko , Mizuguchi Tomohiko , Shimonaga Koji , Hama Seiji , Tsuji Toshio
Published: June 2022

Background

The Trail Making Test Part-B (TMT-B) is an attention functional test to investigate cognitive dysfunction. It requires the ability to recognize not only numbers but also letters. We analyzed the relationship between brain lesions in stroke patients and their TMT-B performance.

Methods

From the TMT-B, two parameters (score and completion time) were obtained. The subjects were classified into several relevant groups by their scores and completion times through a data-driven analysis (k-means clustering). The score-classified groups were characterized by low (≤10), moderate (10 < score < 25), and high (25) scores. In terms of the completion time, the subjects were classified into four groups. The lesion degree in the brain was calculated for each of the 116 regions classified by automated anatomical labeling (AAL). For each group, brain sites with a significant difference (corrected p < 0.1) between each of the 116 regions were determined by a Wilcoxon Rank–Sum significant difference test.

Results

Lesions at the cuneus and the superior occipital gyrus, which are mostly involved in visual processing, were significant (corrected p < 0.1) in the low-score group. Furthermore, the moderate-score group showed more-severe lesion degrees (corrected p < 0.05) in the regions responsible for the linguistic functions, such as the superior temporal gyrus and the supramarginal gyrus. As for the completion times, lesions in the calcarine, the cuneus, and related regions were significant (corrected p < 0.1) in the fastest group as compared to the slowest group. These regions are also involved in visual processing.

Conclusion

The TMT-B results revealed that the subjects in the low-score group or the slowest- group mainly had damage in the visual area, whereas the subjects in the moderate-score group mainly had damage in the language area. These results suggest the potential utility of TMT-B performance in the lesion site.
A Randomized Clinical Trial to Evaluate the Effects of Safinamide on Apathetic Non-demented Patients With Parkinson's Disease
Authors: Kulisevsky Jaime , Martínez-Horta Saul , Campolongo Antonia , Pascual-Sedano Berta , Marín-Lahoz Juan , Bejr-kasem Helena , Aracil-Bolaños Ignacio , Horta-Barba Andrea , Puig-Davi Arnau , Pagonabarraga Javier
Published: June 2022

Background

Apathy is highly prevalent and disabling in Parkinson's disease (PD). Pharmacological options for its management lack sufficient evidence.

Objective

We studied the effects of safinamide on apathy in PD.

Methods

Prospective, 24-week, two-site, randomized, double-blind, placebo-controlled, parallel-group exploratory study in non-demented PD on stable dopaminergic therapy randomized 1:1 to adjunct safinamide (50 mg/day for 2 weeks and 100 mg/day for 22 weeks) or placebo. The primary endpoint was the mean change from baseline to week 24 on the Apathy Scale (AS) total score. Secondary endpoints included changes in cognition, activities of daily living, motor scores, the impression of change, and safety and tolerability measures.

Results

In total, 30 participants (active treatment = 15; placebo = 15; 80% showing clinically significant apathetic symptoms according to the AS) were enrolled, and included in the intention-to-treat analysis. Change in AS (ANOVA) showed a trend to significance [p = 0.059] mediated by a more marked decrease in AS score with safinamide (−7.5 ± 6.9) than with placebo (−2.8 ± 5.7). Post-hoc analysis (paired t-test) showed a significant positive change in the AS score between 12-week and 24-week [p = 0.001] only in the active group. No significant or trend changes were found for any of the secondary outcome variables. Adverse events were few and only mild in both treatment groups.

Conclusions

Safinamide was safe and well-tolerated, but failed to provide evidence of improved apathy. The positive trend observed in the post-hoc analyses deserves to be studied in depth in larger studies.

Trial Registration

EudraCT 2017-003254-17.
Gradient Patterns of Age-Related Diffusivity Changes in Cerebral White Matter
Authors: Boban Jasmina , Thurnher Majda M. , Boban Nikola , Law Meng , Jahanshad Neda , Nir Talia M. , Lendak Dajana F. , Kozic Dusko
Published: June 2022

The current concept of brain aging proposes three gradient patterns of changes in white matter that occur during healthy brain aging: antero-posterior, supero-inferior, and the myelodegeneration-retrogenesis (or the “last-in-first-out”) concept. The aim of this study was to correlate white matter diffusivity measures (fractional anisotropy-FA, mean diffusivity-MD, radial diffusivity-RD, and axial diffusivity-AD) in healthy volunteers with chronological age and education level, in order to potentially incorporate the findings with proposed patterns of physiological brain aging. The study was performed on 75 healthy participants of both sexes, with an average age of 37.32 ± 11.91 years underwent brain magnetic resonance imaging (MRI) with diffusion tensor imaging (DTI). DTI was performed using tract-based spatial statistics (TBSS), with the analysis of four parameters: FA, MD, RD, and AD. Skeletonized measures were averaged in 29 regions of interest in white matter. Correlations between age and DTI measures and between education-level and DTI measures were performed using Pearson's correlation test. To correct for multiple comparisons, we applied a Bonferroni correction to the p-values. Significance was set at p ≤ 0.001. A significant negative correlation of FA with age was observed in posterior thalamic radiation (PTR) (p< 0.001). A significant positive correlation between age and MD was observed in sagittal stratum (SS) (p< 0.001), between age and RD in PTR, SS, and retrolenticular internal capsule (p< 0.001), and between age and AD in the body of the corpus callosum (p< 0.001). There were no significant correlations of DTI parameters with educational level. According to our study, RD showed the richest correlations with age, out of all DTI metrics. FA, MD, and RD showed significant changes in the diffusivity of projection fibers, while AD presented diffusivity changes in the commissural fibers. The observed heterogeneity in diffusivity changes across the brain cannot be explained by a single aging gradient pattern, since it seems that different patterns of degradation are true for different fiber tracts that no currently available theory can globally explain age-related changes in the brain. Additional factors, such as the effect of somatosensory decline, should be included as one of the important covariables to the existing patterns.
Video Head Impulse Test Findings in Patients With Benign Paroxysmal Positional Vertigo Secondary to Idiopathic Sudden Sensorineural Hearing Loss
Authors: Liu Yingzhao , Leng Yangming , Zhou Renhong , Liu Jingjing , Wang Hongchang , Xia Kaijun , Liu Bo , Xiao Hongjun
Published: June 2022

Benign paroxysmal positional vertigo (BPPV) is amongst the most common causes of episodic vestibular syndrome. It can be classified as idiopathic and secondary types according to the causative factors, and the underlying mechanism between idiopathic (i-BPPV) and secondary BPPV (s-BPPV) may differ. Idiopathic sudden sensorineural hearing loss (ISSNHL) has been considered as a common inner ear disease that precipitates s-BPPV. Yet, few studies have addressed the functional impairment of the semicircular canal (SCC) system in patients with s-BPPV associated with ISSNHL. Our purpose was to explore the pathophysiological mechanism and investigate the clinical implications of video head impulse test (vHIT) in these patients. Here, the clinical and laboratory data of patients with BPPV secondary to ISSNHL, including the results of vHIT, were retrospectively reviewed, and compared with those of patients with i-BPPV. Pathological vHIT findings (low vestibulo-ocular reflex gain and re-fixation saccade), which mainly affected the posterior SCC, were more common in the s-BPPV group than in the i-BPPV group (41.9 and 0%, respectively). The incidence of horizontal SCC involvement was also higher in the s-BPPV group (45.16 and 16.67%, respectively). Furthermore, patients with s-BPPV showed lower vHIT gains of the posterior and horizontal SCCs in affected ears than in unaffected ears. Compared to i-BPPV, posterior SCC paresis detected by vHIT is more prevalent in BPPV secondary to ISSNHL. This dysfunction may be associated mainly with vestibular impairments caused by ISSNHL, and not with BPPV per se.
Immune–Inflammatory Biomarkers Predict Cognition and Social Functioning in Patients With Type 2 Diabetes Mellitus, Major Depressive Disorder, Bipolar Disorder, and Schizophrenia: A 1-Year Follow-Up Study
Authors: Garés-Caballer Marta , Sánchez-Ortí Joan Vicent , Correa-Ghisays Patricia , Balanzá-Martínez Vicent , Selva-Vera Gabriel , Vila-Francés Joan , Magdalena-Benedito Rafael , San-Martin Constanza , Victor Victor M. , Escribano-Lopez Irene , Hernandez-Mijares Antonio , Vivas-Lalinde Juliana , Vieta Eduard , Leza Juan C. , Tabarés-Seisdedos Rafael
Published: June 2022

Background

Systemic, low-grade immune–inflammatory activity, together with social and neurocognitive performance deficits are a transdiagnostic trait of people suffering from type 2 diabetes mellitus (T2DM) and severe mental illnesses (SMIs), such as schizophrenia (SZ), major depressive disorder (MDD), and bipolar disorder (BD). We aimed to determine if immune–inflammatory mediators were significantly altered in people with SMIs or T2DM compared with healthy controls (HC) and whether these biomarkers could help predict their cognition and social functioning 1 year after assessment.

Methods

We performed a prospective, 1-year follow-up cohort study with 165 participants at baseline (TB), including 30 with SZ, 42 with BD, 35 with MDD, 30 with T2DM, and 28 HC; and 125 at 1-year follow-up (TY), and determined executive domain (ED), global social functioning score (GSFS), and peripheral blood immune–inflammatory and oxidative stress biomarkers.

Results

Participants with SMIs and T2DM showed increased peripheral levels of inflammatory markers, such as interleukin-10 (p < 0.01; η2p = 0.07) and tumor necrosis factor-α (p < 0.05; η2p = 0.08); and oxidative stress biomarkers, such as reactive oxygen species (ROS) (p < 0.05; η2p = 0.07) and mitochondrial ROS (p < 0.01; η2p = 0.08). The different combinations of the exposed biomarkers anticipated 46–57.3% of the total ED and 23.8–35.7% of GSFS for the participants with SMIs.

Limitations

Participants' treatment, as usual, was continued without no specific interventions; thus, it was difficult to anticipate substantial changes related to the psychopharmacological pattern.

Conclusion

People with SMIs show significantly increased levels of peripheral immune–inflammatory biomarkers, which may contribute to the neurocognitive and social deficits observed in SMIs, T2DM, and other diseases with systemic immune–inflammatory activation of chronic development. These parameters could help identify the subset of patients who could benefit from immune–inflammatory modulator strategies to ameliorate their functional outcomes.
Toward Improved Diagnosis Accuracy and Treatment of Children, Adolescents, and Young Adults With Ependymoma: The International SIOP Ependymoma II Protocol
Authors: Leblond Pierre , Massimino Maura , English Martin , Ritzmann Timothy A. , Gandola Lorenza , Calaminus Gabriele , Thomas Sophie , Pérol David , Gautier Julien , Grundy Richard G. , Frappaz Didier
Published: June 2022

Background:

The clinical management of ependymoma in childhood and adolescence is complex and the clinicobiopathological correlates of outcome remain poorly understood. This international SIOP Ependymoma II (SIOP EPII) trial aims to improve the outcome of patients with ependymoma.

Methods

SIOP EPII includes any patient <22 years at diagnosis with ependymoma, stratified by age, tumor location, and outcome of the initial surgery. Centralized pathology and imaging is required for diagnosis confirmation. SIOP EPII included three randomized studies according to age, postoperative residue, and suitability to receive radiotherapy. Patients ineligible for interventional strata are followed-up in an observational study. The staging phase aims to determine if central neurosurgical and radiological postoperative MRI reviews increase the resection rate. Patients ≥12 months with (i) no residual disease are randomly assigned in a phase III trial to evaluate the efficacy of post-radiation 16-week chemotherapy (VEC + CDDP) on PFS (stratum I); (ii) centrally confirmed measurable inoperable residual disease are allocated to randomized frontline chemotherapy phase II study (VEC vs. VEC + high-dose methotrexate) and considered for a second-look surgery (stratum II). If second-look surgery is not feasible or tumor residuum remains, patients receive 8 Gy-boost radiotherapy after conformal radiotherapy (phase I). (iii) Patients < 12 months (18 months in the UK) or not eligible to receive radiotherapy are randomized in a phase II study to receive chemotherapy (alternated myelosuppressive and nonmyelosuppressive chemotherapy), with or without valproate (stratum III). To overcome the limitations encountered in the preliminary conclusions of the ACNS-0831 study, a SIOP EPII dedicated on-study amendment has been planned to definitively conclude the relevance of maintenance chemotherapy in stratum I. Secondary outcomes include overall survival, quality of life, neuropsychological and neuroendocrine outcomes, safety, and identification of key prognostic biomarkers (BIOMECA).

Clinical Trial Registration

ClinicalTrials.gov, identifier: NCT02265770.
A Prosperous Application of Hydrogels With Extracellular Vesicles Release for Traumatic Brain Injury
Authors: Chen Yang , Lin Jingquan , Yan Wei
Published: June 2022

Traumatic brain injury (TBI) is one of the leading causes of disability worldwide, becoming a heavy burden to the family and society. However, the complexity of the brain and the existence of blood-brain barrier (BBB) do limit most therapeutics effects through simple intravascular injection. Hence, an effective therapy promoting neurological recovery is urgently required. Although limited spontaneous recovery of function post-TBI does occur, increasing evidence indicates that exosomes derived from stem cells promote these endogenous processes. The advantages of hydrogels for transporting drugs and stem cells to target injured sites have been discussed in multitudinous studies. Therefore, the combined employment of hydrogels and exosomes for TBI is worthy of further study. Herein, we review current research associated with the application of hydrogels and exosomes for TBI. We also discuss the possibilities and advantages of exosomes and hydrogels co-therapies after TBI.
A New Paradigm in Parkinson's Disease Evaluation With Wearable Medical Devices: A Review of STAT-ONTM
Authors: Rodríguez-Martín Daniel , Cabestany Joan , Pérez-López Carlos , Pie Marti , Calvet Joan , Samà Albert , Capra Chiara , Català Andreu , Rodríguez-Molinero Alejandro
Published: June 2022

In the past decade, the use of wearable medical devices has been a great breakthrough in clinical practice, trials, and research. In the Parkinson's disease field, clinical evaluation is time limited, and healthcare professionals need to rely on retrospective data collected through patients' self-filled diaries and administered questionnaires. As this often leads to inaccurate evaluations, a more objective system for symptom monitoring in a patient's daily life is claimed. In this regard, the use of wearable medical devices is crucial. This study aims at presenting a review on STAT-ONTM, a wearable medical device Class IIa, which provides objective information on the distribution and severity of PD motor symptoms in home environments. The sensor analyzes inertial signals, with a set of validated machine learning algorithms running in real time. The device was developed for 12 years, and this review aims at gathering all the results achieved within this time frame. First, a compendium of the complete journey of STAT-ONTM since 2009 is presented, encompassing different studies and developments in funded European and Spanish national projects. Subsequently, the methodology of database construction and machine learning algorithms design and development is described. Finally, clinical validation and external studies of STAT-ONTM are presented.
Longitudinal Alterations in Gait Features in Growing Children With Duchenne Muscular Dystrophy
Authors: Vandekerckhove Ines , Van den Hauwe Marleen , De Beukelaer Nathalie , Stoop Elze , Goudriaan Marije , Delporte Margaux , Molenberghs Geert , Van Campenhout Anja , De Waele Liesbeth , Goemans Nathalie , De Groote Friedl , Desloovere Kaat
Published: June 2022

Prolonging ambulation is an important treatment goal in children with Duchenne muscular dystrophy (DMD). Three-dimensional gait analysis (3DGA) could provide sensitive parameters to study the efficacy of clinical trials aiming to preserve ambulation. However, quantitative descriptions of the natural history of gait features in DMD are first required. The overall goal was to provide a full delineation of the progressive gait pathology in children with DMD, covering the entire period of ambulation, by performing a so-called mixed cross-sectional longitudinal study. Firstly, to make our results comparable with previous literature, we aimed to cross-sectionally compare 31 predefined gait features between children with DMD and a typically developing (TD) database (1). Secondly, we aimed to explore the longitudinal changes in the 31 predefined gait features in growing boys with DMD using follow-up 3DGA sessions (2). 3DGA-sessions (n= 124) at self-selected speed were collected in 27 boys with DMD (baseline age: 4.6–15 years). They were repeatedly measured over a varying follow-up period (range: 6 months–5 years). The TD group consisted of 27 children (age: 5.4–15.6 years). Per measurement session, the spatiotemporal parameters, and the kinematic and kinetic waveforms were averaged over the selected gait cycles. From the averaged waveforms, discrete gait features (e.g., maxima and minima) were extracted. Mann-WhitneyUtests were performed to cross-sectionally analyze the differences between DMD at baseline and TD (1). Linear mixed effect models were performed to assess the changes in gait features in the same group of children with DMD from both a longitudinal (i.e., increasing time) as well as a cross-sectional perspective (i.e., increasing baseline age) (2). At baseline, the boys with DMD differed from the TD children in 17 gait features. Additionally, 21 gait features evolved longitudinally when following-up the same boys with DMD and 25 gait features presented a significant cross-sectional baseline age-effect. The current study quantitatively described the longitudinal alterations in gait features in boys with DMD, thereby providing detailed insight into how DMD gait deteriorates. Additionally, our results highlight that gait features extracted from 3DGA are promising outcome measures for future clinical trials to quantify the efficacy of novel therapeutic strategies.
Retrospective Analysis of Task-Specific Effects on Brain Activity After Stroke: A Pilot Study
Authors: Demers Marika , Varghese Rini , Winstein Carolee
Published: June 2022

Background

Evidence supports cortical reorganization in sensorimotor areas induced by constraint-induced movement therapy (CIMT). However, only a few studies examined the neural plastic changes as a function of task specificity. This retrospective analysis aims to evaluate the functional brain activation changes during a precision and a power grasp task in chronic stroke survivors who received 2-weeks of CIMT compared to a no-treatment control group.

Methods

Fourteen chronic stroke survivors, randomized to CIMT (n= 8) or non-CIMT (n= 6), underwent functional MRI (fMRI) before and after a 2-week period. Two behavioral measures, the 6-item Wolf Motor Function Test (WMFT-6) and the Motor Activity Log (MAL), and fMRI brain scans were collected before and after a 2-week period. During scan runs, participants performed two different grasp tasks (precision, power). Pre to post changes in laterality index (LI) were compared by group and task for two predetermined motor regions of interest: dorsal premotor cortex (PMd) and primary motor cortex (MI).

Results

In contrast to the control group, the CIMT group showed significant improvements in the WMFT-6. For the MAL, both groups showed a trend toward greater improvements from baseline. Two weeks of CIMT resulted in a relative increase in activity in a key region of the motor network, PMd of the lesioned hemisphere, under precision grasp task conditions compared to the non-treatment control group. No changes in LI were observed in MI for either task or group.

Conclusion

These findings provide preliminary evidence for task-specific effects of CIMT in the promotion of recovery-supportive cortical reorganization in chronic stroke survivors.
Effects of Noisy Galvanic Vestibular Stimulation on the Muscle Activity and Joint Movements in Different Standing Postures Conditions
Authors: Mitsutake Tsubasa , Taniguchi Takanori , Nakazono Hisato , Yoshizuka Hisayoshi , Sakamoto Maiko
Published: June 2022

Objective

Noisy galvanic vestibular stimulation (nGVS) is an effective method for stabilizing posture; however, little is known regarding the detailed muscle activity and joint movement in the standing posture. This study aimed to clarify the changes in the lower limb muscle activity and joint angular velocity by nGVS intervention using the simultaneous assessment method of inertial measurement units and surface electromyography (EMG).

Methods

Seventeen healthy participants were assessed for their physical responses under four conditions (standing on a firm surface with eyes-open/eyes-closed, and a foam surface with eyes-open/eyes-closed) without stimulation (baseline) and with stimulation (sham or nGVS). Noise stimuli were applied for 30 s at a level below the perceptual threshold. The body control response was evaluated using EMG activity and angular velocity of the lower limbs.

Result

Regarding the change from baseline for each parameter, there was a significant interactive effect of EMG activity in the muscle type × intervention and EMG activity and angular velocity in the condition × intervention. Post hoc analysis revealed that the angular velocity was significantly decreased in the abduction-adduction direction in the standing on a foam surface with eyes-closed condition compared to that with eyes-open in the nGVS intervention.

Conclusion

Our results suggest that nGVS altered physical responses in different standing postural conditions. The present study is exploratory and therefore the evidence should be investigated in future studies specifically target those muscle activities and joint motion parameters.
SparNet: A Convolutional Neural Network for EEG Space-Frequency Feature Learning and Depression Discrimination
Authors: Deng Xin , Fan Xufeng , Lv Xiangwei , Sun Kaiwei
Published: June 2022

Depression affects many people around the world today and is considered a global problem. Electroencephalogram (EEG) measurement is an appropriate way to understand the underlying mechanisms of major depressive disorder (MDD) to distinguish depression from normal control. With the development of deep learning methods, many researchers have adopted deep learning models to improve the classification accuracy of depression recognition. However, there are few studies on designing convolution filters for spatial and frequency domain feature learning in different brain regions. In this study, SparNet, a convolutional neural network composed of five parallel convolutional filters and the SENet, is proposed to learn EEG space-frequency domain characteristics and distinguish between depressive and normal control. The model is trained and tested by the cross-validation method of subject division. The results show that SparNet achieves a sensitivity of 95.07%, a specificity of 93.66%, and an accuracy of 94.37% in classification. Therefore, our results can conclude that the proposed SparNet model is effective in detecting depression using EEG signals. It also indicates that the combination of spatial information and frequency domain information is an effective way to identify patients with depression.
Benchmarking Neuromorphic Hardware and Its Energy Expenditure
Authors: Ostrau Christoph , Klarhorst Christian , Thies Michael , Rückert Ulrich
Published: June 2022

We propose and discuss a platform overarching benchmark suite for neuromorphic hardware. This suite covers benchmarks from low-level characterization to high-level application evaluation using benchmark specific metrics. With this rather broad approach we are able to compare various hardware systems including mixed-signal and fully digital neuromorphic architectures. Selected benchmarks are discussed and results for several target platforms are presented revealing characteristic differences between the various systems. Furthermore, a proposed energy model allows to combine benchmark performance metrics with energy efficiency. This model enables the prediction of the energy expenditure of a network on a target system without actually having access to it. To quantify the efficiency gap between neuromorphics and the biological paragon of the human brain, the energy model is used to estimate the energy required for a full brain simulation. This reveals that current neuromorphic systems are at least four orders of magnitude less efficient. It is argued, that even with a modern fabrication process, two to three orders of magnitude are remaining. Finally, for selected benchmarks the performance and efficiency of the neuromorphic solution is compared to standard approaches.
Data-Driven Platform Framework for Digital Whole-Process Expressway Construction Management
Authors: Chen Shu-Yang , Zhang Jing-Xiao , Ni Qi-Chang , Skitmore Martin , Ballesteros-Pérez Pablo , Ke Yong-Jian , Zuo Jian , Sun Hao-Jie
Published: June 2022

To increase the speed and efficiency of expressways construction, information management is being gradually introduced into the construction process. However, progress is limited due to the complexity of expressway engineering and application limitations of information technology. Design and delivery are still dominated by paper files, and the management of test and inspection data is still relatively extensive. Research to date into digital expressway construction has been piecemeal and fragmented with a lack of research related to the whole construction process and a data-centric information management system yet to be realized. In response, through literature research and semi-structured interviews, the framework of a data-driven digital whole-process highway construction management platform was determined. A whole process management platform was established according to the framework, and the functional application of the proposed platform was explained through a case. The framework is proposed from the perspective of the whole process of collaborative sharing., which provides a new way of thinking to solve the problems existing in the current field of expressway construction whole-process management. It also provides data-centric management, electronic design and delivery, a refined workflow, and an efficient management process.
Transactivation of TrkB Receptors by Oxytocin and Its G Protein-Coupled Receptor
Authors: Mitre Mariela , Saadipour Khalil , Williams Kevin , Khatri Latika , Froemke Robert C. , Chao Moses V.
Published: June 2022

Brain-derived Neurotrophic Factor (BDNF) binds to the TrkB tyrosine kinase receptor, which dictates the sensitivity of neurons to BDNF. A unique feature of TrkB is the ability to be activated by small molecules in a process called transactivation. Here we report that the brain neuropeptide oxytocin increases BDNF TrkB activity in primary cortical neurons and in the mammalian neocortex during postnatal development. Oxytocin produces its effects through a G protein-coupled receptor (GPCR), however, the receptor signaling events that account for its actions have not been fully defined. We find oxytocin rapidly transactivates TrkB receptors in bath application of acute brain slices of 2-week-old mice and in primary cortical culture by increasing TrkB receptor tyrosine phosphorylation. The effects of oxytocin signaling could be distinguished from the related vasopressin receptor. The transactivation of TrkB receptors by oxytocin enhances the clustering of gephyrin, a scaffold protein responsible to coordinate inhibitory responses. Because oxytocin displays pro-social functions in maternal care, cognition, and social attachment, it is currently a focus of therapeutic strategies in autism spectrum disorders. Interestingly, oxytocin and BDNF are both implicated in the pathophysiology of depression, schizophrenia, anxiety, and cognition. These results imply that oxytocin may rely upon crosstalk with BDNF signaling to facilitate its actions through receptor transactivation.
Tilapia Skin Peptides Ameliorate Cyclophosphamide-Induced Anxiety- and Depression-Like Behavior via Improving Oxidative Stress, Neuroinflammation, Neuron Apoptosis, and Neurogenesis in Mice
Authors: Zhao Yun-Tao , Yin Haowen , Hu Chuanyin , Zeng Jian , Zhang Shilin , Chen Shaohong , Zheng Wenjing , Li Mengjiao , Jin Leigang , Liu You , Wu Wenjin , Liu Shucheng
Published: June 2022

Anxiety- and depression-like behavior following chemotherapy treatment occurs in cancer patients with high probability and no specific therapeutics are available for treatment and prevention of this complication. Here, tilapia skin peptides (TSP), a novel enzymatically hydrolyzed bioactive peptide mixture, obtained from tilapia (Oreochromis mossambicus) scraps, were studied on cyclophosphamide (CP)-induced anxiety- and depression-like behavior in mice. Mice were received intraperitoneal injection of CP for 2 weeks, while TSP was administered for 4 weeks. After the end of the animal experiment, behavioral, biochemical, and molecular tests were carried out. The mice decreased preference for sugar water, increased immobility time in the forced swimming and tail suspension test, and decreased travel distance in the open field test in the Model group, compared with the Control group. Abnormal changes in behavioral tests were significantly improved after the TSP treatment. Additionally, abnormalities on superoxide dismutase, malondialdehyde, glutathione peroxidase were rescued by administration of 1000 mg/kg/d TSP in mice than that of the Model group. TSP has normalized the expression of Iba-1 and the levels of TNF-α and IL-1β in the hippocampus of mice, which indicated that TSP could observably ameliorate neuroinflammatory response in the hippocampus of mice. TSP ameliorated the apoptosis of hippocampal neurons of CA1 and CA3 regions in the TSP group vs. the Model group. The number of doublecortin positive cells was drastically increased by administering 1000 mg/kg/d TSP in mice vs. the Model group. Furthermore, TSP reversed the Nrf2/HO-1 signaling pathway, BDNF/TrkB/CREB signaling pathway, and reduced the Bcl-2/Bax/caspase-3 apoptosis pathway. In conclusion, TSP could restore CP-induced anxiety- and depression-like behavior via improving oxidative stress, neuroinflammation, neuron apoptosis, and neurogenesis in mice hippocampus.