bluuebunny/crossref_metadata_2025 huggingface dataset:
Long Noncoding RNAs as Emerging Regulators of COVID-19
Authors: Yang Qinzhi , Lin Fang , Wang Yanan , Zeng Min , Luo Mao
Published: August 2021

Coronavirus disease 2019 (COVID-19), which has high incidence rates with rapid rate of transmission, is a pandemic that spread across the world, resulting in more than 3,000,000 deaths globally. Currently, several drugs have been used for the clinical treatment of COVID-19, such as antivirals (radecivir, baritinib), monoclonal antibodies (tocilizumab), and glucocorticoids (dexamethasone). Accumulating evidence indicates that long noncoding RNAs (lncRNAs) are essential regulators of virus infections and antiviral immune responses including biological processes that are involved in the regulation of COVID-19 and subsequent disease states. Upon viral infections, cellular lncRNAs directly regulate viral genes and influence viral replication and pathology through virus-mediated changes in the host transcriptome. Additionally, several host lncRNAs could help the occurrence of viral immune escape by inhibiting type I interferons (IFN-1), while others could up-regulate IFN-1 production to play an antiviral role. Consequently, understanding the expression and function of lncRNAs during severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection will provide insights into the development of lncRNA-based methods. In this review, we summarized the current findings of lncRNAs in the regulation of the strong inflammatory response, immune dysfunction and thrombosis induced by SARS-CoV-2 infection, discussed the underlying mechanisms, and highlighted the therapeutic challenges of COVID-19 treatment and its future research directions.
Genetic Diversity and Population Structure of the Antarctic Toothfish, Dissostichus mawsoni, Using Mitochondrial and Microsatellite DNA Markers
Authors: Choi Hee-kyu , Jang Ji Eun , Byeon Seo Yeon , Kim Yu Rim , Maschette Dale , Chung Sangdeok , Choi Seok-Gwan , Kim Hyun-Woo , Lee Hyuk Je
Published: August 2021

The Antarctic toothfish, Dissostichus mawsoni, serves as a valuable fishery resource around the Antarctic Continent since 1997, managed by the Commission for the Conservation of Antarctic Marine Living Resources (CCAMLR). Although delineating genetic or stock structure of populations is crucial for improving fishery management of this species, its number of genetic populations and genetic diversity levels remain ambiguous. In the present study, we assessed the population genetic and phylogeographic structure of the Antarctic toothfish across 20 geographic localities spanning from Subareas 88 (88.1, 88.2, and 88.3) to Subareas 58 (58.4 and 58.5) by using mitochondrial DNA (mtDNA) cytochrome oxidase I (COI) and 16S rRNA (16S) sequences and seven nuclear microsatellite loci. MtDNA revealed a low level of polymorphism (h = 0.571, π = 0.0006) with 40 haplotypes in 392 individuals, connected only by 1–5 mutational steps, which is indicative of shallow evolutionary history. Microsatellites showed a range of allelic richness (AR) from 6.328 (88.3 RB3) to 7.274 (88.3 RB6) within populations. Overall genetic diversity was generally higher in Subareas 58 than in Subareas 88, suggesting that effective population size (NE) is larger in Subareas 58. The results of population analyses using microsatellites suggest that the sampled populations are likely to comprise a well-admixed single gene pool (i.e., one genetic stock), perhaps due to high contemporary gene flow occurring during the prolonged larval phase of this fish. However, given weak, but significant microsatellite differentiation found in six population-pairs, the possibility of existence of multiple genetic populations could not be completely excluded. The mtDNA AMOVA suggests a genetic break between the Subareas 88 and 58 groups (FCT = 0.011, P = 0.004). Moreover, mtDNA genetic distances (FST) between populations were proportionally greater as geographic distances increase. The patterns of isolation by distance (IBD) shown only in mtDNA, but not in microsatellites might suggest that population differentiation or divergence processes underwent faster in mtDNA than microsatellites, due to its NE being only one-quarter of nuclear DNA. Temporal stability in the genetic structure of D. mawsoni is also indicated by the results of no genetic differentiation between juveniles and adults. The findings of this study will help to design effective stock management strategies for this valuable fishery resource. We suggest that a long-term genetic monitoring is needed to understand the population structure and dynamics of toothfish in response to ongoing climate changes.
Short- and Long-Term Effectiveness of Coral Disease Treatments
Authors: Neely Karen L. , Shea Colin P. , Macaulay Kevin A. , Hower Emily K. , Dobler Michelle A.
Published: August 2021

Since 2014, stony coral tissue loss disease (SCTLD) has led to large-scale mortality of over 20 coral species throughout the Florida Reef Tract. In 2019, in-water disease intervention strategies were implemented to treat affected corals. Two treatment strategies were employed: (1) topical application of an amoxicillin paste directly to disease margins, and (2) application of a chlorinated epoxy to disease margins as well as an adjacent “disease break” trench. Effectiveness of treatments on 2,379 lesions from 725 corals representing five species was evaluated using mixed effects logistic regression models which demonstrated substantially greater effectiveness of amoxicillin compared to chlorine-treated lesions across all species up to 3 months post-treatment. As a result of the failed chlorinated epoxy treatments, any new lesions that appeared during subsequent monitoring events were treated with amoxicillin paste, and all corals were monitored and treated as needed approximately every 2 months for up to 24 months. The health status of 1664 amoxicillin-treated corals during each monitoring event was used to model the probability of a coral being uninfected over time. Models included species and geographic regions as variables. The appearance of new lesions (reinfection rates) varied by species, and offshore sites showed greater reinfection rates than inshore sites; however, all sites and species exhibited a decreased probability of reinfection with time since initial treatment. We conclude that topical amoxicillin treatments are highly effective at halting SCTLD lesions and that through initial and follow-up treatments as needed, colonies and reef sites will progress toward a lower prevalence of SCTLD.
Reproduction Under Stress: Acute Effect of Low Salinities and Heat Waves on Reproductive Cycle of Four Ecologically and Commercially Important Bivalves
Authors: Vázquez Elsa , Woodin Sarah A. , Wethey David S. , Peteiro Laura G. , Olabarria Celia
Published: August 2021

The impacts of climate change on the structure and functioning of estuaries is a major focus of concern, even more when the affected species support important fisheries as the bivalves Ruditapes decussatus, Ruditapes philippinarum, Venerupis corrugata, and Cerastoderma edule in Europe. Their reproductive performance, in the context of climate stressors, had not been investigated so far. Our objective was to experimentally evaluate acute stress effects over gonad development after 6 days of low salinity stress in autumn, winter and spring as well as 4 days of heatwave stress during emersion in summer. These are the most probable extreme events that bivalves should face in our latitudes. Four different salinity ramps (5–20, 10–25, 15–30, 30–30) were created during simulated tidal cycles in mesocosms for the low salinity experiments. Also four sediment heatwaves at emersion (20–20, 20–27, 20–32, 20–37°C) were done during simulated tidal cycle. Both low salinity and heatwave stresses over such short periods compromised reproduction; the acute response was species-specific and varied with the time of the year, and therefore, with the stage of the gametogenic cycle. In December, during sexual resting and the beginning of gametogenesis, a delay in gametogenesis at lower salinities was recorded in the four species. However, at the peak of the reproductive period (March and May), different responses were observed: abnormal oocytes in R. decussatus and resorption of gametes with haemocytic infiltration in R. philippinarum and V. corrugata. Likewise sediment temperatures higher than 32°C provoked gonadal resorption and severe haemocytic invasion in V. corrugata, R. decussatus, and C. edule but had no effect in R. philippinarum. These responses to both environmental stressors might be related to the allocation of energy from reproduction toward defense and repair mechanisms to ensure survival. Contrastingly, low salinities triggered massive spawning in C. edule that could lead to a mismatch between the presence of larvae and phytoplankton, causing potentially starvation and thus reducing recruitment success. Reproduction of theses bivalves would be compromised if low salinity episodes in winter and spring, even for short periods of time such as those in these experiments, are followed by a heatwave in summer. Furthermore the impact would be magnified if this situation happens during consecutive years preventing replenishment of the shellfish beds.
Experimental Study and Mechanism Analysis of Concrete-Filled Square Steel Tubular Columns Reinforced by Rhombic Stirrups Under Axial Compression
Authors: Chen Zongping , Ning Fan , Mo Linlin
Published: August 2021

The square steel tube component has a beautiful appearance, simple joint connection, and it is widely available. However, the uneven distribution of effective constraints in the cross-section of a square steel tube hinders its application. A novel concrete-filled square steel tubular column was tested under axial compression. There were 11 specimens [10 concrete-filled square steel tube columns reinforced with rhombic stirrups with 90-degree internal angle (SSSC specimens) and 1 concrete-filled square steel tube column (SC specimen)]. The load-displacement curves, the law of failure process, failure mode, mechanism analysis, energy consumption, ductility, and stiffness degradation were described, we then investigated the influence of stirrup diameter, stirrup side length, stirrup spacing, steel tube thickness, aspect ratio, and steel ratio on the mechanical properties of the specimens. The results show that the failure process of the SSSC specimens was basically the same. The ultimate failure mode of the specimens with an aspect ratio of 4 was local buckling failure. The specimens with an aspect ratio of 5 and 6 failed due to bending failure in the plastic stage. The steel tube bulged out in different degrees in most of the debonding areas. The longitudinal bars also produced outward bending deformation in the larger bulging area of the steel tube. Some of the stirrups were broken in the later stage of loading. The characteristics of load-displacement curve changed with the changing of stirrup spacing. The strength of longitudinal constraint had an obvious influence on the bearing capacity. In a certain range of steel ratio (ρs = 8.97% ∼ 9.05%), the weakening of the lateral restraint of the stirrup cage had a greater adverse effect on the bearing capacity than the weakening of the effective restraint of the corner. In a certain range of steel ratio (ρs = 8.97% ∼ 9.49%), strengthening the effective corner constraint of stirrups improved the stiffness of the specimen, however, the ductility performance was reduced. The opposite was true for strengthening the lateral constraint of the stirrup cage.
Angiocrine Regulation of Epithelial Barrier Integrity in Inflammatory Bowel Disease
Authors: Stürzl Michael , Kunz Meik , Krug Susanne M. , Naschberger Elisabeth
Published: August 2021

Inflammatory bowel disease describes chronic inflammatory disorders. The incidence of the disease is rising. A major step in disease development is the breakdown of the epithelial cell barrier. Numerous blood vessels are directly located underneath this barrier. Diseased tissues are heavily vascularized and blood vessels significantly contribute to disease progression. The gut-vascular barrier (GVB) is an additional barrier controlling the entry of substances into the portal circulation and to the liver after passing the first epithelial barrier. The presence of the GVB rises the question, whether the vascular and endothelial barriers may communicate bi-directionally in the regulation of selective barrier permeability. Communication from epithelial to endothelial cells is well-accepted. In contrast, little is known on the respective backwards communication. Only recently, perfusion-independent angiocrine functions of endothelial cells were recognized in a way that endothelial cells release specific soluble factors that may directly act on the epithelial barrier. This review discusses the putative involvement of angiocrine inter-barrier communication in the pathogenesis of IBD.
New Isotopes for the Treatment of Pancreatic Cancer in Collaboration With CERN: A Mini Review
Authors: Burkhardt Claudia , Bühler Léo , Viertl David , Stora Thierry
Published: August 2021

The use of radioactivity in medicine has been developed over a century. The discovery of radioisotopes and their interactions with living cells and tissue has led to the emergence of new diagnostic and therapeutic modalities. The CERN-MEDICIS infrastructure, recently inaugurated at the European Center for Nuclear Research (CERN), provides a wide range of radioisotopes of interest for diagnosis and treatment in oncology. Our objective is to draw attention to the progress made in nuclear medicine in collaboration with CERN and potential future applications, in particular for the treatment of aggressive tumors such as pancreatic adenocarcinoma, through an extensive review of literature. Fifty seven out of two hundred and ten articles, published between 1997 and 2020, were selected based on relevancy. Meetings were held with a multi-disciplinary team, including specialists in physics, biological engineering, chemistry, oncology and surgery, all actively involved in the CERN-MEDICIS project. In summary, new diagnostic, and therapeutic modalities are emerging for the treatment of pancreatic adenocarcinoma. Targeted radiotherapy or brachytherapy could be combined with existing therapies to improve the quality of life and survival of these patients. Many studies are still in the pre-clinical stage but open new paths for patients with poor prognosis.
DiTing: A Pipeline to Infer and Compare Biogeochemical Pathways From Metagenomic and Metatranscriptomic Data
Authors: Xue Chun-Xu , Lin Heyu , Zhu Xiao-Yu , Liu Jiwen , Zhang Yunhui , Rowley Gary , Todd Jonathan D. , Li Meng , Zhang Xiao-Hua
Published: August 2021

Metagenomics and metatranscriptomics are powerful methods to uncover key micro-organisms and processes driving biogeochemical cycling in natural ecosystems. Databases dedicated to depicting biogeochemical pathways (for example, metabolism of dimethylsulfoniopropionate (DMSP), which is an abundant organosulfur compound) from metagenomic/metatranscriptomic data are rarely seen. Additionally, a recognized normalization model to estimate the relative abundance and environmental importance of pathways from metagenomic and metatranscriptomic data has not been organized to date. These limitations impact the ability to accurately relate key microbial-driven biogeochemical processes to differences in environmental conditions. Thus, an easy-to-use, specialized tool that infers and visually compares the potential for biogeochemical processes, including DMSP cycling, is urgently required. To solve these issues, we developed DiTing, a tool wrapper to infer and compare biogeochemical pathways among a set of given metagenomic or metatranscriptomic reads in one step, based on the Kyoto Encyclopedia of Genes and Genomes (KEGG) and a manually created DMSP cycling gene database. Accurate and specific formulae for over 100 pathways were developed to calculate their relative abundance. Output reports detail the relative abundance of biogeochemical pathways in both text and graphical format. DiTing was applied to simulated metagenomic data and resulted in consistent genetic features of simulated benchmark genomic data. Subsequently, when applied to natural metagenomic and metatranscriptomic data from hydrothermal vents and the Tara Ocean project, the functional profiles predicted by DiTing were correlated with environmental condition changes. DiTing can now be confidently applied to wider metagenomic and metatranscriptomic datasets, and it is available at https://github.com/xuechunxu/DiTing.
Arthropod-Microbiota Integration: Its Importance for Ecosystem Conservation
Authors: Schapheer Constanza , Pellens Roseli , Scherson Rosa
Published: August 2021

Recent reports indicate that the health of our planet is getting worse and that genuine transformative changes are pressing. So far, efforts to ameliorate Earth’s ecosystem crises have been insufficient, as these often depart from current knowledge of the underlying ecological processes. Nowadays, biodiversity loss and the alterations in biogeochemical cycles are reaching thresholds that put the survival of our species at risk. Biological interactions are fundamental for achieving biological conservation and restoration of ecological processes, especially those that contribute to nutrient cycles. Microorganism are recognized as key players in ecological interactions and nutrient cycling, both free-living and in symbiotic associations with multicellular organisms. This latter assemblage work as a functional ecological unit called “holobiont.” Here, we review the emergent ecosystem properties derived from holobionts, with special emphasis on detritivorous terrestrial arthropods and their symbiotic microorganisms. We revisit their relevance in the cycling of recalcitrant organic compounds (e.g., lignin and cellulose). Finally, based on the interconnection between biodiversity and nutrient cycling, we propose that a multicellular organism and its associates constitute an Ecosystem Holobiont (EH). This EH is the functional unit characterized by carrying out key ecosystem processes. We emphasize that in order to meet the challenge to restore the health of our planet it is critical to reduce anthropic pressures that may threaten not only individual entities (known as “bionts”) but also the stability of the associations that give rise to EH and their ecological functions.
Biological Characterization and Evolution of Bacteriophage T7-△holin During the Serial Passage Process
Authors: Xu Hai , Bao Xi , Hong Weiming , Wang Anping , Wang Kaimin , Dong Hongyan , Hou Jibo , Govinden Roshini , Deng Bihua , Chenia Hafizah Y.
Published: August 2021

Bacteriophage T7 gene 17.5 coding for the only known holin is one of the components of its lysis system, but the holin activity in T7 is more complex than a single gene, and evidence points to the existence of additional T7 genes with holin activity. In this study, a T7 phage with a gene 17.5 deletion (T7-△holin) was rescued and its biological characteristics and effect on cell lysis were determined. Furthermore, the genomic evolution of mutant phage T7-△holin during serial passage was assessed by whole-genome sequencing analysis. It was observed that deletion of gene 17.5 from phage T7 delays lysis time and enlarges the phage burst size; however, this biological characteristic recovered to normal lysis levels during serial passage. Scanning electron microscopy showed that the two opposite ends of E. coli BL21 cells swell post-T7-△holin infection rather than drilling holes on cell membrane when compared with T7 wild-type infection. No visible progeny phage particle accumulation was observed inside the E. coli BL21 cells by transmission electron microscopy. Following serial passage of T7-△holin from the 1st to 20th generations, the mRNA levels of gene 3.5 and gene 19.5 were upregulated and several mutation sites were discovered, especially two missense mutations in gene 19.5, which indicate a potential contribution to the evolution of the T7-△holin. Although the burst size of T7-△holin increased, high titer cultivation of T7-△holin was not achieved by optimizing the culture process. Accordingly, these results suggest that gene 19.5 is a potential lysis-related component that needs to be studied further and that the T7-△holin strain with its gene 17.5 deletion is not adequate to establish the high-titer phage cultivation process.
Comparative Analysis of Structural and Dynamical Features of Ribosome Upon Association With mRNA Reveals Potential Role of Ribosomal Proteins
Authors: Bheemireddy Sneha , Sandhya Sankaran , Srinivasan Narayanaswamy
Published: August 2021

Ribosomes play a critical role in maintaining cellular proteostasis. The binding of messenger RNA (mRNA) to the ribosome regulates kinetics of protein synthesis. To generate an understanding of the structural, mechanistic, and dynamical features of mRNA recognition in the ribosome, we have analysed mRNA-protein interactions through a structural comparison of the ribosomal complex in the presence and absence of mRNA. To do so, we compared the 3-Dimensional (3D) structures of components of the two assembly structures and analysed their structural differences because of mRNA binding, using elastic network models and structural network-based analysis. We observe that the head region of 30S ribosomal subunit undergoes structural displacement and subunit rearrangement to accommodate incoming mRNA. We find that these changes are observed in proteins that lie far from the mRNA-protein interface, implying allostery. Further, through perturbation response scanning, we show that the proteins S13, S19, and S20 act as universal sensors that are sensitive to changes in the inter protein network, upon binding of 30S complex with mRNA and other initiation factors. Our study highlights the significance of mRNA binding in the ribosome complex and identifies putative allosteric sites corresponding to alterations in structure and/or dynamics, in regions away from mRNA binding sites in the complex. Overall, our work provides fresh insights into mRNA association with the ribosome, highlighting changes in the interactions and dynamics of the ribosome assembly because of the binding.
Age-Associated Neurological Complications of COVID-19: A Systematic Review and Meta-Analysis
Authors: Sullivan Brianne N. , Fischer Tracy
Published: August 2021

The outbreak of the novel and highly infectious severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has resulted in hundreds of millions of infections and millions of deaths globally. Infected individuals that progress to coronavirus disease-19 (COVID-19) experience upper and lower respiratory complications that range in severity and may lead to wide-spread inflammation and generalized hypoxia or hypoxemia that impacts multiple organ systems, including the central and peripheral nervous systems. Since the SARS-CoV-2 outbreak, multiple reports continue to emerge that detail neurological symptoms, ranging from relatively mild (e.g., impaired taste and/or smell) to severe (e.g., stroke), suggesting SARS-CoV-2 may be neurotropic and/or contribute to nervous system injury through direct and/or indirect mechanisms. To gain insight into the types of neurological complications associated with SARS-CoV-2 infection and their possible relationship with age, sex, COVID-19 severity, and comorbidities, we performed a systematic review of case reports and series published in 2020 – April 4, 2021 of infected patients with neurological manifestations. Meta-analyses were conducted using individual patient data from reports where these data could be extracted. Here, we report neurological injury occurs across the lifespan in the context of infection, with and without known comorbidities, and with all disease severities, including asymptomatic patients. Older individuals, however, are more susceptible to developing life-threatening COVID-19 and cerebrovascular disease (CVD), such as stroke. A mild but inverse correlation with age was seen with CNS inflammatory diseases, such as encephalitis, as well as taste and/or smell disorders. When reported, increased age was also associated with comorbid cardiovascular risk factors, including hypertension, diabetes mellitus, and lipid disorders, but not with obesity. Obesity did correlate with development of critical COVID-19. Discussion into potential pathophysiological mechanisms by which neurological symptoms arise and long-term consequences of infection to the nervous system is also provided.
In vivo Direct Conversion of Astrocytes to Neurons Maybe a Potential Alternative Strategy for Neurodegenerative Diseases
Authors: Wang Youcui , Zhang Xiaoqin , Chen Fenghua , Song Ning , Xie Junxia
Published: August 2021

Partly because of extensions in lifespan, the incidence of neurodegenerative diseases is increasing, while there is no effective approach to slow or prevent neuronal degeneration. As we all know, neurons cannot self-regenerate and may not be replaced once being damaged or degenerated in human brain. Astrocytes are widely distributed in the central nervous system (CNS) and proliferate once CNS injury or neurodegeneration occur. Actually, direct reprogramming astrocytes into functional neurons has been attracting more and more attention in recent years. Human astrocytes can be successfully converted into neurons in vitro. Notably, in vivo direct reprogramming of astrocytes into functional neurons were achieved in the adult mouse and non-human primate brains. In this review, we briefly summarized in vivo direct reprogramming of astrocytes into functional neurons as regenerative strategies for CNS diseases, mainly focusing on neurodegenerative diseases such as Parkinson’s disease (PD), Alzheimer’s disease (AD), and Huntington’s disease (HD). We highlight and outline the advantages and challenges of direct neuronal reprogramming from astrocytes in vivo for future neuroregenerative medicine.
Auditory Threshold Variability in the SAMP8 Mouse Model of Age-Related Hearing Loss: Functional Loss and Phenotypic Change Precede Outer Hair Cell Loss
Authors: Peixoto Pinheiro Barbara , Adel Youssef , Knipper Marlies , Müller Marcus , Löwenheim Hubert
Published: August 2021

Age-related hearing loss (ARHL) is the most common sensory deficit in aging society, which is accompanied by increased speech discrimination difficulties in noisy environments, social isolation, and cognitive decline. The audiometric degree of ARHL is largely correlated with sensory hair cell loss in addition to age-related factors not captured by histopathological analysis of the human cochlea. Previous studies have identified the senescence-accelerated mouse prone strain 8 (SAMP8) as a model for studying ARHL and age-related modifications of the cochlear redox environment. However, the SAMP8 population exhibits a large variability in auditory function decline over age, whose underlying cause remains unknown. In this study, we analyzed auditory function of SAMP8 mice by measuring auditory brainstem response (ABR) thresholds at the age of 6 weeks (juvenile), 12 weeks (young adult), and 24 weeks (adult). Consistent with previous studies, SAMP8 mice exhibit an early progressive, age-related decline of hearing acuity. However, a spatiotemporal cytohistological analysis showed that the significant increase in threshold variability was not concurrently reflected in outer hair cell (OHC) loss observed in the lower and upper quartiles of the ABR threshold distributions over age. This functional loss was found to precede OHC loss suggesting that age-related phenotypic changes may be contributing factors not represented in cytohistological analysis. The expression of potassium channels KCNQ4 (KV7.4), which mediates the current IK,ncrucial for the maintenance of OHC membrane potential, and KCNQ1 (KV7.1), which is an essential component in potassium circulation and secretion into the endolymph generating the endocochlear potential, showed differences between these quartiles and age groups. This suggests that phenotypic changes in OHCs or the stria vascularis due to variable oxidative deficiencies in individual mice may be predictors of the observed threshold variability in SAMP8 mice and their progressive ARHL. In future studies, further phenotypic predictors affected by accumulated metabolic challenges over age need to be investigated as potentially underlying causes of ARHL preceding irreversible OHC loss in the SAMP8 mouse model.
Shifts in Gait Signatures Mark the End of Lifespan in Mice, With Sex Differences in Timing
Authors: Broom Lauren , Stephen Jessica , Nayar Varun , VanderHorst Veronique G.
Published: August 2021

Reduced walking speed is a hallmark of functional decline in aging across species. An age-related change in walking style may represent an additional key marker signifying deterioration of the nervous system. Due to the speed dependence of gait metrics combined with slowing of gait during aging, it has been challenging to determine whether changes in gait metrics represent a change in style. In this longitudinal study we employed gait signatures to separate changes in walking style and speed in mice. We compared gait signatures at mature adult age with middle aged, old and geriatric time points and included female and male sub-cohorts to examine sex differences in nature or timing signature shifts. To determine whether gait signature shifts occurred independently from a decline in other mobility domains we measured balance and locomotor activity. We found that walking speed declined early, whereas gait signatures shifted very late during the aging process. Shifts represented longer swing time and stride length than expected for speed, as in slow motion, and were preceded by a decline in other mobility domains. The pattern of shifts was similar between female and male cohorts, but with sex differences in timing. We conclude that changes in walking style, speed and other mobility domains represent separate age-related phenomena. These findings call for careful, sex specific selection of type and timing of outcome measures in mechanistic or interventional studies. The pattern of age-related gait signature shifts is distinct from patterns seen in neurodegenerative conditions and may be a translatable marker for the end of the lifespan.
Stormorken Syndrome Caused by a Novel STIM1 Mutation: A Case Report
Authors: Jiang Li-Jun , Zhao Xue , Dou Zhi-Yan , Su Qing-Xiao , Rong Zan-Hua
Published: August 2021

Objective: To identify the gene mutation of Stormorken syndrome and review the published Stromal Interaction Molecule 1 (STIM1) mutation phenotype.

Methods: We described the clinical and molecular aspects of a Chinese female with Stormorken syndrome by laboratory tests, muscle biopsies, and genetic analysis. We used this information to summarize all the mutation sites reported in the literature. We also reviewed the clinical features of published cases with a gain of function mutations of STIM1.

Results: A 12-year-old Chinese female presented with skin purpura in the lower limbs and stroke-like episodes. Muscle biopsy and microscopic examination revealed atrophy in her skeletal muscle. Genetic analysis identified a novel heterozygous missense mutation, a c.1095G>C transition (NM_003156.3), which caused a p.K365N amino acid substitution in the protein and affected a STIM1-orai1-activation region (SOAR).

Conclusions: The novel variant c.1095G>C transition (NM_003156.3) was located in the SOAR, which expands the phenotypic spectrum of STIM1 variants in human disorders and may define the molecular basis of Stormorken syndrome.
Using Base-ml to Learn Classification of Common Vestibular Disorders on DizzyReg Registry Data
Authors: Vivar Gerome , Strobl Ralf , Grill Eva , Navab Nassir , Zwergal Andreas , Ahmadi Seyed-Ahmad
Published: August 2021

Background:Multivariable analyses (MVA) and machine learning (ML) applied on large datasets may have a high potential to provide clinical decision support in neuro-otology and reveal further avenues for vestibular research. To this end, we build base-ml, a comprehensive MVA/ML software tool, and applied it to three increasingly difficult clinical objectives in differentiation of common vestibular disorders, using data from a large prospective clinical patient registry (DizzyReg).

Methods:Base-ml features a full MVA/ML pipeline for classification of multimodal patient data, comprising tools for data loading and pre-processing; a stringent scheme for nested and stratified cross-validation including hyper-parameter optimization; a set of 11 classifiers, ranging from commonly used algorithms like logistic regression and random forests, to artificial neural network models, including a graph-based deep learning model which we recently proposed; a multi-faceted evaluation of classification metrics; tools from the domain of “Explainable AI” that illustrate the input distribution and a statistical analysis of the most important features identified by multiple classifiers.

Results:In the first clinical task, classification of the bilateral vestibular failure (N= 66) vs. functional dizziness (N= 346) was possible with a classification accuracy ranging up to 92.5% (Random Forest). In the second task, primary functional dizziness (N= 151) vs. secondary functional dizziness (following an organic vestibular syndrome) (N= 204), was classifiable with an accuracy ranging from 56.5 to 64.2% (k-nearest neighbors/logistic regression). The third task compared four episodic disorders, benign paroxysmal positional vertigo (N= 134), vestibular paroxysmia (N= 49), Menière disease (N= 142) and vestibular migraine (N= 215). Classification accuracy ranged between 25.9 and 50.4% (Naïve Bayes/Support Vector Machine). Recent (graph-) deep learning models classified well in all three tasks, but not significantly better than more traditional ML methods. Classifiers reliably identified clinically relevant features as most important toward classification.

Conclusion:The three clinical tasks yielded classification results that correlate with the clinical intuition regarding the difficulty of diagnosis. It is favorable to apply an array of MVA/ML algorithms rather than a single one, to avoid under-estimation of classification accuracy. Base-ml provides a systematic benchmarking of classifiers, with a standardized output of MVA/ML performance on clinical tasks. To alleviate re-implementation efforts, we provide base-ml as an open-source tool for the community.
Computational Study of Hemodynamic Changes Induced by Overlapping and Compacting of Stents and Flow Diverter in Cerebral Aneurysms
Authors: Kim Sunghan , Yang Hyeondong , Hong Ineui , Oh Je Hoon , Kim Yong Bae
Published: August 2021

Purpose: The flow diversion effect of an intracranial stent is closely related to its metal coverage rate (MCR). In this study, the flow diversion effects of Enterprise and low-profile visualized intraluminal support (LVIS) stents are compared with those of a Pipeline flow diverter, focusing on the MCR change. Moreover, the changes in the flow diversion effect caused by the additional manipulations of overlapping and compaction are verified using computational fluid dynamics (CFD) analysis.

Methods: CFD analysis was performed using virtually generated stents mounted in an idealized aneurysm model. First, the flow diversion effects of single Enterprise, LVIS, and Pipeline devices were analyzed. The Enterprise and LVIS were sequentially overlapped and compared with a Pipeline, to evaluate the effect of stent overlapping. The effect of compacting a stent was evaluated by comparing the flow diversion effects of a single and two compacted LVIS with those of two overlapped, uncompacted LVIS and uncompacted and compacted Pipeline. Quantitative analysis was performed to evaluate the hemodynamic parameters of energy loss, average velocity, and inflow rate.

Results: Statistically significant correlations were observed between the reduction rates of the hemodynamic parameters and MCR. The single LVIS without compaction induced a reduction in all the hemodynamic parameters comparable to those of the three overlapped Enterprise. Moreover, the two overlapped, uncompacted LVIS showed a flow diversion effect as large as that induced by the single uncompacted Pipeline. Compacted stents induced a better flow diversion effect than uncompacted stents. The single compacted LVIS induced a flow diversion effect similar to that induced by the two uncompacted LVIS or single uncompacted Pipeline.

Conclusions: The MCR of a stent correlates with its flow diversion effect. Overlapping and compaction can increase the MCR of an intracranial stent and achieve a flow diversion effect as large as that observed with a flow diverter.
Altered Brain Functional Network Topology in Lung Cancer Patients After Chemotherapy
Authors: You Jia , Zhang Juan , Shang Song'an , Gu Wei , Hu Lanyue , Zhang Yujie , Xiong Zhenyu , Chen Yu-Chen , Yin Xindao
Published: August 2021

Purpose: This study aimed to explore the topological features of brain functional network in lung cancer patients before and after chemotherapy using graph theory.

Methods: Resting-state functional magnetic resonance imaging scans were obtained from 44 post-chemotherapy and 46 non-chemotherapy patients as well as 49 healthy controls (HCs). All groups were age- and gender-matched. Then, the topological features of brain functional network were assessed using graph theory analysis.

Results: At the global level, compared with the HCs, both the non-chemotherapy group and the post-chemotherapy group showed significantly increased values in sigma (p < 0.05), gamma (p < 0.05), and local efficiency, Eloc (p < 0.05). The post-chemotherapy group and the non-chemotherapy group did not differ significantly in the above-mentioned parameters. At the nodal level, when non-chemotherapy or post-chemotherapy patients were compared with the HCs, abnormal nodal centralities were mainly observed in widespread brain regions. However, when the post-chemotherapy group was compared with the non-chemotherapy group, significantly decreased nodal centralities were observed primarily in the prefrontal–subcortical regions.

Conclusions: These results indicate that lung cancer and chemotherapy can disrupt the topological features of functional networks, and chemotherapy may cause a pattern of prefrontal–subcortical brain network abnormality. As far as we know, this is the first study to report that altered functional brain networks are related to lung cancer and chemotherapy.
A Review of Studies Leveraging Multimodal TMS-fMRI Applications in the Pathophysiology and Treatment of Schizophrenia
Authors: Baliga Sachin Pradeep , Mehta Urvakhsh Meherwan
Published: August 2021

The current review provides an overview of the existing literature on multimodal transcranial magnetic stimulation, and functional magnetic resonance imaging (TMS/fMRI) studies in individuals with schizophrenia and discusses potential future avenues related to the same. Multimodal studies investigating pathophysiology have explored the role of abnormal thalamic reactivity and have provided further evidence supporting the hypothesis of schizophrenia as a disorder of aberrant connectivity and cortical plasticity. Among studies examining treatment, low-frequency rTMS for the management of persistent auditory verbal hallucinations (AVH) was the most studied. While multimodal TMS/fMRI studies have provided evidence of involvement of local speech-related and distal networks on stimulation of the left temporoparietal cortex, current evidence does not suggest the superiority of fMRI based neuronavigation over conventional methods or of active rTMS over sham for treatment of AVH. Apart from these, preliminary findings suggest a role of rTMS in treating deficits in neurocognition, social cognition, and self-agency. However, most of these studies have only examined medication-resistant symptoms and have methodological concerns arising from small sample sizes and short treatment protocols. That being said, combining TMS with fMRI appears to be a promising approach toward elucidating the pathophysiology of schizophrenia and could also open up a possibility toward developing personalized treatment for its persistent and debilitating symptoms.
Variation in Neonatal Nutrition Practice and Implications: A Survey of Australia and New Zealand Neonatal Units
Authors: McLeod Gemma , Farrent Shelley , Gilroy Melissa , Page Denise , Oliver Colleen J. , Richmond Fiona , Cormack Barbara E.
Published: August 2021

Background:Significant global variation exists in neonatal nutrition practice, including in assigned milk composition values, donor milk usage, fortification regimens, probiotic choice and in methods used to calculate and report nutrition and growth outcomes, making it difficult to synthesize data to inform evidence-based, standardized nutritional care that has potential to improve neonatal outcomes. The Australasian Neonatal Dietitians' Network (ANDiN) conducted a survey to determine the degree to which neonatal nutritional care varies across Australia and New Zealand (A&NZ) and to highlight potential implications.

Materials and Methods:A two-part electronic neonatal nutritional survey was emailed to each ANDiN member (n= 50). Part-One was designed to examine individual dietetic practice; Part-Two examined site-specific nutrition policies and practices. Descriptive statistics were used to examine the distribution of responses.

Results:Survey response rate: 88%. Across 24 NICU sites, maximum fluid targets varied (150–180 mL.kg.d−1); macronutrient composition estimates for mothers' own(MOM) and donor (DM) milk varied (Energy (kcal.dL−1) MOM: 65–72; DM 69–72: Protein (g.dL−1): MOM: 1.0–1.5; DM: 0.8–1.3); pasteurized DM or unpasteurized peer-to-peer DM was not available in all units; milk fortification commenced at different rates and volumes; a range of energy values (kcal.g−1) for protein (3.8–4.0), fat (9.0–10.0), and carbohydrate (3.8–4.0) were used to calculate parenteral and enteral intakes; probiotic choice differed; and at least seven different preterm growth charts were employed to monitor growth.

Discussion:Our survey identifies variation in preterm nutrition practice across A&NZ of sufficient magnitude to impact nutrition interventions and neonatal outcomes. This presents an opportunity to use the unique skillset of neonatal dietitians to standardize practice, reduce uncertainty of neonatal care and improve the quality of neonatal research.
MAPK10 Expression as a Prognostic Marker of the Immunosuppressive Tumor Microenvironment in Human Hepatocellular Carcinoma
Authors: Li Huahui , Li Yuting , Zhang Ying , Tan Binbin , Huang Tuxiong , Xiong Jixian , Tan Xiangyu , Ermolaeva Maria A. , Fu Li
Published: August 2021

Hepatocellular carcinoma (HCC) remains a devastating malignancy worldwide due to lack of effective therapy. The immune-rich contexture of HCC tumor microenvironment (TME) makes this tumor an appealing target for immune-based therapies; however, the immunosuppressive TME is still a major challenge for more efficient immunotherapy in HCC. Using bioinformatics analysis based on the TCGA database, here we found that MAPK10 is frequently down-regulated in HCC tumors and significantly correlates with poor survival of HCC patients. HCC patients with low MAPK10 expression have lower expression scores of tumor infiltration lymphocytes (TILs) and stromal cells in the TME and increased scores of tumor cells than those with high MAPK10 expression. Further transcriptomic analyses revealed that the immune activity in the TME of HCC was markedly reduced in the low-MAPK10 group of HCC patients compared to the high-MAPK10 group. Additionally, we identified 495 differentially expressed immune-associated genes (DIGs), with 482 genes down-regulated and 13 genes up-regulated in parallel with the decrease of MAPK10 expression. GO enrichment and KEGG pathway analyses indicated that the biological functions of these DIGs included cell chemotaxis, leukocyte migration and positive regulation of the response to cytokine–cytokine receptor interaction, T cell receptor activation and MAPK signaling pathway. Protein–protein interaction (PPI) analyses of the 495 DIGs revealed five potential downstream hub genes of MAPK10, including SYK, CBL, VAV1, LCK, and CD3G. Several hub genes such as SYK, LCK, and VAV1 could respond to the immunological costimulatory signaling mediated by the transmembrane protein ICAM1, which was identified as a down-regulated DIG associated with low-MAPK10 expression. Moreover, ectopic overexpression or knock-down of MAPK10 could up-regulate or down-regulate ICAM1 expression via phosphorylation of c-jun at Ser63 in HCC cell lines, respectively. Collectively, our results demonstrated that MAPK10 down-regulation likely contributes to the immunosuppressive TME of HCC, and this gene might serve as a potential immunotherapeutic target and a prognostic factor for HCC patients.
The EIF4A3/CASC2/RORA Feedback Loop Regulates the Aggressive Phenotype in Glioblastomas
Authors: Zhao Junshuang , Jiang Yang , Chen Lian , Ma Yue , Zhang Haiying , Zhou Jinpeng , Li Hao , Jing Zhitao
Published: August 2021

Glioblastoma (GBM) is a common and refractory subtype of high-grade glioma with a poor prognosis. The epithelial-mesenchymal transition (EMT) is an important cause of enhanced glioblastoma invasiveness and tumor recurrence. Our previous study found that retinoic acid receptor-related orphan receptor A (RORA) is a nuclear receptor and plays an important role in inhibiting proliferation and tumorigenesis of glioma. We further confirmed RORA was downregulated in GBM. Thus, we determined whether RORA was involved in the migration, invasion, and EMT of GBM. Human GBM cell lines, U87 and T98G, and patient-derived glioma stem cells (GSCs), GSC2C and GSC4D, were used for in vitro and in vivo experiments. The expressions of RORA, CASC2, and EIF4A3 in GBM cells and GSCs were detected by RT-qPCR and western blotting. The biological effects of RORA, CASC2, and EIF4A3 on GBM migration, invasion, and EMT were evaluated using the migration assay, transwell assay, immunofluorescence staining, and xenograft experiments. We found that RORA inhibited the migration, invasion, and EMT of GBM. CASC2 could bind to, maintain the stability, and promote the nuclear translocation of RORA protein. EIF4A3 could downregulate CASC2 expression via inducing its cleavage, while RORA transcriptionally inhibited EIF4A3 expression, which formed a feedback loop among EIF4A3/CASC2/RORA. Moreover, gene set enrichment analysis (GSEA) and in vitro and in vivo experiments showed RORA inhibited the aggressiveness of GBM by negatively regulating the TGF-β1/Smad signaling pathway. Therefore, The EIF4A3/CASC2/RORA feedback loop regulated TGF-β1/Smad signaling pathway might become a promising therapeutic strategy for GBM treatment.
Anticarin β Inhibits Human Glioma Progression by Suppressing Cancer Stemness via STAT3
Authors: Zhang Min , Dai Zhi , Zhao Xudong , Wang Gan , Lai Ren
Published: August 2021

Glioma is the most common form of malignant brain cancer. It is very difficult to cure malignant glioma because of the presence of glioma stem cells, which are a barrier to cure, have high tumorigenesis, associated with drug resistance, and responsible for relapse by regulating stemness genes. In this study, our results demonstrated that anticarin β, a natural compound from Antiaris toxicaria, can effectively and selectively suppress proliferation and cause apoptosis in glioma cells, which has an IC50 that is 100 times lower than that in mouse normal neural stem cells. Importantly, cell sphere formation assay and real time-quantitative analysis reveal that anticarin β inhibits cancer stemness by modulating related stemness gene expression. Additionally, anticarin β induces DNA damage to regulate the oncogene expression of signal transducer and activator of transcription 3 (STAT3), Akt, mitogen-activated protein kinases (MAPKs), and eventually leading to apoptosis. Furthermore, anticarin β effectively inhibits glioma growth and prolongs the lifts pan of tumor-bearing mice without systemic toxicity in the orthotopic xenograft mice model. These results suggest that anticarin β is a promising candidate inhibitor for malignant glioma.