bluuebunny/crossref_metadata_2025 huggingface dataset:
Akt Phosphorylation of Hepatitis C Virus NS5B Regulates Polymerase Activity and Hepatitis C Virus Infection
Authors: Sabariegos Rosario , Albentosa-González Laura , Palmero Blanca , Clemente-Casares Pilar , Ramírez Eugenio , García-Crespo Carlos , Gallego Isabel , de Ávila Ana Isabel , Perales Celia , Domingo Esteban , Mas Antonio
Published: October 2021

Hepatitis C virus (HCV) is a single-stranded RNA virus of positive polarity [ssRNA(+)] that replicates its genome through the activity of one of its proteins, called NS5B. This viral protein is responsible for copying the positive-polarity RNA genome into a negative-polarity RNA strand, which will be the template for new positive-polarity RNA genomes. The NS5B protein is phosphorylated by cellular kinases, including Akt. In this work, we have identified several amino acids of NS5B that are phosphorylated by Akt, with positions S27, T53, T267, and S282 giving the most robust results. Site-directed mutagenesis of these residues to mimic (Glu mutants) or prevent (Ala mutants) their phosphorylation resulted in a reduced NS5B in vitro RNA polymerase activity, except for the T267E mutant, the only non-conserved position of all those that are phosphorylated. In addition, in vitro transcribed RNAs derived from HCV complete infectious clones carrying mutations T53E/A and S282E/A were transfected in Huh-7.5 permissive cells, and supernatant viral titers were measured at 6 and 15 days post-transfection. No virus was rescued from the mutants except for T53A at 15 days post-transfection whose viral titer was statistically lower as compared to the wild type. Therefore, phosphorylation of NS5B by cellular kinases is a mechanism of viral polymerase inactivation. Whether this inactivation is a consequence of interaction with cellular kinases or a way to generate inactive NS5B that may have other functions are questions that need further experimental work.
Contamination in Reference Sequence Databases: Time for Divide-and-Rule Tactics
Authors: Lupo Valérian , Van Vlierberghe Mick , Vanderschuren Hervé , Kerff Frédéric , Baurain Denis , Cornet Luc
Published: October 2021

Contaminating sequences in public genome databases is a pervasive issue with potentially far-reaching consequences. This problem has attracted much attention in the recent literature and many different tools are now available to detect contaminants. Although these methods are based on diverse algorithms that can sometimes produce widely different estimates of the contamination level, the majority of genomic studies rely on a single method of detection, which represents a risk of systematic error. In this work, we used two orthogonal methods to assess the level of contamination among National Center for Biotechnological Information Reference Sequence Database (RefSeq) bacterial genomes. First, we applied the most popular solution, CheckM, which is based on gene markers. We then complemented this approach by a genome-wide method, termed Physeter, which now implements a k-folds algorithm to avoid inaccurate detection due to potential contamination of the reference database. We demonstrate that CheckM cannot currently be applied to all available genomes and bacterial groups. While it performed well on the majority of RefSeq genomes, it produced dubious results for 12,326 organisms. Among those, Physeter identified 239 contaminated genomes that had been missed by CheckM. In conclusion, we emphasize the importance of using multiple methods of detection while providing an upgrade of our own detection tool, Physeter, which minimizes incorrect contamination estimates in the context of unavoidably contaminated reference databases.
Allogenous Selection of Mutational Collateral Resistance: Old Drugs Select for New Resistance Within Antibiotic Families
Authors: Baquero Fernando , Martínez José L. , Novais Ângela , Rodríguez-Beltrán Jerónimo , Martínez-García Laura , Coque Teresa M. , Galán Juan Carlos
Published: October 2021

Allogeneous selection occurs when an antibiotic selects for resistance to more advanced members of the same family. The mechanisms of allogenous selection are (a) collateral expansion, when the antibiotic expands the gene and gene-containing bacterial populations favoring the emergence of other mutations, inactivating the more advanced antibiotics; (b) collateral selection, when the old antibiotic selects its own resistance but also resistance to more modern drugs; (c) collateral hyper-resistance, when resistance to the old antibiotic selects in higher degree for populations resistant to other antibiotics of the family than to itself; and (d) collateral evolution, when the simultaneous or sequential use of antibiotics of the same family selects for new mutational combinations with novel phenotypes in this family, generally with higher activity (higher inactivation of the antibiotic substrates) or broader spectrum (more antibiotics of the family are inactivated). Note that in some cases, collateral selection derives from collateral evolution. In this article, examples of allogenous selection are provided for the major families of antibiotics. Improvements in minimal inhibitory concentrations with the newest drugs do not necessarily exclude “old” antibiotics of the same family of retaining some selective power for resistance to the newest agents. If this were true, the use of older members of the same drug family would facilitate the emergence of mutational resistance to the younger drugs of the family, which is frequently based on previously established resistance traits. The extensive use of old drugs (particularly in low-income countries and in farming) might be significant for the emergence and selection of resistance to the novel members of the family, becoming a growing source of variation and selection of resistance to the whole family. In terms of future research, it could be advisable to focus antimicrobial drug discovery more on the identification of new targets and new (unique) classes of antimicrobial agents, than on the perpetual chemical exploitation of classic existing ones.
Comparative Genome Analysis of the Genus Thiothrix Involving Three Novel Species, Thiothrix subterranea sp. nov. Ku-5, Thiothrix litoralis sp. nov. AS and “Candidatus Thiothrix anitrata” sp. nov. A52, Revealed the Conservation of the Pathways of Dissimilatory Sulfur Metabolism and Variations in the Genetic Inventory for Nitrogen Metabolism and Autotrophic Carbon Fixation
Authors: Ravin Nikolai V. , Rudenko Tatyana S. , Smolyakov Dmitry D. , Beletsky Alexey V. , Rakitin Andrey L. , Markov Nikita D. , Fomenkov Alexey , Sun Luo , Roberts Richard J. , Novikov Andrey A. , Karnachuk Olga V. , Grabovich Margarita Y.
Published: October 2021

Two strains of filamentous, colorless sulfur bacteria were isolated from bacterial fouling in the outflow of hydrogen sulfide-containing waters from a coal mine (Thiothrix sp. Ku-5) and on the seashore of the White Sea (Thiothrix sp. AS). Metagenome-assembled genome (MAG) A52 was obtained from a sulfidic spring in the Volgograd region, Russia. Phylogenetic analysis based on the 16S rRNA gene sequences showed that all genomes represented the genus Thiothrix. Based on their average nucleotide identity and digital DNA-DNA hybridization data these new isolates and the MAG represent three species within the genus Thiothrix with the proposed names Thiothrix subterranea sp. nov. Ku-5T, Thiothrix litoralis sp. nov. AST, and “Candidatus Thiothrix anitrata” sp. nov. A52. The complete genome sequences of Thiothrix fructosivorans QT and Thiothrix unzii A1T were determined. Complete genomes of seven Thiothrix isolates, as well as two MAGs, were used for pangenome analysis. The Thiothrix core genome consisted of 1,355 genes, including ones for the glycolysis, the tricarboxylic acid cycle, the aerobic respiratory chain, and the Calvin cycle of carbon fixation. Genes for dissimilatory oxidation of reduced sulfur compounds, namely the branched SOX system (SoxAXBYZ), direct (soeABC) and indirect (aprAB, sat) pathways of sulfite oxidation, sulfur oxidation complex Dsr (dsrABEFHCEMKLJONR), sulfide oxidation systems SQR (sqrA, sqrF), and FCSD (fccAB) were found in the core genome. Genomes differ in the set of genes for dissimilatory reduction of nitrogen compounds, nitrogen fixation, and the presence of various types of RuBisCO.
The Weak Small RNA-Binding Activity of the 2b Proteins of Subgroup II Cucumber Mosaic Virus Strains Is Insufficient for RNA Silencing Suppression
Authors: Gao Yingying , Yang Jinrui , Zhang Xiaobei , Chen Aizhong , Gu Zhouhang , Du Zhiyou
Published: October 2021

The 2b proteins encoded by cucumber mosaic virus (CMV) subgroup I strains suppress RNA silencing primarily by competitively binding small RNAs (sRNAs) in the host cell cytoplasm. Interestingly, 2b proteins encoded by CMV subgroup II strains accumulate predominantly in nuclei. Here we determined that whereas the 2b protein (Fny2b) of subgroup IA strain Fny-CMV is highly effective in suppressing both sense RNA-induced and inverted repeat-induced posttranscriptional gene silencing, the 2b protein (LS2b) of the subgroup II strain LS-CMV was not as effective. Reducing nuclear accumulation of LS2b by mutating a residue in its nuclear localization sequence had no effect on RNA silencing suppressor activity, while attenuated viral symptoms. Electrophoretic mobility shift assays showed that the sRNA binding of LS2b was weaker and more selective than that of Fny2b. The domain determining the differential sRNA-binding ability was delimited to the putative helix α1 region. Moreover, LS2b mutants that completely lost suppressor activity still retained their weak sRNA-binding ability, suggesting that sRNA binding is not sufficient for LS2b to suppress RNA silencing. Considering the subgroup I strain-encoded 2b proteins that require sRNA-binding ability for the suppression of RNA silencing, we suggest that in addition to binding sRNA, the 2b proteins of subgroup II CMV strains would require extra biological activities to achieve RNA silencing inhibition.
Transgenic Mice Expressing Human α-Synuclein 1-103 Fragment as a Novel Model of Parkinson’s Disease
Authors: Tian Ye , He Mingyang , Pan Lina , Yuan Xin , Xiong Min , Meng Lanxia , Yao Zhaohui , Yu Zhui , Ye Keqiang , Zhang Zhentao
Published: October 2021

Parkinson’s disease (PD) is one of the most common neurodegenerative disorders. However, its cellular and molecular mechanisms still wrap in the mist. This is partially caused by the absence of appropriate animal models mimicking sporadic PD that constitutes the majority of cases. Previously, we reported that a cysteine protease, asparagine endopeptidase (AEP), is activated in an age-dependent manner, and cleaves α-synuclein in the brain of sporadic PD patients. The AEP-derived α-synuclein 1-103 fragment is required for the pathogenesis of PD. Thus, we designed and characterized a novel transgenic mouse line expressing α-synuclein 1-103 (designated N103 mice). This model shows an abundant accumulation of pathological α-synuclein in the central nervous system, loss of dopaminergic neurons in the substantia nigra, and progressive striatal synaptic degeneration. The N103 mice also manifest age-dependent PD-like behavioral impairments. Notably, the mice show weight loss and constipation, which are the common non-motor symptoms in PD. The RNA-sequencing analysis found that the transcriptomics pattern was extensively altered in N103 mice. In conclusion, the N103 mouse line, as a brand-new tool, might provide new insights into PD research.
Ordinal Prediction Model of 90-Day Modified Rankin Scale in Ischemic Stroke
Authors: Zhang Michelle Y. , Mlynash Michael , Sainani Kristin L. , Albers Gregory W. , Lansberg Maarten G.
Published: October 2021

Background and Purpose: Prediction models for functional outcomes after ischemic stroke are useful for statistical analyses in clinical trials and guiding patient expectations. While there are models predicting dichotomous functional outcomes after ischemic stroke, there are no models that predict ordinal mRS outcomes. We aimed to create a model that predicts, at the time of hospital discharge, a patient's modified Rankin Scale (mRS) score on day 90 after ischemic stroke.

Methods: We used data from three multi-center prospective studies: CRISP, DEFUSE 2, and DEFUSE 3 to derive and validate an ordinal logistic regression model that predicts the 90-day mRS score based on variables available during the stroke hospitalization. Forward selection was used to retain independent significant variables in the multivariable model.

Results: The prediction model was derived using data on 297 stroke patients from the CRISP and DEFUSE 2 studies. National Institutes of Health Stroke Scale (NIHSS) at discharge and age were retained as significant (p < 0.001) independent predictors of the 90-day mRS score. When applied to the external validation set (DEFUSE 3, n = 160), the model accurately predicted the 90-day mRS score within one point for 78% of the patients in the validation cohort.

Conclusions: A simple model using age and NIHSS score at time of discharge can predict 90-day mRS scores in patients with ischemic stroke. This model can be useful for prognostication in routine clinical care and to impute missing data in clinical trials.
Case Report: A False Negative Case of Anti-Yo Paraneoplastic Myelopathy
Authors: Bartley Christopher M. , Parikshak Neelroop N. , Ngo Thomas T. , Alexander Jessa A. , Zorn Kelsey C. , Alvarenga Bonny D. , Kang Min K. , Pedriali Massimo , Pleasure Samuel J. , Wilson Michael R.
Published: October 2021

The development of autoimmune antibody panels has improved the diagnosis of paraneoplastic neurological disorders (PNDs) of the brain and spinal cord. Here, we present a case of a woman with a history of breast cancer who presented with a subacute sensory ataxia that progressed over 18 months. Her examination and diagnostic studies were consistent with a myelopathy. Metabolic, infectious, and autoimmune testing were non-diagnostic. However, she responded to empirical immunosuppression, prompting further workup for an autoimmune etiology. An unbiased autoantibody screen utilizing phage display immunoprecipitation sequencing (PhIP-Seq) identified antibodies to the anti-Yo antigens cerebellar degeneration related protein 2 like (CDR2L) and CDR2, which were subsequently validated by immunoblot and cell-based overexpression assays. Furthermore, CDR2L protein expression was restricted to HER2 expressing tumor cells in the patient's breast tissue. Recent evidence suggests that CDR2L is likely the primary antigen in anti-Yo paraneoplastic cerebellar degeneration, but anti-Yo myelopathy is poorly characterized. By immunostaining, we detected neuronal CDR2L protein expression in the murine and human spinal cord. This case demonstrates the diagnostic utility of unbiased assays in patients with suspected PNDs, supports prior observations that anti-Yo PND can be associated with isolated myelopathy, and implicates CDR2L as a potential antigen in the spinal cord.
Neurodegeneration Over 3 Years Following Ischaemic Stroke: Findings From the Cognition and Neocortical Volume After Stroke Study
Authors: Brodtmann Amy , Werden Emilio , Khlif Mohamed Salah , Bird Laura J. , Egorova Natalia , Veldsman Michele , Pardoe Heath , Jackson Graeme , Bradshaw Jennifer , Darby David , Cumming Toby , Churilov Leonid , Donnan Geoffrey
Published: October 2021

Background: Stroke survivors are at high risk of dementia, associated with increasing age and vascular burden and with pre-existing cognitive impairment, older age. Brain atrophy patterns are recognised as signatures of neurodegenerative conditions, but the natural history of brain atrophy after stroke remains poorly described. We sought to determine whether stroke survivors who were cognitively normal at time of stroke had greater total brain (TBV) and hippocampal volume (HV) loss over 3 years than controls. We examined whether stroke survivors who were cognitively impaired (CI) at 3 months following their stroke had greater brain volume loss than cognitively normal (CN) stroke participants over the next 3 years.

Methods: Cognition And Neocortical Volume After Stroke (CANVAS) study is a multi-centre cohort study of first-ever or recurrent adult ischaemic stroke participants compared to age- and sex-matched community controls. Participants were followed with MRI and cognitive assessments over 3 years and were free of a history of cognitive impairment or decline at inclusion. Our primary outcome measure was TBV change between 3 months and 3 years; secondary outcomes were TBV and HV change comparing CI and CN participants. We investigated associations between group status and brain volume change using a baseline-volume adjusted linear regression model with robust standard error.

Results: Ninety-three stroke (26 women, 66.7 ± 12 years) and 39 control participants (15 women, 68.7 ± 7 years) were available at 3 years. TBV loss in stroke patients was greater than controls: stroke mean (M) = 20.3 cm3 ± SD 14.8 cm3; controls M = 14.2 cm3 ± SD 13.2 cm3; [adjusted mean difference 7.88 95%CI (2.84, 12.91) p-value = 0.002]. TBV decline was greater in those stroke participants who were cognitively impaired (M = 30.7 cm3; SD = 14.2 cm3) at 3 months (M = 19.6 cm3; SD = 13.8 cm3); [adjusted mean difference 10.42; 95%CI (3.04, 17.80), p-value = 0.006]. No statistically significant differences in HV change were observed.

Conclusions: Ischaemic stroke survivors exhibit greater neurodegeneration compared to stroke-free controls. Brain atrophy is greater in stroke participants who were cognitively impaired early after their stroke. Early cognitive impairment was associated greater subsequent atrophy, reflecting the combined impacts of stroke and vascular brain burden. Atrophy rates could serve as a useful biomarker for trials testing interventions to reduce post-stroke secondary neurodegeneration.

Clinical Trail Registration:http://www.clinicaltrials.gov, identifier: NCT02205424.
The Effect of Lower-Body Blood Flow Restriction on Static and Perturbated Stable Stand in Young, Healthy Adults
Authors: Willberg Christina , Zentgraf Karen , Behringer Michael
Published: October 2021

Muscular fatigue can affect postural control processes by impacting on the neuromuscular and somatosensory system. It is assumed that this leads to an increased risk of injury, especially in sports such as alpine skiing that expose the body to strong and rapidly changing external forces. In this context, posture constraints and contraction-related muscular pressure may lead to muscular deoxygenation. This study investigates whether these constraints and pressure affect static and dynamic postural control. To simulate impaired blood flow in sports within a laboratory task, oxygen saturation was manipulated locally by using an inflatable cuff to induce blood flow restriction (BFR). Twenty-three subjects were asked to stand on a perturbatable platform used to assess postural-related movements. Using a 2 × 2 within-subject design, each participant performed postural control tasks both with and without BFR. BFR resulted in lower oxygenation of the m. quadriceps femoris (p = 0.024) and was associated with a significantly lower time to exhaustion (TTE) compared to the non-restricted condition [F(1,19) = 16.22, p < 0.001, ηp2 = 0.46]. Perturbation resulted in a significantly increased TTE [F(1,19) = 7.28, p = 0.014, ηp2 = 0.277]. There were no significant effects on static and dynamic postural control within the saturation conditions. The present data indicate that BFR conditions leads to deoxygenation and a reduced TTE. Postural control and the ability to regain stability after perturbation were not affected within this investigation.
Altered Cortical-Striatal Network in Patients With Hemifacial Spasm
Authors: Gao Wenwen , Yang Dong , Zhang Zhe , Du Lei , Liu Bing , Liu Jian , Chen Yue , Wang Yige , Liu Xiuxiu , Yang Aocai , Lv Kuan , Xue Jiajia , Ma Guolin
Published: October 2021

Objective: Hemifacial spasm (HFS) is a kind of motor disorder, and the striatum plays a significant role in motor function. The purpose of this study was to explore the alterations of the cortical-striatal network in HFS using resting-state functional magnetic resonance imaging (fMRI).

Methods: The fMRI data of 30 adult patients with primary unilateral HFS (15 left-side and 15 right-side) and 30 healthy controls were collected. Six subregions of the striatum in each hemisphere were selected for functional connectivity (FC) analysis. One-sample t-test was used to analyze the intragroup FC of the HFS group and the control group. Two-sample t-test was used to compare the difference of FC between the two groups. The correlation between the abnormal FC and severity of HFS was evaluated by using the Spearman correlation analysis.

Results: Compared with the controls, the striatal subregions had altered FC with motor and orbitofrontal cortex in patients with HFS. The altered FC between striatal subregions and motor cortex was correlated with the spasm severity in patients with HFS.

Conclusion: The FC of the cortical-striatal network was altered in primary HFS, and these alterations were correlated with the severity of HFS. This study indicated that the cortical-striatal network may play different roles in the underlying pathological mechanism of HFS.
Expression of FLRT2 in Postnatal Central Nervous System Development and After Spinal Cord Injury
Authors: Li Juntan , Shinoda Yo , Ogawa Shuhei , Ikegaya Shunsuke , Li Shuo , Matsuyama Yukihiro , Sato Kohji , Yamagishi Satoru
Published: October 2021

Fibronectin and leucine-rich transmembrane (FLRT) proteins are necessary for various developmental processes and in pathological conditions. FLRT2 acts as a homophilic cell adhesion molecule, a heterophilic repulsive ligand of Unc5/Netrin receptors, and a synaptogenic molecule; the last feature is mediated by binding to latrophilins. Although the function of FLRT2 in regulating cortical migration at the late gestation stage has been analyzed, little is known about the expression pattern of FLRT2 during postnatal central nervous system (CNS) development. In this study, we used Flrt2-LacZ knock-in (KI) mice to analyze FLRT2 expression during CNS development. At the early postnatal stage, FLRT2 expression was largely restricted to several regions of the striatum and deep layers of the cerebral cortex. In adulthood, FLRT2 expression was more prominent in the cerebral cortex, hippocampus, piriform cortex (PIR), nucleus of the lateral olfactory tract (NLOT), and ventral medial nucleus (VM) of the thalamus, but lower in the striatum. Notably, in the hippocampus, FLRT2 expression was confined to the CA1 region and partly localized on pre- and postsynapses whereas only few expression was observed in CA3 and dentate gyrus (DG). Finally, we observed temporally limited FLRT2 upregulation in reactive astrocytes around lesion sites 7 days after thoracic spinal cord injury. These dynamic changes in FLRT2 expression may enable multiple FLRT2 functions, including cell adhesion, repulsion, and synapse formation in different regions during CNS development and after spinal cord injury.
Influence of Vitamin D3 Supplementation on Infliximab Effectiveness in Chinese Patients With Crohn's Disease: A Retrospective Cohort Study
Authors: Xia Sheng-long , Min Quan-jia , Shao Xiao-xiao , Lin Dao-po , Ma Guo-long , Wu Hao , Cao Shu-guang , Jiang Yi
Published: October 2021

Background: It remains uncertain whether vitamin D3 (vitD3) supplementation is beneficial for remission of Crohn's disease (CD). The influence of vitD3 supplementation on Infliximab (IFX) effectiveness was analyzed in Chinese CD patients.

Methods: In this retrospective cohort study, moderate-to-severe CD patients, who were bio-naïve and prescribed with IFX treatment for at least 54 weeks, were recorded from January 2014 to December 2019. VitD3 supplementation was defined as patients additionally took oral vitD3 (125 IU/d) within 3 days after the first infusion and persisted in the whole follow-up period. Disease activity was assessed using Harvey-Bradshaw Index (HBI). Serum cytokine profiles (IL-2, IL-4, IL-6, IL-10, TNF-α, and IFN-γ) were quantitatively analyzed in a subset of all patients at baseline and 54-week after intervention.

Results: Among 73 enrolled patients, 37 took vitD3 regularly (D3-patients), the others (non-D3-patients) did not. At 54-week, the mean 25-hydroxyvitaminD level increased in D3-patients (20.33 vs. 15.07 ng/mL, P < 0.001). The clinical remission rate was higher in D3-patients compared to non-D3-patients (83.8 vs. 61.6%, P = 0.030). The decrease of HBI from baseline to 54-week was more in D3-patients than non-D3-patients (7.41 ± 3.0 vs. 6.28 ± 2.75, P = 0.023). Furthermore, vitD3 supplementation was independently related to the increase of remission rate at 54-week in D3-patients (β = −1.667, P = 0.015). The benefit of vitD3 supplementation was significant only in patients with deficient vitD3 (all P < 0.05), but not in non-deficient vitD3. A total of nine patients (four non-D3-patients and five D3-patients) were selected to determine serum cytokine profiles after 54-week IFX treatment. In non-D3-patients, the decreases of TNF-α and IL-6 at 54-week were more obvious than at baseline (P = 0.032, 0.022, respectively). In D3-patients, however, only IL-10 increased at 54-week compared with its baseline value (P = 0.037).

Conclusions: VitD3 supplementation could improve IFX effectiveness in CD patients, especially for patients with vitD3 deficiency. This beneficial effect of vitD3 supplementation probably arose from the up-regulation of IL-10.

Trial Registration: NCT04606017.
Effect of Saengshik Supplementation on the Gut Microbial Composition of Healthy Korean Adults: A Single-Group Pilot Study
Authors: Shin Ji-Hee , Ahn Yong Ju , Chung Won-Hyong , Lim Mi Young , Hong Seungpyo , Kim Joong-Hark , Park Mi Houn , Nam Young-Do
Published: October 2021

Saengshik is a type of meal-replacement product or dietary supplement comprising an uncooked and dried plant-based food mixture with various health-promoting properties, such as antidiabetic, anti-dyslipidemic, antioxidant, and anticancer properties. Although these properties are considered attributable to the various bioactive components absorbed through the intestine and its remolding effect on intestinal microorganisms, the effect of Saengshik supplementation on gut microbiota profiles has not yet been studied. In this study, we investigated the effect of Saengshik administration on the composition of gut microbiota. This single-group design trial was conducted on 102 healthy men and women who received 40 g/day of Saengshik powder for 8 weeks, during which stool samples were collected at two fixed time points (baseline and the endpoint) for gut microbiota-profiling analysis. We observed a significant decrease in the α-diversity of gut microbiota after Saengshik consumption (P < 0.05), with significant changes identified in the composition of major microbial taxa, such as Bacteroidetes (P < 0.0001), Proteobacteria, Actinobacteria, and Verrucomicrobia (P < 0.0001). Notably, the gut microbial response was related to the inter-individual variability of habitual dietary intake and enterotype at baseline. To the best of our knowledge, this is the first study investigating the effects of Saengshik intake on changes in gut microbiota, with the results suggesting that individual habitual diet patterns and gut microbial shapes should be considered key aspects in Saengshik-mediated health-promotion effects.
LncRNA OTUD6B-AS1 Induces Cisplatin Resistance in Cervical Cancer Cells Through Up-Regulating Cyclin D2 via miR-206
Authors: Hou Hui , Yu Rong , Zhao Haiping , Yang Hao , Hu Yuchong , Hu Yue , Guo Junmei
Published: October 2021

Cervical cancer is one of the most common gynecological cancers. Cisplatin resistance remains a major hurdle in the successful treatment of cervical cancer. Aberrant expression of long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) are implicated in cisplatin resistance. However, the regulatory functions of lncRNAs and miRNAs in cervical cancer cisplatin resistance and the underlying mechanisms are still elusive. Our qRT-PCR assays verified that miR-206 levels were down-regulated in cisplatin-resistant cervical cancer cells. The introduction of miR-206 sensitized cisplatin-resistant cervical cancer cells to cisplatin. Our qRT-PCR and luciferase reporter assays showed that Cyclin D2 (CCND2) was the direct target for miR-206 in cervical cancer cells. The cisplatin-resistant cervical cancer cells expressed higher CCND2 expression than the parental cells, whereas inhibition of CCND2 could sensitize the resistant cells to cisplatin treatment. Furthermore, we demonstrated that lncRNA OTUD6B-AS1 was up-regulated in cisplatin-resistant cervical cancer cells, and knocking down OTUD6B-AS1 expression induced re-acquirement of chemosensitivity to cisplatin in cervical cancer cells. We also showed that OTUD6B-AS1 up-regulated the expression of CCND2 by sponging miR-206. Low miR-206 and high OTUD6B-AS1 expression were associated with significantly poorer overall survival. Taken together, these results suggest that OTUD6B-AS1-mediated down-regulation of miR-206 increases CCND2 expression, leading to cisplatin resistance. Modulation of these molecules may be a therapeutic approach for cisplatin-resistant cervical cancer.
The Effect of Martial Arts Training on Cognitive and Psychological Functions in At-Risk Youths
Authors: Harwood-Gross Anna , Lambez Bar , Feldman Ruth , Zagoory-Sharon Orna , Rassovsky Yuri
Published: October 2021

The current study assessed whether an extended program of martial arts training was a viable intervention for at-risk youths in improving cognitive and psychological functions. Adolescent boys attending specialized education facilities for at-risk youths took part in regular sport lessons or martial arts practice twice a week for 6 months. Hormonal reactivity was assessed during initial training, and measures of psychological (aggression, self-esteem) and cognitive (inhibition, flexibility, speed of processing, and attention) functions were assessed before and immediately following the intervention. Participants in the martial arts training demonstrated significant improvement in the domains of inhibition and shifting and speed of processing. Additionally, initial hormonal reactivity (oxytocin and cortisol) to the intervention predicted significant post-intervention change on several measures of cognitive and psychological functioning. Specifically, oxytocin reactivity predicted improvement in processing speed, as well as reduction of aggression, whereas cortisol reactivity predicted increases in self-esteem. This pioneering, ecologically valid study demonstrates the initial efficacy of this enjoyable, readily available, group intervention for at-risk boys and suggests potential mechanisms that may mediate the process of change.
Risk Factors for Progression of Chronic Kidney Disease With Glomerular Etiology in Hospitalized Children
Authors: He Guohua , Li Chenglong , Zhong Xuhui , Wang Fang , Wang Haibo , Shi Ying , Gan Lanxia , Ding Jie
Published: October 2021

Aim: To Identify association between risk factors to Chronic kidney disease (CKD) stage 5 in children with glomerular diseases in children in China.

Methods: The Hospital Quality Monitoring System database was used to extract data for the study cohort. The primary outcome included progression to CKD stage 5 or dialysis. Cox regression was used to assess potential risk factors. Patients with lower stages (CKD stage 1 and 2) and higher stages (CKD stage 3 and 4) at baseline were analyzed separately.

Results: Of 819 patients (4,089 hospitalization records), 172 (21.0%) patients reached the primary outcome during a median followed-up of 11.4 months. In the lower stages group, factors associated with the primary outcome included older age [Hazard Ratio (HR), 1.21; 95% confidence interval (CI), 1.10–1.34] and out-of-pocket payment (HR, 4.14; 95% CI, 1.57–10.95). In the higher stages group, factors associated with the primary outcome included CKD stage 4 (HR, 2.31; 95% CI, 1.48–3.62) and hypertension (HR, 1.99; 95% CI, 1.29–3.07). The medical migration rate was 38.2% in this study population.

Conclusion: There are different risk factors for progression to the primary outcome in different stages in CKD with glomerular etiology. Further prospective studies are needed to assess these risk factors. The high medical migration rate reflected the regional disparities in the accessibility of pediatric kidney care between regions.
Early Postnatal Comprehensive Biomarkers Cannot Identify Extremely Preterm Infants at Risk of Developing Necrotizing Enterocolitis
Authors: Hoffsten Alice , Markasz Laszlo , Lilja Helene Engstrand , Olsson Karl Wilhelm , Sindelar Richard
Published: October 2021

Background: Necrotizing enterocolitis (NEC) is a fatal disease where current diagnostic tools are insufficient for preventing NEC. Early predictive biomarkers could be beneficial in identifying infants at high risk of developing NEC.

Objective: To explore early biomarkers for predicting NEC in extremely preterm infants (EPIs).

Methods: Blood samples were collected on day 2 (median 1.7; range 1.5–2.0) from 40 EPI (median 25 gestational weeks; range 22–27): 11 developed NEC and 29 did not (controls). In each infant, 189 inflammatory, oncological, and vascular proteomic biomarkers were quantified through Proximity Extension Assay. Biomarker expression and clinical data were compared between the NEC group and Controls. Based on biomarker differences, controls were sorted automatically into three subgroups (1, 2, and 3) by a two-dimensional hierarchical clustering analysis.

Results: None of the biomarkers differed in expression between all controls and the NEC group. Two biomarkers were higher in Control 1, and 16 biomarkers were lower in Control group 2 compared with the NEC group. No biomarker distinguished Control 3 from the NEC group. Perinatal data were similar in the whole population.

Conclusions: Early postnatal comprehensive biomarkers do not identify EPIs at risk of developing NEC in our study. Future studies of predictors of NEC should include sequential analysis of comprehensive proteomic markers in large cohorts.
Research Trends and Collaboration Patterns on Polymyxin Resistance: A Bibliometric Analysis (2010–2019)
Authors: Quincho-Lopez Alvaro , Pacheco-Mendoza Josmel
Published: October 2021

Background: Antimicrobial resistance is a serious public health problem that has become a global threat. Special attention should be given to polymyxins (polymyxin B and colistin) which, since their reintroduction into clinical practice, are considered “last resort” drugs. The objective of this study is to perform a bibliometric analysis of scientific research on polymyxin resistance.

Methods: Scopus was used to retrieve documents relevant to polymyxin resistance from 2010 to 2019. Data was exported to Microsoft Excel for table presentation. SciVal was used for volume and citation analysis as well as collaboration patterns. Also, we extracted data regarding the top documents, authors, countries, institutions, and the metrics of journals. VantagePoint and VOSviewer were used for geographical distribution of worldwide research and keyword co-occurrence analysis, respectively.

Results: A total of 1,409 documents were retrieved. The retrieved documents received 25.0 citations per document. Articles (73.88%) and letters (18.09%) were the most frequent types of documents. During 2010–2019, there was a significant growth in publications (p-value < 0.001). The received citations were 35,209 with a peak in 2016 (11,250 citations). China and the United States led the scientific production with 299 (21.2%) and 238 (16.9%) publications, respectively. Little or no contribution came from central Asia, Sub-Saharan Africa, and Latin America. Chinese institutions have caused the greatest impact, with University of Zhejiang (China) being the most prolific institution on the subject (88 documents). In terms of the most productive journals, Antimicrobial Agents and Chemotherapy ranked first with 196 (13.9%) documents. Most of the documents were published in quartile one journals and only had national collaboration (43.2%). Analysis of keyword co-occurrence revealed that research on polymyxin resistance during the last decade has focused on its relationship with public health, pharmacology, and genetics.

Conclusion: The number of documents on polymyxin resistance has increased significantly in the recent years, with a steep growth from 2016 onwards. China and the United States led the scientific production. Most of the documents were published in high-quality journals. Greater joint efforts and more contribution from central Asia, Sub-Saharan Africa, and Latin America are still needed to tackle this global problem.
Medicinal Plants for Mitigating Pain and Inflammatory-Related Conditions: An Appraisal of Ethnobotanical Uses and Patterns in South Africa
Authors: Aremu Adeyemi O. , Pendota Srinivasa C.
Published: October 2021

In South Africa, traditional medicine remains the first point of call for a significant proportion of the population seeking primary healthcare needs. This is particularly important for treating common conditions including pain and inflammation which are often associated with many disease conditions. This review focuses on the analysis of the trend and pattern of plants used for mitigating pain and inflammatory-related conditions in South African folk medicine. An extensive search was conducted using various scientific databases and popular ethnobotanical literature focusing on South African ethnobotany. Based on the systematic analysis, 38 sources were selected to generate the inventory of 495 plants from 99 families that are considered as remedies for pain and inflammatory-related conditions (e.g., headache, toothache, backache, menstrual pain, and rheumatism) among different ethnic groups in South Africa. The majority (55%) of the 38 studies were recorded in three provinces, namely, KwaZulu-Natal, Limpopo, and Western Cape. In terms of the number of mentions, the most popular plants used for pain and inflammatory-related conditions in South Africa were Ricinus communis L. (10), Aloe ferox Mill. (8), Pentanisia prunelloides subsp. latifolia (Hochst.) Verdc. (8), Dodonaea viscosa Jacq var. angustifolia (L.f) Benth. (8), (L.) W.T.Aiton. (7) Ruta graveolens L. (7), and Solanum aculeastrum Dunal. (7). The top five plant families represented were Asteraceae (13%), Fabaceae (8%), Apocynaceae (4.3%), Asparagaceae (4%), and Lamiaceae (4%). An estimated 54% of the recorded plants were woody (trees and shrubs) in nature, while the leaves (27%) and roots (25%) were the most dominant plant parts. The use of plants for alleviating pain and inflammatory-related conditions remains popular in South African folk medicine. The lagging ethnobotanical information from provinces such as North West, Gauteng, and Free State remains a gap that needs to be pursued meticulously in order to have a complete country-wide database.
Genome Mining-Based Discovery of Blenny Fish-Derived Peptides Targeting the Mouse κ-Opioid Receptor
Authors: Muratspahić Edin , Retzl Bernhard , Duerrauer Leopold , Freissmuth Michael , Becker Christian F. W. , Gruber Christian W.
Published: October 2021

Over the past years, peptides have attracted increasing interest for G protein-coupled receptor (GPCR) drug discovery and development. Peptides occupy a unique chemical space that is not easily accessible for small molecules and antibodies and provide advantages over these ligand classes such as lower toxicity and higher selectivity. The κ-opioid receptor (KOR) is a prototypic GPCR and an appealing therapeutic target for the development of safer and more effective analgesics. Recently, peptides have emerged as analgesic drug candidates with improved side effect profiles. We have previously identified plant-derived peptides, which activate KOR. Based on this precedent, here we relied on publicly available databases to discover novel KOR peptide ligands by genome mining. Using human preprodynorphin as a query, we identified blenny fish-derived peptides, referred to as blenniorphins, capable of binding to and activating KOR with nanomolar affinity and potency, respectively. Additionally, the blenniorphins altered β-arrestin-2 recruitment at the KOR. Our study demonstrates the utility of genome mining to identify peptide GPCR ligands with intriguing pharmacological properties and unveils the potential of blenny fishes as a source for novel KOR ligands.
A Three-Dimensional Numerical Model of an Active Cell Cortex in the Viscous Limit
Authors: Bächer Christian , Khoromskaia Diana , Salbreux Guillaume , Gekle Stephan
Published: October 2021

The cell cortex is a highly dynamic network of cytoskeletal filaments in which motor proteins induce active cortical stresses which in turn drive dynamic cellular processes such as cell motility, furrow formation or cytokinesis during cell division. Here, we develop a three-dimensional computational model of a cell cortex in the viscous limit including active cortical flows. Combining active gel and thin shell theory, we base our computational tool directly on the force balance equations for the velocity field on a discretized and arbitrarily deforming cortex. Since our method is based on the general force balance equations, it can easily be extended to more complex biological dependencies in terms of the constitutive laws or a dynamic coupling to a suspending fluid. We validate our algorithm by investigating the formation of a cleavage furrow on a biological cell immersed in a passive outer fluid, where we successfully compare our results to axi-symmetric simulations. We then apply our fully three-dimensional algorithm to fold formation and to study furrow formation under the influence of non-axisymmetric disturbances such as external shear. We report a reorientation mechanism by which the cell autonomously realigns its axis perpendicular to the furrow plane thus contributing to the robustness of cell division under realistic environmental conditions.
Effects of Different Levels of Variability and Pressure Support Ventilation on Lung Function in Patients With Mild–Moderate Acute Respiratory Distress Syndrome
Authors: Ball Lorenzo , Sutherasan Yuda , Fiorito Martina , Dall'Orto Antonella , Maiello Lorenzo , Vargas Maria , Robba Chiara , Brunetti Iole , D'Antini Davide , Raimondo Pasquale , Huhle Robert , Schultz Marcus J. , Rocco Patricia R. M. , Gama de Abreu Marcelo , Pelosi Paolo
Published: October 2021

Background: Variable pressure support ventilation (vPSV) is an assisted ventilation mode that varies the level of pressure support on a breath-by-breath basis to restore the physiological variability of breathing activity. We aimed to compare the effects of vPSV at different levels of variability and pressure support (ΔPS) in patients with acute respiratory distress syndrome (ARDS).

Methods: This study was a crossover randomized clinical trial. We included patients with mild to moderate ARDS already ventilated in conventional pressure support ventilation (PSV). The study consisted of two blocks of interventions, and variability during vPSV was set as the coefficient of variation of the ΔPS level. In the first block, the effects of three levels of variability were tested at constant ΔPS: 0% (PSV0%, conventional PSV), 15% (vPSV15%), and 30% (vPSV30%). In the second block, two levels of variability (0% and variability set to achieve ±5 cmH2O variability) were tested at two ΔPS levels (baseline ΔPS and ΔPS reduced by 5 cmH2O from baseline). The following four ventilation strategies were tested in the second block: PSV with baseline ΔPS and 0% variability (PSVBL) or ±5 cmH2O variability (vPSVBL), PSV with ΔPS reduced by 5 cmH2O and 0% variability (PSV−5) or ±5 cmH2O variability (vPSV−5). Outcomes included gas exchange, respiratory mechanics, and patient-ventilator asynchronies.

Results: The study enrolled 20 patients. In the first block of interventions, oxygenation and respiratory mechanics parameters did not differ between vPSV15% and vPSV30% compared with PSV0%. The variability of tidal volume (VT) was higher with vPSV15% and vPSV30% compared with PSV0%. The incidence of asynchronies and the variability of transpulmonary pressure (PL) were higher with vPSV30% compared with PSV0%. In the second block of interventions, different levels of pressure support with and without variability did not change oxygenation. The variability of VT and PL was higher with vPSV−5 compared with PSV−5, but not with vPSVBL compared with PSVBL.

Conclusion: In patients with mild-moderate ARDS, the addition of variability did not improve oxygenation at different pressure support levels. Moreover, high variability levels were associated with worse patient-ventilator synchrony.

Clinical Trial Registration:www.clinicaltrials.gov, identifier: NCT01683669.
Characterization of tmt-opsin2 in Medaka Fish Provides Insight Into the Interplay of Light and Temperature for Behavioral Regulation
Authors: Zekoll Theresa , Waldherr Monika , Tessmar-Raible Kristin
Published: October 2021

One of the big challenges in the study of animal behavior is to combine molecular-level questions of functional genetics with meaningful combinations of environmental stimuli. Light and temperature are important external cues, influencing the behaviors of organisms. Thus, understanding the combined effect of light and temperature changes on wild-type vs. genetically modified animals is a first step to understand the role of individual genes in the ability of animals to cope with changing environments. Many behavioral traits can be extrapolated from behavioral tests performed from automated motion tracking combined with machine learning. Acquired datasets, typically complex and large, can be challenging for subsequent quantitative analyses. In this study, we investigate medaka behavior of tmt-opsin2 mutants vs. corresponding wild-types under different light and temperature conditions using automated tracking combined with a convolutional neuronal network and a Hidden Markov model-based approach. The temperatures in this study can occur in summer vs. late spring/early autumn in the natural habitat of medaka fish. Under summer-like temperature, tmt-opsin2 mutants did not exhibit changes in overall locomotion, consistent with previous observations. However, detailed analyses of fish position revealed that the tmt-opsin2 mutants spent more time in central locations of the dish, possibly because of decreased anxiety. Furthermore, a clear difference in location and overall movement was obvious between the mutant and wild-types under colder conditions. These data indicate a role of tmt-opsin2 in behavioral adjustment, at least in part possibly depending on the season.