bluuebunny/crossref_metadata_2025 huggingface dataset:
How Does COVID-19 Pandemic Impact on Incidence of Clostridioides difficile Infection and Exacerbation of Its Gastrointestinal Symptoms?
Authors: Azimirad Masoumeh , Noori Maryam , Raeisi Hamideh , Yadegar Abbas , Shahrokh Shabnam , Asadzadeh Aghdaei Hamid , Bentivegna Enrico , Martelletti Paolo , Petrosillo Nicola , Zali Mohammad Reza
Published: December 2021

Coronavirus disease 2019 (COVID-19) has rapidly spread all over the world with a very high rate of mortality. Different symptoms developed by COVID-19 infection and its impacts on various organs of the human body have highlighted the importance of both coinfections and superinfections with other pathogens. The gastrointestinal (GI) tract is vulnerable to infection with COVID-19 and can be exploited as an alternative transmission route and target for virus entry and pathogenesis. The GI manifestations of COVID-19 disease are associated with severe disease outcomes and death in all age groups, in particular, elderly patients. Empiric antibiotic treatments for microbial infections in hospitalized patients with COVID-19 in addition to experimental antiviral and immunomodulatory drugs may increase the risk of antibiotic-associated diarrhea (AAD) and Clostridioides difficile infection (CDI). Alterations of gut microbiota are associated with depletion of beneficial commensals and enrichment of opportunistic pathogens such as C. difficile. Hence, the main purpose of this review is to explain the likely risk factors contributing to higher incidence of CDI in patients with COVID-19. In addition to lung involvement, common symptoms observed in COVID-19 and CDI such as diarrhea, highlight the significance of bacterial infections in COVID-19 patients. In particular, hospitalized elderly patients who are receiving antibiotics might be more prone to CDI. Indeed, widespread use of broad-spectrum antibiotics such as clindamycin, cephalosporins, penicillin, and fluoroquinolones can affect the composition and function of the gut microbiota of patients with COVID-19, leading to reduced colonization resistance capacity against opportunistic pathogens such as C. difficile, and subsequently develop CDI. Moreover, patients with CDI possibly may have facilitated the persistence of SARS-CoV-2 viral particles in their feces for approximately one month, even though the nasopharyngeal test turned negative. This coinfection may increase the potential transmissibility of both SARS-CoV-2 and C. difficile by fecal materials. Also, CDI can complicate the outcome of COVID-19 patients, especially in the presence of comorbidities or for those patients with prior exposure to the healthcare setting. Finally, physicians should remain vigilant for possible SARS-CoV-2 and CDI coinfection during the ongoing COVID-19 pandemic and the excessive use of antimicrobials and biocides.
Association Between Ambient Air Pollutants Exposure and Preterm Birth in Women Who Underwent in vitro Fertilization: A Retrospective Cohort Study From Hangzhou, China
Authors: Shi Wenming , Jiang Meiyan , Kan Lena , Zhang Tiantian , Yu Qiong , Wu Zexuan , Xue Shuya , Fei Xiaoyang , Jin Changbo
Published: December 2021

Objectives: Exposure to air pollutants has been linked to preterm birth (PTB) after natural conception. However, few studies have explored the effects of air pollution on PTB in patients who underwent in vitro fertilization (IVF). We aimed to investigate the association between ambient air pollutants exposure and PTB risk in IVF patients.

Methods: This retrospective cohort study included 2,195 infertile women who underwent IVF treatment from January 2017 and September 2020 in Hangzhou Women's Hospital. Totally 1,005 subjects who underwent a first fresh embryo(s) transfer cycle were analyzed in this study. Residential exposure to ambient six air pollutants (PM2.5, PM10, SO2, NO2, CO, O3) during various periods of the IVF timeline were estimated by satellite remote-sensing and ground measurement. Cox proportional hazards models for discrete time were used to explore the association between pollutants exposure and incident PTB, with adjustment for confounders. Stratified analyses were employed to explore the effect modifiers.

Results: The clinical pregnancy and PTB rates were 61.2 and 9.3%, respectively. We found that PM2.5 exposure was significantly associated with an increased risk of PTB during 85 days before oocyte retrieval [period A, adjusted hazard ratio, HR=1.09, 95%CI: 1.02–1.21], gonadotropin start to oocyte retrieval [period B, 1.07 (1.01–1.19)], first trimester of pregnancy [period F, 1.06 (1.01–1.14)], and the entire IVF pregnancy [period I, 1.07 (1.01–1.14)], respectively. An interquartile range increment in PM10 during periods A and B was significantly associated with PTB at 1.15 (1.04–1.36), 1.12 (1.03–1.28), and 1.14 (1.01–1.32) for NO2 during period A. The stratified analysis showed that the associations were stronger for women aged <35 years and those who underwent two embryos transferred.

Conclusions: Our study suggests ambient PM2.5, PM10, and NO2 exposure were significantly associated with elevated PTB risk in IVF patients, especially at early stages of IVF cycle and during pregnancy.
Stapled Anoplin as an Antibacterial Agent
Authors: Wojciechowska Monika , Macyszyn Julia , Miszkiewicz Joanna , Grzela Renata , Trylska Joanna
Published: December 2021

Anoplin is a linear 10-amino acid amphipathic peptide (Gly-Leu-Leu-Lys-Arg-Ile-Lys-Thr-Leu-Leu-NH2) derived from the venom sac of the solitary wasp. It has broad antimicrobial activity, including an antibacterial one. However, the inhibition of bacterial growth requires several dozen micromolar concentrations of this peptide. Anoplin is positively charged and directly interacts with anionic biological membranes forming an α-helix that disrupts the lipid bilayer. To improve the bactericidal properties of anoplin by stabilizing its helical structure, we designed and synthesized its analogs with hydrocarbon staples. The staple was introduced at two locations resulting in different charges and amphipathicity of the analogs. Circular dichroism studies showed that all modified anoplins adopted an α-helical conformation, both in the buffer and in the presence of membrane mimics. As the helicity of the stapled anoplins increased, their stability in trypsin solution improved. Using the propidium iodide uptake assay in Escherichia coli and Staphylococcus aureus, we confirmed the bacterial membrane disruption by the stapled anoplins. Next, we tested the antimicrobial activity of peptides on a range of Gram-negative and Gram-positive bacteria. Finally, we evaluated peptide hemolytic activity on sheep erythrocytes and cytotoxicity on human embryonic kidney 293 cells. All analogs showed higher antimicrobial activity than unmodified anoplin. Depending on the position of the staple, the peptides were more effective either against Gram-negative or Gram-positive bacteria. Anoplin[5-9], with a lower positive charge and increased hydrophobicity, had higher activity against Gram-positive bacteria but also showed hemolytic and destructive effects on eukaryotic cells. Contrary, anoplin[2-6] with a similar charge and amphipathicity as natural anoplin effectively killed Gram-negative bacteria, also pathogenic drug-resistant strains, without being hemolytic and toxic to eukaryotic cells. Our results showed that anoplin charge, amphipathicity, and location of hydrophobic residues affect the peptide destructive activity on the cell wall, and thus, its antibacterial activity. This means that by manipulating the charge and position of the staple in the sequence, one can manipulate the antimicrobial activity.
Improving Small-Molecule Force Field Parameters in Ligand Binding Studies
Authors: Raniolo Stefano , Limongelli Vittorio
Published: December 2021

Small molecules are major players of many chemical processes in diverse fields, from material science to biology. They are made by a combination of carbon and heteroatoms typically organized in system-specific structures of different complexity. This peculiarity hampers the application of standard force field parameters and their in silico study by means of atomistic simulations. Here, we combine quantum-mechanics and atomistic free-energy calculations to achieve an improved parametrization of the ligand torsion angles with respect to the state-of-the-art force fields in the paradigmatic molecular binding system benzamidine/trypsin. Funnel-Metadynamics calculations with the new parameters greatly reproduced the high-resolution crystallographic ligand binding mode and allowed a more accurate description of the binding mechanism, when the ligand might assume specific conformations to cross energy barriers. Our study impacts on future drug design investigations considering that the vast majority of marketed drugs are small-molecules.
The Cordyceps militaris-Derived Polysaccharide CM1 Alleviates Atherosclerosis in LDLR(-/-) Mice by Improving Hyperlipidemia
Authors: Yin Fan , Lin Ping , Yu Wen-Qian , Shen Nuo , Li Yuan , Guo Shou-Dong
Published: December 2021

Atherosclerotic cardiovascular disease has a high mortality worldwide. Our lab previously purified a polysaccharide designated as CM1 with (1→4)-β-D-Glcp and (1→2)-α-D-Manp glycosyls as the backbone. In this study, we investigated the anti-atherosclerosis effect of CM1 and the underlying mechanisms of action in a low-density lipoprotein receptor knockout (LDLR(-/-) mouse model. It was found that CM1 significantly decreased the formation of atherosclerotic plaques. Mechanistically, CM1 enhanced plasma level of apolipoprotein A-I and decreased the plasma levels of triglyceride, apolipoprotein B, and total cholesterol. In the absence of LDLR, CM1 elevated the expression of very low-density lipoprotein receptor for liver uptake of plasma apolipoprotein B-containing particles and reduced hepatic triglyceride synthesis by inhibiting sterol regulatory element binding protein 1c. CM1 improved lipids excretion by increasing the liver X receptor α/ATP-binding cassette G5 pathway in small intestine. CM1 reduced lipogenesis and lipolysis by inhibiting peroxisome proliferator-activated receptor γ and adipose triglyceride lipase in epididymal fat. Furthermore, CM1 improved lipid profile in C57BL/6J mice. Collectively, CM1 can modulate lipid metabolism by multiple pathways, contributing to reduced plasma lipid level and formation of atherosclerotic plaques in LDLR(−/−) mice. This molecule could be explored as a potential compound for prevention and treatment of hyperlipidemia and atherosclerosis.
Comparative Analysis of anti-Shine- Dalgarno Function in Flavobacterium johnsoniae and Escherichia coli
Authors: McNutt Zakkary A. , Gandhi Mai D. , Shatoff Elan A. , Roy Bappaditya , Devaraj Aishwarya , Bundschuh Ralf , Fredrick Kurt
Published: December 2021

The anti-Shine-Dalgarno (ASD) sequence of 16S rRNA is highly conserved across Bacteria, and yet usage of Shine-Dalgarno (SD) sequences in mRNA varies dramatically, depending on the lineage. Here, we compared the effects of ASD mutagenesis in Escherichia coli, a Gammaproteobacteria which commonly employs SD sequences, and Flavobacterium johnsoniae, a Bacteroidia which rarely does. In E. coli, 30S subunits carrying any single substitution at positions 1,535–1,539 confer dominant negative phenotypes, whereas subunits with mutations at positions 1,540–1,542 are sufficient to support cell growth. These data suggest that CCUCC (1,535–1,539) represents the functional core of the element in E. coli. In F. johnsoniae, deletion of three ribosomal RNA (rrn) operons slowed growth substantially, a phenotype largely rescued by a plasmid-borne copy of the rrn operon. Using this complementation system, we found that subunits with single mutations at positions 1,535–1,537 are as active as control subunits, in sharp contrast to the E. coli results. Moreover, subunits with quadruple substitution or complete replacement of the ASD retain substantial, albeit reduced, activity. Sedimentation analysis revealed that these mutant subunits are overrepresented in the subunit fractions and underrepresented in polysome fractions, suggesting some defect in 30S biogenesis and/or translation initiation. Nonetheless, our collective data indicate that the ASD plays a much smaller role in F. johnsoniae than in E. coli, consistent with SD usage in the two organisms.
The role of Mesothelin signaling in Portal Fibroblasts in the pathogenesis of cholestatic liver fibrosis
Authors: Fuji Hiroaki , Miller Grant , Nishio Takahiro , Koyama Yukinori , Lam Kevin , Zhang Vivian , Loomba Rohit , Brenner David , Kisseleva Tatiana
Published: December 2021

Liver fibrosis develops in response to chronic toxic or cholestatic injury, and is characterized by apoptosis of damaged hepatocytes, development of inflammatory responses, and activation of Collagen Type I producing myofibroblasts that make liver fibrotic. Two major cell types, Hepatic Stellate Cells (HSCs) and Portal Fibroblasts (PFs) are the major source of hepatic myofibroblasts. Hepatotoxic liver injury activates Hepatic Stellate Cells (aHSCs) to become myofibroblasts, while cholestatic liver injury activates both aHSCs and Portal Fibroblasts (aPFs). aPFs comprise the major population of myofibroblasts at the onset of cholestatic injury, while aHSCs are increasingly activated with fibrosis progression. Here we summarize our current understanding of the role of aPFs in the pathogenesis of cholestatic fibrosis, their unique features, and outline the potential mechanism of targeting aPFs in fibrotic liver.
Computational Insights Into the Effects of the R190K and N121Q Mutations on the SARS-CoV-2 Spike Complex With Biliverdin
Authors: Qu Zhiyuan , Li Kaihang , Geng Xiaoju , Huang Bo , Gao Jian
Published: December 2021

The SARS-CoV-2 spike has been regarded as the main target of antibody design against COVID-19. Two single-site mutations, R190K and N121Q, were deemed to weaken the binding affinity of biliverdin although the underlying molecular mechanism is still unknown. Meanwhile, the effect of the two mutations on the conformational changes of “lip” and “gate” loops was also elusive. Thus, molecular dynamics simulation and molecular mechanics/generalized Born surface area (MM/GBSA) free energy calculation were conducted on the wild-type and two other SARS-CoV-2 spike mutants. Our simulations indicated that the R190K mutation causes Lys190 to form six hydrogen bonds, guided by Asn99 and Ile101, which brings Lys190 closer to Arg102 and Asn121, thereby weakening the interaction energy between biliverdin and Ile101 as well as Lys190. For the N121Q mutation, Gln121 still maintained a hydrogen bond with biliverdin; nevertheless, the overall binding mode deviated significantly under the reversal of the side chain of Phe175. Moreover, the two mutants would stabilize the lip loop, which would restrain the meaningful upward movement of the lip. In addition, N121Q significantly promoted the gate loop deviating to the biliverdin binding site and compressed the site. This work would be useful in understanding the dynamics binding biliverdin to the SARS-CoV-2 spike.
Unraveling the Influence of K280 Acetylation on the Conformational Features of Tau Core Fragment: A Molecular Dynamics Simulation Study
Authors: Zou Yu , Guan Lulu
Published: December 2021

Abnormal aggregation of the microtubule-associated protein Tau is closely associated with tauopathies, including Alzheimer’s disease and chronic traumatic encephalopathy. The hexapeptide 275VQIINK280 (PHF6*), a fibril-nucleating core motif of Tau, has been shown to play a vital role in the aggregation of Tau. Mounting experiment evidence demonstrated the acetylation of a single-lysine residue K280 in the PHF6* was a critical event for the formation of pathological Tau amyloid deposits. However, the underlying mechanisms by which K280 acetylation affects Tau aggregation at the atomic level remain elusive. In this work, we performed replica exchange molecular dynamics simulations to investigate the influence of acetylation of K280 on the aggregation of PHF6*. Our simulations show that acetylation of K280 not only enhances the self-assembly capability of PHF6* peptides but also increases the β-sheet structure propensity of the PHF6*. The inter-molecular interactions among PHF6* peptides are strengthened by the acetylation of K280, resulting in an increased ordered β-sheet-rich conformations of the PHF6* assemblies along with a decrease of the structural diversity. The residue-pairwise contact frequency analysis shows that K280 acetylation increases the interactions among the hydrophobic chemical groups from PHF6* peptides, which promotes the aggregation of PHF6*. This study offers mechanistic insights into the effects of acetylation on the aggregation of PHF6*, which will be helpful for an in-depth understanding of the relationship between acetylation and Tau aggregation at the molecular level.
Combining Transcranial Direct Current Stimulation With Tai Chi to Improve Dual-Task Gait Performance in Older Adults With Mild Cognitive Impairment: A Randomized Controlled Trial
Authors: Liao Ying-Yi , Liu Mu-N , Wang Han-Cheng , Walsh Vincent , Lau Chi Ieong
Published: December 2021

Introduction: Engaging in a secondary task while walking increases motor-cognitive interference and exacerbates fall risk in older adults with mild cognitive impairment (MCI). Previous studies have demonstrated that Tai Chi (TC) may improve cognitive function and dual-task gait performance. Intriguingly, with emerging studies also indicating the potential of transcranial direct current stimulation (tDCS) in enhancing such motor-cognitive performance, whether combining tDCS with TC might be superior to TC alone is still unclear. The purpose of this study was to investigate the effects of combining tDCS with TC on dual-task gait in patients with MCI.

Materials and Methods: Twenty patients with MCI were randomly assigned to receive either anodal or sham tDCS, both combined with TC, for 36 sessions over 12 weeks. Subjects received 40 min of TC training in each session. During the first 20 min, they simultaneously received either anodal or sham tDCS over the left dorsolateral prefrontal cortex. Outcome measures included dual-task gait performance and other cognitive functions.

Results: There were significant interaction effects between groups on the cognitive dual task walking. Compared to sham, the anodal tDCS group demonstrated a greater improvement on cadence and dual task cost of speed.

Conclusion: Combining tDCS with TC may offer additional benefits over TC alone in enhancing dual-task gait performance in patients with MCI.

Clinical Trial Registration: [www.ClinicalTrials.gov], identifier [TCTR20201201007].
A Dynamic Nomogram for 3-Month Prognosis for Acute Ischemic Stroke Patients After Endovascular Therapy: A Pooled Analysis in Southern China
Authors: Huang Zhi-Xin , Li Yong-Kun , Li Shi-Zhan , Huang Xian-Jun , Chen Ying , Hong Quan-Long , Cai Qian-Kun , Han Yun-Fei
Published: December 2021

Cerebral edema (CDE) is a common complication in patients with acute ischemic stroke (AIS) and can reduce the benefit of endovascular therapy (EVT). To determine whether certain risk factors are associated with a poor prognosis mediated by CDE after EVT. The 759 patients with anterior circulation stroke treated by EVT at three comprehensive stroke centers in China from January 2014 to October 2020 were analyzed. Patients underwent follow-up for 3 months after inclusion. The primary endpoint was a measure of a poor prognosis (modified Rankin Scale score ≥ 3) at 3 months assessed in all patients receiving EVT. Least absolute shrinkage and selection operator and multivariate logistic regression were used to select variables for the prognostic nomogram. Based on these variables, the nomogram was established and validated. In addition, structural equation modeling was used to explore the pathways linking CDE and a poor prognosis. Seven predictors were identified, namely, diabetes, age, baseline Alberta Stroke Program Early CT score, modified Thrombolysis in Cerebral Infarction score, early angiogenic CDE, National Institutes of Health Stroke Scale score, and collateral circulation. The nomogram consisting of these variables showed the best performance, with a large area under the curve in both the internal validation set (0.850; sensitivity, 0.737; specificity, 0.887) and external validation set (0.875; sensitivity, 0.752; specificity, 0.878). In addition, CDE (total path coefficient = 0.24, P < 0.001) served as a significant moderator. A nomogram for predicting a poor prognosis after EVT in AIS patients was established and validated with CDE as a moderator.
A Novel Immune Classification for Predicting Immunotherapy Responsiveness in Patients With Adamantinomatous Craniopharyngioma
Authors: Yuan Feng , Cai Xiangming , Zhu Junhao , Yuan Lei , Wang Yingshuai , Tang Chao , Cong Zixiang , Ma Chiyuan
Published: December 2021

Adamantinomatous craniopharyngioma (ACP) is the most common tumor of the sellar region in children. The aggressive behavior of ACP challenges the treatment for it. However, immunotherapy is rarely studied in ACP. In this research, we performed unsupervised cluster analysis on the 725 immune-related genes and arrays of 39 patients with ACP patients in GSE60815 and GSE94349 databases. Two novel immune subtypes were identified, namely immune resistance (IR) subtype and immunogenic (IG) subtype. Interestingly, we found that the ACPs with IG subtype (34.78%, 8/23) were more likely to respond to immunotherapy than the ACPs with IR subtype (6.25%, 1/16) via tumor immune dysfunction and exclusion (TIDE) method. Simultaneously, the enrichment analysis indicated that the differentially expressed genes (DEGs) (p < 0.01, FDR < 0.01) of the IG subtype were chiefly involved in inflammatory and immune responses. However, the DEGs of the IR subtype were mainly involved in RNA processing. Next, immune infiltration analysis revealed a higher proportion of M2 macrophage in the IG subtype than that in the IR subtype. Compared with the IR subtype, the expression levels of immune checkpoint molecules (PD1, PDL1, PDL2, TIM3, CTLA4, Galectin9, LAG3, and CD86) were significantly upregulated in the IG subtype. The ssGSEA results demonstrated that the biofunction of carcinogenesis in the IG subtype was significantly enriched, such as lymphocyte infiltration, mesenchymal phenotype, stemness maintenance, and tumorigenic cytokines, compared with the IR subtype. Finally, a WDR89 (the DEG between IG and IR subtype)-based nomogram model was constructed to predict the immune classification of ACPs with excellent performance. This predictive model provided a reliable classification assessment tool for clinicians and aids treatment decision-making in the clinic.
Associations of the Disrupted Functional Brain Network and Cognitive Function in End-Stage Renal Disease Patients on Maintenance Hemodialysis: A Graph Theory-Based Study of Resting-State Functional Magnetic Resonance Imaging
Authors: Zhang Die , Chen Yingying , Wu Hua , Lin Lin , Xie Qing , Chen Chen , Jing Li , Wu Jianlin
Published: December 2021

Objective: Cognitive impairment (CI) is a common neurological complication in patients with end-stage renal disease undergoing maintenance hemodialysis (MHD). Brain network analysis based on graph theory is a promising tool for studying CI. Therefore, the purpose of this study was to analyze the changes of functional brain networks in patients on MHD with and without CI by using graph theory and further explore the underlying neuropathological mechanism of CI in these patients.

Methods: A total of 39 patients on MHD (19 cases with CI and 20 without) and 25 healthy controls (HCs) matched for age, sex, and years of education were enrolled in the study. Resting-state functional magnetic resonance imaging (rs-fMRI) and T1-weighted high-resolution anatomical data were obtained, and functional brain networks for each subject were constructed. The brain network parameters at the global and regional levels were calculated, and a one-way analysis of covariance was used to compare the differences across the three groups. The associations between the changed graph-theory parameters and cognitive function scores in patients on MHD were evaluated using Spearman correlation analysis.

Results: Compared with HCs, the global parameters [sigma, gamma, and local efficiency (Eloc)] in both patient groups decreased significantly (p < 0.05, Bonferroni corrected). The clustering coefficient (Cp) in patients with CI was significantly lower than that in the other two groups (p < 0.05, Bonferroni corrected). The regional parameters were significantly lower in the right superior frontal gyrus, dorsolateral (SFGdor) and gyrus rectus (REC) of patients with CI than those of patients without CI; however the nodal local efficiency in the left amygdala was significantly increased (all p < 0.05, Bonferroni corrected). The global Cp and regional parameters in the three brain regions (right SFGdor, REC, and left amygdala) were significantly correlated with the cognitive function scores (all FDR q < 0.05).

Conclusion: This study confirmed that the topology of the functional brain network was disrupted in patients on MHD with and without CI and the disruption of brain network was more severe in patients with CI. The abnormal brain network parameters are closely related to cognitive function in patients on MHD.
Reading Specific Small Saccades Predict Individual Phonemic Awareness and Reading Speed
Authors: Rima Samy , Schmid Michael C.
Published: December 2021

Small fixational eye-movements are a fundamental aspect of vision and thought to reflect fine shifts in covert attention during active viewing. While the perceptual benefits of these small eye movements have been demonstrated during a wide range of experimental tasks including during free viewing, their function during reading remains surprisingly unclear. Previous research demonstrated that readers with increased microsaccade rates displayed longer reading speeds. To what extent increased fixational eye movements are, however, specific to reading and might be indicative of reading skill deficits remains, however, unknown. To address this topic, we compared the eye movement scan paths of 13 neurotypical individuals and 13 subjects diagnosed with developmental dyslexia during short story reading and free viewing of natural scenes. We found that during reading only, dyslexics tended to display small eye movements more frequently compared to neurotypicals, though this effect was not significant at the population level, as it could also occur in slow readers not diagnosed as dyslexics. In line with previous research, neurotypical readers had twice as many regressive compared to progressive microsaccades, which did not occur during free viewing. In contrast, dyslexics showed similar amounts of regressive and progressive small fixational eye movements during both reading and free viewing. We also found that participants with smaller fixational saccades from both neurotypical and dyslexic samples displayed reduced reading speeds and lower scores during independent tests of reading skill. Slower readers also displayed greater variability in the landing points and temporal occurrence of their fixational saccades. Both the rate and spatio-temporal variability of fixational saccades were associated with lower phonemic awareness scores. As none of the observed differences between dyslexics and neurotypical readers occurred during control experiments with free viewing, the reported effects appear to be directly related to reading. In summary, our results highlight the predictive value of small saccades for reading skill, but not necessarily for developmental dyslexia.
Sexual Dimorphism of Early Transcriptional Reprogramming in Dorsal Root Ganglia After Peripheral Nerve Injury
Authors: Chernov Andrei V. , Shubayev Veronica I.
Published: December 2021

Peripheral nerve injury induces genome-wide transcriptional reprogramming of first-order neurons and auxiliary cells of dorsal root ganglia (DRG). Accumulating experimental evidence suggests that onset and mechanistic principles of post-nerve injury processes are sexually dimorphic. We examined largely understudied aspects of early transcriptional events in DRG within 24 h after sciatic nerve axotomy in mice of both sexes. Using high-depth RNA sequencing (>50 million reads/sample) to pinpoint sexually dimorphic changes related to regeneration, immune response, bioenergy, and sensory functions, we identified a higher number of transcriptional changes in male relative to female DRG. In males, the decline in ion channel transcripts was accompanied by the induction of innate immune cascades via TLR, chemokine, and Csf1-receptor axis and robust regenerative programs driven by Sox, Twist1/2, and Pax5/9 transcription factors. Females demonstrated nerve injury-specific transcriptional co-activation of the actinin 2 network. The predicted upstream regulators and interactive networks highlighted the role of novel epigenetic factors and genetic linkage to sex chromosomes as hallmarks of gene regulation post-axotomy. We implicated epigenetic X chromosome inactivation in the regulation of immune response activity uniquely in females. Sexually dimorphic regulation of MMP/ADAMTS metalloproteinases and their intrinsic X-linked regulator Timp1 contributes to extracellular matrix remodeling integrated with pro-regenerative and immune functions. Lexis1 non-coding RNA involved in LXR-mediated lipid metabolism was identified as a novel nerve injury marker. Together, our data identified unique early response triggers of sex-specific peripheral nerve injury regulation to gain mechanistic insights into the origin of female- and male-prevalent sensory neuropathies.
Misreporting of Energy Intake From Food Records Completed by Adolescents: Associations With Sex, Body Image, Nutrient, and Food Group Intake
Authors: Jones Louise , Ness Andy , Emmett Pauline
Published: December 2021

Background and Objectives:A healthy diet during adolescence is important for growth and pubertal development. Assessing the diet of adolescents may be challenging as the behavioural factors and food habits which impact on what they eat may also affect how they report dietary intake. This study assesses factors associated with the misreporting of dietary intake.

Methods:Adolescents (n= 4,844; average age 13.8 years) from the Avon Longitudinal Study of Parents and Children (ALSPAC) completed a 3-day diet record. Misreporting was estimated using an individualised method, and adolescents were categorised by reporting status. Foods were categorised as core and noncore foods to evaluate diet quality. Body composition measurements were recorded at a research clinic. Information on dieting, weight concern, family socioeconomic status, and parental BMI were collectedviaquestionnaires. Binary logistic regression was performed, in boys and girls separately, to investigate factors associated with underreporting of dietary intake.

Results:Girls were much more likely than boys to be dissatisfied with their weight and to diet, but showed similar levels of underreporting (~67%). In adjusted regression analysis underreporters (UR) were more likely to be overweight or obese: OR in boys 2.8 (95% CI 1.7–4.8) and in girls 2.2 (95% CI 1.5–3.2). Dissatisfaction with weight and dieting were positively associated, and perception of being underweight negatively associated with underreporting in boys. Perception of being overweight, dieting, and exact age were positively associated with underreporting in girls. UR obtained a greater percentage of energy from protein and a smaller percentage of energy from fat; they reported greater intake of core foods and lower intakes of non-core foods than plausible reporters.

Conclusion:A large proportion of adolescents underreported their dietary energy intake. This was associated with their body weight status and body image and had a differential effect on their estimated food and macronutrient intakes. Assessment of misreporting status is essential when collecting and interpreting dietary information from adolescents.
NDUFC1 Is Upregulated in Gastric Cancer and Regulates Cell Proliferation, Apoptosis, Cycle and Migration
Authors: Xu Liang , Chen Xiuxiu , Jiang Hongtao , Xu Jian , Wang Lixia , Sun Yuemin
Published: December 2021

Gastric cancer is one of the most common primary tumors of the digestive system. NADH: ubiquinone oxidoreductase subunit C1 (NDUFC1), which is an accessory subunit of the NADH dehydrogenase (complex I), is responsible for the transportation of electrons from NADH to the respiratory chain essential for the oxidative phosphorylation. However, little is known about the roles of NDUFC1 in carcinogenesis. In this study, NDUFC1 protein level in NSCLC tissues was tested by immunohistochemistry (IHC) staining. NDUFC1 mRNA level in gastric cancer cell lines was determined by qRT-PCR. MGC-803 and SGC-7901 cells were transfected with shNDUFC1 lentivirus designed to silence NDUFC1. MTT assay, CCK8 assay, wound healing assay and transwell migration assay were conducted. Cell cycle and apoptosis were detected by flow cytometry. In vivo experiments were performed using nude mice. The results indicated that overexpressed NDUFC1 in gastric cancer was related to more serious tumor infiltrates, a higher risk of lymphatic metastasis, a higher proportion of positive lymph nodes, and a more advanced tumor stage. Compared with shCtrl groups, MGC-803 and SGC-7901 of shNDUFC1 groups had lower abilities of proliferation and migration, higher levels of apoptosis. NDUFC1 knockdown also inhibited SGC-7901 cell growth in vivo and suppressed Ki67 expression in xenograft tumors. More importantly, we found that NDUFC1 downregulation made the levels of P-Akt, P-mTOR, CCND1, CDK6, PIK3CA, Bcl-2, Survivin, and XIAP decreased, and that PI3K/AKT signaling pathway agonist SC79 rescued the inhibitory effects on cell proliferation and migration, reversed the promoted effects on cell apoptosis caused by NDUFC1 knockdown. More importantly, compared with NDUFC1 knockdown group, the expression of P-Akt, Bcl-2, Survivin, and XIAP was raised in shNDUFC1 + SC79 group. Thus, our suspicion was that NDUFC1 exacerbates NSCLC progression via PI3K/Akt pathway. Taken together, our study indicated that targeting NDUFC1 could open innovative perspectives for new multi-targeting approaches in the treatment of gastric cancer.
Role of HMGB1 in Cisplatin-Persistent Lung Adenocarcinoma Cell Lines
Authors: Chavez-Dominguez Rodolfo L. , Perez-Medina Mario A. , Lopez-Gonzalez Jose S. , Galicia-Velasco Miriam , Matias-Florentino Margarita , Avila-Rios Santiago , Rumbo-Nava Uriel , Salgado-Aguayo Alfonso , Gonzalez-Gonzalez Claudia , Aguilar-Cazares Dolores
Published: December 2021

Significant advances have been made recently in the development of targeted therapy for lung adenocarcinoma. However, platinum-based chemotherapy remains as the cornerstone in the treatment of this neoplasm. This is the treatment option for adenocarcinomas without EGFR gain-of-function mutations or tumors that have developed resistance to targeted therapy. The High-Mobility Group Box 1 (HMGB1) is a multifunctional protein involved in intrinsic resistance to cisplatin. HMGB1 is released when cytotoxic agents, such as cisplatin, induce cell death. In the extracellular milieu, HMGB1 acts as adjuvant to induce an antitumor immune response. However, the opposite effect favoring tumor progression has also been reported. In this study, the effects of cisplatin in lung adenocarcinoma cell lines harboring clinically relevant mutations, such as EGFR mutations, were studied. Subcellular localization of HMGB1 was detected in the cell lines and in viable cells after a single exposure to cisplatin, which are designated as cisplatin-persistent cells. The mRNA expression of the receptor for advanced glycation end products (RAGE), TLR-2, and TLR-4 receptors was measured in parental cell lines and their persistent variants. Finally, changes in plasma HMGB1 from a cohort of lung adenocarcinoma patients without EGFR mutation and treated with cisplatin-based therapy were analyzed. Cisplatin-susceptible lung adenocarcinoma cell lines died by apoptosis or necrosis and released HMGB1. In cisplatin-persistent cells, nuclear relocalization of HMGB1 and overexpression of HMGB1 and RAGE, but not TLR-2 or TLR-4, were observed. In tumor cells, this HMGB1–RAGE interaction may be associated with the development of cisplatin resistance. The results indicate a direct relationship between the plasma levels of HMGB1 and overall survival. In conclusion, HMGB1 may be an effective biomarker associated with increased overall survival of lung adenocarcinoma patients.
Circular RNA CircPVT1 Inhibits 5-Fluorouracil Chemosensitivity by Regulating Ferroptosis Through MiR-30a-5p/FZD3 Axis in Esophageal Cancer Cells
Authors: Yao Wenjian , Wang Jianjun , Meng Fanruo , Zhu Zibo , Jia Xiangbo , Xu Lei , Zhang Quan , Wei Li
Published: December 2021

Background

CircPVT1 is demonstrated to promote cancer progression in esophageal squamous cell carcinoma (ESCC). However, the role and potential functional mechanisms of circPVT1 in regulating 5-fluorouracil (5-FU) chemosensitivity remain largely unknown.

Methods

ESCC cells resistant to 5-FU were induced with continuous increasing concentrations of 5-FU step-wisely. A cell counting kit-8 assay was used to analyze the viability of ESCC cells. LDH release assay kit was used to evaluate the cytotoxicity. RT-qPCR was used to assess the expression level of non-coding RNAs and cDNAs. Luciferase was used to confirm the interaction between non-coding RNAs and targets. Western blotting was used to detect the expression of downstream signaling proteins. Flow cytometry and ferroptosis detection assay kit were utilized to measure the ferroptosis of ESCC cells.

Results

CircPVT1 was significantly upregulated in ESCC cells resistant to 5-FU. Knockdown of circPVT1 enhanced the 5-FU chemosensitivity of ESCC cells resistant to 5-FU by increasing cytotoxicity and downregulating multidrug-resistant associated proteins, including P-gp and MRP1. Luciferase assay showed that circPVT1 acted as a sponge of miR-30a-5p, and Frizzled3 (FZD3) was a downstream target of miR-30a-5p. The enhanced 5-FU chemosensitivity by circPVT1 knockdown was reversed with miR-30a-5p inhibitor. Besides, the increased 5-FU chemosensitivity by miR-30a-5p mimics was reversed with FZD3 overexpression. Furthermore, knockdown of circPVT1 increased ferroptosis through downregulating p-β-catenin, GPX4, and SLC7A11 while miR-30a-5p inhibition and FZD3 overexpression reversed the phenotype by upregulating p-β-catenin, GPX4, and SLC7A11.

Conclusions

These results suggested a key role for circPVT1 in ESCC 5-FU-chemosensitivity in regulating the Wnt/β-catenin pathway and ferroptosis via miR-30a-5p/FZD3 axis, which might be a potential target in ESCC therapy.
Case Report: Early Association of Vemurafenib to Standard Chemotherapy in Multisystem Langerhans Cell Histiocytosis in a Newborn: Taking a Chance for a Better Outcome?
Authors: Gaspari Stefania , Di Ruscio Valentina , Stocchi Francesca , Carta Roberto , Becilli Marco , De Ioris Maria Antonietta
Published: December 2021

Langerhans cell histiocytosis (LCH) is due to aberrant monoclonal proliferation and accumulation of dendritic cells, ranging from a self-limiting local condition to a rapidly progressive multisystem disease with poor prognosis. Pathogenic cells originate from a myeloid-derived precursor characterized by an activation of the MAPK/ERK signaling pathway in about 70% of cases. In particular, BRAF V600E mutation is usually associated with a more severe clinical course and poor response to chemotherapy. We report on a newborn with multisystem LCH in life-threatening medical conditions. At diagnosis, the patient was successfully treated with the early association of BRAF inhibitor Vemurafenib to standard chemotherapy representing a new approach in first-line treatment. A rapid clinical improvement with a prompt fever regression from day 2 and complete resolution of skin lesions by week 2 were observed; laboratory data normalized as well. Vemurafenib was discontinued after 12 months of treatment. No signs of relapse occurred after 12 months of discontinuation. This case indicates that early combination of target therapy with standard treatment may induce rapid response and prolonged disease remission without significant toxicities in infants. This approach represents a valid and safe option as first-line treatment in multisystem disease, especially in high-risk patients.
Differential Serum and Urine CRP, IP-10, and TRAIL Levels in Pediatric Urinary Tract Infection
Authors: Ashkenazi-Hoffnung Liat , Livni Gilat , Scheuerman Oded , Berger Itay , Eden Eran , Oved Kfir , Shani Liran , Kronenfeld Gali , Simon Einav , Boico Olga , Navon Roy , Gottlieb Tanya M. , Barash Eran , Paz Meital , Yuhas Yael , Berent Eva , Ashkenazi Shai
Published: December 2021

Background: It is estimated that clinical evaluation and urinalysis are unable to diagnose >10% of urinary tract infections (UTI) in young children. TNF-related apoptosis induced ligand (TRAIL), interferon gamma induced protein-10 (IP-10), and C-reactive protein (CRP) exhibit differential expression in the blood in response to bacterial vs. viral infection. We assessed if the urinary and serum levels of these host biomarkers discriminate UTI, nephronia, and response to antibiotic treatment.

Methods: Hospitalized febrile children aged <18 years with suspected UTI based on abnormal urinalysis were recruited prospectively between 2016 and 2018; also, non-febrile controls were recruited. Following urine culture results and hospitalization course, participants were divided into three groups based on AAP criteria and expert adjudication: UTI, viral infection, and indeterminate.

Results: Seventy-three children were enrolled, 61 with suspected UTI and 12 non-febrile controls. Of the 61 with suspected UTI, 40 were adjudicated as UTI, 10 viral infection, and 11 as indeterminate. Urinary CRP and IP-10 levels were significantly higher in the UTI group (p ≤ 0.05). Urinary CRP differentiated UTI from non-bacterial etiology in children under and over 3 months of age, with AUCs 0.98 (95% CI: 0.93–1.00) and 0.82 (0.68–0.95), respectively. Similarly, urinary IP-10 discriminated with AUCs of 0.80 (0.59–1.00) and 0.90 (0.80–1.00), respectively. Serum CRP and IP-10 levels were significantly higher in UTI cases with nephronia (p ≤ 0.03). UTI-induced changes in the levels of urinary and serum biomarkers resolved during recovery.

Conclusions: CRP, IP-10, and TRAIL represent biomarkers with potential to aid the clinician in diagnosis and management of UTI.
New Insights Into Cancer Chronotherapies
Authors: Zhou Jingxuan , Wang Jiechen , Zhang Xiaozhao , Tang Qingming
Published: December 2021

Circadian clocks participate in the coordination of various metabolic and biological activities to maintain homeostasis. Disturbances in the circadian rhythm and cancers are closely related. Circadian clock genes are differentially expressed in many tumors, and accelerate the development and progression of tumors. In addition, tumor tissues exert varying biological activities compared to normal tissues due to resetting of altered rhythms. Thus, chronotherapeutics used for cancer treatment should exploit the timing of circadian rhythms to achieve higher efficacy and mild toxicity. Due to interpatient differences in circadian functions, our findings advocate an individualized precision approach to chronotherapy. Herein, we review the specific association between circadian clocks and cancers. In addition, we focus on chronotherapies in cancers and personalized biomarkers for the development of precision chronotherapy. The understanding of circadian clocks in cancer will provide a rationale for more effective clinical treatment of tumors.
Coffee Consumption and Non-alcoholic Fatty Liver Disease: An Umbrella Review and a Systematic Review and Meta-analysis
Authors: Kositamongkol Chayanis , Kanchanasurakit Sukrit , Auttamalang Chiraphong , Inchai Nutkamon , Kabkaew Thanatchaporn , Kitpark Sarunporn , Chaiyakunapruk Nathorn , Duangjai Acharaporn , Saokaew Surasak , Phisalprapa Pochamana
Published: December 2021

Background: The effects of coffee consumption on hepatic outcomes are controversial. This study investigated the associations between coffee consumption and the incidence of non-alcoholic fatty liver disease (NAFLD) in the general population and the reduction of liver fibrosis among patients with NAFLD.

Methods: The study consisted of two parts: an umbrella review and a systematic review and meta-analysis (SRMA). The searches for each part were performed separately using PubMed, EMBASE, Cochrane, Scopus, and CINAHL databases. All articles published up to September 2021 were reviewed. To be eligible, studies for the umbrella review were required to report outcomes that compared the risks of NAFLD in the general population and/or liver fibrosis in patients with NAFLD who did and did not drink coffee. Our SRMA included primary studies reporting the effects of coffee consumption on NAFLD-related outcomes. The outcomes were pooled using a random-effects model and reported in both qualitative and quantitative terms (pooled risk ratio, odds ratio, and weighted mean difference).

Results: We identified four published SRMAs during the umbrella review. Most studies showed that individuals in the general population who regularly drank coffee were significantly associated with a lower NAFLD incidence than those who did not. Our SRMA included nine studies on the effects of coffee consumption on NAFLD incidence. Pooled data from 147,875 subjects showed that coffee consumption was not associated with a lower NAFLD incidence in the general population. The between-study heterogeneity was high (I2, 72–85%). Interestingly, among patients with NAFLD (5 studies; n = 3,752), coffee consumption was significantly associated with a reduction in liver fibrosis (odds ratio, 0.67; 95% CI, 0.55 to 0.80; I2, 3%). There were no differences in the coffee consumption of the general population and of those with NAFLD (4 studies; n = 19,482) or by patients with no/mild liver fibrosis and those with significant fibrosis (4 studies; n = 3,331).

Conclusions: There are contrasting results on the effects of coffee on NAFLD prevention in the general population. Benefits of coffee consumption on liver fibrosis were seen among patients with NAFLD.

Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021226607, identifier CRD42021226607
Collisions of Nucleons with Atoms: Calculated Cross Sections and Monte Carlo Simulation
Authors: Salvat Francesc , Quesada José Manuel
Published: December 2021

After a summary description of the theory of elastic collisions of nucleons with atoms, we present the calculation of a generic database of differential and integrated cross sections for the simulation of multiple elastic collisions of protons and neutrons with kinetic energies larger than 100 keV. The relativistic plane-wave Born approximation, with binding and Coulomb-deflection corrections, has been used to calculate a database of proton-impact ionization of K-shell and L-, M-, and N-subshells of neutral atoms These databases cover the whole energy range of interest for all the elements in the periodic system, from hydrogen to einsteinium (Z = 1–99); they are provided as part of the penh distribution package. The Monte Carlo code system penh for the simulation of coupled electron-photon-proton transport is extended to account for the effect of the transport of neutrons (released in proton-induced nuclear reactions) in calculations of dose distributions from proton beams. A simplified description of neutron transport, in which neutron-induced nuclear reactions are described as a fractionally absorbing process, is shown to give simulated depth-dose distributions in good agreement with those generated by the Geant4 code. The proton-impact ionization database, combined with the description of atomic relaxation data and electron transport in penelope, allows the simulation of proton-induced x-ray emission spectra from targets with complex geometries.