bluuebunny/crossref_metadata_2025 huggingface dataset:
Establishment of a human pluripotent stem cell-derived MKX-td Tomato reporter system
Authors: Fujisawa Yuki , Ming Lu , Yamada Daisuke , Takao Tomoka , Takarada Takeshi
Published: November 2022

Tendon regeneration is difficult because detailed knowledge about tendon progenitor cells (TPCs), which produce tenocytes to repair tendon tissue, has not been revealed. Mohawk homeobox (MKX) is a marker of TPCs or tenocytes, but a human pluripotent stem cell (hPSC)-based reporter system that visualizes MKX+ cells has not been developed. Here, we established an hPSC-derived MKX-tdTomato reporter cell line and tested the induction ratio of MKX-tdTomato+ cells using our stepwise/xeno-free differentiation protocol. MKX-tdTomato+ cells were generated with high efficiency and expressed tendon-specific markers, including MKX, SCX, TNMD, and COL1A1. Our MKX-tdTomato hPSC line would be a useful tool for studying the development or regeneration of tendon tissue.
Recent advances on small molecules in osteogenic differentiation of stem cells and the underlying signaling pathways
Authors: Ahmadi Armin , Mazloomnejad Radman , Kasravi Mohammadreza , Gholamine Babak , Bahrami Soheyl , Sarzaeem Mohammad Mahdi , Niknejad Hassan
Published: November 2022

Bone-related diseases are major contributors to morbidity and mortality in elderly people and the current treatments result in insufficient healing and several complications. One of the promising areas of research for healing bone fractures and skeletal defects is regenerative medicine using stem cells. Differentiating stem cells using agents that shift cell development towards the preferred lineage requires activation of certain intracellular signaling pathways, many of which are known to induce osteogenesis during embryological stages. Imitating embryological bone formation through activation of these signaling pathways has been the focus of many osteogenic studies. Activation of osteogenic signaling can be done by using small molecules. Several of these agents, e.g., statins, metformin, adenosine, and dexamethasone have other clinical uses but have also shown osteogenic capacities. On the other hand, some other molecules such as T63 and tetrahydroquinolines are not as well recognized in the clinic. Osteogenic small molecules exert their effects through the activation of signaling pathways known to be related to osteogenesis. These pathways include more well-known pathways including BMP/Smad, Wnt, and Hedgehog as well as ancillary pathways including estrogen signaling and neuropeptide signaling. In this paper, we review the recent data on small molecule-mediated osteogenic differentiation, possible adjunctive agents with these molecules, and the signaling pathways through which each small molecule exerts its effects.

Graphical Abstract
How Streptococcus suis escapes antibiotic treatments
Authors: Uruén Cristina , García Carla , Fraile Lorenzo , Tommassen Jan , Arenas Jesús
Published: November 2022

Streptococcus suisis a zoonotic agent that causes sepsis and meningitis in pigs and humans.S. suisinfections are responsible for large economic losses in pig production. The lack of effective vaccines to prevent the disease has promoted the extensive use of antibiotics worldwide. This has been followed by the emergence of resistance against different classes of antibiotics. The rates of resistance to tetracyclines, lincosamides, and macrolides are extremely high, and resistance has spread worldwide. The genetic origin ofS. suisresistance is multiple and includes the production of target-modifying and antibiotic-inactivating enzymes and mutations in antibiotic targets.S. suisgenomes contain traits of horizontal gene transfer. Many mobile genetic elements carry a variety of genes that confer resistance to antibiotics as well as genes for autonomous DNA transfer and, thus,S. suiscan rapidly acquire multiresistance. In addition,S. suisforms microcolonies on host tissues, which are associations of microorganisms that generate tolerance to antibiotics through a variety of mechanisms and favor the exchange of genetic material. Thus, alternatives to currently used antibiotics are highly demanded. A deep understanding of the mechanisms by whichS. suisbecomes resistant or tolerant to antibiotics may help to develop novel molecules or combinations of antimicrobials to fight these infections. Meanwhile, phage therapy and vaccination are promising alternative strategies, which could alleviate disease pressure and, thereby, antibiotic use.
FABP4-mediated lipid droplet formation in Streptococcus uberis-infected macrophages supports host defence
Authors: Wan Zhixin , Fu Shaodong , Wang Zhenglei , Xu Yuanyuan , Zhou Yuanyuan , Lin Xinguang , Lan Riguo , Han Xiangan , Luo Zhenhua , Miao Jinfeng
Published: November 2022

Foamy macrophages containing prominent cytoplasmic lipid droplets (LDs) are found in a variety of infectious diseases. However, their role in Streptococcus uberis-induced mastitis is unknown. Herein, we report that S. uberis infection enhances the fatty acid synthesis pathway in macrophages, resulting in a sharp increase in LD levels, accompanied by a significantly enhanced inflammatory response. This process is mediated by the involvement of fatty acid binding protein 4 (FABP4), a subtype of the fatty acid-binding protein family that plays critical roles in metabolism and inflammation. In addition, FABP4 siRNA inhibitor cell models showed that the deposition of LDs decreased, and the mRNA expression of Tnf, Il1b and Il6 was significantly downregulated after gene silencing. As a result, the bacterial load in macrophages increased. Taken together, these data demonstrate that macrophage LD formation is a host-driven component of the immune response to S. uberis. FABP4 contributes to promoting inflammation via LDs, which should be considered a new target for drug development to treat infections.
Identification of protein profile in metacyclic and amastigote-like stages of Leishmania tropica: a proteomic approach
Authors: Ashrafmansouri Marzieh , Amiri-Dashatan Nasrin , Ahmadi Nayebali
Published: November 2022

Leishmaniasis is a tropical disease that leads to various clinical phenotypes. This study aimed to investigate protein expression changes in metacyclic and amastigote-like stages of L. tropica isolated from Iranian cutaneous leishmaniasis patients. Isolated samples were cultured and species type identified using PCR–RFLP technique. The promastigotes were grown in RPMI1640 media and differentiated to metacyclic and amastigote-like forms, followed by the extracted proteins of both successive stages carried out for proteomics and bioinformatics analysis. Using SWATH-MS quantitative proteomics technique, a total 176 and 155 distinct proteins were identified in metacyclic and axenic amastigote stages, respectively. Of these, 65 proteins were altered significantly (p-value < 0.05 and fold change ≥ 2) between studied stages. Several gene ontology (GO) categories were enriched for biological process during conversion of metacyclic promastigotes into amastigote-like, which “metabolic process” (GO: 0044281, P-Value: 6.52e-5), and “translation” (GO: 0006412, p-value: 5.01e–14) were disclosed as the top category in up and down-regulated proteins, respectively. Also, the KEGG pathway analysis indicated “metabolic pathways” and “ribosome” term as the most important pathways in up and down-regulated proteins, respectively. According to protein interaction network analysis, enolase (ENOL) has been detected as main hub proteins during differentiation, followed by Putative NADH-dependent fumarate reductase (LmjF.35.1180) and 40S ribosomal protein S2 (LmjF.32.0450). Overall, protein changes possibly play important roles in L. tropica biology. Anabolic pathways were down-regulated, whereas catabolic pathways were up-regulated during L. tropica differentiation. These protein expression changes could provide parasite survival in host macrophages, and could use as novel potential drug and vaccine targets for leishmaniasis.

Graphical Abstract
mTORC1-c-Myc pathway rewires methionine metabolism for HCC progression through suppressing SIRT4 mediated ADP ribosylation of MAT2A
Authors: Zhao Liang , Su Huizhao , Liu Xiaomeng , Wang Hongquan , Feng Yukuan , Wang Yan , Chen Haiqiang , Dai Luo , Lai Shihui , Xu Siqi , Li Chong , Hao Jihui , Tang Bo
Published: November 2022

Background

Exploiting cancer metabolism during nutrient availability holds immense potential for the clinical and therapeutic benefits of hepatocellular carcinoma (HCC) patients. Dietary methionine is a metabolic dependence of cancer development, but how the signal transduction integrates methionine status to achieve the physiological demand of cancer cells remains unknown.

Methods

Low or high levels of dietary methionine was fed to mouse models with patient-derived xenograft or diethyl-nitrosamine induced liver cancer. RNA sequence and metabolomics were performed to reveal the profound effect of methionine restriction on gene expression and metabolite changes. Immunostaining, sphere formation assays, in vivo tumourigenicity, migration and self-renewal ability were conducted to demonstrate the efficacy of methionine restriction and sorafenib.

Results

We discovered that mTORC1-c-Myc-SIRT4 axis was abnormally regulated in a methionine-dependent manner and affected the HCC progression. c-Myc rewires methionine metabolism through TRIM32 mediated degradation of SIRT4, which regulates MAT2A activity by ADP-ribosylation on amino acid residue glutamic acid 111. MAT2A is a key enzyme to generate S-adenosylmethionine (SAM). Loss of SIRT4 activates MAT2A, thereby increasing SAM level and dynamically regulating gene expression, which triggers the high proliferation rate of tumour cells. SIRT4 exerts its tumour suppressive function with targeted therapy (sorafenib) by affecting methionine, redox and nucleotide metabolism.

Conclusions

These findings establish a novel characterization of the signaling transduction and the metabolic consequences of dietary methionine restriction in malignant liver tissue of mice. mTORC1, c-Myc, SIRT4 and ADP ribosylation site of MAT2A are promising clinical and therapeutic targets for the HCC treatment.
Right ventricular free wall longitudinal strain is independently associated with mortality in mechanically ventilated patients with COVID-19
Authors: McErlane James , McCall Philip , Willder Jennifer , Berry Colin , Shelley Ben ,   the COVID-RV investigators, Reece A. , Kitchen C. , Gillies M. , Dabek V. , Irvine V. , MacBrayne J. , Sim K. , Scott T. , Trumper E. , Savage F. , Allan A. , Falconer J. , Coutts A. , McDonald A. , Rutherford J. , Christie D. , Jardine C. , Puxty A. , Hughes M. , Cathcart S. , Sim M. , Docking B. , Thornton M. , Greatorex B. , Rae J. , Barr C. , Bradley C. , Barrett F. , Campbell R. , Clarke N. , Mascarenhas M. , Matheson J. , McDonald D. , O Hara M. , O keeffe L. , Gemmell L. , Price R. , McHendry M. , McLaughlan D. , Herman C. , Elliot H. , Meehan S. , Allan J. , Finn D. , Brannan G. , Wood S. , Watson T. , Ross K. , Tatarkowska N. , Boyle R. , Lee E. , Strachan D. , Morrison A. , Lucie P. , Lochrin C. , Clements S. , Vigni D. , Stanley B. , Messow C. M.
Published: November 2022

Background

Right ventricular (RV) dysfunction has been commonly reported in patients with Coronavirus disease 2019 (COVID-19), and is associated with mortality in mixed cohorts of patients requiring and not requiring invasive mechanical ventilation (IMV). Using RV-speckle tracking echocardiography (STE) strain analysis, we aimed to identify the prevalence of RV dysfunction (diagnosed by abnormal RV-STE) in patients with COVID-19 that are exclusively undergoing IMV, and assess association between RV dysfunction and 30 day mortality. We performed a prospective multicentre study across 10 ICUs in Scotland from 2/9/20 to 22/3/21. One-hundred-and-four echocardiography scans were obtained from adult patients at a single timepoint between 48 h after intubation, and day 14 of intensive care unit admission. We analysed RV-STE using RV free-wall longitudinal strain (RVFWLS), with an abnormal cutoff of  > −20%. We performed survival analysis using Kaplan–Meier, log rank, and multivariate cox-regression (prespecified covariates were age, gender, ethnicity, severity of illness, and time since intubation).

Results

Ninety-four/one-hundred-and-four (90.4%) scans had images adequate for RVFWLS. Mean RVFWLS was −23.0% (5.2), 27/94 (28.7%) of patients had abnormal RVFWLS. Univariate analysis with Kaplan–Meier plot and log-rank demonstrated that patients with abnormal RVFWLS have a significant association with 30-day mortality (p = 0.047). Multivariate cox-regression demonstrated that abnormal RVFWLS is independently associated with 30-day mortality (Hazard-Ratio 2.22 [1.14–4.39], p = 0.020).

Conclusions

Abnormal RVFWLS (> −20%) is independently associated with 30-day mortality in patients with COVID-19 undergoing IMV. Strategies to prevent RV dysfunction, and treatment when identified by RVFWLS, may be of therapeutic benefit to these patients.

Trial Registration: Retrospectively registered 21st Feb 2021. ClinicalTrials.gov Identifier: NCT04764032.
Adverse outcomes with extracorporeal adsorbent blood treatments in toxic systemic inflammation: a perspective on possible mechanisms
Authors: Matson James , Lange Paul , Honore Patrick M. , Chung Kevin K.
Published: November 2022

Background

Extracorporeal blood purification (EBP) treatments may be used in patients with sepsis and related conditions to mitigate toxic systemic inflammation, prevent or reverse vital organ injury, and improve outcome. These treatments lack demonstrable efficacy, but are generally considered safe. However, since late 2020, four clinical studies of EBP treatment using adsorbent devices in inflammatory disease reported significantly increased patient mortality associated with the adsorbent treatments. Criticisms of study design and execution were published, but revealed no decisive flaws. None of these critiques considered possible toxic effects of the adsorbent treatments per se.

Perspective and conclusion

In adsorbent EBP treatment of systemic inflammatory disease the adsorbent media are deployed in patient blood or plasma flow for the purpose of broad spectrum, non-specific adsorptive removal of inflammatory mediators. Adsorption and sequestration of inflammatory mediators by adsorbent media is intended to reduce mediator concentrations in circulating blood and neutralize their activity. However, in the past two decades developments in both biomedical engineering and the science of cytokine molecular dynamics suggest that immobilization of inflammatory proteins on solid scaffolds or molecular carriers may stabilize protein structure and preserve or amplify protein function. It is unknown if these mechanisms are operative in EBP adsorbent treatments. If these mechanisms are operative, then the adsorbent medium could become reactive, promoting inflammatory activity which could result in negative outcomes. Considering the recent reports of harm with adsorbent treatments in diverse inflammatory conditions, caution urges investigation of these potentially harmful mechanisms in these devices. Candidate mechanisms for possible inquiry are discussed.
Effective maNagement of depression among patients witH cANCEr (ENHANCE): a protocol for a hybrid systematic review and network meta-analysis of randomised controlled trials of interventions for depressive symptoms
Authors: Pertl Maria M. , Perez Sergio , Collier Sonya , Guinan Emer , Monahan Garret , Verling Katie , Wallace Emma , Walsh Aisling , Doyle Frank
Published: November 2022

Background

Depression is common among patients with cancer and is associated with lower treatment participation, lower satisfaction with care, poorer quality of life, greater symptom burden and higher healthcare costs. Various types of interventions (e.g. pharmacological, psychotherapy) are used for the treatment of depression. However, evidence for these among patients with cancer is limited. Furthermore, the relative effectiveness and acceptability of different approaches are unknown because a direct comparison between all available treatments has not been carried out. We will address this by conducting a network meta-analysis (NMA) of interventions for depression among people with cancer using a hybrid overview of reviews and systematic review methodology.

Methods

We will search for and extract data from systematic reviews of randomised controlled trials (RCTs) of depression interventions for patients with cancer from inception, before performing a supplemental search for more recent RCTs. We will include RCTs comparing pharmacological, psychotherapy, exercise, combination therapy, collaborative care or complementary and alternative medicine interventions with pill placebo, no treatment, waitlist, treatment as usual or minimal treatment control groups, or directly in head-to-head trials, among adults who currently have cancer or have a history of any cancer and elevated depressive symptoms (scores above a cut-off on validated scales or meeting diagnostic criteria). Our primary outcomes will be change in depressive symptoms (standardised mean difference) and intervention acceptability (% who withdrew). Our secondary outcomes will be 6-month change in depressive symptoms, health-related quality of life, adverse events and mortality. We will independently screen for eligibility, extract data and assess risk of bias using the RoB 2 tool. We will use frequentist random-effects multivariate NMA in Stata, rankograms and surface under the cumulative ranking curves to synthesise evidence and obtain a ranking of intervention groups. We will explore heterogeneity and inconsistency using local and global measures and evaluate the credibility of results using the Confidence in NEtwork Meta-Analysis (CINeMA) framework.

Discussion

Our findings will provide the best available evidence for managing depression among patients with cancer. Such information will help to inform clinical guidelines, evidence-based treatment decisions and future research by identifying gaps in the current literature.

Systematic review registration

Submitted to PROSPERO (record number: 290145), awaiting registration.
Evidence for pharmacological interventions to reduce cardiovascular risk for patients with chronic kidney disease: a study protocol of an evidence map
Authors: Colombijn Julia M. T. , Idema Demy L. , van der Braak Kim , Spijker Rene , Meijvis Sabine C. A. , Bots Michiel L. , Hooft Lotty , Verhaar Marianne C. , Vernooij Robin W. M.
Published: November 2022

Background

Patients with chronic kidney disease (CKD) require a personalised strategy for cardiovascular risk management (CVRM) to reduce their high risk of cardiovascular morbidity and mortality. Despite their high risk, patients with CKD appear to be underrepresented in randomised controlled trials (RCTs) for pharmacological CVRM interventions to reduce cardiovascular risk (pharmacological CVRM interventions). As a result, it remains unclear whether the efficacy of these interventions found in patients without CKD is similarly applicable to patients with CKD. This evidence map aims to provide an overview of the availability of the evidence from pharmacological CVRM trials for patients with CKD by assessing how often patients with reduced kidney function are specifically excluded or included from RCTs on pharmacological CVRM interventions and whether studies report efficacy estimates of interventions specifically for kidney patients.

Methods

We will perform a systematic literature search in ClinicalTrials.gov to identify relevant planned, ongoing, and completed RCTs on a broad range of CVRM medications after which we will retrieve the published protocols and papers via ClinicalTrials.gov itself, Embase, MEDLINE, or Google Scholar. We will include RCTs that investigate the efficacy of platelet inhibitors, anticoagulants, antihypertensives, glucose-lowering medication, and lipid-lowering medication on all-cause mortality, cardiovascular mortality, cardiovascular morbidity, and end-stage kidney disease in patients with a cardiovascular history or a major risk factor for cardiovascular disease. Two reviewers will independently screen trial records and their corresponding full-text publications to determine eligibility and extract data. Outcomes of interest are the exclusion of patients with reduced kidney function from RCTs and whether the study population was restricted to kidney patients or subgroup analyses were performed on kidney function. Results will be visualised in an evidence map.

Discussion

The availability of evidence on the efficacy and safety of pharmacological CVRM interventions in patients with CKD might be limited. Hence, we will identify knowledge gaps for future research. At the same time, the availability of evidence, or lack thereof, might warrant caution from healthcare decision-makers in making strong recommendations based on the extrapolation of results from studies to patients who were explicitly excluded from participation.

Systematic review registration

PROSPERO CRD42022296746.
Roles of N6-methyladenosine (m6A) modifications in gynecologic cancers: mechanisms and therapeutic targeting
Authors: Chen Jiahua , Guo Bao , Liu Xiaojing , Zhang Jing , Zhang Junhui , Fang Yuan , Zhu Suding , Wei Bing , Cao Yunxia , Zhan Lei
Published: November 2022

Uterine and ovarian cancers are the most common gynecologic cancers. N6−methyladenosine (m6A), an important internal RNA modification in higher eukaryotes, has recently become a hot topic in epigenetic studies. Numerous studies have revealed that the m6A-related regulatory factors regulate the occurrence and metastasis of tumors and drug resistance through various mechanisms. The m6A-related regulatory factors can also be used as therapeutic targets and biomarkers for the early diagnosis of cancers, including gynecologic cancers. This review discusses the role of m6A in gynecologic cancers and summarizes the recent advancements in m6A modification in gynecologic cancers to improve the understanding of the occurrence, diagnosis, treatment, and prognosis of gynecologic cancers.
Anticipatory and consummatory pleasure in eating disorders
Authors: Dolan Sarah C. , Reilly Erin E. , Brown Tiffany A. , Shott Megan E. , Frank Guido K. W.
Published: November 2022

Background

Recent research suggests that anhedonia, or the inability to experience pleasure, is elevated in individuals with eating disorders (EDs). However, past literature has only studied anhedonia in EDs as a unidimensional construct rather than separately examining anticipatory (i.e., prediction of pleasure for a future event) and consummatory (i.e., enjoyment of a present event) pleasure. Given that these subcomponents of pleasure have distinct neurobiological correlates, studying pleasure as a multifaceted construct may yield important insights into the underlying mechanisms of binge eating or food restriction.

Methods

A sample of 124 women with anorexia nervosa, bulimia nervosa, or other specified feeding or eating disorder and 84 control women (CW) completed self-report measures of anticipatory pleasure, consummatory pleasure, ED symptoms, depression, harm avoidance, and anxiety.

Results

Individuals with EDs endorsed significantly lower anticipatory pleasure than CW, but there were no significant group differences in consummatory pleasure. Further, there were no significant differences in self-reported pleasure among ED diagnostic groups. Within the ED sample, anticipatory pleasure but not consummatory pleasure was positively related to binge eating frequency and significantly negatively correlated with cognitive ED symptoms, state and trait anxiety, and harm avoidance. Both anticipatory and consummatory pleasure was negatively associated with depression.

Conclusion

The results of the current study suggest that lower pleasure across the ED spectrum may be due to deficits in anticipatory, but not consummatory, pleasure. Future research should continue to explore the behavioral, affective, and neural correlates of anticipatory pleasure in EDs to characterize better how it relates to the onset and maintenance of binge eating and other eating disorder pathology.
Visuospatial perspective-taking in social-emotional development: enhancing young children’s mind and emotion understanding via block building training
Authors: Caldwell Melissa Pearl , Cheung Him , Cheung Sum-Kwing , Li Jian-Bin , Carrey Siu Tik-Sze
Published: November 2022

Background

Theory of Mind (ToM) refers to the ability to represent one's own and others' mental states, and emotion understanding involves appropriately comprehending and responding to others' emotional cues in social interactions. Individual differences in mind and emotion understanding have been associated strongly with verbal ability and interaction and, as such, existing training for children's ToM and emotion understanding is mostly language-based. Building on the literature on embodied cognition, this study proposes that mind and emotion understanding could be facilitated by one's visuospatial experience in simulating other's frames of reference.

Methods

This protocol consists of two training studies. Study 1 will examine if visuospatial perspective-taking training promotes ToM and emotion understanding. Participants will consist of 96 4.5-year-olds and will be randomly assigned to one of two training groups: the altercentric block building group (trained to be visuospatial perspective-takers), or the egocentric block building group (no visuospatial perspective-taking is involved). Study 2 will compare the engagement of visuospatial perspective-taking and verbal interaction in the development of mind and emotion understanding. Participants will consist of 120 4.5-year-olds. They will be randomly assigned to one of three training groups: the socialized altercentric block building (both visuospatial perspective-taking and verbal interaction), the parallel altercentric block building (visuospatial perspective-taking only), or the paired dialogic reading (verbal interaction only).

Conclusions

In terms of theoretical implications, the potential causal relationship between visuospatial perspective-taking and ToM and emotion understanding may shed new insights on what underlies the development of mental state understanding. The findings of this study also have practical implications: researchers and educators may popularize visuospatial perspective-taking training in the form of block-building games if it is found to be effective in complementing conventional language-based theory-of-mind training.
Verifying the usefulness of the theory of planned behavior model for predicting illegal use of online content: the role of outcome expectancies and social loafing
Authors: Choi Yulee , Suh Kyung Hyun
Published: November 2022

Background

Currently, laypeople can earn profit by producing content; therefore, it should be noted that the unauthorized use of intellectual creations or possessions can cause legal issues and undermine the producers’ desire to create. This study verified the usefulness of the theory of planned behavior (TPB) model for predicting the illegal use of online content among South Korean college students and examined the roles played by outcome expectancies and social loafing in this model.

Methods

The participants, 369 male and female Korean college students, were aged between 18 and 31 years (M = 22.12, SD = 2.33). We measured the illegal use of online content and the factors of the TPB model, as well as outcome expectancies and social loafing with regard to participants’ illegal use of online content. Correlational analysis, stepwise regression analysis, path analysis for the TPB model, and analyses of the moderated model were performed using SPSS and AMOS.

Results

All TPB factors, outcome expectancies, and social loafing were positively correlated with the illegal use of online content. Stepwise regression analysis showed that intention, social loafing, outcome expectancies, and perceived behavioral control were significant predictors of the illegal use of online content. A TPB model, including a direct path from perceived behavioral control to behavior, was validated to analyze the illegal use of online content. This model was found to be moderated by outcome expectancy.

Conclusion

This study suggests that the TPB is useful for predicting the illegal use of online content and that outcome expectancies and social loafing also play an important role in the illegal use of online content among college students. The findings of this study provide useful information for future research and could aid in preventing illegal online content use among adolescents and young adults.
EIF1AX mutation in thyroid tumors: A retrospective analysis of cytology, histopathology and co-mutation profiles
Authors: Elsherbini Noha , Kim Dong Hyun , Payne Richard J. , Hudson Thomas , Forest Véronique-Isabelle , Hier Michael P. , Payne Alexandra E. , Pusztaszeri Marc P.
Published: November 2022

Background

The EIF1AX mutation has been identified in various benign and malignant thyroid lesions, with a higher prevalence in poorly differentiated thyroid carcinoma (PDTC) and anaplastic thyroid carcinoma, especially when combined with RAS or TP53 mutation. However, data and clinical significance of EIF1AX mutations in thyroid nodules is still limited. We investigated the prevalence of EIF1AX mutations and co-mutations in cytologically indeterminate thyroid nodules at our institution.

Methods

A 5-year retrospective analysis was performed on surgically resected thyroid nodules with identified EIF1AX mutations on molecular testing with ThyroseqV3®. Mutation type and presence of co-mutations were correlated with histopathologic diagnosis and clinical characteristics. Histopathology diagnoses were subsequently categorized as benign, borderline, malignant or aggressive malignant (≥ 10% PDTC component). Chi-square test was used to compare the malignancy associations of the: 1) A113_splice mutation compared to non-A113_splice mutations 2) singular A113_splice mutations compared to singular non-A113_splice mutations. Fisher's Exact Test was used to determine the association of A113_splice mutation with aggressive malignancies compared to non-A113_splice mutations. A p value of 0.05 or less was considered statistically significant.

Results

Out of 1583 patients who underwent FNA, 621 had further molecular testing. 31 cases (5%) harbored EIF1AX mutations. Of these cases, 12 (38.7%) were malignant, 2 (6.5%) were borderline, and 17 (55%) were benign. 4/31 cases (13%) were aggressive malignant (≥ 10% PDTC component). The most prevalent mutation was the A113_splice mutation at the junction of intron 5 and exon 6 (48%). All other mutations, except one, were located at the N-terminal in exon 2. 7/31 cases (22.6%) harbored ≥ 1 co-mutation(s), including 4 RAS, 3 TP53, 1 TERT and 1 PIK3CA, with 86% of them being malignant. All 4 nodules with RAS co-mutations were malignant including one PDTC.

Conclusion

Our study reports the largest cohort of EIF1AX mutations in Bethesda III/IV FNA samples with surgical follow-up to our knowledge. The presence of the EIF1AX mutation confers a 45.2% risk of malignancy (ROM) or borderline after surgery. However, the coexistence of EIF1AX mutations with other driver mutations such as RAS, TERT or TP53 conferred an 86% ROM. While 55% of thyroid nodules were benign at the time of surgery, the possible malignant transformation of these nodules, had they not been resected, is unknown. Finally, 13% of the nodules with EIF1AX mutations were aggressive with a significant PDTC component. These findings can further aid in clinical decisions for patients with thyroid nodules.

Graphic Abstract
Comparison of passive versus active transcutaneous bone anchored hearing devices in the pediatric population
Authors: Shoman Nael M. , Khan Usman , Hong Paul
Published: November 2022

Objective

Transcutaneous bone anchored hearing devices (BAHDs) were introduced in an effort to avoid potential complications associated with the abutment of percutaneous BAHDs. Transcutaneous BAHDs can be active or passive. While studies have demonstrated good outcomes with both, a direct comparison of audiological and clinical outcomes of these devices in the pediatric population has not yet been studied.

Study design

Retrospective, multicenter study.

Setting

Two tertiary academic centers.

Methods

Between 2015 and 2019, all patients who received an active transcutaneous BAHD (Bonebridge, BB) at one center, and patients that received a passive transcutaneous BAHD (Attract, AT) at another center, were included in this study. Exclusion criteria included age > 18 years, and mixed hearing loss or single-sided deafness. Study outcomes included patient demographics, indications, complications and preoperative and one-year postoperative audiometric data.

Results

Eighteen BB and eight AT patients met the inclusion criteria. The age range was 5–16 years. There were no significant differences in complication outcomes. Both devices demonstrated similar mean improvements in hearing thresholds at frequencies of 250 Hz (38 dB Active vs. 38 dB Passive), 500 Hz (34 dB vs. 42 dB), 1000 Hz (34 dB vs. 40 dB) and 2000 Hz (31 dB vs. 22 dB). The BB was significantly more effective at frequencies of 4000 Hz (28 dB vs. 7 dB) and 8000 Hz (29 dB vs. 6 dB) ( p < 0.05).

Conclusion

This is the first study comparing audiological outcomes between an active and a passive transcutaneous BAHD in the pediatric population. While both devices improved audiometric outcomes in the low and mid frequencies, the active BAHD demonstrated significantly better outcomes in the higher frequencies.

Graphical Abstract
Otolaryngology-Head and Neck Surgery clinical electives in undergraduate medicine: A cross-sectional observational study
Authors: Jaszkul Katrina M. , Grzybowski Marysia , Phillips Timothy
Published: November 2022

Background

Otolaryngology-Head and Neck Surgery (OHNS) electives provide medical students opportunities for knowledge acquisition, mentorship, and career exploration. Given the importance of electives on medical student education, this study examines OHNS clinical electives prior to their cancellation in 2020 due to the COVID-19 pandemic.

Methods

An anonymous 29-question electronic survey was created using the program “Qualtrics.” Themes included elective structure and organization, elective clinical and non-clinical teaching, evaluation of students, and the influence of electives on the Canadian Residency Match (CaRMS). The survey was distributed through the Canadian Society of Otolaryngology e-newsletter and e-mailed to all OHNS undergraduate and postgraduate program directors across Canada.

Results

Forty-two responses were received. The vast majority of respondents felt that visiting electives were important and should return post-COVID-19 (97.6%). Most said they provide more in-depth or hands-on teaching (52.4% and 59.6%, respectively). However, there was great variability in the feedback, types of teaching and curriculum provided to elective students. It was estimated that 77% of current residents at the postgraduate program that responders were affiliated with participated in an elective at their program.

Conclusions

Prior to the cancellation of visiting electives in 2020 due to the COVID-19 pandemic, electives played an important role in OHNS undergraduate medical education and career planning for students wishing to pursue a career in OHNS. Electives also provide the opportunity for the evaluation of students by OHNS postgraduate programs.
The impacts of performance-based assessment on reading comprehension achievement, academic motivation, foreign language anxiety, and students’ self-efficacy
Authors: Heydarnejad Tahereh , Tagavipour Fariba , Patra Indrajit , Farid Khafaga Ayman
Published: November 2022

The types of assessment tasks affect the learners’ psychological well-being and the process of learning. For years, educationalists were in search of finding and implementing accurate and convenient approaches to assess learners efficiently. Despite the significant role of performance-based assessment (PBA) in affecting second/foreign language (L2) learning processes, few empirical studies have tried to explore how PBA affects reading comprehension achievement (RCA), academic motivation (AM), foreign language anxiety (FLA), and students’ self-efficacy (SS-E). To fill this lacuna of research, the current study intended to gauge the impact of PBA on the improvement of RCA, AM, FLA, and SS-E in English as a foreign language (EFL) context. In so doing, a sample of 88 intermediate EFL learners were randomly divided into experimental group (EG) and CG (control group). During this research (16 sessions), the learners in the CG (N = 43) received the tradition assessment. In contrast, the learners in the EG (N = 45) were exposed to some modification based on the underpinning theories of PBA. Data inspection applying the one-way multivariate analysis of variance (i.e., the one-way MANOVA) indicated that the learners in the EG outperformed their counterparts in the CG. The results highlighted the significant contributions of PBA in fostering RCA, AM, FLA, and S-E beliefs. The implications of this study may redound to the benefits of language learners, teachers, curriculum designers, and policy makers in providing opportunities for further practice of PBA.
Prominent astrocytic alpha-synuclein pathology with unique post-translational modification signatures unveiled across Lewy body disorders
Authors: Altay Melek Firat , Liu Alan King Lun , Holton Janice L. , Parkkinen Laura , Lashuel Hilal A.
Published: November 2022

Alpha-synuclein (aSyn) is a pre-synaptic monomeric protein that can form aggregates in neurons in Parkinson’s disease (PD), Parkinson’s disease with dementia (PDD) and dementia with Lewy bodies (DLB), and in oligodendrocytes in multiple system atrophy (MSA). Although aSyn in astrocytes has previously been described in PD, PDD and DLB, the biochemical properties and topographical distribution of astrocytic aSyn have not been studied in detail. Here, we present a systematic investigation of aSyn astrocytic pathology using an expanded antibody toolset covering the entire sequence and key post-translational modifications (PTMs) of aSyn in Lewy body disorders (LBDs) and in MSA. Astrocytic aSyn was detected in the limbic cortical regions of LBDs but were absent in main pathological regions of MSA. The astrocytic aSyn was revealed only with antibodies against the mid N-terminal and non-amyloid component (NAC) regions covering aSyn residues 34–99. The astroglial accumulations were negative to canonical aSyn aggregation markers, including p62, ubiquitin and aSyn pS129, but positive for phosphorylated and nitrated forms of aSyn at Tyrosine 39 (Y39), and not resistant to proteinase K. Our findings suggest that astrocytic aSyn accumulations represent a major part of aSyn pathology in LBDs and possess a distinct sequence and PTM signature that is characterized by both N- and C-terminal truncations and modifications at Y39. This is the first description that aSyn accumulations are made solely from N- and C-terminally cleaved aSyn species and the first report demonstrating that astrocytic aSyn is a mixture of Y39 phosphorylated and nitrated species. These observations underscore the importance of systematic characterization of aSyn accumulations in different cell types to capture the aSyn pathological diversity in the brain. Our findings combined with further studies on the role of astrocytic pathology in the progression of LBDs can pave the way towards identifying novel disease mechanisms and therapeutic targets.
Highly stretchable strain sensors with improved sensitivity enabled by a hybrid of carbon nanotube and graphene
Authors: Wang Leilei , Choi Jungwook
Published: November 2022

The development of high-performance strain sensors has attracted significant attention in the field of smart wearable devices. However, stretchable strain sensors usually suffer from a trade-off between sensitivity and sensing range. In this study, we investigate a highly sensitive and stretchable piezoresistive strain sensor composed of a hybrid film of 1D multi-walled carbon nanotube (MWCNT) and 2D graphene that forms a percolation network on Ecoflex substrate by spray coating. The mass of spray-coated MWCNT and graphene and their mass ratio are modulated to overcome the trade-off between strain sensitivity and sensing range. We experimentally found that a stable percolation network is formed by 0.18 mg of MWCNTs (coating area of 200 mm2), with a maximum gauge factor (GF) of 1,935.6 and stretchability of 814.2%. By incorporating the 0.36 mg of graphene into the MWCNT film (i.e., a mass ratio of 1:2 between MWCNT and graphene), the GF is further improved to 12,144.7 in a strain range of 650–700%. This high GF is caused by the easy separation of the graphene network under the applied strain due to its two-dimensional (2D) shape. High stretchability originates from the high aspect ratio of MWCNTs that bridges the randomly distributed graphenes, maintaining a conductive network even under sizeable tensile strain. Furthermore, a small difference in work function between MWCNT and graphene and their stable percolation network enables sensitive UV light detection even under a significant strain of 300% that cannot be achieved by sensors composed of MWCNT- or graphene-only. The hybrids of MWCNT and graphene provide an opportunity to achieve high-performance stretchable devices.
Automatic engagement estimation in smart education/learning settings: a systematic review of engagement definitions, datasets, and methods
Authors: Karimah Shofiyati Nur , Hasegawa Shinobu
Published: November 2022

Background

Recognizing learners’ engagement during learning processes is important for providing personalized pedagogical support and preventing dropouts. As learning processes shift from traditional offline classrooms to distance learning, methods for automatically identifying engagement levels should be developed.

Objective

This article aims to present a literature review of recent developments in automatic engagement estimation, including engagement definitions, datasets, and machine learning-based methods for automation estimation. The information, figures, and tables presented in this review aim at providing new researchers with insight on automatic engagement estimation to enhance smart learning with automatic engagement recognition methods.

Methods

A literature search was carried out using Scopus, Mendeley references, the IEEE Xplore digital library, and ScienceDirect following the four phases of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA): identification, screening, eligibility, and inclusion. The selected studies included research articles published between 2010 and 2022 that focused on three research questions (RQs) related to the engagement definitions, datasets, and methods used in the literature. The article selection excluded books, magazines, news articles, and posters.

Results

Forty-seven articles were selected to address the RQs and discuss engagement definitions, datasets, and methods. First, we introduce a clear taxonomy that defines engagement according to different types and the components used to measure it. Guided by this taxonomy, we reviewed the engagement types defined in the selected articles, with emotional engagement (n = 40; 65.57%) measured by affective cues appearing most often (n = 38; 57.58%). Then, we reviewed engagement and engagement-related datasets in the literature, with most studies assessing engagement with external observations (n = 20; 43.48%) and self-reported measures (n = 9; 19.57%). Finally, we summarized machine learning (ML)-based methods, including deep learning, used in the literature.

Conclusions

This review examines engagement definitions, datasets and ML-based methods from forty-seven selected articles. A taxonomy and three tables are presented to address three RQs and provide researchers in this field with guidance on enhancing smart learning with automatic engagement recognition. However, several key challenges remain, including cognitive and personalized engagement and ML issues that may affect real-world implementations.
Observation of ionospheric Alfven resonator with double spectral resonance structures at low latitude station, Shillong ($$dipole L=1.08$$)
Authors: Adhitya P. , Nosé Masahito , Bulusu Jayashree , Vichare Geeta , Sinha A. K.
Published: November 2022

Spectral Resonance Structures (SRS) of Ionospheric Alfven Resonator (IAR) are investigated by analysing the magnetic field data of a high sampling frequency induction coil magnetometer, installed at a low latitude Indian station, Shillong$$(25.56^\circ N, 91.86^\circ E, dipole L=1.08 )$$

(
25
.

56
∘

N
,
91
.

86
∘

E
,
d
i
p
o
l
e
L
=
1.08
)

. One of the distinguishing features of IAR resonance structure observed at this latitude is the excitation of two spectral resonance structures simultaneously, one with a small frequency separation and the other with a large frequency separation of subsequent harmonics. The seasonal variation shows that the occurrence of double SRS is more favoured during winter, where, out of the total IAR events observed during winter, about $$47\%$$

47
%

show clear signatures of double SRS and no double SRS are observed during summer. We have examined the altitudinal variation of refractive index using IRI 2016 model to understand the role of local ionospheric conditions in the formation of double spectral resonance structures. Our study reveals that the excitation of double SRS is related to the E-region to F-region variability of refractive index of the ionosphere. We also report that the double spectral resonance structures at Shillong are always observed only in the $${B}_{x}$$

B
x

component of the magnetic field variation.

Graphical Abstract
Lithological structure of western Pacific lithosphere reconstructed from mantle xenoliths in a petit-spot volcano
Authors: Mikuni Kazuto , Hirano Naoto , Akizawa Norikatsu , Yamamoto Junji , Machida Shiki , Tamura Akihiro , Hagiwara Yuuki , Morishita Tomoaki
Published: November 2022

The lithospheric mantle, formed at the mid-ocean ridge as a residue of crustal production, comprises theoretically depleted peridotite, but more fertile components (e.g., lherzolite and pyroxenite) have been reported, creating an enigmatic picture of the lithosphere. The oceanic lithosphere has also been found to be locally modified by intraplate magmatism as proposed from geochemistry of mantle xenolith. Petit-spot xenoliths are particularly notable as direct evidence of old lithospheric mantle and expected to retain essential information about oceanic lithosphere prior to its subduction. In this study, we report on the lithological structure of Pacific lithosphere aged at 160 Ma, just subducting into Mariana Trench, based on petrology and chemistry of ultramafic xenoliths from a petit-spot knoll, and then, we suggest the occurrence of petit-spot melt infiltration resulting in mantle metasomatism and formation of pyroxene-rich vein. Our petit-spot ultramafic xenoliths can be divided into three main types: a depleted peridotite as a residue of crust production, an enriched peridotite, and fertile pyroxenites as the product of melt–rock interactions prior to entrapment. Geothermobarometry also suggests that the depleted peridotite was derived from the uppermost lithospheric mantle, whereas the enriched peridotite and Al-augite pyroxenites were obtained from deeper layers of the lithosphere. Moreover, thermal gradient of the lithosphere estimated from these data is considerably hotter than pristine geotherm estimated on the basis of plate age. Hence, we could illustrate that the oldest portion of the Pacific lithosphere (160 Ma), which was not observed before, was locally fertilized and heated by prior multiple petit-spot magmatic events, and pyroxene-rich metasomatic veins penetrated from the base to the middle/upper lithosphere. Such local lithospheric fertilization is plausible at the plate-bending field, and the nature of Pacific Plate subducting into Mariana Trench may be partly different from what has been assumed so far.