bluuebunny/crossref_metadata_2025 huggingface dataset:
Signaling Pathway and Small-Molecule Drug Discovery of FGFR: A Comprehensive Review
Authors: Zheng Jia , Zhang Wei , Li Linfeng , He Yi , Wei Yue , Dang Yongjun , Nie Shenyou , Guo Zufeng
Published: April 2022

Targeted therapy is a groundbreaking innovation for cancer treatment. Among the receptor tyrosine kinases, the fibroblast growth factor receptors (FGFRs) garnered substantial attention as promising therapeutic targets due to their fundamental biological functions and frequently observed abnormality in tumors. In the past 2 decades, several generations of FGFR kinase inhibitors have been developed. This review starts by introducing the biological basis of FGF/FGFR signaling. It then gives a detailed description of different types of small-molecule FGFR inhibitors according to modes of action, followed by a systematic overview of small-molecule-based therapies of different modalities. It ends with our perspectives for the development of novel FGFR inhibitors.
Estimating the Neutralizing Effect and Titer Correlation of Semi-Quantitative Anti-SARS-CoV-2 Antibody Immunoassays
Authors: Lee Beomki , Ko Jae-Hoon , Park Jiho , Moon Hee-Won , Baek Jin Yang , Jung Sunhee , Lim Hee-Young , Kim Kyung-Chang , Huh Kyungmin , Cho Sun Young , Kang Cheol-In , Chung Doo Ryeon , Huh Hee Jae , Chung Chi Ryang , Kim Yae-Jean , Joo Eun-Jeong , Kang Eun-Suk , Peck Kyong Ran
Published: April 2022

For the clinical application of semi-quantitative anti-SARS-CoV-2 antibody tests, the analytical performance and titer correlation of the plaque reduction neutralization test (PRNT) need to be investigated. We evaluated the analytical performance and PRNT titer-correlation of one surrogate virus neutralization test (sVNT) kit and three chemiluminescent assays. We measured the total antibodies for the receptor-binding domain (RBD) of the spike protein, total antibodies for the nucleocapsid protein (NP), and IgG antibodies for the RBD. All three chemiluminescent assays showed high analytical performance for the detection of SARS-CoV-2 infection, with a sensitivity ≥ 98% and specificity ≥ 99%; those of the sVNT were slightly lower. The representativeness of the neutralizing activity of PRNT ND50≥ 20 was comparable among the four immunoassays (Cohen’s kappa ≈ 0.80). Quantitative titer correlation for high PRNT titers of ND50≥ 50, 200, and 1,000 was investigated with new cut-off values; the anti-RBD IgG antibody kit showed the best performance. It also showed the best linear correlation with PRNT titer in both the acute and convalescent phases (Pearson’s R 0.81 and 0.72, respectively). Due to the slowly waning titer of anti-NP antibodies, the correlation with PRNT titer at the convalescent phase was poor. In conclusion, semi-quantitative immunoassay kits targeting the RBD showed neutralizing activity that was correlated by titer; measurement of anti-NP antibodies would be useful for determining past infections.
Molecular Approaches for the Validation of the Baboon as a Nonhuman Primate Model for the Study of Zika Virus Infection
Authors: Mask Emma , Hodara Vida L. , Callery Jessica E. , Parodi Laura M. , Obregon-Perko Veronica , Yagi Shigeo , Glenn Jeremy , Frost Patrice , Clemmons Elizabeth , Patterson Jean L. , Cox Laura A. , Giavedoni Luis D.
Published: April 2022

Nonhuman primates (NHP) are particularly important for modeling infections with viruses that do not naturally replicate in rodent cells. Zika virus (ZIKV) has been responsible for sporadic epidemics, but in 2015 a disseminated outbreak of ZIKV resulted in the World Health Organization declaring it a global health emergency. Since the advent of this last epidemic, several NHP species, including the baboon, have been utilized for modeling and understanding the complications of ZIKV infection in humans; several health issues related to the outcome of infection have not been resolved yet and require further investigation. This study was designed to validate, in baboons, the molecular signatures that have previously been identified in ZIKV-infected humans and macaque models. We performed a comprehensive molecular analysis of baboons during acute ZIKV infection, including flow cytometry, cytokine, immunological, and transcriptomic analyses. We show here that, similar to most human cases, ZIKV infection of male baboons tends to be subclinical, but is associated with a rapid and transient antiviral interferon-based response signature that induces a detectable humoral and cell-mediated immune response. This immunity against the virus protects animals from challenge with a divergent ZIKV strain, as evidenced by undetectable viremia but clear anamnestic responses. These results provide additional support for the use of baboons as an alternative animal model to macaques and validate omic techniques that could help identify the molecular basis of complications associated with ZIKV infections in humans.
Intonational Cues to Segmental Contrasts in the Native Language Facilitate the Processing of Intonational Cues to Lexical Stress in the Second Language
Authors: Kim Hyoju , Tremblay Annie
Published: April 2022

This study examines whether second language (L2) learners' processing of an intonationally cued lexical contrast is facilitated when intonational cues signal a segmental contrast in the native language (L1). It does so by investigating Seoul Korean and French listeners' processing of intonationally cued lexical-stress contrasts in English. Neither Seoul Korean nor French has lexical stress; instead, the two languages have similar intonational systems where prominence is realized at the level of the Accentual Phrase. A critical difference between the two systems is that French has only one tonal pattern underlying the realization of the Accentual Phrase, whereas Korean has two underlying tonal patterns that depend on the laryngeal feature of the phrase-initial segment. The L and H tonal cues thus serve to distinguish segments at the lexical level in Korean but not in French; Seoul Korean listeners are thus hypothesized to outperform French listeners when processing English lexical stress realized only with (only) tonal cues (H* on the stressed syllable). Seoul Korean and French listeners completed a sequence-recall task with four-item sequences of English words that differed in intonationally cued lexical stress (experimental condition) or in word-initial segment (control condition). The results showed higher accuracy for Seoul Korean listeners than for French listeners only when processing English lexical stress, suggesting that the processing of an intonationally cued lexical contrast in the L2 is facilitated when intonational cues signal a segmental contrast in the L1. These results are interpreted within the scope of the cue-based transfer approach to L2 prosodic processing.
Non-Newtonian Endothelial Shear Stress Simulation: Does It Matter?
Authors: Thondapu Vikas , Shishikura Daisuke , Dijkstra Jouke , Zhu Shuang J. , Revalor Eve , Serruys Patrick W. , van Gaal William J. , Poon Eric K. W. , Ooi Andrew , Barlis Peter
Published: April 2022

Patient-specific coronary endothelial shear stress (ESS) calculations using Newtonian and non-Newtonian rheological models were performed to assess whether the common assumption of Newtonian blood behavior offers similar results to a more realistic but computationally expensive non-Newtonian model. 16 coronary arteries (from 16 patients) were reconstructed from optical coherence tomographic (OCT) imaging. Pulsatile CFD simulations using Newtonian and the Quemada non-Newtonian model were performed. Endothelial shear stress (ESS) and other indices were compared. Exploratory indices including local blood viscosity (LBV) were calculated from non-Newtonian simulation data. Compared to the Newtonian results, the non-Newtonian model estimates significantly higher time-averaged ESS (1.69 (IQR 1.36)Pa versus 1.28 (1.16)Pa, p < 0.001) and ESS gradient (0.90 (1.20)Pa/mm versus 0.74 (1.03)Pa/mm, p < 0.001) throughout the cardiac cycle, under-estimating the low ESS (<1Pa) area (37.20 ± 13.57% versus 50.43 ± 14.16%, 95% CI 11.28–15.18, p < 0.001). Similar results were also found in the idealized artery simulations with non-Newtonian median ESS being higher than the Newtonian median ESS (healthy segments: 0.8238Pa versus 0.6618Pa, p < 0.001 proximal; 0.8179Pa versus 0.6610Pa, p < 0.001 distal; stenotic segments: 0.8196Pa versus 0.6611Pa, p < 0.001 proximal; 0.2546Pa versus 0.2245Pa, p < 0.001 distal) On average, the non-Newtonian model has a LBV of 1.45 times above the Newtonian model with an average peak LBV of 40-fold. Non-Newtonian blood model estimates higher quantitative ESS values than the Newtonian model. Incorporation of non-Newtonian blood behavior may improve the accuracy of ESS measurements. The non-Newtonian model also allows calculation of exploratory viscosity-based hemodynamic indices, such as local blood viscosity, which may offer additional information to detect underlying atherosclerosis.
Varicose Veins and Risk of Venous Thromboembolic Diseases: A Two-Sample-Based Mendelian Randomization Study
Authors: Li Ruihao , Chen Zuoguan , Gui Liang , Wu Zhiyuan , Miao Yuqing , Gao Qing , Diao Yongpeng , Li Yongjun
Published: April 2022

Background:

Varicose veins are found to be associated with increased risk of venous thromboembolism (VTE) in many observational studies, but whether varicose veins are causally associated with VTE remains unclear. Therefore, we used a series of Mendelian randomization (MR) methods to investigate that association.

Methods

23 independent single-nucleotide polymorphisms (SNPs) for varicose veins were obtained from the Pan UK Biobank analysis. The outcomes datasets for deep vein thrombosis (DVT), pulmonary embolism (PE) and venous thromboembolism (VTE) were obtained from the FinnGen study. Before analysis, body mass index (BMI) and height were included as confounders in our MR model. Basic MR [inverse-variance weighted (IVW), weight-median, penalized weighted-median and MR-Egger methods] and MR-PRESSO were performed against each outcome using the whole SNPs and SNPs after excluding those associated with confounders. If causal associations were suggested for any outcome, a basic MR validation analysis, a multivariable MR analysis with BMI and height, a Causal Analysis Using Summary Effect estimates (CAUSE), and a two-step MR analysis with BMI and height, would follow.

Results

Using 21 qualified SNPs, the IVW method (OR: 1.173, 95% CI: 1.070–1.286, p < 0.001, FDR = 0.002), the weighted median method (OR: 1.255, 95% CI: 1.106–1.423, p < 0.001, FDR = 0.001), the penalized weighted median method (OR: 1.299, 95% CI: 1.128–1.495, p < 0.001, FDR = 0.001) and the MR-PRESSO (OR: 1.165, 95% CI: 1.067–1.273, p = 0.003, FDR = 0.009) suggested potential causal effect of varicose veins on DVT, but no cause effect was found for PE and VTE. Excluding SNPs associated with confounders yielded similar results. The causal association with DVT was validated using a self-reported DVT cohort (IVW, OR: 1.107, 95% CI: 1.041–1.178, p = 0.001). The causal association maintained after adjustment for height (OR = 1.105, 95% CI: 1.028–1.188, p = 0.007), BMI (OR = 1.148, 95% CI: 1.059–1.244, p < 0.001) and them both (OR = 1.104, 95% CI: 1.035–1.177, p = 0.003). The causal association also survived the strict CAUSE (p = 0.018). Finally, in two-step MR, height and BMI were found to have causal effects on both varicose veins and DVT.

Conclusion

Genetically predicted varicose veins may have a causal effect on DVT and may be one of the mediators of obesity and taller height that predispose to DVT.
Risk Stratification by Coronary Perfusion Pressure in Left Ventricular Systolic Dysfunction Patients Undergoing Revascularization: A Propensity Score Matching Analysis
Authors: Hsieh Ming-Jer , Chen Chun-Chi , Chen Dong-Yi , Lee Cheng-Hung , Ho Ming-Yun , Yeh Jih-Kai , Huang Yu-Chang , Lu Yu-Ying , Chang Chieh-Yu , Wang Chao-Yung , Chang Shang-Hung , Hsieh I-Chang
Published: April 2022

Background

Coronary perfusion pressure (CPP) and coronary artery stenosis are responsible for myocardial perfusion. However, how CPP-related survival outcome affects revascularization is unclear.

Objective

The aim of this study is to investigate the prognostic role of CPP in patients with left ventricular systolic dysfunction (LVSD) undergoing percutaneous coronary intervention (PCI) with complete revascularization (CR) or reasonable incomplete revascularization (RIR).

Methods

We retrospectively screened 6,076 consecutive patients in a registry. The residual synergy between percutaneous coronary intervention with Taxus and cardiac surgery (SYNTAX) score (rSS) was used to define CR (rSS = 0) and RIR (0<rSS≤8). Propensity score matching was performed to reduce bias between RIR and CR. The primary endpoint was all-cause mortality.

Results

In total, 816 patients with LVSD who underwent CR or RIR were enrolled. After a mean follow-up of 4.6 years, 134 patients died. Both CPP and RIR independently predicted mortality in the total population. After 1:1 matching, 175 pairs of RIR and CR were found in patients with CPP > 42 mmHg. Moreover, 101 pairs of RIR and CR were present in patients with CPP ≤ 42 mmHg. In patients with CPP > 42 mmHg, RIR was not significantly different from CR in long-term mortality [hazard ratio (HR) 1.20; 95% confidence interval (CI):0.70–2.07; p = 0.513]; However, in patients with CPP≤42 mmHg, RIR had a significantly higher mortality risk than CR (HR 2.39; 95% CI: 1.27–4.50; p = 0.007).

Conclusions

The CPP had a risk stratification role in selecting different revascularization strategies in patients with LVSD. When patients with LVSD had CPP > 42 mmHg, RIR was equivalent to CR in survival. However, when patients with LVSD had CPP ≤ 42 mmHg, RIR had a significantly higher mortality risk than CR.
Assessing the Contribution of Glacier Melt to Discharge in the Tropics: The Case of Study of the Antisana Glacier 12 in Ecuador
Authors: Gualco Luis Felipe , Maisincho Luis , Villacís Marcos , Campozano Lenin , Favier Vincent , Ruiz-Hernández Jean-Carlos , Condom Thomas
Published: April 2022

Tropical glaciers are excellent indicators of climate variability due to their fast response to temperature and precipitation variations. At same time, they supply freshwater to downstream populations. In this study, a hydro-glaciological model was adapted to analyze the influence of meteorological forcing on melting and discharge variations at Glacier 12 of Antisana volcano (4,735–5,720 m above sea level (a.s.l.), 1.68 km2, 0°29′S; 78°9′W). Energy fluxes and melting were calculated using a distributed surface energy balance model using 20 altitude bands from glacier snout to the summit at 30-min resolution for 684 days between 2011 and 2013. The discharge was computed using linear reservoirs for snow, firn, ice, and moraine zones. Meteorological variables were recorded at 4,750 m.a.s.l. in the ablation area and distributed through the altitudinal range using geometrical corrections, and measured lapse rate. The annual specific mass balance (−0.61 m of water equivalent -m w.e. y−1-) and the ablation gradient (22.76 kg m−2 m−1) agree with the values estimated from direct measurements. Sequential validations allowed the simulated discharge to reproduce hourly and daily discharge variability at the outlet of the catchment. The latter confirmed discharge simulated (0.187 m3 s−1) overestimates the streamflow measured. Hence it did not reflect the net meltwater production due to possible losses through the complex geology of the site. The lack of seasonality in cloud cover and incident short-wave radiation force the reflected short-wave radiation via albedo to drive melting energy from January to June and October to December. Whereas the wind speed was the most influencing variable during the July-September season. Results provide new insights on the behaviour of glaciers in the inner tropics since cloudiness and precipitation occur throughout the year yielding a constant short-wave attenuation and continuous variation of snow layer thickness.
RETRACTED: The Impact of WebQuest-Based Sheltered Instruction on Improving Academic Writing Skills, Soft Skills, and Minimizing Writing Anxiety
Authors: Salem Ashraf Atta Mohamed S.
Published: April 2022

WebQuest is an inquiry-oriented learning tool in which the majority of the information learners interact with, comes from Internet resources, according to Bernie Dodge, who conceived and named the concept (Dodge, 1997). Students are given a job and instructed to do it using Web resources. The current study explores the impact of learning in a sheltered Internet environment, “WebQuest,” on improving the academic writing skills of English for Academic Purposes (EAP) non-native English speakers. It also investigates the impact of using sheltered online instruction on improving the soft skills of EAP language learners. In addition, the study assesses the impact of sheltered online instruction on reducing the writing anxiety levels of writers in the International English Language Testing System (IELTS; Writing Task 1 and 2). To reach such end, three groups of EAP learners were selected to participate in the study adopting three learning styles: sheltered online instruction (the experimental group, 15 ESP university students), unsheltered online instruction (free Google search) (the first control group, 19 students), and sheltered offline instruction (the second control group, 20 students). Instruments used included a sample of the IELTS writing test, Brookings Soft Skills Rating Card, and Second Language Writing Anxiety Inventory (SLWAI). Sequential exploratory mixed method was used as it consists of both quantitative and qualitative data analyses for the elaborate explanation of results. Successive rounds of data analyses showed the plentiful gains of the EAP students in their academic writing skills and the level of their soft skills. It is also revealed that EAP students are not as anxious and reluctant to write as before. In addition, the analysis of the students’ responses to the semi-structured interview revealed that learning in sheltered Internet environments represents an interesting as well as motivating learning experience. Therefore, it is necessary for WebQuest to be implemented as a sheltered online instruction strategy in language learning and to design sheltered Internet environments other than WebQuest to improve the quality of the teaching process.
Creating Space for Reflection: Meaning-Making Feedback in Instrumental/Vocal Lessons
Authors: Sandberg-Jurström Ragnhild
Published: April 2022

In higher music education, problems have been reported regarding students’ lack of independence in one-to-one instrumental/vocal lessons, little space for reflection, and education based on a hierarchical master–apprentice tradition, regulating and restricting students’ opportunities to learn and reflect. This article concerns video-recorded feedback activities in one-to-one instrumental/vocal lessons in specialist music teacher education, paying special attention to the space offered for student self-reflection and independence. The data comprise video-recorded one-to-one instrumental/vocal lessons between students and teachers. A social semiotic perspective is used to study representations of feedback meaning-making in the interaction between students and teachers as well as the understandings and approaches related to traditions and norms in music education. The findings indicate that feedback is constructed through two contrasting discourses, resulting in various ways of realizing feedback related to reflection opportunities. The negotiating discourse emphasizes opportunities for student self-reflections, drawing on current institutional curricula and government requirements regarding reflection abilities. In contrast, the controlling discourse emphasizes constraints on such opportunities, connected to the hierarchical master–apprentice music tradition. The feedback approaches realizing these discourses are described in terms of space for conversation or exploration as well as a call for attention or re-creation, evident in all studied lessons. The discussion addresses some didactic issues regarding the findings.
Hybrid Close-Loop Systems Versus Predictive Low-Glucose Suspend and Sensor-Augmented Pump Therapy in Patients With Type 1 Diabetes: A Single-Center Cohort Study
Authors: Lunati Maria Elena , Morpurgo Paola Silvia , Rossi Antonio , Gandolfi Alessandra , Cogliati Irene , Bolla Andrea Mario , Plebani Laura , Vallone Luciana , Montefusco Laura , Pastore Ida , Cimino Vincenzo , Argenti Sabrina , Volpi Graziella , Zuccotti Gian Vincenzo , Fiorina Paolo
Published: April 2022

Introduction

Predictive low-glucose suspend (PLGS) and hybrid closed-loop (HCL) systems may improve glucose control and quality of life in type 1 diabetic individuals. This is a cross-sectional, single-center study to compare the effect on metabolic control and glucose variability of PLGS and HCL systems as compared to standard sensor-augmented pump (SAP) therapy.

Methods

We retrospectively analyzed 136 adults (men/women 69/67, mean age 47.3 ± 13.9 years) with T1D on insulin pump therapy, divided accordingly to type of insulin pump system (group 1: SAP, 24 subjects; group 2: PLGS, 49 subjects; group 3: HCL, 63 subjects). The groups were matched for age, gender, years of disease, years of CSII use, and CGM wear time.

Results

The analysis of CGM metrics, in the three groups, showed a statistically significant different percentage of time within the target range, defined as 70–180 mg/dl, with a higher percentage in group 3 and significantly less time spent in the hypoglycemic range in groups 2 and 3. The three groups were statistically different also for the glucose management indicator and coefficient of variation percentage, which were progressively lower moving from group 1 to group 3. In the HCL group, 52.4% of subjects reached a percentage of time passed in the euglycemic range above 70%, as compared to 32.7% in those with PLGS and 20.2% in those with SAP. A positive correlation between the higher percentage of TIR and the use of auto-mode was evident in the HCL group. Finally, the three groups did not show any statistical differences regarding the quality-of-life questionnaire, but there was a significant negative correlation between CV and perceived CSII-use convenience (r = -0.207, p = 0.043).

Conclusion

HCL systems were more effective in improving glucose control and in reducing the risk of hypoglycemia in patients with type 1 diabetes, thereby mitigating risk for acute and chronic complications and positively affecting diabetes technologies’ acceptance.
Hyperglycemia and Physical Impairment in Frail Hypertensive Older Adults
Authors: Pansini Antonella , Lombardi Angela , Morgante Maria , Frullone Salvatore , Marro Anna , Rizzo Mario , Martinelli Giuseppe , Boccalone Eugenio , De Luca Antonio , Santulli Gaetano , Mone Pasquale
Published: April 2022

Background

Frailty is a multidimensional condition typical of elders. Frail older adults have a high risk of functional decline, hospitalization, and mortality. Hypertension is one of the most common comorbidities in elders. Hyperglycemia (HG) is frequently observed in frail older adults, and represents an independent predictor of worst outcomes, with or without diabetes mellitus (DM). We aimed at investigating the impact of HG on physical impairment in frailty.

Methods

We studied consecutive older adults with frailty and hypertension at the ASL (local health unit of the Italian Ministry of Health) of Avellino, Italy, from March 2021 to September 2021. Exclusion criteria were: age <65 years, no frailty, no hypertension, left ventricular ejection fraction <25%, previous myocardial infarction, previous primary percutaneous coronary intervention and/or coronary artery bypass grafting. Blood glucose, Hb1Ac, and creatinine were measured in all patients. Physical frailty was assessed applying the Fried Criteria; we performed a 5-meter gait speed (5mGS) test in all patients.

Results

149 frail hypertensive older adults were enrolled in the study, of which 82 had normoglycemia (NG), and 67 had HG. We observed a significantly slower 5mGS in the HG group compared to the NG group (0.52 ± 0.1 vs. 0.69 ± 0.06; p<0.001). Moreover, we found a strong and significant correlation between 5mGS and glycemia (r: 0.833; p<0.001). A multivariable linear regression analysis using 5mGS as a dependent variable revealed a significant independent association with glycemia (p<0.001) after adjusting for likely confounders.

Conclusions

HG drives physical impairment in frail hypertensive older adults independently of DM.
Cardiovascular Autonomic Neuropathy in Type 1 Diabetes Is Associated With Disturbances in TCA, Lipid, and Glucose Metabolism
Authors: Hansen Christian S. , Suvitaival Tommi , Theilade Simone , Mattila Ismo , Lajer Maria , Trošt Kajetan , Ahonen Linda , Hansen Tine W. , Legido-Quigley Cristina , Rossing Peter , Ahluwalia Tarunveer S.
Published: April 2022

Introduction

Diabetic cardiovascular autonomic neuropathy (CAN) is associated with increased mortality and morbidity. To explore metabolic mechanisms associated with CAN we investigated associations between serum metabolites and CAN in persons with type 1 diabetes (T1D).

Materials and Methods

Cardiovascular reflex tests (CARTs) (heart rate response to: deep breathing; lying-to-standing test; and the Valsalva maneuver) were used to diagnose CAN in 302 persons with T1D. More than one pathological CARTs defined the CAN diagnosis. Serum metabolomics and lipidomic profiles were analyzed with two complementary non-targeted mass-spectrometry methods. Cross-sectional associations between metabolites and CAN were assessed by linear regression models adjusted for relevant confounders.

Results

Participants were median (IQR) aged 55(49, 63) years, 48% males with diabetes duration 39(32, 47) years, HbA1c 63(55,69) mmol/mol and 34% had CAN. A total of 75 metabolites and 106 lipids were analyzed. In crude models, the CAN diagnosis was associated with higher levels of hydroxy fatty acids (2,4- and 3,4-dihydroxybutanoic acids, 4−deoxytetronic acid), creatinine, sugar derivates (ribitol, ribonic acid, myo-inositol), citric acid, glycerol, phenols, phosphatidylcholines and lower levels of free fatty acids and the amino acid methionine (p<0.05). Upon adjustment, positive associations with the CAN diagnoses were retained for hydroxy fatty acids, tricarboxylic acid (TCA) cycle-based sugar derivates, citric acid, and phenols (P<0.05).

Conclusion

Metabolic pathways, including the TCA cycle, hydroxy fatty acids, phosphatidylcholines and sugar derivatives are associated with the CAN diagnosis in T1D. These pathway may be part of the pathogeneses leading to CAN and may be modifiable risk factors for the complication.
Identification of Inflammation-Related Biomarkers in Diabetes of the Exocrine Pancreas With the Use of Weighted Gene Co-Expression Network Analysis
Authors: Li Guoqing , Sun Jinfang , Zhang Jun , Lv Yingqi , Liu Dechen , Zhu Xiangyun , Qi Liang , Chen Zhiwei , Ye Zheng , Su Xianghui , Li Ling
Published: April 2022

Diabetes of the exocrine pancreas (DEP), also commonly described as pancreatogenic diabetes mellitus, is a type of diabetes secondary to abnormalities in pancreatic or exocrine secretion of the pancreas. However, its pathogenesis is not yet known. The aim of this article was to explore the biomarkers of DEP and their potential molecular mechanisms. Based on GSE76896 dataset, which was acquired from Gene Expression Omnibus (GEO), we identified 373 genes by weighted gene co-expression network analysis (WGCNA) and differential expression analysis. In addition, protein–protein interaction (PPI) network analysis and cytoHubba were used to screen potential hub genes. Five hub genes were determined, comprising Toll-like receptor 4 (TLR4), ITGAM, ITGB2, PTPRC, and CSF1R. Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways suggested macrophage activation and Toll-like receptor signaling pathway as important pathophysiological features of DEP. CIBERSORT suggested that TLR4 may regulate the immune pathway via macrophages. Next, we validated the expression and receiver operating characteristic curve (ROC) of the hub genes using the GSE164416 dataset. In addition, we used miRNet to predict the target miRNAs of hub genes and intersected them with common miRNAs in diabetes from the Human MicroRNA Disease Database (HMDD), which was used to propose a possible mechanistic model for DEP. The miRNA–mRNA network showed that has-miR-155-5p/has-miR-27a-3p/has-miR-21-5p-TLR4 might lead to TLR4 signaling pathway activation in DEP. In conclusion, we identified five hub genes, namely, TLR4, ITGAM, ITGB2, PTPRC, and CSF1R, as biomarkers to aid in the diagnosis of DEP and conducted an in-depth study of the pathogenesis of DEP at the genetic level.
Rehabilitation of Individuals With Diabetes Mellitus: Focus on Diabetic Myopathy
Authors: Bassi-Dibai Daniela , Santos-de-Araújo Aldair Darlan , Dibai-Filho Almir Vieira , de Azevedo Lisiane Fernanda Simeão , Goulart Cássia da Luz , Luz Gabriela Costa Pontes , Burke Patrick Rademaker , Garcia-Araújo Adriana Sanches , Borghi-Silva Audrey
Published: April 2022

Diabetes mellitus (DM) is a chronic metabolic disease characterized by high blood glucose levels, causing serious damage to the cardiovascular, respiratory, renal and other systems. The prevalence of type 2 diabetes mellitus (T2DM) was 6.28% in 2017, considering all age groups worldwide (prevalence rate of 6,059 cases per 100,000), and its global prevalence is projected to increase to 7,079 cases per 100,000 by 2030. Furthermore, these individuals are often affected by diabetic myopathy, which is the failure to preserve muscle mass and function in the course of DM. This happens in type 1 diabetes mellitus (T1DM) and T2DM. As skeletal muscle plays a key role in locomotion and glucose homeostasis, diabetic myopathy may contribute to additional complications of the disease. In addition, chronic hyperglycemia is associated with lung functional changes seen in patients with DM, such as reduced lung volumes and compliance, inspiratory muscle strength, and lung elastic recoil. Thus, the weakness of the inspiratory muscles, a consequence of diabetic myopathy, can influence exercise tolerance. Thus, moderate strength training in T2DM can contribute to the gain of peripheral muscle strength. Although the literature is robust on the loss of mass and consequent muscle weakness in diabetic myopathy, triggering pathophysiological factors, the impact on functional capacity, as well as the prescription of physical exercise for this condition deserves to be further explored. This review aims to explore the consequences of diabetic myopathy and its implication in rehabilitation from prescription to safety in the practice of physical exercises for these individuals.
Optimal Planning of Integrated Energy System Considering Convertibility Index
Authors: Wang Ying , Zhao Jing , Zheng Tao , Fan Kai , Zhang Kaifeng
Published: April 2022

Nowadays, developing an integrated energy system (IES) is considered as an effective pattern to improve energy efficiency and reduce energy supply costs. This study proposes a new index—convertibility index (CI)—to quantitatively assess the flexibility of the IES regarding the energy conversion processes between different energy flow types. Based on the CI constraint, a planning problem is modeled as a bi-level optimization problem. To solve the proposed bi-level problem, a hybrid genetic algorithm (GA)—MILP algorithm—is developed. A case study is carried out to verify the effectiveness of the proposed method. The results show that the total cost of the IES will increase with the CI constraint. For a given case study, the total cost increases by 26.2% when the CI decreases to 0.7 and increases by 3.7% when the CI increases to 1.6. Sensitivity analysis shows that the total numbers and capacities of conversion devices show an overall increasing trend with the increase in the CIs. Meanwhile, the total cost decreases quickly at first and then slightly increases, which, in a whole, shows a “Nike” shape. With different CI constraints, the IES MW per CI ranges from 31.8 to 37.5 MW, and the average cost increase is 2.229 million yuan (2.1%/0.1 CI).
Effects of Multiple Injection Strategies on Heavy-Duty Diesel Energy Distributions and Emissions Under High Peak Combustion Pressures
Authors: Zhang Zhao , Liu Haifeng , Yue Zongyu , Wu Yangyi , Kong Xiangen , Zheng Zunqing , Yao Mingfa
Published: April 2022

Peak combustion pressures (PCP) are increased in heavy-duty diesel engines to obtain higher thermal efficiency. Fuel injection strategy has been a major measure to improve the combustion and emissions of diesel engines. But most existing work of multi-injection strategies was not limited by PCP or was conducted under lower PCP (∼15 MPa). In this study, an experimental study is conducted to further improve the understanding of injection strategies on engine performance under a relative higher peak combustion pressure at 20 MPa. The four tested injection strategies are single main injection, pilot-main injection, main-post injection, and pilot-main-post injection. The effects of PCP on brake thermal efficiency (BTE) and other engine performances are also investigated under the same NOx emissions conditions. Results indicate that more advanced injection timing can obtain higher BTE, while the injection pressure has less effects on BTE as it is higher than 120 MPa. For double-injection, the smaller interval on pilot-main or main-post and the less pilot or post mass improves BTE and emissions. The PCPs are linearly correlated to the BTE, peak average temperature, and peak pressure rise rate (PRR), and the increment of BTE, peak average temperature, and peak PRR are about 0.3%, 30 K, and 0.1 MPa/CA for every 1 MPa increase in PCP, respectively. This also means that the improvement on BTE by the increase of PCP imparts greater thermal and mechanical loads on engine materials and components. At 20 MPa PCP, based on the optimized injection strategies, the BTE of all four strategies is about 42.8%, and the peak PRR of all four strategies is about 0.8 MPa/CA. At a given NOx emission of 17.4 g/kWh and approximate 20 MPa PCP, all four injection strategies have minor effects on distribution of fuel energy and emissions. Therefore, it can be concluded that the injection strategies have fewer effects on BTE and emissions at the higher peak combustion pressure of 20 MPa; the main purpose of injection strategies is to reduce the peak PRR or reach the potentially required temperature for aftertreatment devices.
Construction Method of the Distribution Transform Load Feature Database Based on Deep Convolutional Autoencoder
Authors: Xu Bin , Gao Yuan , Liu Jun , Lu Yang , Yang Yifeng , Xu Feng , Xu Xiaoqing
Published: April 2022

With the large-scale access of distributed resources to distribution network operation, there are more and more prosumers on the user side. It forms the basis of load prediction and demand-side management to identify different power consumption patterns and establish a typical load characteristic database according to the load data of prosumers. Therefore, a method to build a prosumer load characteristic database based on a deep convolutional autoencoder is proposed. First, the autoencoder network was used to extract the features of the load data collected to reduce the data dimension. Then, the density weight canopy algorithm was used to precluster the data after dimensionality reduction to obtain the initial clustering center and the optimal clustering number K value. The pre-clustering results were combined with the k-means algorithm for clustering, and the typical load characteristic database of prosumers was obtained. Finally, the comparison between the clustering index and the traditional k-means clustering algorithm and the improved k-means direct clustering algorithm proves that the method can effectively improve the accuracy of clustering results.
Non-Mycorrhizal Fungal Presence Within Roots Increases Across an Urban Gradient in Berlin, Germany
Authors: Whitehead James , Hempel Stefan , Rillig Matthias C.
Published: April 2022

Symbioses between plants and fungi are important in both promoting plant fitness and maintaining soil structure. The ways in which these relationships change across an urban gradient is subject to debate. Here we measured root colonisation including the presence of arbuscular mycorrhizal fungi, non-mycorrhizal fungi, and root hair presence. We found no evidence of changes in levels of arbuscular mycorrhizal fungal colonisation across an urban gradient, colonisation levels being driven instead by plant community. However, we did observe an increase in non-mycorrhizal fungal colonisation in association with increasing urbanity. Additionally, we observed an urban-related increase in root hair presence. Using principal component analysis we were able to provide strong evidence for these patterns being driven by an “urban syndrome”, rather than soil chemistry. Our findings have important implications for the wider understanding of abiotic stresses on fungal endophyte presence and shed light on the impacts of urbanity upon plant roots.
Lack of Statistical Rigor in DNA Barcoding Likely Invalidates the Presence of a True Species' Barcode Gap
Authors: Phillips Jarrett D. , Gillis Daniel J. , Hanner Robert H.
Published: April 2022

DNA barcoding has been largely successful in satisfactorily exposing levels of standing genetic diversity for a wide range of taxonomic groups through the employment of only one or a few universal gene markers. However, sufficient coverage of geographically-broad intra-specific haplotype variation within genomic databases like the Barcode of Life Data Systems (BOLD) and GenBank remains relatively sparse. As reference sequence libraries continue to grow exponentially in size, there is now the need to identify novel ways of meaningfully analyzing vast amounts of available DNA barcode data. This is an important issue to address promptly for the routine tasks of specimen identification and species discovery, which have seen broad adoption in areas as diverse as regulatory forensics and resource conservation. Here, it is demonstrated that the interpretation of DNA barcoding data is lacking in statistical rigor. To highlight this, focus is set specifically on one key concept that has become a household name in the field: the DNA barcode gap. Arguments outlined herein specifically center on DNA barcoding in animal taxa and stem from three angles: (1) the improper allocation of specimen sampling effort necessary to capture adequate levels of within-species genetic variation, (2) failing to properly visualize intra-specific and interspecific genetic distances, and (3) the inconsistent, inappropriate use, or absence of statistical inferential procedures in DNA barcoding gap analyses. Furthermore, simple statistical solutions are outlined which can greatly propel the use of DNA barcoding as a tool to irrefutably match unknowns to knowns on the basis of the barcoding gap with a high degree of confidence. Proposed methods examined herein are illustrated through application to DNA barcode sequence data from Canadian Pacific fish species as a case study.
Investigation of Chromosomal Structural Abnormalities in Patients With Undiagnosed Neurodevelopmental Disorders
Authors: Cao Ye , Luk Ho Ming , Zhang Yanyan , Chau Matthew Hoi Kin , Xue Shuwen , Cheng Shirley S. W. , Li Albert Martin , Chong Josephine S. C. , Leung Tak Yeung , Dong Zirui , Choy Kwong Wai , Lo Ivan Fai Man
Published: April 2022

Background: Structural variations (SVs) are various types of the genomic rearrangements encompassing at least 50 nucleotides. These include unbalanced gains or losses of DNA segments (copy number changes, CNVs), balanced rearrangements (such as inversion or translocations), and complex combinations of several distinct rearrangements. SVs are known to play a significant role in contributing to human genomic disorders by disrupting the protein-coding genes or the interaction(s) with cis-regulatory elements. Recently, different types of genome sequencing-based tests have been introduced in detecting various types of SVs other than CNVs and regions with absence of heterozygosity (AOH) with clinical significance.

Method: In this study, we applied the mate-pair low pass (∼4X) genome sequencing with large DNA-insert (∼5 kb) in a cohort of 100 patients with neurodevelopmental disorders who did not receive informative results from a routine CNV investigation. Read-depth-based CNV analysis and chimeric-read-pairs analysis were used for CNV and SV analyses. The region of AOH was indicated by a simultaneous decrease in the rate of heterozygous SNVs and increase in the rate of homozygous SNVs.

Results: First, we reexamined the 25 previously reported CNVs among 24 cases in this cohort. The boundaries of these twenty-five CNVs including 15 duplications and 10 deletions detected were consistent with the ones indicated by the chimeric-read-pairs analysis, while the location and orientation were determined in 80% of duplications (12/15). Particularly, one duplication was involved in complex rearrangements. In addition, among all the 100 cases, 10% of them were detected with rare or complex SVs (>10 Kb), and 3% were with multiple AOH (≥5 Mb) locating in imprinting chromosomes identified. In particular, one patient with an overall value of 214.5 Mb of AOH identified on 13 autosomal chromosomes suspected parental consanguinity.

Conclusion: In this study, mate-pair low-pass GS resolved a significant proportion of CNVs with inconclusive significance, and detected additional SVs and regions of AOH in patients with undiagnostic neurodevelopmental disorders. This approach complements the first-tier CNV analysis for NDDs, not only by increasing the resolution of CNV detection but also by enhancing the characterization of SVs and the discovery of potential causative regions (or genes) contributory to could be complex in composition NDDs.
Interest in Cancer Predisposition Testing and Carrier Screening Offered as Part of Routine Healthcare Among an Ethnically Diverse Sample of Young Women
Authors: Kaphingst Kimberly A. , Bather Jemar R. , Daly Brianne M. , Chavez-Yenter Daniel , Vega Alexis , Kohlmann Wendy K.
Published: April 2022

Sequencing technologies can inform individuals’ risks for multiple conditions, supporting population-level screening approaches. Prior research examining interest in genetic testing has not generally examined the context of population-based approaches offered in routine healthcare or among ethnically diverse populations. Cancer predisposition testing and carrier screening could be offered broadly to women of reproductive age. This study therefore examined interest in these tests when offered as part of routine care, and predictors of interest, among an ethnically diverse sample of women aged 20–35. We conducted an online English-language survey of 450 women; 39% identified as Latina. We examined predictors of interest for two outcomes, interest in testing in the next year and level of interest, in multivariable logistic regression models and stratified analyses by Latina ethnicity. More than half of respondents reported being interested in cancer predisposition testing (55%) and carrier screening (56%) in the next year; this did not differ by ethnicity. About 26% reported being very interested in cancer predisposition testing and 27% in carrier screening. Latina respondents (32%) were more likely to be very interested in cancer predisposition testing than non-Latina respondents (22%;p< 0.03). In multivariable models, having higher worry about genetic risks, higher genetic knowledge, and higher perceived importance of genetic information were associated with higher interest across multiple models. Predictors of interest were generally similar by ethnicity. Our findings show substantial interest in both cancer predisposition testing and carrier screening among young women as part of routine healthcare with similar interest between Latina and non-Latina women. Efforts to broadly offer such testing could be important in improving access to genetic information. It will be critical to develop tools to help healthcare providers communicate about genetic testing and to address the needs of those who have less prior knowledge about genetics to support informed decision making.
A NK Cell Odyssey: From Bench to Therapeutics Against Hematological Malignancies
Authors: Ramos-Mejia Veronica , Arellano-Galindo Jose , Mejía-Arangure Juan Manuel , Cruz-Munoz Mario Ernesto
Published: April 2022

In 1975 two independent groups noticed the presence of immune cells with a unique ability to recognize and eliminate transformed hematopoietic cells without any prior sensitization or expansion of specific clones. Since then, NK cells have been the axis of thousands of studies that have resulted until June 2021, in more than 70 000 publications indexed in PubMed. As result of this work, which include approachesin vitro,in vivo, andin natura, it has been possible to appreciate the role played by the NK cells, not only as effectors against specific pathogens, but also as regulators of the immune response. Recent advances have revealed previous unidentified attributes of NK cells including the ability to adapt to new conditions under the context of chronic infections, or their ability to develop some memory-like characteristics. In this review, we will discuss significant findings that have rule our understanding of the NK cell biology, the developing of these findings into new concepts in immunology, and how these conceptual platforms are being used in the design of strategies for cancer immunotherapy.
TNF-α-Secreting Lung Tumor-Infiltrated Monocytes Play a Pivotal Role During Anti-PD-L1 Immunotherapy
Authors: De Ridder Kirsten , Locy Hanne , Piccioni Elisa , Zuazo Miren Ibarra , Awad Robin Maximilian , Verhulst Stefaan , Van Bulck Mathias , De Vlaeminck Yannick , Lecocq Quentin , Reijmen Eva , De Mey Wout , De Beck Lien , Ertveldt Thomas , Pintelon Isabel , Timmermans Jean-Pierre , Escors David , Keyaerts Marleen , Breckpot Karine , Goyvaerts Cleo
Published: April 2022

Immune checkpoint blockade (ICB) of the PD-1 pathway revolutionized the survival forecast for advanced non-small cell lung cancer (NSCLC). Yet, the majority of PD-L1+ NSCLC patients are refractory to anti-PD-L1 therapy. Recent observations indicate a pivotal role for the PD-L1+ tumor-infiltrating myeloid cells in therapy failure. As the latter comprise a heterogenous population in the lung tumor microenvironment, we applied an orthotopic Lewis Lung Carcinoma (LLC) model to evaluate 11 different tumor-residing myeloid subsets in response to anti-PD-L1 therapy. While we observed significantly reduced fractions of tumor-infiltrating MHC-IIlow macrophages and monocytes, serological levels of TNF-α restored in lung tumor-bearing mice. Notably, we demonstrated in vivo and in vitro that anti-PD-L1 therapy mediated a monocyte-specific production of, and response to TNF-α, further accompanied by their significant upregulation of CD80, VISTA, LAG-3, SIRP-α and TIM-3. Nevertheless, co-blockade of PD-L1 and TNF-α did not reduce LLC tumor growth. A phenomenon that was partly explained by the observation that monocytes and TNF-α play a Janus-faced role in anti-PD-L1 therapy-mediated CTL stimulation. This was endorsed by the observation that monocytes appeared crucial to effectively boost T cell-mediated LLC killing in vitro upon combined PD-L1 with LAG-3 or SIRP-α blockade. Hence, this study enlightens the biomarker potential of lung tumor-infiltrated monocytes to define more effective ICB combination strategies.