bluuebunny/crossref_metadata_2025 huggingface dataset:
Parental Book-Reading to Preterm Born Infants in NICU: The Effects on Language Development in the First Two Years
Authors: Neri Erica , De Pascalis Leonardo , Agostini Francesca , Genova Federica , Biasini Augusto , Stella Marcello , Trombini Elena
Published: October 2021

Background: After preterm birth, infants are at high risk for delays in language development. A promising intervention to reduce this risk is represented by the exposure to parental voices through book-reading in Neonatal Intensive Care Units (NICU). This study investigated the possible advantages of book-reading to preterm neonates during their NICU stay on their subsequent language development. Methods: 100 families of preterm infants were recruited. The parents of 55 preterm infants (Reading Group) received a colored picture-book on NICU admission and were supported to read to their neonate as often as possible and to continue after hospital discharge. Forty-five infants (Control Group) were recruited before the beginning of the intervention. Infant language development was assessed with the Hearing and Language quotients of the Griffith Mental Development Scale at the corrected ages of 3, 6, 9, 12, 18 and 24 months. Results: Regardless of group membership, Hearing and Language mean quotients decreased between 9 and 18 months; nevertheless, this decrease was considerably reduced in the Reading group, compared to the Control Group. Conclusions: Reading in NICUs represents a suitable intervention that could positively influence language development and parent-infant relationships in preterm children. The study findings support its implementation as a preventive measure.
Establishment of a Rapid Detection System for ISG20-Dependent SARS-CoV-2 Subreplicon RNA Degradation Induced by Interferon-α
Authors: Furutani Yutaka , Toguchi Mariko , Higuchi Shoko , Yanaka Kaori , Gailhouste Luc , Qin Xian-Yang , Masaki Takahiro , Ochi Sae , Matsuura Tomokazu
Published: October 2021

Inhaled nebulized interferon (IFN)-α and IFN-β have been shown to be effective in the management of coronavirus disease 2019 (COVID-19). We aimed to construct a virus-free rapid detection system for high-throughput screening of IFN-like compounds that induce viral RNA degradation and suppress the replication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We prepared a SARS-CoV-2 subreplicon RNA expression vector which contained the SARS-CoV-2 5′-UTR, the partial sequence of ORF1a, luciferase, nucleocapsid, ORF10, and 3′-UTR under the control of the cytomegalovirus promoter. The expression vector was transfected into Calu-3 cells and treated with IFN-α and the IFNAR2 agonist CDM-3008 (RO8191) for 3 days. SARS-CoV-2 subreplicon RNA degradation was subsequently evaluated based on luciferase levels. IFN-α and CDM-3008 suppressed SARS-CoV-2 subreplicon RNA in a dose-dependent manner, with IC50 values of 193 IU/mL and 2.54 μM, respectively. HeLa cells stably expressing SARS-CoV-2 subreplicon RNA were prepared and treated with the IFN-α and pan-JAK inhibitor Pyridone 6 or siRNA-targeting ISG20. IFN-α activity was canceled with Pyridone 6. The knockdown of ISG20 partially canceled IFN-α activity. Collectively, we constructed a virus-free rapid detection system to measure SARS-CoV-2 RNA suppression. Our data suggest that the SARS-CoV-2 subreplicon RNA was degraded by IFN-α-induced ISG20 exonuclease activity.
Deciphering Evolutionary Dynamics and Lineage Plasticity in Aggressive Prostate Cancer
Authors: Kyprianou Natasha , Lucien Fabrice
Published: October 2021

This Special Issue focuses on the molecular mechanisms involved in therapeutic resistance, lineage plasticity, and phenotypic reprogramming leading to prostate cancer recurrence and, ultimately, lethal disease [...]
Ectomycorrhizal Fungal Strains Facilitate Cd2+ Enrichment in a Woody Hyperaccumulator under Co-Existing Stress of Cadmium and Salt
Authors: Deng Chen , Zhu Zhimei , Liu Jian , Zhang Ying , Zhang Yinan , Yu Dade , Hou Siyuan , Zhang Yanli , Yao Jun , Zhang Huilong , Zhao Nan , Sa Gang , Zhang Yuhong , Ma Xujun , Zhao Rui , Polle Andrea , Chen Shaoliang
Published: October 2021

Cadmium (Cd2+) pollution occurring in salt-affected soils has become an increasing environmental concern in the world. Fast-growing poplars have been widely utilized for phytoremediation of soil contaminating heavy metals (HMs). However, the woody Cd2+-hyperaccumulator, Populus × canescens, is relatively salt-sensitive and therefore cannot be directly used to remediate HMs from salt-affected soils. The aim of the present study was to testify whether colonization of P. × canescens with ectomycorrhizal (EM) fungi, a strategy known to enhance salt tolerance, provides an opportunity for affordable remediation of Cd2+-polluted saline soils. Ectomycorrhization with Paxillus involutus strains facilitated Cd2+ enrichment in P. × canescens upon CdCl2 exposures (50 μM, 30 min to 24 h). The fungus-stimulated Cd2+ in roots was significantly restricted by inhibitors of plasmalemma H+-ATPases and Ca2+-permeable channels (CaPCs), but stimulated by an activator of plasmalemma H+-ATPases. NaCl (100 mM) lowered the transient and steady-state Cd2+ influx in roots and fungal mycelia. Noteworthy, P. involutus colonization partly reverted the salt suppression of Cd2+ uptake in poplar roots. EM fungus colonization upregulated transcription of plasmalemma H+-ATPases (PcHA4, 8, 11) and annexins (PcANN1, 2, 4), which might mediate Cd2+ conductance through CaPCs. EM roots retained relatively highly expressed PcHAs and PcANNs, thus facilitating Cd2+ enrichment under co-occurring stress of cadmium and salinity. We conclude that ectomycorrhization of woody hyperaccumulator species such as poplar could improve phytoremediation of Cd2+ in salt-affected areas.
DNA Methylation and Type 2 Diabetes: Novel Biomarkers for Risk Assessment?
Authors: Raciti Gregory Alexander , Desiderio Antonella , Longo Michele , Leone Alessia , Zatterale Federica , Prevenzano Immacolata , Miele Claudia , Napoli Raffaele , Beguinot Francesco
Published: October 2021

Diabetes is a severe threat to global health. Almost 500 million people live with diabetes worldwide. Most of them have type 2 diabetes (T2D). T2D patients are at risk of developing severe and life-threatening complications, leading to an increased need for medical care and reduced quality of life. Improved care for people with T2D is essential. Actions aiming at identifying undiagnosed diabetes and at preventing diabetes in those at high risk are needed as well. To this end, biomarker discovery and validation of risk assessment for T2D are critical. Alterations of DNA methylation have recently helped to better understand T2D pathophysiology by explaining differences among endophenotypes of diabetic patients in tissues. Recent evidence further suggests that variations of DNA methylation might contribute to the risk of T2D even more significantly than genetic variability and might represent a valuable tool to predict T2D risk. In this review, we focus on recent information on the contribution of DNA methylation to the risk and the pathogenesis of T2D. We discuss the limitations of these studies and provide evidence supporting the potential for clinical application of DNA methylation marks to predict the risk and progression of T2D.
Emerging Importance of Tyrosine Kinase Inhibitors against Cancer: Quo Vadis to Cure?
Authors: Mongre Raj Kumar , Mishra Chandra Bhushan , Shukla Arvind Kumar , Prakash Amresh , Jung Samil , Ashraf-Uz-Zaman Md , Lee Myeong-Sok
Published: October 2021

GLOBOCAN 2020 estimated more than 19.3 million new cases, and about 10 million patients were deceased from cancer in 2020. Clinical manifestations showed that several growth factor receptors consisting of transmembrane and cytoplasmic tyrosine kinase (TK) domains play a vital role in cancer progression. Receptor tyrosine kinases (RTKs) are crucial intermediaries of the several cellular pathways and carcinogenesis that directly affect the prognosis and survival of higher tumor grade patients. Tyrosine kinase inhibitors (TKIs) are efficacious drugs for targeted therapy of various cancers. Therefore, RTKs have become a promising therapeutic target to cure cancer. A recent report shows that TKIs are vital mediators of signal transduction and cancer cell proliferation, angiogenesis, and apoptosis. In this review, we discuss the structure and function of RTKs to explore their prime role in cancer therapy. Various TKIs have been developed to date that contribute a lot to treating several types of cancer. These TKI based anticancer drug molecules are also discussed in detail, incorporating their therapeutic efficacy, mechanism of action, and side effects. Additionally, this article focuses on TKIs which are running in the clinical trial and pre-clinical studies. Further, to gain insight into the pathophysiological mechanism of TKIs, we also reviewed the impact of RTK resistance on TKI clinical drugs along with their mechanistic acquired resistance in different cancer types.
Whey-Derived Peptides at the Heart of the COVID-19 Pandemic
Authors: Chamata Yara , Jackson Kim G. , Watson Kimberly A. , Jauregi Paula
Published: October 2021

The renin–angiotensin system (RAS) is a key regulator of blood pressure and hypertension. Angiotensin-converting enzyme 2 (ACE2) and angiotensin-converting enzyme I (ACE) are two main components of the RAS that play a major role in blood pressure homeostasis. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uses ACE2 as a receptor to enter cells. Despite some controversies, numerous studies have reported a significant association between the use of ACE inhibitors and reduced risk of COVID-19. In our previous studies, we produced and identified peptide sequences present in whey hydrolysates exhibiting high ACE inhibitory activity. Therefore, the aim of this work is to obtain an improved understanding of the function of these natural peptides as RAS inhibitors and investigate their potential therapeutic role in the COVID-19 pandemic. The molecular interactions between peptides IPP, LIVTQ, IIAE, LVYPFP, and human ACE2 were assessed by employing a molecular docking approach. The results show that natural whey-derived peptides have a dual inhibitory action against both ACE and ACE2. This dual activity distinguishes these ACE inhibitory peptides from synthetic drugs, such as Captopril and Lisinopril which were not shown to inhibit ACE2 activity, and may represent a potential strategy in the treatment of COVID-19.
Targeting Cancer Stem Cells by Dietary Agents: An Important Therapeutic Strategy against Human Malignancies
Authors: Deldar Abad Paskeh Mahshid , Asadi Shafagh , Zabolian Amirhossein , Saleki Hossein , Khoshbakht Mohammad Amin , Sabet Sina , Naghdi Mohamad Javad , Hashemi Mehrdad , Hushmandi Kiavash , Ashrafizadeh Milad , Mirzaei Sepideh , Zarrabi Ali , Sethi Gautam
Published: October 2021

As a multifactorial disease, treatment of cancer depends on understanding unique mechanisms involved in its progression. The cancer stem cells (CSCs) are responsible for tumor stemness and by enhancing colony formation, proliferation as well as metastasis, and these cells can also mediate resistance to therapy. Furthermore, the presence of CSCs leads to cancer recurrence and therefore their complete eradication can have immense therapeutic benefits. The present review focuses on targeting CSCs by natural products in cancer therapy. The growth and colony formation capacities of CSCs have been reported can be attenuated by the dietary agents. These compounds can induce apoptosis in CSCs and reduce tumor migration and invasion via EMT inhibition. A variety of molecular pathways including STAT3, Wnt/β-catenin, Sonic Hedgehog, Gli1 and NF-κB undergo down-regulation by dietary agents in suppressing CSC features. Upon exposure to natural agents, a significant decrease occurs in levels of CSC markers including CD44, CD133, ALDH1, Oct4 and Nanog to impair cancer stemness. Furthermore, CSC suppression by dietary agents can enhance sensitivity of tumors to chemotherapy and radiotherapy. In addition to in vitro studies, as well as experiments on the different preclinical models have shown capacity of natural products in suppressing cancer stemness. Furthermore, use of nanostructures for improving therapeutic impact of dietary agents is recommended to rapidly translate preclinical findings for clinical use.
Fat of the Gut: Epithelial Phospholipids in Inflammatory Bowel Diseases
Authors: Boldyreva Lidiya V. , Morozova Maryana V. , Saydakova Snezhanna S. , Kozhevnikova Elena N.
Published: October 2021

Inflammatory bowel diseases (IBD) comprise a distinct set of clinical symptoms resulting from chronic inflammation within the gastrointestinal (GI) tract. Despite the significant progress in understanding the etiology and development of treatment strategies, IBD remain incurable for thousands of patients. Metabolic deregulation is indicative of IBD, including substantial shifts in lipid metabolism. Recent data showed that changes in some phospholipids are very common in IBD patients. For instance, phosphatidylcholine (PC)/phosphatidylethanolamine (PE) and lysophosphatidylcholine (LPC)/PC ratios are associated with the severity of the inflammatory process. Composition of phospholipids also changes upon IBD towards an increase in arachidonic acid and a decrease in linoleic and a-linolenic acid levels. Moreover, an increase in certain phospholipid metabolites, such as lysophosphatidylcholine, sphingosine-1-phosphate and ceramide, can result in enhanced intestinal inflammation, malignancy, apoptosis or necroptosis. Because some phospholipids are associated with pathogenesis of IBD, they may provide a basis for new strategies to treat IBD. Current attempts are aimed at controlling phospholipid and fatty acid levels through the diet or via pharmacological manipulation of lipid metabolism.
Identification and Fine Mapping of a Locus Related to Leaf Up-Curling Trait (Bnuc3) in Brassica napus
Authors: Wan Shubei , Qin Zongping , Jiang Xiaomei , Yang Mao , Chen Wenjing , Wang Yangming , Ni Fei , Guan Yijian , Guan Rongzhan
Published: October 2021

Leaf trait is an important target trait in crop breeding programs. Moderate leaf curling may be a help for improving crop yield by minimizing the shadowing by leaves. Mining locus for leaf curling trait is of significance for plant genetics and breeding researches. The present study identified a novel rapeseed accession with up-curling leaf, analyzed the up-curling leaf trait inheritance, and fine mapped the locus for up-curling leaf property (Bnuc3) in Brassica napus. Genetic analysis revealed that the up-curling leaf trait is controlled by a single dominant locus, named BnUC3. We performed an association study of BnUC3 with single nucleotide polymorphism (SNP) markers using a backcross population derived from the homozygous up-curling leaf line NJAU-M1295 and the canola variety ‘zhongshuang11’ with typical flat leaves, and mapped the BnUC3 locus in a 1.92 Mb interval of chromosome A02 of B. napus. To further map BnUC3, 232 simple sequence repeat (SSR) primers and four pairs of Insertion/Deletion (InDel) primers were developed for the mapping interval. Among them, five SSR markers and two InDel markers were polymorphic. By these markers, the mapping interval was narrowed to 92.0 kb using another F2 population. This fine mapping interval has 11 annotated genes among which BnaA02T0157000ZS were inferred to be candidate casual genes for up-curling leaf based on the cloned sequence analysis, gene functionality, and gene expression analysis. The current study laid a foundational basis for further elucidating the mechanism of BnUC3 and breeding of variety with up-curling leaf.
Monocytes and Macrophages Serve as Potent Prostaglandin D2 Sources during Acute, Non-Allergic Pulmonary Inflammation
Authors: Rittchen Sonja , Jandl Katharina , Lanz Ilse , Reiter Bernhard , Ferreirós Nerea , Kratz Daniel , Lindenmann Jörg , Brcic Luka , Bärnthaler Thomas , Atallah Reham , Olschewski Horst , Sturm Eva M. , Heinemann Akos
Published: October 2021

Acute respiratory inflammation, most commonly resulting from bacterial or viral infection, is one of the leading causes of death and disability worldwide. The inflammatory lipid mediator prostaglandin D2 (PGD2) and its rate-limiting enzyme, hematopoietic PGD synthase (hPGDS), are well-known drivers of allergic pulmonary inflammation. Here, we sought to investigate the source and role of hPGDS-derived PGD2 in acute pulmonary inflammation. Murine bronchoalveolar monocytes/macrophages from LPS- but not OVA-induced lung inflammation released significant amounts of PGD2. Accordingly, human monocyte-derived macrophages expressed high basal levels of hPGDS and released significant levels of PGD2 after LPS/IFN-γ, but not IL-4 stimulation. Human peripheral blood monocytes secreted significantly more PGD2 than monocyte-derived macrophages. Using human precision-cut lung slices (PCLS), we observed that LPS/IFN-γ but not IL-4/IL-13 drive PGD2 production in the lung. HPGDS inhibition prevented LPS-induced PGD2 release by human monocyte-derived macrophages and PCLS. As a result of hPGDS inhibition, less TNF-α, IL-6 and IL-10 could be determined in PCLS-conditioned medium. Collectively, this dataset reflects the time-dependent release of PGD2 by human phagocytes, highlights the importance of monocytes and macrophages as PGD2 sources and suggests that hPGDS inhibition might be a potential therapeutic option for acute, non-allergic lung inflammation.
Djnedd4L Is Required for Head Regeneration by Regulating Stem Cell Maintenance in Planarians
Authors: Tian Qingnan , Sun Yujia , Gao Tingting , Li Jiaxin , Fang Huimin , Zhang Shoutao
Published: October 2021

SUMOylation and ubiquitylation are homologous processes catalyzed by homologous enzymes, and they are involved in nearly all aspects of eukaryotic biology. Planarians, which have the remarkable ability to regenerate their central nervous system (CNS), provide an excellent opportunity to investigate the molecular processes of CNS regeneration in vivo. In this study, we analyzed gene expression profiles during head regeneration with an RNA-seq-based screening approach and found that Djnedd4L and Djubc9 were required for head regeneration in planarians. RNA interference targeting of Djubc9 caused the phospho-H3 mitotic cells to decrease in quantity, or even become absent as a part of the Djubc9 RNAi phenotype, which also showed the collapse of the stem cell lineage along with the reduced expression of epidermal differentiation markers. Furthermore, we found that Djnedd4L RNAi induced increased cell division and promoted the premature differentiation during regeneration. Taken together, our findings show that Djubc9 and Djnedd4L are required for stem cell maintenance in the planarian Dugesia japonica, which helps to elucidate the role of SUMOylation and ubiquitylation in regulating the regeneration process.
Factors That Determine the Adoption Intention of Direct Mobile Purchases through Social Media Apps
Authors: Saprikis Vaggelis , Avlogiaris Giorgos
Published: October 2021

In the last few years, a number of social media e-business models including the social networking giants of Facebook, Pinterest and Instagram have offered direct purchase abilities to both their users and the involved enterprises. Hence, individuals can buy directly without having to leave the social media website. At the same time, there is a significant increase in the number of online purchases through mobile devices. To add to this, nowadays, the vast majority of internet users prefer to surf via their smartphone rather than a desktop PC. The aforementioned facts reveal the abilities and potential dynamics of Mobile Social Commerce (MSC), which is considered not only the present but also the future of e-commerce, as well as an area of prosperous academic and managerial concern. In spite of its several extant abilities and its booming future, MSC has been little examined until now. Therefore, this study aims to determine the factors that impact smartphone users’ behavioral intention to adopt direct purchases through social media apps in a country where these kinds of m-services are not yet available. In specific, it extends the well-established Unified Theory of Acceptance and Use of Technology (UTAUT) model with the main ICT facilitators (i.e., convenience, reward and security) and inhibitors (i.e., risk and anxiety). The suggested conceptual model aims to increase the understanding on the topic and strengthen the importance of this major type of MSC. Convenience sampling was applied to gather the data and Structural Equation Modeling (SEM) was then performed to investigate the research hypotheses of the proposed conceptual model. The results show that performance expectancy exerts a positive impact on behavioral intention. Furthermore, all ICT facilitators examined do impact significantly on smartphone users’ decision to adopt direct mobile purchases through social media apps, whereas anxiety exerts a negative effect.
Determinants of Exercise Capacity Following ST-Elevation Myocardial Infarction (STEMI)
Authors: Klimis Harry , Ferkh Aaisha , Brown Paula , Zecchin Robert , Altman Mikhail , Thomas Liza
Published: October 2021

Background: Abnormal left ventricular systolic and diastolic function and reduced exercise capacity are associated with worse prognosis following ST-elevation myocardial infarction (STEMI). However, evidence is lacking on the determinants of exercise capacity following STEMI. We sought to determine the impact of systolic and diastolic dysfunction on exercise capacity and outcomes following first-ever STEMI. Methods: In a retrospective analysis of 139 consecutive STEMI patients who had a transthoracic echocardiogram following STEMI and completed exercise treadmill testing, the primary outcome was to identify clinical and echocardiographic determinants of exercise capacity, and the secondary outcome was to identify determinants of major adverse cardiac events (MACEs). Results: Mean number of metabolic equivalents (METs > 8) was used as a cut-off. Age, female sex, anterior infarction, abnormal diastolic function, minimum left atrial indexed volume (LAVImin) ≥ 18 mL/m2, average e’, and E/e’ were associated with METs ≤ 8, but not left ventricular ejection fraction (LVEF). On multivariate analysis, LAVImin (OR 4.3, 95%CI 1.3–14.2; p = 0.017), anterior infarction (OR 2.6, 95%CI 1.2–5.9; p = 0.022), and abnormal diastolic function (OR 3.73, 95%CI 1.7–8.4; p = 0.001) were independent predictors of METs ≤ 8. On Kaplan–Meier analysis, METs ≤ 8 (p = 0.01) and abnormal diastolic function (p = 0.04) were associated with MACEs (median follow-up 2.3 years). METs ≤ 8 was an independent predictor of MACEs (HR 3.4, 95%CI 1.2–9.8; p = 0.02). Conclusions: Following first-ever STEMI, increased LAVImin, anterior infarction, and abnormal diastolic function were independent predictors of reduced exercise capacity. Furthermore, reduced exercise capacity was an independent predictor of MACEs. These results highlight important prognostic and therapeutic implications related to abnormal diastolic function in STEMI patients that are distinct from those with LV systolic impairment.
Low Dose of Direct Oral Anticoagulants after Left Atrial Appendage Occlusion
Authors: Cepas-Guillen Pedro Luis , Flores-Umanzor Eduardo , Regueiro Ander , Brugaletta Salvatore , Ibañez Cristina , Sanchis Laura , Sitges Marta , Rodés-Cabau Josep , Sabaté Manel , Freixa Xavier
Published: October 2021

The optimal antithrombotic strategy following left atrial appendage occlusion (LAAO) is not yet clearly established. Low-dose non-vitamin K antagonist oral anticoagulants (NOAC) might represent a valid alternative, but data regarding their usage is scarce. The aim of this study was to examine the efficacy and safety of low-dose NOAC compared to single (SAPT) or dual antiplatelet therapies (DAPT) after LAAO. We included consecutive patients with non-valvular atrial fibrillation who underwent LAAO and received low-dose apixaban, SAPT, or DAPT at discharge. The primary objective of this study included an efficacy endpoint (thromboembolic events and device related thrombosis (DRT)) and a safety endpoint (incidence of major bleeding) within the first three months after LAAO. A total of 139 patients were included. This group involved SAPT in 26 (18%), DAPT in 73 (53%), and apixaban in 40 (29%) patients. Follow-up at three-months showed no significant differences in the primary efficacy endpoint (2 (8%) SAPT, 3 (4%) DAPT and 0 (0%) apixaban; p value = 0.25). In contrast, the primary safety endpoint occurred more frequently in DAPT patients (7 (10%) DAPT, 0 (0%), SAPT and 0 with apixaban; p value = 0.03). Combining both efficacy and safety outcomes, low dose apixaban had a lower rate of events (2 (8%) with SAPT, 9 (12%) with DAPT and 0 (0%) with apixaban; p = 0.046). Low-dose apixaban after LAAO may be a valid alternative to DAPT and SAPT as depicted by the reduction in the occurrence of major bleedings and combined DRT/major bleedings respectively. Randomized data will be necessary to validate this strategy.
Circulating Extracellular Vesicles Are Associated with Disease Severity and Interleukin-6 Levels in COPD: A Pilot Study
Authors: Nieri Dario , Daniele Marta , Lombardi Stefania , Bazzan Erica , Santerini Sabrina , De Cusatis Giovanna , Vagaggini Barbara , Cosio Manuel G. , Saetta Marina , Paggiaro Pierluigi , Celi Alessandro , Neri Tommaso
Published: October 2021

Chronic obstructive pulmonary disease (COPD) is a complex condition in which systemic inflammation plays a role in extrapulmonary manifestations, including cardiovascular diseases: interleukin (IL)-6 has a role in both COPD and atherogenesis. The 2011 GOLD document classified patients according to FEV1, symptoms, and exacerbations history, creating four groups, from A (less symptoms/low risk) to D (more symptoms/high risk). Extracellular vesicles (EV) represent potential markers in COPD: nevertheless, no studies have explored their value in association to both disease severity and inflammation. We conducted a pilot study to analyze circulating endothelial-(E) and monocyte-derived (M) EV levels in 35 COPD patients, who were grouped according to the 2011 GOLD document; the relationship between EV and plasmatic markers of inflammation was analyzed. We found a statistically significant trend for increasing EEV, MEV, IL-6, from group A to D, and a significant correlation between EEV and IL-6. The associations between both EEV and MEV and disease severity, and between EEV and IL-6, suggest a significant interplay between pulmonary disease and inflammation, with non-respiratory cells (endothelial cells and monocytes) involvement, along with the progression of the disease. Thus, EV might help identify a high-risk population for extrapulmonary events, especially in the most severe patients.
Depression Mediates the Relationship between Childhood Trauma and Internet Addiction in Female but Not Male Chinese Adolescents and Young Adults
Authors: Dong Xue , Zhang Ruxin , Zhornitsky Simon , Le Thang M. , Wang Wuyi , Li Chiang-Shan R. , Zhang Sheng
Published: October 2021

Internet addiction is associated with a range of psychological risk factors such as childhood trauma and depression. Studies have also suggested sex differences in internet and other behavioral addictions. However, it remains unclear how childhood trauma, depression and internet addiction inter-relate differently between the sexes. A total of 1749 adolescents and young adults aged 12–27 participated in a survey of sociodemographic characteristics and standardized assessments to evaluate internet addiction (Internet Addiction Test), childhood trauma (Childhood Trauma Questionnaire) and depression (Beck Depression Inventory). Mediation and path analyses were used to examine the relationship between childhood trauma, depression and internet addiction. Internet-addicted females relative to males showed more severe depression but the control participants showed the opposite. Childhood trauma was associated with depression for both internet-addicted males and females; however, internet-addicted females but not males showed significant associations between depression and the severity of internet addiction as well as between childhood trauma and the severity of internet addiction. Further, in females, depression mediated the correlations between all types of childhood trauma and the severity of internet addiction. A path analysis suggested that sexual abuse and emotional neglect contributed most significantly to internet addiction when all types of childhood trauma were examined in one model. The findings suggest sex differences in the relationship between childhood trauma, depression and internet addiction. Childhood trauma contributes to internet addiction through depression only in females. The findings may guide future prevention and intervention strategies of internet addiction.
Diagnosing Neurally Mediated Syncope Using Classification Techniques
Authors: Hussain Shahadat , Raza Zahid , Kumar T V Vijay , Goswami Nandu
Published: October 2021

Syncope is a medical condition resulting in the spontaneous transient loss of consciousness and postural tone with spontaneous recovery. The diagnosis of syncope is a challenging task, as similar types of symptoms are observed in seizures, vertigo, stroke, coma, etc. The advent of Healthcare 4.0, which facilitates the usage of artificial intelligence and big data, has been widely used for diagnosing various diseases based on past historical data. In this paper, classification-based machine learning is used to diagnose syncope based on data collected through a head-up tilt test carried out in a purely clinical setting. This work is concerned with the use of classification techniques for diagnosing neurally mediated syncope triggered by a number of neurocardiogenic or cardiac-related factors. Experimental results show the effectiveness of using classification-based machine learning techniques for an early diagnosis and proactive treatment of neurally mediated syncope.
A Pragmatic Benchmarking Study of an Evidence-Based Personalised Approach in 1938 Adolescents with High-Risk Idiopathic Scoliosis
Authors: Negrini Stefano , Donzelli Sabrina , Negrini Francesco , Arienti Chiara , Zaina Fabio , Peers Koen
Published: October 2021

Combining evidence-based medicine and shared decision making, current guidelines support an evidence-based personalised approach (EBPA) for idiopathic scoliosis in adolescents (AIS). EBPA is considered important for adolescents’ compliance, which is particularly difficult in AIS. Benchmarking to existing Randomised Controlled Trials (RCTs) as paradigms of single treatments, we aimed to check the effectiveness and burden of care of an EBPA in high-risk AIS. This study’s design features a retrospective observation of a prospective database including 25,361 spinal deformity patients < 18 years of age. Participants consisted of 1938 AIS, 11–45° Cobb, Risser stage 0–2, who were studied until the end of growth. EBPA included therapies classified for burdensomeness according to current guidelines. Using the same inclusion criteria of the RCTs on exercises, plastic, and elastic bracing, out of the 1938 included, we benchmarked 590, 687, and 884 participants, respectively. We checked clinically significant results and burden of care, calculating Relative Risk of success (RR) and Number Needed to Treat (NNT) for efficacy (EA) and intent-to-treat analyses. At the end of growth, 19% of EBPA participants progressed, while 33% improved. EBPA showed 2.0 (1.7–2.5) and 2.9 (1.7–4.9) RR of success versus Weinstein and Coillard’s studies control groups, respectively. Benchmarked to plastic or elastic bracing, EBPA had 1.4 (1.2–1.5) and 1.7 (1.2–2.5) RR of success, respectively. The EBPA treatment burden was greater than RCTs in 48% of patients, and reduced for 24% and 42% versus plastic and elastic bracing, respectively. EBPA showed to be from 40% to 70% more effective than benchmarked individual treatments, with low NNT. The burden of treatment was frequently reduced, but it had to be increased even more frequently.
Diabetes Mellitus and Its Impact on Patient-Profile and In-Hospital Outcomes in Peripheral Artery Disease
Authors: Keller Karsten , Schmitt Volker H. , Vosseler Markus , Brochhausen Christoph , Münzel Thomas , Hobohm Lukas , Espinola-Klein Christine
Published: October 2021

Background: In patients with peripheral artery disease (PAD), the impact of diabetes mellitus (DM) on patient-profile and adverse in-hospital events is not well investigated. Methods: The German nationwide inpatient sample 2005–2019 was used for this analysis. Hospitalized PAD patients were stratified for DM and the influence of DM on patient-profile and adverse in-hospital events was investigated. Results: Our study comprised 2,654,871 hospitalizations (54.3% aged ≥70 years, 36.7% females) of patients with PAD in Germany 2005–2019. Among these, 864,691 (32.6%) patients had DM and 76,716 (2.9%) died during hospitalization. Diabetic PAD patients revealed an aggravated cardiovascular profile (Charlson Comorbidity Index: 6.0 (5.0–8.0) vs. 4.0 (3.0–5.0), p < 0.001). PAD patients with DM showed a higher rate of in-hospital mortality (3.5% vs. 2.6%, p < 0.001), as well as major adverse cardiovascular and cerebrovascular events (MACCE, 4.7% vs. 3.3%, p < 0.001) and had more often operated with amputation surgery (16.4% vs. 9.1%, p < 0.001). DM was an independent predictor of in-hospital mortality (OR 1.077 (95%CI 1.060–1.093), p < 0.001) and MACCE (OR 1.118 (95%CI 1.103–1.133), p < 0.001). In addition, amputations were also associated with DM (OR 1.804 (95%CI 1.790–1.818)), p < 0.001). Conclusions: DM is associated with an unfavorable clinical patient-profile and higher risk for adverse events in PAD patients, including substantially increased in-hospital mortality as well as MACCE rate, and were more often associated with amputation surgeries.
Viscoelastic Testing and Coagulopathy of Traumatic Brain Injury
Authors: Bradbury Jamie L. , Thomas Scott G. , Sorg Nikki R. , Mjaess Nicolas , Berquist Margaret R. , Brenner Toby J. , Langford Jack H. , Marsee Mathew K. , Moody Ashton N. , Bunch Connor M. , Sing Sandeep R. , Al-Fadhl Mahmoud D. , Salamah Qussai , Saleh Tarek , Patel Neal B. , Shaikh Kashif A. , Smith Stephen M. , Langheinrich Walter S. , Fulkerson Daniel H. , Sixta Sherry
Published: October 2021

A unique coagulopathy often manifests following traumatic brain injury, leading the clinician down a difficult decision path on appropriate prophylaxis and therapy. Conventional coagulation assays—such as prothrombin time, partial thromboplastin time, and international normalized ratio—have historically been utilized to assess hemostasis and guide treatment following traumatic brain injury. However, these plasma-based assays alone often lack the sensitivity to diagnose and adequately treat coagulopathy associated with traumatic brain injury. Here, we review the whole blood coagulation assays termed viscoelastic tests and their use in traumatic brain injury. Modified viscoelastic tests with platelet function assays have helped elucidate the underlying pathophysiology and guide clinical decisions in a goal-directed fashion. Platelet dysfunction appears to underlie most coagulopathies in this patient population, particularly at the adenosine diphosphate and/or arachidonic acid receptors. Future research will focus not only on the utility of viscoelastic tests in diagnosing coagulopathy in traumatic brain injury, but also on better defining the use of these tests as evidence-based and/or precision-based tools to improve patient outcomes.
The Application of Exercise Training for Diabetic Peripheral Neuropathy
Authors: Holmes Clifton J. , Hastings Mary K.
Published: October 2021

Diabetic peripheral neuropathy (DPN) is the presence of symptoms and/or signs of peripheral nerve dysfunction in people with diabetes after the exclusion of other causes. It is associated with pain, paresthesia, sensory loss, muscle atrophy with fat infiltration, and muscular dysfunction typically starting distally in the feet and progressing proximally. Muscle deterioration within the leg and foot can lead to muscle dysfunction, reduced mobility, and increases the risk of disability, ulceration, and amputation. Exercise training is an established method for increasing the different components of physical fitness, including enhancing body composition and improving neuromuscular strength. A number of experimental studies have utilized exercise training to treat various impairments associated with DPN, such as nerve conduction velocity, pain tolerance, and balance. However, the broad spectrum of exercise training modalities implemented and differences in target outcome measurements have made it difficult to understand the efficacy of exercise training interventions or provide appropriate exercise prescription recommendations. Therefore, the aims of this review were to (1) briefly describe the pathophysiology of DPN and (2) discuss the effects of exercise training interventions on sensorimotor, metabolic, and physical functions in people with DPN.
Vascular Complications in TAVR: Incidence, Clinical Impact, and Management
Authors: Mach Markus , Okutucu Sercan , Kerbel Tillmann , Arjomand Aref , Fatihoglu Sefik Gorkem , Werner Paul , Simon Paul , Andreas Martin
Published: October 2021

Transcatheter aortic valve replacement (TAVR) has replaced surgical aortic valve replacement as the new gold standard in elderly patients with severe aortic valve stenosis. However, alongside this novel approach, new complications emerged that require swift diagnosis and adequate management. Vascular access marks the first step in a TAVR procedure. There are several possible access sites available for TAVR, including the transfemoral approach as well as transaxillary/subclavian, transcarotid, transapical, and transcaval. Most cases are primarily performed through a transfemoral approach, while other access routes are mainly conducted in patients not suitable for transfemoral TAVR. As vascular access is achieved primarily by large bore sheaths, vascular complications are one of the major concerns during TAVR. With rising numbers of TAVR being performed, the focus on prevention and successful management of vascular complications will be of paramount importance to lower morbidity and mortality of the procedures. Herein, we aimed to review the most common vascular complications associated with TAVR and summarize their diagnosis, management, and prevention of vascular complications in TAVR.
Liver Injury in Patients with Coronavirus Disease 2019 (COVID-19)—A Narrative Review
Authors: Łykowska-Szuber Liliana , Wołodźko Karolina , Rychter Anna Maria , Szymczak-Tomczak Aleksandra , Krela-Kaźmierczak Iwona , Dobrowolska Agnieszka
Published: October 2021

While respiratory symptoms are prevalent in SARS-CoV-2 infected patients, growing evidence indicates that COVID-19 affects a wide variety of organs. Coronaviruses affect not only the respiratory system, but also the circulatory, nervous and digestive systems. The most common comorbidities in COVID-19 patients are hypertension, followed by diabetes, cardiovascular, and respiratory disease. Most conditions predisposing to SARS-CoV-2 infection are closely related to the metabolic syndrome. Obesity and chronic diseases, including liver disease, are associated with the induction of pro-inflammatory conditions and a reduction in immune response disorders, leading to the suspicion that these conditions may increase the susceptibility to SARS-CoV2 infection and the risk of complications. The definition of liver damage caused by COVID-19 has not yet been established. COVID-19 may contribute to both primary and secondary liver injury in people with pre-existing chronic disease and impaired liver reserves, leading to exacerbation of underlying disease, liver decompensation, or acute chronic liver failure. Therefore, many researchers have interpreted it as clinical or laboratory abnormalities in the course of the disease and treatment in patients with or without pre-existing liver disease. The research results available so far indicate that patients with liver disease require special attention in the event of COVID-19 infection.
On a Variational and Convex Model of the Blake–Zisserman Type for Segmentation of Low-Contrast and Piecewise Smooth Images
Authors: Burrows Liam , Theljani Anis , Chen Ke
Published: October 2021

This paper proposes a new variational model for segmentation of low-contrast and piecewise smooth images. The model is motivated by the two-stage image segmentation work of Cai–Chan–Zeng (2013) for the Mumford–Shah model. To deal with low-contrast images more effectively, especially in treating higher-order discontinuities, we follow the idea of the Blake–Zisserman model instead of the Mumford–Shah. Two practical ideas are introduced here: first, a convex relaxation idea is used to derive an implementable formulation, and second, a game reformulation is proposed to reduce the strong dependence of coupling parameters. The proposed model is then analysed for existence and further solved by an ADMM solver. Numerical experiments can show that the new model outperforms the current state-of-the-art models for some challenging and low-contrast images.
A Novel Standard-Cell-Based Implementation of the Digital OTA Suitable for Automatic Place and Route
Authors: Palumbo Gaetano , Scotti Giuseppe
Published: October 2021

This paper presents a novel implementation of a digital-based Operational Transconductance Amplifier (OTA) which has been recently introduced in the technical literature as a fully digital alternative to the conventional differential pair to implement low voltage analog amplifiers and comparators. The proposed implementation does not make use of resistors, floating gate resistors nor C-Muller elements and is made up of only digital gates usually available in the standard cell libraries. The resulting analog circuit schematic can be described using structural VHDL or Verilog languages and is suitable to be integrated in an automatic synthesis and place and route flow for digital circuits. The proposed digital-based amplifier has been implemented in a commercial 130 nm CMOS process by using an automatic place and route flow for layout generation starting from the Verilog netlist. Post layout simulations are presented to show the performance of the proposed circuit and compare it against the state of the art.
Elucidation of the Natural Function of Sophorolipids Produced by Starmerella bombicola
Authors: De Clercq Veerle , Roelants Sophie L. K. W. , Castelein Martijn G. , De Maeseneire Sofie L. , Soetaert Wim K.
Published: October 2021

The yeast Starmerella bombicola distinguishes itself from other yeasts by its potential of producing copious amounts of the secondary metabolites sophorolipids (SLs): these are glycolipid biosurfactants composed out of a(n) (acetylated) sophorose moiety and a lipid tail. Although SLs are the subject of numerous research papers and have been commercialized, e.g., in eco-friendly cleaning solutions, the natural function of SLs still remains elusive. This research article investigates several hypotheses for why S. bombicola invests that much energy in the production of SLs, and we conclude that the main natural function of SLs in S. bombicola is niche protection: (1) the extracellular storage of an energy-rich, yet metabolically less accessible carbon source that can be utilized by S. bombicola upon conditions of starvation with (2) antimicrobial properties. In this way, S. bombicola creates a dual advantage in competition with other microorganisms. Additionally, SLs can expedite growth on rapeseed oil, composed of triacylglycerols which are hydrophobic substrates present in the yeasts’ environment, for a non-SL producing strain (Δcyp52M1). It was also found that—at least under lab conditions—SLs do not provide protection against high osmotic pressure prevalent in sugar-rich environments such as honey or nectar present in the natural habitat of S. bombicola.
A Transient Receptor Potential-like Calcium Ion Channel in the Filamentous Fungus Aspergillus nidulans
Authors: Wang Hongchen , Chen Qiuyi , Zhang Shizhu , Lu Ling
Published: October 2021

Transient Receptor Potential (TRP) proteins constitute a superfamily that encodes transmembrane ion channels with highly diverse permeation and gating properties. Filamentous fungi possess putative TRP channel-encoded genes, but their functions remain elusive. Here, we report that a putative TRP-like calcium channel, trpR, in the filamentous fungus Aspergillus nidulans, performs important roles in conidiation and in adapting to cell wall disruption reagents in a high temperature-induced defect-dependent manner, especially under a calcium-limited culture condition. The genetic and functional relationship between TrpR and the previously identified high-affinity calcium channels CchA/MidA indicates that TrpR has an opposite response to CchA/MidA when reacting to cell wall disruption reagents and in regulating calcium transients. However, a considerable addition of calcium can rescue all the defects that occur in TrpR and CchA/MidA, meaning that calcium is able to bypass the necessary requirement. Nevertheless, the colocalization at the membrane of the Golgi for TrpR and the P-type Golgi Ca2+ ATPase PmrA suggests two channels that may work as ion transporters, transferring Ca2+ from the cytosol into the Golgi apparatus and maintaining cellular calcium homeostasis. Therefore, combined with data for the trpR deletion mutant revealing abnormal cell wall structures, TrpR works as a Golgi membrane calcium ion channel that involves cell wall integration.
Context-Dependent Stability and Robustness of Genetic Toggle Switches with Leaky Promoters
Authors: Gyorgy Andras
Published: October 2021

Multistable switches are ubiquitous building blocks in both systems and synthetic biology. Given their central role, it is thus imperative to understand how their fundamental properties depend not only on the tunable biophysical properties of the switches themselves, but also on their genetic context. To this end, we reveal in this article how these factors shape the essential characteristics of toggle switches implemented using leaky promoters such as their stability and robustness to noise, both at single-cell and population levels. In particular, our results expose the roles that competition for scarce transcriptional and translational resources, promoter leakiness, and cell-to-cell heterogeneity collectively play. For instance, the interplay between protein expression from leaky promoters and the associated cost of relying on shared cellular resources can give rise to tristable dynamics even in the absence of positive feedback. Similarly, we demonstrate that while promoter leakiness always acts against multistability, resource competition can be leveraged to counteract this undesirable phenomenon. Underpinned by a mechanistic model, our results thus enable the context-aware rational design of multistable genetic switches that are directly translatable to experimental considerations, and can be further leveraged during the synthesis of large-scale genetic systems using computer-aided biodesign automation platforms.