bluuebunny/crossref_metadata_2025 huggingface dataset:
Skeletal Muscle Microvascular Dysfunction in Obesity-Related Insulin Resistance: Pathophysiological Mechanisms and Therapeutic Perspectives
Authors: Ugwoke Chiedozie Kenneth , Cvetko Erika , Umek Nejc
Published: January 2022

Obesity is a worrisomely escalating public health problem globally and one of the leading causes of morbidity and mortality from noncommunicable disease. The epidemiological link between obesity and a broad spectrum of cardiometabolic disorders has been well documented; however, the underlying pathophysiological mechanisms are only partially understood, and effective treatment options remain scarce. Given its critical role in glucose metabolism, skeletal muscle has increasingly become a focus of attention in understanding the mechanisms of impaired insulin function in obesity and the associated metabolic sequelae. We examined the current evidence on the relationship between microvascular dysfunction and insulin resistance in obesity. A growing body of evidence suggest an intimate and reciprocal relationship between skeletal muscle microvascular and glucometabolic physiology. The obesity phenotype is characterized by structural and functional changes in the skeletal muscle microcirculation which contribute to insulin dysfunction and disturbed glucose homeostasis. Several interconnected etiologic molecular mechanisms have been suggested, including endothelial dysfunction by several factors, extracellular matrix remodelling, and induction of oxidative stress and the immunoinflammatory phenotype. We further correlated currently available pharmacological agents that have deductive therapeutic relevance to the explored pathophysiological mechanisms, highlighting a potential clinical perspective in obesity treatment.
Albumin Expands Albumin Reabsorption Capacity in Proximal Tubule Epithelial Cells through a Positive Feedback Loop between AKT and Megalin
Authors: Silva-Aguiar Rodrigo P. , Peruchetti Diogo B. , Florentino Lucas S. , Takiya Christina M. , Marzolo María-Paz , Dias Wagner B. , Pinheiro Ana Acacia S. , Caruso-Neves Celso
Published: January 2022

Renal proximal tubule cells (PTECs) act as urine gatekeepers, constantly and efficiently avoiding urinary protein waste through receptor-mediated endocytosis. Despite its importance, little is known about how this process is modulated in physiologic conditions. Data suggest that the phosphoinositide-3-kinase (PI3K)/protein kinase B (AKT) pathway regulates PTEC protein reabsorption. Here, we worked on the hypothesis that the physiologic albumin concentration and PI3K/AKT pathway form a positive feedback loop to expand endocytic capacity. Using LLC-PK1 cells, a model of PTECs, we showed that the PI3K/AKT pathway is required for megalin recycling and surface expression, affecting albumin uptake. Inhibition of this pathway stalls megalin at EEA1+ endosomes. Physiologic albumin concentration (0.01 mg/mL) activated AKT; this depends on megalin-mediated albumin endocytosis and requires previous activation of PI3K/mTORC2. This effect is correlated to the increase in albumin endocytosis, a phenomenon that we refer to as “albumin-induced albumin endocytosis”. Mice treated with L-lysine present decreased albumin endocytosis leading to proteinuria and albuminuria associated with inhibition of AKT activity. Renal cortex explants obtained from control mice treated with MK-2206 decreased albumin uptake and promoted megalin internalization. Our data highlight the mechanism behind the capacity of PTECs to adapt albumin reabsorption to physiologic fluctuations in its filtration, avoiding urinary excretion.
HDAC2 Is Involved in the Regulation of BRN3A in Melanocytes and Melanoma
Authors: Heppt Markus V. , Wessely Anja , Hornig Eva , Kammerbauer Claudia , Graf Saskia A. , Besch Robert , French Lars E. , Matthies Alexander , Kuphal Silke , Kappelmann-Fenzl Melanie , Bosserhoff Anja K. , Berking Carola
Published: January 2022

The neural crest transcription factor BRN3A is essential for the proliferation and survival of melanoma cells. It is frequently expressed in melanoma but not in normal melanocytes or benign nevi. The mechanisms underlying the aberrant expression of BRN3A are unknown. Here, we investigated the epigenetic regulation of BRN3A in melanocytes and melanoma cell lines treated with DNA methyltransferase (DNMT), histone acetyltransferase (HAT), and histone deacetylase (HDAC) inhibitors. DNMT and HAT inhibition did not significantly alter BRN3A expression levels, whereas panHDAC inhibition by trichostatin A led to increased expression. Treatment with the isoform-specific HDAC inhibitor mocetinostat, but not with PCI-34051, also increased BRN3A expression levels, suggesting that class I HDACs HDAC1, HDAC2, and HDAC3, and class IV HDAC11, were involved in the regulation of BRN3A expression. Transient silencing of HDACs 1, 2, 3, and 11 by siRNAs revealed that, specifically, HDAC2 inhibition was able to increase BRN3A expression. ChIP-Seq analysis uncovered that HDAC2 inhibition specifically increased H3K27ac levels at a distal enhancer region of the BRN3A gene. Altogether, our data suggest that HDAC2 is a key epigenetic regulator of BRN3A in melanocytes and melanoma cells. These results highlight the importance of epigenetic mechanisms in regulating melanoma oncogenes.
Small Heat Shock Protein 22 Improves Cognition and Learning in the Tauopathic Brain
Authors: Rodriguez Ospina Santiago , Blazier Danielle , Criado-Marrero Marangelie , Gould Lauren , Gebru Niat , Beaulieu-Abdelahad David , Wang Xinming , Remily-Wood Elizabeth , Chaput Dale , Stevens Stanley , Uversky Vladimir , Bickford Paula , Dickey Chad , Blair Laura
Published: January 2022

The microtubule-associated protein tau pathologically accumulates and aggregates in Alzheimer’s disease (AD) and other tauopathies, leading to cognitive dysfunction and neuronal loss. Molecular chaperones, like small heat-shock proteins (sHsps), can help deter the accumulation of misfolded proteins, such as tau. Here, we tested the hypothesis that the overexpression of wild-type Hsp22 (wtHsp22) and its phosphomimetic (S24,57D) Hsp22 mutant (mtHsp22) could slow tau accumulation and preserve memory in a murine model of tauopathy, rTg4510. Our results show that Hsp22 protected against deficits in synaptic plasticity and cognition in the tauopathic brain. However, we did not detect a significant change in tau phosphorylation or levels in these mice. This led us to hypothesize that the functional benefit was realized through the restoration of dysfunctional pathways in hippocampi of tau transgenic mice since no significant benefit was measured in non-transgenic mice expressing wtHsp22 or mtHsp22. To identify these pathways, we performed mass spectrometry of tissue lysates from the injection site. Overall, our data reveal that Hsp22 overexpression in neurons promotes synaptic plasticity by regulating canonical pathways and upstream regulators that have been characterized as potential AD markers and synaptogenesis regulators, like EIF4E and NFKBIA.
Genome-Wide CRISPR/Cas9-Based Screening for Deubiquitinase Subfamily Identifies Ubiquitin-Specific Protease 11 as a Novel Regulator of Osteogenic Differentiation
Authors: Kaushal Kamini , Tyagi Apoorvi , Karapurkar Janardhan Keshav , Kim Eun-Jung , Tanguturi Parthasaradhireddy , Kim Kye-Seong , Jung Han-Sung , Ramakrishna Suresh
Published: January 2022

The osteoblast differentiation capacity of mesenchymal stem cells must be tightly regulated, as inadequate bone mineralization can lead to osteoporosis, and excess bone formation can cause the heterotopic ossification of soft tissues. The balanced protein level of Msh homeobox 1 (MSX1) is critical during normal osteogenesis. To understand the factors that prevent MSX1 protein degradation, the identification of deubiquitinating enzymes (DUBs) for MSX1 is essential. In this study, we performed loss-of-function-based screening for DUBs regulating MSX1 protein levels using the CRISPR/Cas9 system. We identified ubiquitin-specific protease 11 (USP11) as a protein regulator of MSX1 and further demonstrated that USP11 interacts and prevents MSX1 protein degradation by its deubiquitinating activity. Overexpression of USP11 enhanced the expression of several osteogenic transcriptional factors in human mesenchymal stem cells (hMSCs). Additionally, differentiation studies revealed reduced calcification and alkaline phosphatase activity in USP11-depleted cells, while overexpression of USP11 enhanced the differentiation potential of hMSCs. These results indicate the novel role of USP11 during osteogenic differentiation and suggest USP11 as a potential target for bone regeneration.
Analysis of Integrin αIIb Subunit Dynamics Reveals Long-Range Effects of Missense Mutations on Calf Domains
Authors: Anies Sali , Jallu Vincent , Diharce Julien , Narwani Tarun J. , de Brevern Alexandre G.
Published: January 2022

Integrin αIIbβ3, a glycoprotein complex expressed at the platelet surface, is involved in platelet aggregation and contributes to primary haemostasis. Several integrin αIIbβ3 polymorphisms prevent the aggregation that causes haemorrhagic syndromes, such as Glanzmann thrombasthenia (GT). Access to 3D structure allows understanding the structural effects of polymorphisms related to GT. In a previous analysis using Molecular Dynamics (MD) simulations of αIIbCalf-1 domain structure, it was observed that GT associated with single amino acid variation affects distant loops, but not the mutated position. In this study, experiments are extended to Calf-1, Thigh, and Calf-2 domains. Two loops in Calf-2 are unstructured and therefore are modelled expertly using biophysical restraints. Surprisingly, MD revealed the presence of rigid zones in these loops. Detailed analysis with structural alphabet, the Proteins Blocks (PBs), allowed observing local changes in highly flexible regions. The variant P741R located at C-terminal of Calf-1 revealed that the Calf-2 presence did not affect the results obtained with isolated Calf-1 domain. Simulations for Calf-1 + Calf-2, and Thigh + Calf-1 variant systems are designed to comprehend the impact of five single amino acid variations in these domains. Distant conformational changes are observed, thus highlighting the potential role of allostery in the structural basis of GT.
Dual Blockade of TNF and IL-17A Inhibits Inflammation and Structural Damage in a Rat Model of Spondyloarthritis
Authors: Hammoura Ihsan , Fiechter Renee H. , Bryant Shaughn H. , Westmoreland Susan , Kingsbury Gillian , Waegell Wendy , Tas Sander W. , Baeten Dominique L. , van de Sande Marleen G. H. , van Tok Melissa N. , van Duivenvoorde Leonie M.
Published: January 2022

The tumor necrosis factor (TNF) and IL-23/IL-17 axes are the main therapeutic targets in spondyloarthritis. Despite the clinical efficacy of blocking either pathway, monotherapy does not induce remission in all patients and its effect on new bone formation remains unclear. We aimed to study the effect of TNF and IL-17A dual inhibition on clinical disease and structural damage using the HLA-B27/human β2-microglobulin transgenic rat model of SpA. Immunized rats were randomized according to arthritis severity, 1 week after arthritis incidence reached 50%, to be treated twice weekly for a period of 5 weeks with either a dual blockade therapy of an anti-TNF antibody and an anti-IL-17A antibody, a single therapy of either antibody, or PBS as vehicle control. Treatment-blinded observers assessed inflammation and structural damage clinically, histologically and by micro-CT imaging. Both single therapies as well as TNF and IL-17A dual blockade therapy reduced clinical spondylitis and peripheral arthritis effectively and similarly. Clinical improvement was confirmed for all treatments by a reduction of histological inflammation and pannus formation (p < 0.05) at the caudal spine. All treatments showed an improvement of structural changes at the axial and peripheral joints on micro-CT imaging, with a significant decrease for roughness (p < 0.05), which reflects both erosion and new bone formation, at the level of the caudal spine. The effect of dual blockade therapy on new bone formation was more prominent at the axial than the peripheral level. Collectively, our study showed that dual blockade therapy significantly reduces inflammation and structural changes, including new bone formation. However, we could not confirm a more pronounced effect of dual inhibition compared to single inhibition.
Mean Received Resources Meet Machine Learning Algorithms to Improve Link Prediction Methods
Authors: Ayoub Jibouni , Lotfi Dounia , Hammouch Ahmed
Published: January 2022

The analysis of social networks has attracted a lot of attention during the last two decades. These networks are dynamic: new links appear and disappear. Link prediction is the problem of inferring links that will appear in the future from the actual state of the network. We use information from nodes and edges and calculate the similarity between users. The more users are similar, the higher the probability of their connection in the future will be. The similarity metrics play an important role in the link prediction field. Due to their simplicity and flexibility, many authors have proposed several metrics such as Jaccard, AA, and Katz and evaluated them using the area under the curve (AUC). In this paper, we propose a new parameterized method to enhance the AUC value of the link prediction metrics by combining them with the mean received resources (MRRs). Experiments show that the proposed method improves the performance of the state-of-the-art metrics. Moreover, we used machine learning algorithms to classify links and confirm the efficiency of the proposed combination.
Evaluation of Continuous Power-Down Schemes
Authors: Andro-Vasko James , Bein Wolfgang
Published: January 2022

We consider a power-down system with two states—“on” and “off”—and a continuous set of power states. The system has to respond to requests for service in the “on” state and, after service, the system can power off or switch to any of the intermediate power-saving states. The choice of states determines the cost to power on for subsequent requests. The protocol for requests is “online”, which means that the decision as to which intermediate state (or the off-state) the system will switch has to be made without knowledge of future requests. We model a linear and a non-linear system, and we consider different online strategies, namely piece-wise linear, logarithmic and exponential. We provide results under online competitive analysis, which have relevance for the integration of renewable energy sources into the smart grid. Our analysis shows that while piece-wise linear systems are not specific for any type of system, logarithmic strategies work well for slack systems, whereas exponential systems are better suited for busy systems.
Neglected Very Long-Chain Hydrocarbons and the Incorporation of Body Surface Area Metrics Reveal Novel Perspectives for Cuticular Profile Analysis in Insects
Authors: Golian Marek , Bien Tanja , Schmelzle Sebastian , Esparza-Mora Margy Alejandra , McMahon Dino Peter , Dreisewerd Klaus , Buellesbach Jan
Published: January 2022

Most of our knowledge on insect cuticular hydrocarbons (CHCs) stems from analytical techniques based on gas-chromatography coupled with mass spectrometry (GC-MS). However, this method has its limits under standard conditions, particularly in detecting compounds beyond a chain length of around C40. Here, we compare the CHC chain length range detectable by GC-MS with the range assessed by silver-assisted laser desorption/ionization mass spectrometry (Ag-LDI-MS), a novel and rarely applied technique on insect CHCs, in seven species of the order Blattodea. For all tested species, we unveiled a considerable range of very long-chain CHCs up to C58, which are not detectable by standard GC-MS technology. This indicates that general studies on insect CHCs may frequently miss compounds in this range, and we encourage future studies to implement analytical techniques extending the conventionally accessed chain length range. Furthermore, we incorporate 3D scanned insect body surface areas as an additional factor for the comparative quantification of extracted CHC amounts between our study species. CHC quantity distributions differed considerably when adjusted for body surface areas as opposed to directly assessing extracted CHC amounts, suggesting that a more accurate evaluation of relative CHC quantities can be achieved by taking body surface areas into account.
The Diversity of Bacteria Associated with the Invasive Gall Wasp Dryocosmus kuriphilus, Its Galls and a Specialist Parasitoid on Chestnuts
Authors: Yang Xiaohui , Hui Yu , Zhu Daohong , Zeng Yang , Zhao Lvquan , Yang Xuemei , Wang Yumei
Published: January 2022

Dryocosmus kuriphilus (Hymenoptera: Cynipidae) induces galls on chestnut trees, which results in massive yield losses worldwide. Torymus sinensis (Hymenoptera: Torymidae) is a host-specific parasitoid that phenologically synchronizes with D. kuriphilus. Bacteria play important roles in the life cycle of galling insects. The aim of this research is to investigate the bacterial communities and predominant bacteria of D. kuriphilus, T. sinensis, D. kuriphilus galls and the galled twigs of Castanea mollissima. We sequenced the V5–V7 region of the bacterial 16S ribosomal RNA in D. kuriphilus, T. sinensis, D. kuriphilus galls and galled twigs using high-throughput sequencing for the first time. We provide the first evidence that D. kuriphilus shares most bacterial species with T. sinensis, D. kuriphilus galls and galled twigs. The predominant bacteria of D. kuriphilus are Serratia sp. and Pseudomonas sp. Furthermore, the bacterial community structures of D. kuriphilus and T. sinensis clearly differ from those of the other groups. Many species of the Serratia and Pseudomonas genera are plant pathogenic bacteria, and we suggest that D. kuriphilus may be a potential vector of plant pathogens. Furthermore, a total of 111 bacteria are common to D. kuriphilus adults, T. sinensis, D. kuriphilus galls and galled twigs, and we suggest that the bacteria may transmit horizontally among D. kuriphilus, T. sinensis, D. kuriphilus galls and galled twigs on the basis of their ecological associations.
HCV Genotype Has No Influence on the Incidence of Diabetes—EpiTer Multicentre Study
Authors: Rajewski Paweł , Zarębska-Michaluk Dorota , Janczewska Ewa , Gietka Andrzej , Mazur Włodzimierz , Tudrujek-Zdunek Magdalena , Tomasiewicz Krzysztof , Belica-Wdowik Teresa , Baka-Ćwierz Barbara , Dybowska Dorota , Halota Waldemar , Lorenc Beata , Sitko Marek , Garlicki Aleksander , Berak Hanna , Horban Andrzej , Orłowska Iwona , Simon Krzysztof , Socha Łukasz , Wawrzynowicz-Syczewska Marta , Jaroszewicz Jerzy , Deroń Zbigniew , Czauż-Andrzejuk Agnieszka , Citko Jolanta , Krygier Rafał , Piekarska Anna , Laurans Łukasz , Dobracki Witold , Białkowska Jolanta , Tronina Olga , Wietlicka-Piszcz Magdalena , Pawłowska Małgorzata , Flisiak Robert
Published: January 2022

HCV infection is one of the main reasons for liver cirrhosis and hepatocellular carcinoma. In recent years, one finds more and more extrahepatic manifestations of HCV infection, including its possible influence on the development of diabetes. In the presented work, one finds the frequency analysis of the incidence of diabetes among 2898 HCV infected patients treated in Poland, and the assessment of their relevance to the HCV genotype and the progression of fibrosis. The results indicate that the hepatitis C infection seems to be a risk factor for diabetes in persons with more advanced liver fibrosis, for older people, and for the male gender. Thus, one found no differences regarding the frequency of its incidence depending on HCV genotype, including genotype 3.
Plasma Amino Acids May Improve Prediction Accuracy of Cerebral Vasospasm after Aneurysmal Subarachnoid Haemorrhage
Authors: Bobeff Ernest Jan , Bukowiecka-Matusiak Malgorzata , Stawiski Konrad , Wiśniewski Karol , Burzynska-Pedziwiatr Izabela , Kordzińska Magdalena , Kowalski Konrad , Sendys Przemyslaw , Piotrowski Michał , Szczesna Dorota , Stefańczyk Ludomir , Wozniak Lucyna Alicja , Jaskólski Dariusz Jan
Published: January 2022

Aneurysmal subarachnoid haemorrhages (aSAH) account for 5% of strokes and continues to place a great burden on patients and their families. Cerebral vasospasm (CVS) is one of the main causes of death after aSAH, and is usually diagnosed between day 3 and 14 after bleeding. Its pathogenesis remains poorly understood. To verify whether plasma concentration of amino acids have prognostic value in predicting CVS, we analysed data from 35 patients after aSAH (median age 55 years, IQR 39–62; 20 females, 57.1%), and 37 healthy volunteers (median age 50 years, IQR 38–56; 19 females, 51.4%). Fasting peripheral blood samples were collected on postoperative day one and seven. High performance liquid chromatography-mass spectrometry (HPLC-MS) analysis was performed. The results showed that plasma from patients after aSAH featured a distinctive amino acids concentration which was presented in both principal component analysis and direct comparison. No significant differences were noted between postoperative day one and seven. A total of 18 patients from the study group (51.4%) developed CVS. Hydroxyproline (AUC = 0.7042, 95%CI 0.5259–0.8826, p = 0.0248) and phenylalanine (AUC = 0.6944, 95%CI 0.5119–0.877, p = 0.0368) presented significant CVS prediction potential. Combining the Hunt-Hess Scale and plasma levels of hydroxyproline and phenylalanine provided the model with the best predictive performance and the lowest leave-one-out cross-validation of performance error. Our results suggest that plasma amino acids may improve sensitivity and specificity of Hunt-Hess scale in predicting CVS.
Prevention of Periprosthetic Joint Infection in Total Hip and Knee Replacement: One European Consensus
Authors: Gómez-Barrena Enrique , Warren Timothy , Walker Ian , Jain Neil , Kort Nanne , Loubignac François , Newman Simon , Perka Carsten , Spinarelli Antonio , Whitehouse Michael R. , Zagra Luigi , De la Torre Basilio J.
Published: January 2022

Periprosthetic joint infection (PJI) is a devastating complication in total hip and knee replacement. Its prevention is key to decrease the incidence and avoid some consequences that seriously impact patients and health systems. In view of the variety of recommendations and guidelines, we decided to conduct an expert, peer-reviewed European consensus analysis about the pre-, intra-, and postoperative prevention of PJI. A multinational group of practicing orthopedic experts developed a series of 47 consensus statements in 6 main groups of intervention, and a 2-stage Delphi approach was launched with a threshold for agreement at 75% and for very high agreement at more than 90%. A total of 306 orthopedic surgeon responses were gathered from 9 countries. Consensus was reached for 42/47 statements, 31/47 of which achieved a very high consensus. Many preoperative actions gathered strong consensus, although areas like the use of alcoholic chlorhexidine or the timing of hair removal did not attain strong consensus, despite available evidence. Intra- and postoperative actions showed more variability regarding incise drapes, skin suturing techniques, and wound follow-up. This study confirms an important consensus among orthopedic surgeons across Europe in many areas well known to contribute to the prevention of PJI; however, there are still grounds for improvement.
Atrial Functional Tricuspid Regurgitation as a Distinct Pathophysiological and Clinical Entity: No Idiopathic Tricuspid Regurgitation Anymore
Authors: Florescu Diana R. , Muraru Denisa , Volpato Valentina , Gavazzoni Mara , Caravita Sergio , Tomaselli Michele , Ciampi Pellegrino , Florescu Cristina , Bălșeanu Tudor A. , Parati Gianfranco , Badano Luigi P.
Published: January 2022

Functional tricuspid regurgitation (FTR) is a strong and independent predictor of patient morbidity and mortality if left untreated. The development of transcatheter procedures to either repair or replace the tricuspid valve (TV) has fueled the interest in the pathophysiology, severity assessment, and clinical consequences of FTR. FTR has been considered to be secondary to tricuspid annulus (TA) dilation and leaflet tethering, associated to right ventricular (RV) dilation and/or dysfunction (the “classical”, ventricular form of FTR, V-FTR) for a long time. Atrial FTR (A-FTR) has recently emerged as a distinct pathophysiological entity. A-FTR typically occurs in patients with persistent/permanent atrial fibrillation, in whom an imbalance between the TA and leaflet areas results in leaflets malcoaptation, associated with the dilation and loss of the sphincter-like function of the TA, due to right atrium enlargement and dysfunction. According to its distinct pathophysiology, A-FTR poses different needs of clinical management, and the various interventional treatment options will likely have different outcomes than in V-FTR patients. This review aims to provide an insight into the anatomy of the TV, and the distinct pathophysiology of A-FTR, which are key concepts to understanding the objectives of therapy, the choice of transcatheter TV interventions, and to properly use pre-, intra-, and post-procedural imaging.
Gender-Related Clinical Characteristics in Children and Adolescents with ADHD
Authors: De Rossi Pietro , Pretelli Italo , Menghini Deny , D’Aiello Barbara , Di Vara Silvia , Vicari Stefano
Published: January 2022

Attention Deficit/Hyperactivity Disorder (ADHD) is the most frequently diagnosed neurodevelopmental disorder in school-age children, and it is usually associated with a significant impairment in global functioning. Traditionally, boys with ADHD are more likely to be referred for clinical assessments due to a higher prevalence of externalizing symptoms. However, as regards gender-related differential clinical characteristics between boys and girls with ADHD, further investigation is warranted in light of conflicting results found in currently available literature. In fact, a more precise clinical characterization could help increase appropriate diagnoses and treatment planning. In this context, we carried out a retrospective observational study on 715 children and adolescents diagnosed with ADHD from 2018 to 2020 at our center, in order to describe their gender-related clinical characteristics. Boys displayed higher average IQs, but they were comparable to girls in functional impairments and adaptive skills. Girls displayed higher scores on the Attention Problems subscale of the CBCL 6–18 and on several CPRS-R:L subscales, suggesting higher general ADHD symptom severity. Boys showed higher scores on CBCL 6–18 subscales, such as withdrawn/depressed, internalizing, and obsessive-compulsive problems. In conclusion, girls showed more severe ADHD features and lower IQ in clinically referred settings, while boys showed more internalizing problems and obsessive-compulsive symptoms.
Pangenotypic and Genotype-Specific Antivirals in the Treatment of HCV Genotype 4 Infected Patients with HCV Monoinfection and HIV/HCV Coinfection
Authors: Zarębska-Michaluk Dorota , Jaroszewicz Jerzy , Parfieniuk-Kowerda Anna , Pawłowska Małgorzata , Janczewska Ewa , Berak Hanna , Janocha-Litwin Justyna , Klapaczyński Jakub , Tomasiewicz Krzysztof , Piekarska Anna , Krygier Rafał , Citko Jolanta , Tronina Olga , Dobrowolska Krystyna , Flisiak Robert
Published: January 2022

The introduction of the direct-acting antivirals (DAA) has substantially improved the effectiveness of the therapy in patients with chronic hepatitis C. We aimed to compare the efficacy of pangenotypic and genotype-specific DAA in the cohort of genotype (GT) four patients with HCV monoinfection and HIV coinfection. A total of 662 GT4-infected patients treated in 2015–2020—of whom 168 (25.3%) were coinfected with HIV, selected from the retrospective EpiTer-2 database—were enrolled in the analysis. Among HIV-coinfected patients, 54% (90) were treated with genotype-specific regimens and 46% (78) with pangenotypic options, while among HCV-monoinfected patients, the rates were 72% and 28%, respectively. Significantly higher rate of males (67.9% vs. 57.7%, p = 0.01), a lower rate of liver cirrhosis (10.2% vs. 18.1%, p = 0.02), and higher of treatment-naïve patients (87.5% vs. 76.7%, p = 0.003) were documented in the HIV coinfected population. The overall sustained virologic response after exclusion of non-virologic failures was achieved in 98% with no significant difference between HIV-positive and HIV-negative patients, 96.2% vs. 98.5%, respectively. While the genotype-specific regimens resulted in a similar cure rate regardless of the HIV status, the pangenotypic options were more efficacious in patients with HCV monoinfection (99.3% vs. 94.4%, p = 0.05). Hereby, we demonstrated the high effectiveness and good safety profile of the DAA therapy in the population of HCV GT4 infected patients with HIV coinfection supporting the current recommendations to treat HCV/HIV coinfected patients with the same options as those with HCV monoinfection.
Tissue Microarray from Cell Block Material (cbTMA)—An Additional Shot for Cytology in the Predictive Pathology Era: The PD-L1 Experience
Authors: Iaccarino Antonino , Acanfora Gennaro , Pisapia Pasquale , Malapelle Umberto , Bellevicine Claudio , Troncone Giancarlo , Vigliar Elena
Published: January 2022

Generally, predictive biomarker tests are clinically validated on histological formalin-fixed, paraffin-embedded (FFPE) samples. In addition to FFPE samples, cytological samples have also emerged as a useful approach to detect predictive biomarkers. However, as of today, despite the promising results reported in the recent literature, their full implementation in routine clinical practice is still lagging owing to a lack of standardized preparatory protocols, challenging assessments of cyto-histological correlation, and variable inter-observer agreement. The aim of this report was to explore the possibility of implementing a large-scale validation of predictive biomarker testing on cytological material. To this aim, we evaluated the technical feasibility of PD-L1 assessment on a cell block (CB)-derived tissue microarray (cbTMA). Consecutive and unselected CBs prepared from metastatic lymph node fine-needle cytology (FNC) samples were retrospectively collected and used for TMA construction. PD-L1 immunohistochemistry (IHC) was carried out on cbTMA sections with the companion diagnostic kit SP263 assay. TMA contained 33 CB-derived cores. A total of 20 sections were hematoxylin and eosin (H&E) stained. Overall, 29 (88%) samples were visible at least in one H&E-stained slide. Four cases out of five sections stained with the SP263 assay (4/29, 13.8%) showed PD-L1 positivity in neoplastic and/or immune cells; remarkably, no unspecific background was observed. Although our study was based on a limited and non-selected series, our findings do provide proof of concept for the use of cbTMA in predictive biomarker testing on cytological material in large-scale post-clinical trial validation studies, multicenter studies, and quality control programs.
Real-World Use of Isavuconazole as Primary Therapy for Invasive Fungal Infections in High-Risk Patients with Hematologic Malignancy or Stem Cell Transplant
Authors: Dagher Hiba , Hachem Ray , Chaftari Anne-Marie , Jiang Ying , Ali Shahnoor , Deeba Rita , Shah Shivan , Raad Issam
Published: January 2022

(1) Introduction: Invasive fungal infections (IFIs) are a major cause of morbidity and mortality among immunocompromised patients with hematologic malignancies (HM) and stem cell transplants (SCT). Isavuconazole was approved by FDA as a primary therapy for Invasive Aspergillosis (IA) and Mucormycosis. The aim of this study is to look at the real-world use of Isavuconazole in patients with HM and evaluate their clinical outcomes and safety. (2) Methods: We conducted a retrospective study of HM patients at MD Anderson Cancer Center who had definite, probable or possible mold infections between 1 April 2016 and 31 January 2020 and were treated with Isavuconazole for a period of at least 7 days. Clinical and radiological findings were assessed at baseline and at 6 and 12 weeks of follow up. (3) Results: We included 200 HM patients with IFIs that were classified as definite (11), probable (63) and possible (126). Aspergillus spp was the most commonly isolated pathogen. The majority of patients (59%) received prophylaxis with anti-mold therapy and Isavuconazole was used as a primary therapy in 43% of patients, and as salvage therapy in 58%. The switch to Isavuconazole was driven by the failure of the primary therapy in 66% of the cases and by adverse effects in 29%. Isavuconazole was used as monotherapy in 30% of the cases and in combination in 70%. Adverse events possibly related to Isavuconazole were reported in eight patients (4%) leading to drug discontinuation. Moreover, a favorable response with Isavuconazole was observed in 40% at 6 weeks and in 60% at 12 weeks. There was no significant difference between isavuconazole monotherapy and combination therapy (p = 0.16 at 6 weeks and p = 0.06 at 12 weeks). Finally, there was no significant difference in outcome when Isavuconazole was used after failure of other anti-mold prophylaxis or treatment versus when used de novo as an anti-mold therapy (p = 0.68 at 6 weeks and p = 0.25 at 12 weeks). (4) Conclusions: Whether used as first-line therapy or after the failure of other azole and non-azole prophylaxis or therapies, isavuconazole seems to have a promising clinical response and a good safety profile as an antifungal therapy in high-risk cancer patients with hematologic malignancies. Moreover, combination therapy did not improve the outcome compared to Isavuconazole therapy.
Reassessment of Dyfrolomyces and Four New Species of Melomastia from Olive (Olea europaea) in Sichuan Province, China
Authors: Li Wen-Li , Maharachchikumbura Sajeewa S. N. , Cheewangkoon Ratchadawan , Liu Jian-Kui
Published: January 2022

Pleurotremataceae species are saprobes on decaying wood in terrestrial, mangrove, and freshwater habitats. The generic boundary of the family has traditionally been based on morphology. All genera of Pleurotremataceae have a high degree of morphological overlap, of which the generic circumscription of Melomastia and Dyfrolomyces has not been well resolved. Thus, the delimitation of genera has always been challenging. Melomastia traditionally differs from Dyfrolomyces in having 2-septate, oblong, with obtuse-ends ascospores. These main characteristics have been used to distinguish Melomastia from Dyfrolomyces for a long time. However, the above characteristics sometimes overlap among Dyfrolomyces and Melomastia species. Based on the morphology and multigene phylogeny with newly obtained data, we synonymized Dyfrolomyces under Melomastia following up-to-date results. Four novel species (i.e., Melomastia fusispora, M. oleae, M. sichuanensis and M. winteri) collected from the dead branches of Olea europaea L. in Chengdu Olive Base, Sichuan Province in China are introduced based on detailed morphological characterization and phylogenetic analyses of sequences based on nuclear ribosomal (LSU and SSU) and protein-coding gene (tef1-α). The 11 new combinations proposed are Melomastia aquatica (=Dyfrolomyces aquaticus), M. chromolaenae (=D. chromolaenae), M. distoseptata (=D. distoseptatus), M. mangrovei (=D. mangrovei), M. marinospora (=D. marinosporus), M. neothailandica (=D. neothailandicus), M. phetchaburiensis (=D. phetchaburiensis), M. sinensis (=D. sinensis), M. thailandica (=D. thailandica), M. thamplaensis (=D. thamplaensis) and M. tiomanensis (=D. tiomanensis).
Use of Circulating Tumour DNA (ctDNA) for Measurement of Therapy Predictive Biomarkers in Patients with Cancer
Authors: Duffy Michael J. , Crown John
Published: January 2022

Biomarkers that predict likely response or resistance to specific therapies are critical in personalising treatment for cancer patients. Such biomarkers are now available for an increasing number of anti-cancer therapies, especially targeted therapy and immunotherapy. The gold-standard method for determining predictive biomarkers requires tumour tissue. Obtaining tissue, however, is not always possible and even if possible, the amount or quality of tissue obtained may be inadequate for biomarker analysis. Tumour DNA, however, can be released into the bloodstream, giving rise to what is referred to as circulating tumour DNA (ctDNA). In contrast to tissue, blood can be obtained from effectively all patients in a minimally invasive and safe manner. Other advantages of blood over tissue for biomarker testing include a shorter turn-around time and an ability to perform serial measurements. Furthermore, blood should provide a more complete profile of mutations present in heterogeneous tumours than a single-needle tissue biopsy. A limitation of blood vis-à-vis tissue, however, is lower sensitivity and, thus, the possibility of missing an actionable mutation. Despite this limitation, blood-based predictive biomarkers, such as mutant EGFR for predicting response to EGFR tyrosine kinase inhibitors in advanced non-small-cell lung cancer and mutant PIK3CA for predicting response to alpelisib in combination with fulvestrant in advanced breast cancer, may be used when tissue is unavailable. Although tissue remains the gold standard for detecting predictive biomarkers, it is likely that several further blood-based assays will soon be validated and used when tissue is unavailable or unsuitable for analysis.
Prognostic Factors for Mortality, Activity of Daily Living, and Quality of Life in Taiwanese Older Patients within 1 Year Following Hip Fracture Surgery
Authors: Chiang Ming-Hsiu , Huang Yu-Yun , Kuo Yi-Jie , Huang Shu-Wei , Jang Yeu-Chai , Chu Fu-Ling , Chen Yu-Pin
Published: January 2022

Background. Hip fractures among older adults are a major public health concern worldwide. This study investigated the potential clinical factors that predict postoperative 1-year activities of daily living (ADL), quality of life (QoL), and mortality in Taiwanese older adults following hip fracture. Methods. This is a prospective cohort study enrolling older adults (≥60 years) who had undergone hip fracture surgery in a single medical center. The comprehensive clinical history of each patient was examined. QoL, ADL, and mortality events were recorded consecutively at 3, 6, and 12 months after operation. The multiple logistic regression model and the generalized estimating equation (GEE) were adopted to identify contributing factors for mortality and postoperative ADL and QoL prognosis, respectively. Results. Among 377 participants with hip fracture, 48 died within 1 year of the index operation. ADL and QoL considerably decreased at 3 months following hip surgery. Old age, high Charlson Comorbidity Index, and American Society of Anesthesiologists grading were crucial predictors for mortality at the 1-year follow-up. The generalized estimating equation analysis indicated that the length of postoperative follow-up time, serum albumin level, patient cognitive status, and handgrip strength were considerably associated with QoL and ADL recovery prognosis in the Taiwanese older adults following hip fracture. Conclusions. Hip fractures have long-lasting effects on the older adults. Our data imply several prognosis predicting parameters that may assist clinicians in accounting for an individual’s personalized risks in order to improve functional outcomes and reduce mortality.
Post-Intensive Care Syndrome in Survivors from Critical Illness including COVID-19 Patients: A Narrative Review
Authors: Vrettou Charikleia S. , Mantziou Vassiliki , Vassiliou Alice G. , Orfanos Stylianos E. , Kotanidou Anastasia , Dimopoulou Ioanna
Published: January 2022

Current achievements in medical science and technological advancements in intensive care medicine have allowed better support of critically ill patients in intensive care units (ICUs) and have increased survival probability. Post-intensive care syndrome (PICS) is a relatively new term introduced almost 10 years ago, defined as “new or worsening impairments in physical, cognitive, or mental health status arising after critical illness and persisting beyond acute care hospitalization”. A significant percentage of critically ill patients suffer from PICS for a prolonged period of time, with physical problems being the most common. The exact prevalence of PICS is unknown, and many risk factors have been described well. Coronavirus disease 2019 (COVID-19) survivors seem to be at especially high risk for developing PICS. The families of ICU survivors can also be affected as a response to the stress suffered during the critical illness of their kin. This separate entity is described as PICS family (PICS-F). A multidisciplinary approach is warranted for the treatment of PICS, involving healthcare professionals, clinicians, and scientists from different areas. Improving outcomes is both challenging and imperative for the critical care community. The review of the relevant literature and the study of the physical, cognitive, and mental sequelae could lead to the prevention and timely management of PICS and the subsequent improvement of the quality of life for ICU survivors.
Transcription–Replication Coordination
Authors: Saponaro Marco
Published: January 2022

Transcription and replication are the two most essential processes that a cell does with its DNA: they allow cells to express the genomic content that is required for their functions and to create a perfect copy of this genomic information to pass on to the daughter cells. Nevertheless, these two processes are in a constant ambivalent relationship. When transcription and replication occupy the same regions, there is the possibility of conflicts between transcription and replication as transcription can impair DNA replication progression leading to increased DNA damage. Nevertheless, DNA replication origins are preferentially located in open chromatin next to actively transcribed regions, meaning that the possibility of conflicts is potentially an accepted incident for cells. Data in the literature point both towards the existence or not of coordination between these two processes to avoid the danger of collisions. Several reviews have been published on transcription–replication conflicts, but we focus here on the most recent findings that relate to how these two processes are coordinated in eukaryotes, considering advantages and disadvantages from coordination, how likely conflicts are at any given time, and which are their potential hotspots in the genome.
Influence of Adaptive Gap Control Mechanism and Tool Electrodes on Machining Titanium (Ti-6Al-4V) Alloy in EDM Process
Authors: Liu Shoufa , Thangaraj Muthuramalingam , Moiduddin Khaja , Al-Ahmari Abdulrahman M.
Published: January 2022

Titanium alloy is widely used for orthodontic technology and easily machined using the EDM process. In the EDM process, the workpiece and tool electrode must be separated by a continuous air gap during the machining operation to generate discharge energy in this method. In the present study, an endeavor was made to analyze the effects of a servo feed air gap control and tool electrode in the EDM process. The developed mechanical setup consists of a linear action movement with zero backlash along the X-axis, which can be controlled up to 0.03 mm. It was observed that the suggested air gap control scheme can enhance the servo feed mechanism on a machining titanium alloy. A tungsten carbide electrode can enhance the surface measures owing to its ability to produce tiny craters with uniform distribution. Since it produces a little crater and has a higher melting point, a tungsten carbide electrode can create lesser surface roughness than a copper tool and brass tool electrode.
Uncertainties Induced by Processing Parameter Variation in Selective Laser Melting of Ti6Al4V Revealed by In-Situ X-ray Imaging
Authors: Young Zachary A. , Coday Meelap M. , Guo Qilin , Qu Minglei , Hojjatzadeh S. Mohammad H. , Escano Luis I. , Fezzaa Kamel , Sun Tao , Chen Lianyi
Published: January 2022

Selective laser melting (SLM) additive manufacturing (AM) exhibits uncertainties, where variations in build quality are present despite utilizing the same optimized processing parameters. In this work, we identify the sources of uncertainty in SLM process by in-situ characterization of SLM dynamics induced by small variations in processing parameters. We show that variations in the laser beam size, laser power, laser scan speed, and powder layer thickness result in significant variations in the depression zone, melt pool, and spatter behavior. On average, a small deviation of only ~5% from the optimized/reference laser processing parameter resulted in a ~10% or greater change in the depression zone and melt pool geometries. For spatter dynamics, small variation (10 μm, 11%) of the laser beam size could lead to over 40% change in the overall volume of the spatter generated. The responses of the SLM dynamics to small variations of processing parameters revealed in this work are useful for understanding the process uncertainties in the SLM process.
Large Thermal Expansion LTCC System for Cofiring with Integrated Functional Ceramics Layers
Authors: Capraro Beate , Heidenreich Manuel , Töpfer Jörg
Published: January 2022

We have studied the sintering behavior of CT708 LTCC tapes with large CTE of 10.6 ppm/K. This low-k dielectric LTCC material is a quartz-based glass ceramic composite system with partial crystallization of celsian upon firing. The shrinkage, densification and dielectric properties were examined using different heating rates and a sintering temperature of 900 °C. The maximum shrinkage rate is at 836 °C (for a heating rate of 2 K/min) with a sintering density of 95% and a permittivity of ε’ = 5.9 and tan δ = 0.0004 (at 1 GHz). Due to their similar shrinkage and thermal expansion properties, CT708 tapes may be cofired with functional ceramic layers. As an example, we report on cofiring of a multilayer laminate of CT708 and a Sc-substituted hexagonal ferrite for applications as integrated microwave circulator components. This demonstrates the feasibility of cofiring of functional ceramic tapes and tailored LTCC tapes and documents the potential for the realization of complex LTCC multilayer architectures.