bluuebunny/crossref_metadata_2025 huggingface dataset:
Association Between Variants in Calcineurin Inhibitor Pharmacokinetic and Pharmacodynamic Genes and Renal Dysfunction in Adult Heart Transplant Recipients
Authors: Oreschak Kris , Saba Laura M. , Rafaels Nicholas , Ambardekar Amrut V. , Deininger Kimberly M. , Page Robert L. , Lindenfeld JoAnn , Aquilante Christina L.
Published: April 2021

Background: The goal of the study was to assess the relationship between single nucleotide variants (SNVs) in calcineurin inhibitor (CNI) pharmacokinetic and pharmacodynamic genes and renal dysfunction in adult heart transplant (HTx) recipients.

Methods: This retrospective analysis includedN= 192 patients receiving a CNI at 1-year post-HTx. Using a candidate gene approach, 93 SNVs in eight pharmacokinetic and 35 pharmacodynamic genes were chosen for investigation. The primary outcome was renal dysfunction 1-year after HTx, defined as an estimated glomerular filtration rate (eGFR) <45 ml/min/1.73m2.

Results:Renal dysfunction was present in 28.6% of patients 1-year after HTx. Two SNVs [transforming growth factor beta 1 (TGFB1) rs4803455 C > A and phospholipase C beta 1 (PLCB1) rs170549 G > A] were significantly associated with renal dysfunction after accounting for a false discovery rate (FDR) of 20%. In a multiple-SNV adjusted model, variant A allele carriers ofTGFB1rs4803455 had lower odds of renal dysfunction compared to C/C homozygotes [odds ratio (OR) 0.28, 95% CI 0.12–0.62;p= 0.002], whereasPLCB1rs170549 variant A allele carriers had higher odds of the primary outcome vs. patients with the G/G genotype (OR 2.66, 95% CI 1.21–5.84,p= 0.015).

Conclusion: Our data suggest that genetic variation inTGFB1andPLCB1may contribute to the occurrence of renal dysfunction in HTx recipients receiving CNIs. Pharmacogenetic markers, such asTGFB1rs4803455 andPLCB1rs170549, could help identify patients at increased risk of CNI-associated renal dysfunction following HTx, potentially allowing clinicians to provide more precise and personalized care to this population.
One Stone, Two Birds: The Roles of Tim-3 in Acute Myeloid Leukemia
Authors: Wang Zhiding , Chen Jinghong , Wang Mengzhen , Zhang Linlin , Yu Li
Published: April 2021

T cell immunoglobulin and mucin protein 3 (Tim-3) is an immune checkpoint and plays a vital role in immune responses during acute myeloid leukemia (AML). Targeting Tim-3 kills two birds with one stone by balancing the immune system and eliminating leukemia stem cells (LSCs) in AML. These functions make Tim-3 a potential target for curing AML. This review mainly discusses the roles of Tim-3 in the immune system in AML and as an AML LSC marker, which sheds new light on the role of Tim-3 in AML immunotherapy.
The Dual Role of Platelets in the Cardiovascular Risk of Chronic Inflammation
Authors: Zamora Carlos , Cantó Elisabet , Vidal Sílvia
Published: April 2021

Patients with chronic inflammatory diseases often exhibit cardiovascular risk. This risk is associated with the systemic inflammation that persists in these patients, causing a sustained endothelial activation. Different mechanisms have been considered responsible for this systemic inflammation, among which activated platelets have been regarded as a major player. However, in recent years, the role of platelets has become controversial. Not only can this subcellular component release pro- and anti-inflammatory mediators, but it can also bind to different subsets of circulating lymphocytes, monocytes and neutrophils modulating their function in either direction. How platelets exert this dual role is not yet fully understood.
New Insights Into Novel Therapeutic Targets in ANCA-Associated Vasculitis
Authors: Nozaki Yuji
Published: April 2021

Biologics targeting inflammation-related molecules in the immune system have been developed to treat rheumatoid arthritis (RA), and these RA treatments have provided revolutionary advances. Biologics may also be an effective treatment for anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis, particularly in patients with resistance to standard treatments. Despite the accumulation of clinical experience and the increasing understanding of the pathogenesis of vasculitis, it is becoming more difficult to cure vasculitis. The treatment of vasculitis with biologics has been examined in clinical trials, and this has also enhanced our understanding of the pathogenesis of vasculitis. A humanized anti-interleukin-5 monoclonal antibody known as mepolizumab was recently demonstrated to provide clinical benefit in the management of eosinophilic granulomatosis with polyangiitis in refractory and relapsing disease, and additional new drugs for vasculitis are being tested in clinical trials, while others are in abeyance. This review presents the new findings regarding biologics in addition to the conventional immunosuppressive therapy for ANCA-associated vasculitis.
Examining the Underappreciated Role of S-Acylated Proteins as Critical Regulators of Phagocytosis and Phagosome Maturation in Macrophages
Authors: Dixon Charneal L. , Mekhail Katrina , Fairn Gregory D.
Published: April 2021

Phagocytosis is a receptor-mediated process used by cells to engulf a wide variety of particulates, including microorganisms and apoptotic cells. Many of the proteins involved in this highly orchestrated process are post-translationally modified with lipids as a means of regulating signal transduction, membrane remodeling, phagosome maturation and other immunomodulatory functions of phagocytes.S-acylation, generally referred to asS-palmitoylation, is the post-translational attachment of fatty acids to a cysteine residue exposed topologically to the cytosol. This modification is reversible due to the intrinsically labile thioester bond between the lipid and sulfur atom of cysteine, and thus lends itself to a variety of regulatory scenarios. Here we present an overview of a growing number ofS-acylated proteins known to regulate phagocytosis and phagosome biology in macrophages.
Evaluation of the Operational CMEMS and Coastal Downstream Ocean Forecasting Services During the Storm Gloria (January 2020)
Authors: Sotillo Marcos G. , Mourre Baptiste , Mestres Marc , Lorente Pablo , Aznar Roland , García-León Manuel , Liste Maria , Santana Alex , Espino Manuel , Álvarez Enrique
Published: April 2021

Storm Gloria was the 10th named storm in Europe for the 2019–2020 winter season, and it severely affected Spain and France. This powerful storm represents an excellent study case to analyze the capabilities of the different ocean model systems available in the Spanish Mediterranean coasts to simulate extreme events, as well as to assess their suitability to enhance preparedness in maritime disasters with high impacts on coastal areas. Five different operational ocean forecasting services able to predict the storm-induced ocean circulation are evaluated. Three of the systems are delivered by the Copernicus Marine Service (hereafter CMEMS): the CMEMS global scale solution (GLO-1/12°), the specific Mediterranean basin scale one (MED-1/24°), and the regional solution for the Atlantic façade (IBI-1/36°), which includes also part of the western Mediterranean. These CMEMS core products are complemented with two higher resolution models focused on more limited areas, which provide operational forecasts for coastal applications: the WMOP system developed at the Balearic Islands Coastal Observing and Forecasting System (SOCIB) with a horizontal resolution of roughly 2 km and the Puertos del Estado (PdE) SAMOA systems with a 350-m resolution that cover the coastal domains of the Spanish Port Authorities of Barcelona, Tarragona, Castellón and Almeria. Both the WMOP and SAMOA models are nested in CMEMS regional systems (MED and IBI, respectively) and constitute good examples of coastal-scale-oriented CMEMS downstream services. The skill of these five ocean models in reproducing the surface dynamics in the area during Gloria is evaluated using met-ocean in situ measurements from numerous buoys (moored in coastal and open waters) and coastal meteorological stations as a reference to track the effects of the storm in essential ocean variables such as surface current, water temperature, and salinity throughout January 2020. Furthermore, modeled surface dynamics are validated against hourly surface current fields from the two high-frequency radar systems available in the zone (the SOCIB HF-Radar system covering the eastern part of the Ibiza Channel and the PdE one at Tarragona, which covers the Ebro Delta, one of the coastal areas most impacted by Gloria). The results assess the performance of the dynamical downscaling at two different levels: first, within the own CMEMS service (with their regional products, as enhanced solutions with respect to the global one) and second in the coastal down-streaming service side (with very high-resolution models reaching coastal scales). This multi-model study case focused on Storm Gloria has allowed to identify some strengths and limitations of the systems currently in operations, and it can help outlining future model service upgrades aimed at better forecasting extreme coastal events.
Genomic Diversity and Virulence Potential of ESBL- and AmpC-β-Lactamase-Producing Escherichia coli Strains From Healthy Food Animals Across Europe
Authors: Ewers Christa , de Jong Anno , Prenger-Berninghoff Ellen , El Garch Farid , Leidner Ursula , Tiwari Sumeet K. , Semmler Torsten
Published: April 2021

The role of livestock animals as a putative source of ESBL/pAmpC E. coli for humans is a central issue of research. In a large-scale pan-European surveillance, 2,993 commensal Escherichia spp. isolates were recovered from randomly collected fecal samples of healthy cattle, pigs and chickens in various abattoirs. One-hundred Escherichia spp. isolates (0.5% from cattle, 1.3% pigs, 8.0% chickens) fulfilled the criteria for cefotaxime and ceftazidime non-wildtype (EUCAST). In silico screening of WGS data of 99 isolates (98 E. coli and 1 E. fergusonii) revealed blaSHV–12 (32.3%), blaCTX–M–1 (24.2%), and blaCMY–2 (22.2%) as predominant ESBL/pAmpC types. Other types were blaSHV–2 (1.0%), blaCTX–M–2/–14/–15 (1.0/6.1/1.0%), and blaTEM–52 (5.1%). Six isolates revealed AmpC-promoter mutations (position −42 (C > T) and one carried mcr-1. The majority (91.3%) of ESBL/pAmpC genes were located on plasmids. SHV-12 was mainly (50%) encoded on IncI1α plasmids (pST-3/-26/-95), followed by IncX3 (12.5%) and IncK2 (3.1%). The blaTEM–52 genes were located on IncI1α-pST-36 (60%) and IncX1 plasmids (20%). The dominant plasmid lineage among CTX-M-1 isolates was IncI1α (pST-3/-295/-317) (87.5%), followed by IncN-pST-1 (8.3%). CMY-2 was mostly identified on IncI1α (pST-12/-2) (54.5%) and IncK2 (31.8%) plasmids. Several plasmids revealed high similarity to published plasmids from human and animal Enterobacteriaceae. The isolates were assigned to phylogroups A/C (34.7/7.1%), B1 (27.6%), B2 (3.1%), D/F (9.2/10.2%), E (5.1%), and to E. clades (3.0%). With 51 known and 2 novel MLST types, a wide variety of STs was found, including STs previously observed in human isolates (ST10/38/117/131/648). ESBL/AmpC types or STs were rarely correlated with the geographic origin of the isolates or animal species. Virulence gene typing identified extraintestinal pathogenic E. coli (ExPEC; 2.0%), avian pathogenic E. coli (APEC; 51.5%), and atypical enteropathogenic E. coli (EPEC; 6.1%). In conclusion, the high diversity of STs and phylogenetic groups provides hardly any hint for clonal spread of single lineages but hints toward the dissemination of cephalosporin resistance genes in livestock via distinct, globally successful plasmid lineages. Even though a number of isolates could not be assigned to a distinct pathotype, our finding of combined multidrug-resistance and virulence in this facultative pathogen should be considered an additional threat to public health.
Rapid Open-Source SNP-Based Clustering Offers an Alternative to Core Genome MLST for Outbreak Tracing in a Hospital Setting
Authors: Szarvas Judit , Bartels Mette Damkjaer , Westh Henrik , Lund Ole
Published: April 2021

Traditional genotyping methods for infection control of antimicrobial-resistant bacteria in healthcare settings have been supplemented by whole-genome sequencing (WGS), often relying on a gene-based approach, e.g., core genome multilocus sequence typing (cgMLST), to cluster-related samples. In this study, we compared clusters of methicillin-resistant Staphylococcus aureus (MRSA) and Enterococcus faecium analyzed with the commercial cgMLST software Ridom SeqSphere+ and with an open-source single-nucleotide polymorphism (SNP)-based phylogenetic analysis pipeline (PAPABAC). A total of 5,655 MRSA and 2,572 E. faecium patient isolates, collected between 2013 and 2018, were processed. Clusters of 1,844 MRSA and 1,355 E. faecium isolates were compared to cgMLST results, and epidemiological data were included when available. The phylogenies inferred by the two different technologies were highly concordant, and the MRSA SNP tree re-captured known hospital-related outbreaks and epidemiologically linked samples. PAPABAC has the advantage over Ridom SeqSphere+ to generate stable, referable clusters without the need for sequence assembly, and it is a free-of-charge, open-source alternative to the commercial software.
Comparative Whole Genome Analysis of Escherichia coli O157:H7 Isolates From Feedlot Cattle to Identify Genotypes Associated With the Presence and Absence of stx Genes
Authors: Jia Mo , Geornaras Ifigenia , Martin Jennifer N. , Belk Keith E. , Yang Hua
Published: April 2021

A comparative whole genome analysis was performed on three newly sequenced Escherichia coli O157:H7 strains with different stx profiles, previously isolated from feedlot cattle [C1-010 (stx1−, stx2c+), C1-057 (stx−), and C1-067 (stx1+, stx2a+)], as well as five foodborne outbreak strains and six stx-negative strains from NCBI. Phylogenomic analysis demonstrated that the stx2c-carrying C1-010 and stx-negative C1-057 strains were grouped with the six NCBI stx-negative E. coli O157:H7 strains in Cluster 1, whereas the stx2a-carrying C1-067 and five foodborne outbreak strains were clustered together in Cluster 2. Based on different clusters, we selected the three newly sequenced strains, one stx2a-carrying strain, and the six NCBI stx-negative strains and identify their prophages at the stx insertion sites. All stx-carrying prophages contained both the three Red recombination genes (exo, bet, gam) and their repressor cI. On the other hand, the majority of the stx-negative prophages carried only the three Red recombination genes, but their repressor cI was absent. In the absence of the repressor cI, the consistent expression of the Red recombination genes in prophages might result in more frequent gene exchanges, potentially increasing the probability of the acquisition of stx genes. We further investigated each of the 10 selected E. coli O157:H7 strains for their respective unique metabolic pathway genes. Seven unique metabolic pathway genes in the two stx2a-carrying strains and one in the single stx2c-carrying and seven stx-negative strains were found to be associated with an upstream insertion sequence 629 within a conserved region among these strains. The presence of more unique metabolic pathway genes in stx2a-carrying E. coli O157:H7 strains may potentially increase their competitiveness in complex environments, such as feedlot cattle. For the stx2c-carrying and stx-negative E. coli O157:H7 strains, the fact that they were grouped into the same phylogenomic cluster and had the same unique metabolic pathway genes suggested that they may also share closely related evolutionary pathways. As a consequence, gene exchange between them is more likely to occur. Results from this study could potentially serve as a basis to help develop strategies to reduce the prevalence of pathogenic E. coli O157:H7 in livestock and downstream food production environments.
Mink, SARS-CoV-2, and the Human-Animal Interface
Authors: Fenollar Florence , Mediannikov Oleg , Maurin Max , Devaux Christian , Colson Philippe , Levasseur Anthony , Fournier Pierre-Edouard , Raoult Didier
Published: April 2021

Mink are small carnivores of the Mustelidae family. The American mink is the most common and was imported to Europe, Asia, and Latin America for breeding, as its fur is very popular. Denmark, the Netherlands, and China are the biggest producers of mink. Mink farms with a high population density in very small areas and a low level of genetic heterogeneity are places conducive to contagion. The mink’s receptor for SARS-CoV-2 is very similar to that of humans. Experimental models have shown the susceptibility of the ferret, another mustelid, to become infected with SARS-CoV-2 and to transmit it to other ferrets. On April 23, 2020, for the first time, an outbreak of SARS-CoV-2 in a mink farm was reported in the Netherlands. Since then, COVID-19 has reached numerous mink farms in the Netherlands, Denmark, United States, France, Greece, Italy, Spain, Sweden, Poland, Lithuania, and Canada. Not only do mink become infected from each other, but also they are capable of infecting humans, including with virus variants that have mutated in mink. Human infection with variant mink viruses with spike mutations led to the culling in Denmark of all mink in the country. Several animals can be infected with SARS-CoV-2. However, anthropo-zoonotic outbreaks have only been reported in mink farms. The rapid spread of SARS-CoV-2 in mink farms raises questions regarding their potential role at the onset of the pandemic and the impact of mutants on viral fitness, contagiousness, pathogenicity, re-infections with different mutants, immunotherapy, and vaccine efficacy.
Delayed Modeling Approach to Forecast the Periodic Behavior of SARS-2
Authors: Yu Zhenhua , Sohail Ayesha , Nutini Alessandro , Arif Robia
Published: April 2021

The ongoing threat of Coronavirus is alarming. The key players of this virus are modeled mathematically during this research. The transmission rates are hypothesized, with the aid of epidemiological concepts and recent findings. The model reported is extended, by taking into account the delayed dynamics. Time delay reflects the fact that the dynamic behavior of transmission of the disease, at time t depends not only on the state at time t but also on the state in some period τ before time t. The research presented in this manuscript will not only help in understanding the current threat of pandemic (SARS-2), but will also contribute in making precautionary measures and developing control strategies.
Structural Basis of Inhibition of Human Insulin-Regulated Aminopeptidase (IRAP) by Benzopyran-Based Inhibitors
Authors: Vanga Sudarsana Reddy , Åqvist Johan , Hallberg Anders , Gutiérrez-de-Terán Hugo
Published: April 2021

Inhibition of the insulin-regulated aminopeptidase (IRAP) improves memory and cognition in animal models. The enzyme has recently been crystallized and several series of inhibitors reported. We herein focused on one series of benzopyran-based inhibitors of IRAP known as the HFI series, with unresolved binding mode to IRAP, and developed a robust computational model to explain the structure-activity relationship (SAR) and potentially guide their further optimization. The binding model here proposed places the benzopyran ring in the catalytic binding site, coordinating the Zn2+ ion through the oxygen in position 3, in contrast to previous hypothesis. The whole series of HFI compounds was then systematically simulated, starting from this binding mode, using molecular dynamics and binding affinity estimated with the linear interaction energy (LIE) method. The agreement with experimental affinities supports the binding mode proposed, which was further challenged by rigorous free energy perturbation (FEP) calculations. Here, we found excellent correlation between experimental and calculated binding affinity differences, both between selected compound pairs and also for recently reported experimental data concerning the site directed mutagenesis of residue Phe544. The computationally derived structure-activity relationship of the HFI series and the understanding of the involvement of Phe544 in the binding of this scaffold provide valuable information for further lead optimization of novel IRAP inhibitors.
Western Diet Induces Impairment of Liver-Brain Axis Accelerating Neuroinflammation and Amyloid Pathology in Alzheimer's Disease
Authors: Wiȩckowska-Gacek Angelika , Mietelska-Porowska Anna , Chutorański Dominik , Wydrych Małgorzata , Długosz Jan , Wojda Urszula
Published: April 2021

Alzheimer's disease (AD) is an aging-dependent, irreversible neurodegenerative disorder and the most common cause of dementia. The prevailing AD hypothesis points to the central role of altered cleavage of amyloid precursor protein (APP) and formation of toxic amyloid-β (Aβ) deposits in the brain. The lack of efficient AD treatments stems from incomplete knowledge on AD causes and environmental risk factors. The role of lifestyle factors, including diet, in neurological diseases is now beginning to attract considerable attention. One of them is western diet (WD), which can lead to many serious diseases that develop with age. The aim of the study was to investigate whether WD-derived systemic disturbances may accelerate the brain neuroinflammation and amyloidogenesis at the early stages of AD development. To verify this hypothesis, transgenic mice expressing human APP with AD-causing mutations (APPswe) were fed with WD from the 3rd month of age. These mice were compared to APPswe mice, in which short-term high-grade inflammation was induced by injection of lipopolysaccharide (LPS) and to untreated APPswe mice. All experimental subgroups of animals were subsequently analyzed at 4-, 8-, and 12-months of age. APPswe mice at 4- and 8-months-old represent earlier pre-plaque stages of AD, while 12-month-old animals represent later stages of AD, with visible amyloid pathology. Already short time of WD feeding induced in 4-month-old animals such brain neuroinflammation events as enhanced astrogliosis, to a level comparable to that induced by the administration of pro-inflammatory LPS, and microglia activation in 8-month-old mice. Also, WD feeding accelerated increased Aβ production, observed already in 8-month-old animals. These brain changes corresponded to diet-induced metabolic disorders, including increased cholesterol level in 4-months of age, and advanced hypercholesterolemia and fatty liver disease in 8-month-old mice. These results indicate that the westernized pattern of nourishment is an important modifiable risk factor of AD development, and that a healthy, balanced, diet may be one of the most efficient AD prevention methods.
Telemonitoring of Patients With Chronic Traumatic Brain Injury: A Pilot Study
Authors: Raso Maria Girolama , Arcuri Francesco , Liperoti Stefano , Mercurio Luca , Mauro Aldo , Cusato Francesco , Romania Lidia , Serra Sebastiano , Pignolo Loris , Tonin Paolo , Cerasa Antonio
Published: April 2021

Telehealth systems have shown success in the remote management of several neurological disorders, but there is a paucity of evidence in disorders of consciousness (DOC). In this study, we explore the effectiveness of a new telemonitoring system, for monitoring Vegetative State (VS) and Minimally Conscious State (MCS) patients. This was a prospective, mono-center randomized controlled study. We included only traumatic brain injury (TBI) patients who required long-term motor/cognitive assistance having a stable clinical condition. We examined their clinical evolution over ~4 years of the follow-up period. Twenty-two TBI patients were enrolled and equally divided into two groups: one telemonitored at home with our service and the second admitted to a standard long-stay hospitalization (LSH) program. Patients enrolled in the telehealth service (age: 49.9 ± 20.4; 45% female; diagnosis: 36% VS/64% MCS) were demographically and clinically-matched with those admitted to the LSH program (age: 55.1 ± 15; 18% female; diagnosis: 54% VS/46% MCS). Thirty-six percent of patients in the LSH program died before completing follow up evaluation with respect to 18% of death in the group of TBI patients telemonitored at home. At follow-up, patients in LSH and telemonitoring groups showed similar clinical progression, as measured by CRS-r, NCS, WHIM, and LCF scales, as well as by the number of medical complications (i.e., bedsores, infections). Finally, we estimated the total daily cost per patient. Severe TBI patients enrolled in the conventional LSH program cost 262€ every single day, whereas the cost per patient in the telehealth service resulted to be less expensive (93€). Here, we highlight that our telehealth monitoring service is as efficacious as in-person usual care to manage a severe neurological disorder such as TBI in a cost-effective way.
HIV-Associated CD8 Encephalitis: A UK Case Series and Review of Histopathologically Confirmed Cases
Authors: Lucas Sebastian B. , Wong Kum T. , Nightingale Sam , Miller Robert F.
Published: April 2021

HIV-associated CD8-encephalitis (HIV-CD8E) is a severe inflammatory disorder dominated by infiltration of the brain by CD8+ T-lymphocytes. It occurs in people with HIV, typically when the virus is apparently well-controlled by antiretroviral treatment (ART). HIV-CD8E presents with symptoms and signs related to marked cerebral inflammation and swelling, and can lead to coma and death unless treated promptly with corticosteroids. Risk events such as intercurrent infection, antiretroviral therapy interruption, immune reconstitution inflammatory syndrome (IRIS) after starting ART, and concomitant associations such as cerebrospinal fluid (CSF) HIV viral escape have been identified, but the pathogenesis of the disorder is not known. We present the largest case series of HIV-CD8E to date (n = 23), representing histopathologically confirmed cases in the UK. We also summarize the global literature representing all previously published cases with histopathological confirmation (n = 30). A new variant of HIV-CD8E is described, occurring on a background of HIV encephalitis (HIVE).Together these series, totalling 53 patients, provide new insights. CSF HIV viral escape was a frequent finding in HIV-CD8E occurring in 68% of those with CSF available and tested; ART interruption and IRIS were important, both occurring in 27%. Black ethnicity appeared to be a key risk factor; all but two UK cases were African, as were the majority of the previously published cases in which ethnicity was stated. We discuss potential pathogenic mechanisms, but there is no unifying explanation over all the HIV-CD8E scenarios.
ATP1A3-Related Disorders: An Ever-Expanding Clinical Spectrum
Authors: Salles Philippe A. , Mata Ignacio F. , Brünger Tobias , Lal Dennis , Fernandez Hubert H.
Published: April 2021

The Na+/K+ ATPases are Sodium-Potassium exchanging pumps, with a heteromeric α-β-γ protein complex. The α3 isoform is required as a rescue pump, after repeated action potentials, with a distribution predominantly in neurons of the central nervous system. This isoform is encoded by the ATP1A3 gene. Pathogenic variants in this gene have been implicated in several phenotypes in the last decades. Carriers of pathogenic variants in this gene manifest neurological and non-neurological features in many combinations, usually with an acute onset and paroxysmal episodes triggered by fever or other factors. The first three syndromes described were: (1) rapid-onset dystonia parkinsonism; (2) alternating hemiplegia of childhood; and, (3) cerebellar ataxia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS syndrome). Since their original description, an expanding number of cases presenting with atypical and overlapping features have been reported. Because of this, ATP1A3-disorders are now beginning to be viewed as a phenotypic continuum representing discrete expressions along a broadly heterogeneous clinical spectrum.
Spiking Neural Network for Augmenting Electroencephalographic Data for Brain Computer Interfaces
Authors: Singanamalla Sai Kalyan Ranga , Lin Chin-Teng
Published: April 2021

With the advent of advanced machine learning methods, the performance of brain–computer interfaces (BCIs) has improved unprecedentedly. However, electroencephalography (EEG), a commonly used brain imaging method for BCI, is characterized by a tedious experimental setup, frequent data loss due to artifacts, and is time consuming for bulk trial recordings to take advantage of the capabilities of deep learning classifiers. Some studies have tried to address this issue by generating artificial EEG signals. However, a few of these methods are limited in retaining the prominent features or biomarker of the signal. And, other deep learning-based generative methods require a huge number of samples for training, and a majority of these models can handle data augmentation of one category or class of data at any training session. Therefore, there exists a necessity for a generative model that can generate synthetic EEG samples with as few available trials as possible and generate multi-class while retaining the biomarker of the signal. Since EEG signal represents an accumulation of action potentials from neuronal populations beneath the scalp surface and as spiking neural network (SNN), a biologically closer artificial neural network, communicates via spiking behavior, we propose an SNN-based approach using surrogate-gradient descent learning to reconstruct and generate multi-class artificial EEG signals from just a few original samples. The network was employed for augmenting motor imagery (MI) and steady-state visually evoked potential (SSVEP) data. These artificial data are further validated through classification and correlation metrics to assess its resemblance with original data and in-turn enhanced the MI classification performance.
Survival Comparisons of Hepatic Arterial Infusion Chemotherapy With mFOLFOX and Transarterial Chemoembolization in Patients With Unresectable Intrahepatic Cholangiocarcinoma
Authors: Cai Zhiyuan , He Chaobin , Zhao Chongyu , Lin Xiaojun
Published: April 2021

Background

Intrahepatic cholangiocarcinoma (ICC) has a poor prognosis and 40%-60% of patients present with advanced disease at the time of diagnosis. Transarterial chemoembolization (TACE) and hepatic arterial infusion chemotherapy (HAIC) have recently been used in unresectable ICC. The aim of this study was to compare the survival differences of unresectable ICC patients after TACE and HAIC treatment.

Methods

Between March 2011 and October 2019, a total of 126 patients with unresectable ICC, as evident from biopsies and imaging, and who had received TACE or HAIC were enrolled in this study. Baseline characteristics and survival differences were compared between the TACE and HAIC treatment groups.

Results

ICC Patients had significantly higher survival rates after the HAIC treatment, compared with those after TACE treatment [1-year overall survival (OS) rates: 60.2% vs. 42.9%, 2-year OS rates: 38.7% vs. 29.4%, P=0.028; 1-year progression-free survival (PFS) rates: 15.0% vs. 20.0%, 2-year PFS rates: 0% vs. 0%, P=0.641; 1-year only intrahepatic PFS (OIPFS) rates: 35.0% vs. 24.4%, 2-year OIPFS rates: 13.1% vs. 14.6%, P = 0.026]. Multivariate Cox regression analysis showed that HAIC was a significant and independent factor for OS and OIPFS in the study cohort.

Conclusions

HAIC is superior to TACE for treatment of unresectable ICC. A new tumor response evaluation procedure for HAIC treatment in unresectable ICC patients is needed to provide better therapeutic strategies. A randomized clinical trial comparing the survival benefits of HAIC and TACE is therefore being considered.
New Perspectives in Different Gene Expression Profiles for Early and Locally Advanced Non-Small Cell Lung Cancer Stem Cells
Authors: Masciale Valentina , Banchelli Federico , Grisendi Giulia , D’Amico Roberto , Maiorana Antonino , Stefani Alessandro , Morandi Uliano , Dominici Massimo , Aramini Beatrice
Published: April 2021

Introduction

Lung cancer is one of the most common cancers in the world, causing over 1.7 million deaths in 2018. Thus far, no effective treatments against lung cancer for advanced stages have been found. For early stages, although surgery is considered the gold standard treatment, 30–55% of patients develop recurrence within the first 5 years of surgery. Our aim is to assess whether cancer stem cells (CSC) display overexpression of a pool of genes that were previously identified for adenocarcinoma recurrence in patients with early and locally advanced stages of non-small cell lung cancer (NSCLC).

Methods

This cross-sectional study was carried out by harvesting surgical tumor specimens obtained from patients harboring early (I-II) and locally advanced (IIIA) stages of NSCLC. For each patient, cell sorting was performed to identify and isolate the ALDHhigh (CSC) and ALDHlow (cancer cells) populations. The mRNA expressions of 31 recurrence-related genes (target genes) in both ALDHhigh and ALDHlow populations were then assessed and compared.

Results

Surgical specimens were obtained from 22 patients harboring NSCLC. Sixteen (51.6%) out of 31 recurrence-related genes were significantly overexpressed in ALDHhigh cells in the early stages and 9 (29.0%) were overexpressed in the locally advanced stages of NSCLC. Overall, the relative mRNA expressions for these recurrence-related genes were higher in early-stage patients. The average fold change, considering all 31 recurrence-related genes together, was 4.5 (95% CI = 3.1-6.3) in early-stage patients and 1.6 (95% CI = 1.2-2.2) in locally advanced-stage patients.

Conclusions

Our study represents the first attempt toward identifying genes associated with recurrence that are overexpressed in cancer stem cells in patients with early and locally advanced stages of NSCLC. This finding may contribute to the identification of new target therapies tailored for NSCLC stages.
In Vivo and Ex Vivo Pediatric Brain Tumor Models: An Overview
Authors: Li Zhiqin , Langhans Sigrid A.
Published: April 2021

After leukemia, tumors of the brain and spine are the second most common form of cancer in children. Despite advances in treatment, brain tumors remain a leading cause of death in pediatric cancer patients and survivors often suffer from life-long consequences of side effects of therapy. The 5-year survival rates, however, vary widely by tumor type, ranging from over 90% in more benign tumors to as low as 20% in the most aggressive forms such as glioblastoma. Even within historically defined tumor types such as medulloblastoma, molecular analysis identified biologically heterogeneous subgroups each with different genetic alterations, age of onset and prognosis. Besides molecularly driven patient stratification to tailor disease risk to therapy intensity, such a diversity demonstrates the need for more precise and disease-relevant pediatric brain cancer models for research and drug development. Here we give an overview of currently available in vitro and in vivo pediatric brain tumor models and discuss the opportunities that new technologies such as 3D cultures and organoids that can bridge limitations posed by the simplicity of monolayer cultures and the complexity of in vivo models, bring to accommodate better precision in drug development for pediatric brain tumors.
RETRACTED: Akt Inhibition Enhanced the Growth Inhibition Effects of Low-Dose Heavy-Ion Radiation via the PI3K/Akt/p53 Signaling Pathway in C6 Glioblastoma Cells
Authors: Huang Ke , Zhao Wei , Wang Xuqiao , Qiu Yingfei , Liu Zelin , Chen Rui , Liu Wei , Liu Bin
Published: April 2021

Background

Glioma has one of the highest mortality rates of all tumors of the nervous system and commonly used treatments almost always fail to achieve tumor control. Low-dose carbon-ion radiation can effectively target cancer and tumor cells, but the mechanisms of growth inhibition induced by heavy-ion radiation via the PI3K/Akt signaling pathway are unknown, and inhibition by heavy-ion radiation is minor in C6 cells.

Methods

Carbon-ion radiation was used to investigate the effects of heavy-ion radiation on C6 cells, and suppression of Akt was performed using perifosine. MTT assays were used to investigate optimal perifosine treatment concentrations. Clone formation assays were used to investigate the growth inhibition effects of carbon-ion radiation and the effects of radiation with Akt inhibition. Lactate dehydrogenase release, superoxide dismutase activity, and malondialdehyde content were assessed to investigate oxidative stress levels. Expression levels of proteins in the PI3K/Akt/p53 signaling pathway were assessed via western blotting.

Results

The 10% maximum inhibitory concentration of perifosine was 19.95 μM. In clone formation assays there was no significant inhibition of cell growth after treatment with heavy-ion irradiation, whereas perifosine enhanced inhibition. Heavy-ion radiation induced lactate dehydrogenase release, increased the level of malondialdehyde, and reduced superoxide dismutase activity. Akt inhibition promoted these processes. Heavy-ion radiation treatment downregulated Akt expression, and upregulated B-cell lymphoma-2 (Bcl-2) expression. p53 and Bcl-2 expression were significantly upregulated, and Bcl-2-associated X protein (Bax) expression was downregulated. The expression profiles of pAkt, Bcl-2, and Bax were reversed by perifosine treatment. Caspase 3 expression was upregulated in all radiation groups.

Conclusions

The growth inhibition effects of low-dose heavy-ion irradiation were not substantial in C6 cells, and Akt inhibition induced by perifosine enhanced the growth inhibition effects via proliferation inhibition, apoptosis, and oxidative stress. Akt inhibition enhanced the effects of heavy-ion radiation, and the PI3K/Akt/p53 signaling pathway may be a critical component involved in the process.
Co-bedding of Preterm Newborn Pigs Reduces Necrotizing Enterocolitis Incidence Independent of Vital Functions and Cortisol Levels
Authors: Brunse Anders , Peng Yueming , Li Yanqi , Lykkesfeldt Jens , Sangild Per Torp
Published: April 2021

Background:Preterm infants are born with immature organs, leading to morbidities such as necrotizing enterocolitis (NEC), a gut inflammatory disease associated with adverse feeding responses but also hemodynamic and respiratory instability. Skin-to-skin contact including “kangaroo care” may improve infant survival and healthviaimproved vital functions (e.g., pulmonary, cardiovascular) and endocrine influences by adrenal glucocorticoids. Clinical effects of skin-to-skin contact for newborn siblings (“co-bedding”) are not known. Using NEC-susceptible Preterm pigs as models, we hypothesized that co-bedding and exogenous glucocorticoids improve vital functions and NEC resistance.

Methods:In experiment 1, cesarean-delivered, formula-fed Preterm pigs were reared in incubators with (co-bedding, COB,n= 30) or without (single-bedding, SIN,n= 29) a sibling until euthanasia and tissue collection on day four. In experiment 2, single-bedded Preterm pigs were treated postnatally with a tapering dose of hydrocortisone (HC,n= 19, 1–3 mg/kg/d) or saline (CON,n= 19).

Results:Co-bedding reduced NEC incidence (38 vs. 65%,p< 0.05) and increased the density of colonic goblet cells (+20%,p< 0.05) but had no effect on pulmonary and cardiovascular functions (respiration, blood pressure, heart rate, blood gases) or cortisol levels. There were limited differences in intestinal villous architecture and digestive enzyme activities. In experiment 2, HC treatment increased NEC lesions in the small intestine without any effects on pulmonary or cardiovascular functions.

Conclusion:Co-bedding may improve gut function and NEC resistance independently of cardiorespiratory function and cortisol levels, but pharmacological cortisol treatment predispose to NEC. Preterm pigs may be a useful tool to better understand the physiological effects of co-bedding, neonatal stressors and their possible interactions with morbidities in Preterm neonates.
Case Report: Maintenance of Desensitization to Nebulized Colomycin Over 10 Years
Authors: Sieber Justyna , Renner Sabine , Lakatos-Krepcik Andrea , Szépfalusi Zsolt
Published: April 2021

Drug desensitization can be achieved successfully by gradual drug dose increases in different protocols. Most protocols are designed to obtain temporal tolerance. The data on long-term maintenance of drug tolerance is scarce. Based on an IgE-mediated colomycin allergy we describe the maintenance of drug tolerance to nebulized drug for the period of 10 years in a 15-year-old cystic fibrosis patient, proceeded by successful rush intravenous desensitization protocol. The mechanism of drug tolerance is largely speculative; however, long-term maintenance of it seems achievable by continuous local drug application.
Comparative Analysis of Nuclear Matrix Elements of 0νβ+β+ Decay and Muon Capture in 106Cd
Authors: Jokiniemi Lotta , Suhonen Jouni , Kotila Jenni
Published: April 2021

Comparative analyses of the nuclear matrix elements (NMEs) related to the 0νβ+β+ decay of 106Cd to the ground state of 106Pd and the ordinary muon capture (OMC) in 106Cd are performed. This is the first time the OMC NMEs are studied for a nucleus decaying via positron-emitting/electron-capture modes of double beta decay. All the present calculations are based on the proton-neutron quasiparticle random-phase approximation with large no-core single-particle bases and realistic two-nucleon interactions. The effect of the particle-particle interaction parameter gpp of pnQRPA on the NMEs is discussed. In the case of the OMC, the effect of different bound-muon wave functions is studied.
The Degradation of Airway Epithelial Tight Junctions in Asthma Under High Airway Pressure Is Probably Mediated by Piezo-1
Authors: Zhou Jia , Zhou Xiang-dong , Xu Rui , Du Xian-zhi , Li Qi , Li Bin , Zhang Guo-yue , Chen Ling-xiu , Perelman Juliy M. , Kolosov Victor P.
Published: April 2021

Full functioning of the airway physical barrier depends on cellular integrity, which is coordinated by a series of tight junction (TJ) proteins. Due to airway spasm, edema, and mucus obstruction, positive end-expiratory alveolar pressure (also termed auto-PEEP) is a common pathophysiological phenomenon, especially in acute asthma attack. However, the influence of auto-PEEP on small airway epithelial TJs is currently unclear. We performed studies to investigate the effect of extra pressure on small airway epithelial TJs and its mechanism. The results first confirmed that a novel mechanosensitive receptor, piezo-1, was highly expressed in the airway epithelium of asthmatic mice. Extra pressure induced the degradation of occludin, ZO-1 and claudin-18 in primary human small airway epithelial cells (HSAECs), resulting in a decrease in transepithelial electrical resistance (TER) and an increase in cell layer permeability. Through in vitro investigations, we observed that exogenous pressure stimulation could elevate the intracellular calcium concentration ([Ca2+]i) in HSAECs. Downregulation of piezo-1 with siRNA and pretreatment with BAPTA-AM or ALLN reduced the degradation of TJs and attenuated the impairment of TJ function induced by exogenous pressure. These findings indicate the critical role of piezo-1/[Ca2+]i/calpain signaling in the regulation of small airway TJs under extra pressure stimulation.
Using Underwater Pulse Oximetry in Freediving to Extreme Depths to Study Risk of Hypoxic Blackout and Diving Response Phases
Authors: Mulder Eric , Sieber Arne , Schagatay Erika
Published: April 2021

Deep freediving exposes humans to hypoxia and dramatic changes in pressure. The effect of depth on gas exchange may enhance risk of hypoxic blackout (BO) during the last part of the ascent. Our aim was to investigate arterial oxygen saturation (SpO2) and heart rate (HR) in shallow and deep freedives, central variables, which have rarely been studied underwater in deep freediving. Four male elite competitive freedivers volunteered to wear a newly developed underwater pulse oximeter for continuous monitoring of SpO2 and HR during self-initiated training in the sea. Two probes were placed on the temples, connected to a recording unit on the back of the freediver. Divers performed one “shallow” and one “deep” constant weight dive with fins. Plethysmograms were recorded at 30 Hz, and SpO2 and HR were extracted. Mean ± SD depth of shallow dives was 19 ± 3 m, and 73 ± 12 m for deep dives. Duration was 82 ± 36 s in shallow and 150 ± 27 s in deep dives. All divers desaturated more during deeper dives (nadir 55 ± 10%) compared to shallow dives (nadir 80 ± 22%) with a lowest SpO2 of 44% in one deep dive. HR showed a “diving response,” with similar lowest HR of 42 bpm in shallow and deep dives; the lowest value (28 bpm) was observed in one shallow dive. HR increased before dives, followed by a decline, and upon resurfacing a peak after which HR normalized. During deep dives, HR was influenced by the level of exertion across different diving phases; after an initial drop, a second HR decline occurred during the passive “free fall” phase. The underwater pulse oximeter allowed successful SpO2 and HR monitoring in freedives to 82 m depth – deeper than ever recorded before. Divers’ enhanced desaturation during deep dives was likely related to increased exertion and extended duration, but the rapid extreme desaturation to below 50% near surfacing could result from the diminishing pressure, in line with the hypothesis that risk of hypoxic BO may increase during ascent. Recordings also indicated that the diving response is not powerful enough to fully override the exercise-induced tachycardia during active swimming. Pulse oximetry monitoring of essential variables underwater may be an important step to increase freediving safety.
Training and Detraining Effects Following a Static Stretching Program on Medial Gastrocnemius Passive Properties
Authors: Nakamura Masatoshi , Yahata Kaoru , Sato Shigeru , Kiyono Ryosuke , Yoshida Riku , Fukaya Taizan , Nunes João Pedro , Konrad Andreas
Published: April 2021

A stretching intervention program is performed to maintain and improve range of motion (ROM) in sports and rehabilitation settings. However, there is no consensus on the effects of stretching programs on muscle stiffness, likely due to short stretching durations used in each session. Therefore, a longer stretching exercise session may be required to decrease muscle stiffness in the long-term. Moreover, until now, the retention effect (detraining) of such an intervention program is not clear yet. The purpose of this study was to investigate the training (5-week) and detraining effects (5-week) of a high-volume stretching intervention on ankle dorsiflexion ROM (DF ROM) and medial gastrocnemius muscle stiffness. Fifteen males participated in this study and the plantarflexors of the dominant limb were evaluated. Static stretching intervention was performed using a stretching board for 1,800 s at 2 days per week for 5 weeks. DF ROM was assessed, and muscle stiffness was calculated from passive torque and muscle elongation during passive dorsiflexion test. The results showed significant changes in DF ROM and muscle stiffness after the stretching intervention program, but the values returned to baseline after the detraining period. Our results indicate that high-volume stretching intervention (3,600 s per week) may be beneficial for DF ROM and muscle stiffness, but the training effects are dismissed after a detraining period with the same duration of the intervention.