bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phenotypic and genotypic characterization of families with complex intellectual disability identified pathogenic genetic variations in known and novel disease genes
Authors: Darvish Hossein , Azcona Luis J. , Tafakhori Abbas , Mesias Roxana , Ahmadifard Azadeh , Sanchez Elena , Habibi Arman , Alehabib Elham , Johari Amir Hossein , Emamalizadeh Babak , Jamali Faezeh , Chapi Marjan , Jamshidi Javad , Kajiwara Yuji , Paisán-Ruiz Coro 
Published: January 2020

AbstractIntellectual disability (ID), which presents itself during childhood, belongs to a group of neurodevelopmental disorders (NDDs) that are clinically widely heterogeneous and highly heritable, often being caused by single gene defects. Indeed, NDDs can be attributed to mutations at over 1000 loci, and all type of mutations, ranging from single nucleotide variations (SNVs) to large, complex copy number variations (CNVs), have been reported in patients with ID and other related NDDs. In this study, we recruited seven different recessive NDD families with comorbidities to perform a detailed clinical characterization and a complete genomic analysis that consisted of a combination of high throughput SNP-based genotyping and whole-genome sequencing (WGS). Different disease-associated loci and pathogenic gene mutations were identified in each family, including known (n = 4) and novel (n = 2) mutations in known genes (NAGLU, SLC5A2, POLR3B, VPS13A, SYN1, SPG11), and the identification of a novel disease gene (n = 1; NSL1). Functional analyses were additionally performed in a gene associated with autism-like symptoms and epileptic seizures for further proof of pathogenicity. Lastly, detailed genotype-phenotype correlations were carried out to assist with the diagnosis of prospective families and to determine genomic variation with clinical relevance. We concluded that the combination of linkage analyses and WGS to search for disease genes still remains a fruitful strategy for complex diseases with a variety of mutated genes and heterogeneous phenotypic manifestations, allowing for the identification of novel mutations, genes, and phenotypes, and leading to improvements in both diagnostic strategies and functional characterization of disease mechanisms.
Dipeptidyl peptidase-4 inhibition prevents nonalcoholic steatohepatitis–associated liver fibrosis and tumor development in mice independently of its anti-diabetic effects
Authors: Kawakubo Mitsuhiro , Tanaka Miyako , Ochi Kozue , Watanabe Akiko , Saka-Tanaka Marie , Kanamori Yohei , Yoshioka Naoki , Yamashita Satoko , Goto Moritaka , Itoh Michiko , Shirakawa Ibuki , Kanai Sayaka , Suzuki Hiromi , Sawada Makoto , Ito Ayaka , Ishigami Masatoshi , Fujishiro Mitsuhiro , Arima Hiroshi , Ogawa Yoshihiro , Suganami Takayoshi 
Published: January 2020

AbstractNonalcoholic steatohepatitis (NASH) is a hepatic phenotype of the metabolic syndrome, and increases the risk of cirrhosis and hepatocellular carcinoma (HCC). Although increasing evidence points to the therapeutic implications of certain types of anti-diabetic agents in NASH, it remains to be elucidated whether their effects on NASH are independent of their effects on diabetes. Genetically obese melanocortin 4 receptor–deficient (MC4R-KO) mice fed Western diet are a murine model that sequentially develops hepatic steatosis, NASH, and HCC in the presence of obesity and insulin resistance. In this study, we investigated the effect of the dipeptidyl peptidase-4 (DPP-4) inhibitor anagliptin on NASH and HCC development in MC4R-KO mice. Anagliptin treatment effectively prevented inflammation, fibrosis, and carcinogenesis in the liver of MC4R-KO mice. Interestingly, anagliptin only marginally affected body weight, systemic glucose and lipid metabolism, and hepatic steatosis. Histological data and gene expression analysis suggest that anagliptin treatment targets macrophage activation in the liver during the progression from simple steatosis to NASH. As a molecular mechanism underlying anagliptin action, we showed that glucagon-like peptide-1 suppressed proinflammatory and profibrotic phenotypes of macrophages in vitro. This study highlights the glucose metabolism–independent effects of anagliptin on NASH and HCC development.
Onecut-dependent Nkx6.2 transcription factor expression is required for proper formation and activity of spinal locomotor circuits
Authors: Toch Mathilde , Harris Audrey , Schakman Olivier , Kondratskaya Elena , Boulland Jean-Luc , Dauguet Nicolas , Debrulle Stéphanie , Baudouin Charlotte , Hidalgo-Figueroa Maria , Mu Xiuqian , Gow Alexander , Glover Joel C. , Tissir Fadel , Clotman Frédéric 
Published: January 2020

AbstractIn the developing spinal cord, Onecut transcription factors control the diversification of motor neurons into distinct neuronal subsets by ensuring the maintenance of Isl1 expression during differentiation. However, other genes downstream of the Onecut proteins and involved in motor neuron diversification have remained unidentified. In the present study, we generated conditional mutant embryos carrying specific inactivation of Onecut genes in the developing motor neurons, performed RNA-sequencing to identify factors downstream of Onecut proteins in this neuron population, and employed additional transgenic mouse models to assess the role of one specific Onecut-downstream target, the transcription factor Nkx6.2. Nkx6.2 expression was up-regulated in Onecut-deficient motor neurons, but strongly downregulated in Onecut-deficient V2a interneurons, indicating an opposite regulation of Nkx6.2 by Onecut factors in distinct spinal neuron populations. Nkx6.2-null embryos, neonates and adult mice exhibited alterations of locomotor pattern and spinal locomotor network activity, likely resulting from defective survival of a subset of limb-innervating motor neurons and abnormal migration of V2a interneurons. Taken together, our results indicate that Nkx6.2 regulates the development of spinal neuronal populations and the formation of the spinal locomotor circuits downstream of the Onecut transcription factors.
Two genomic regions encoding exopolysaccharide production systems have complementary functions in B. cereus multicellularity and host interaction
Authors: Caro-Astorga Joaquin , Álvarez-Mena Ana , Hierrezuelo Jesús , Guadix Juan Antonio , Heredia-Ponce Zahira , Arboleda-Estudillo Yohanna , González-Munoz Elena , de Vicente Antonio , Romero Diego 
Published: January 2020

AbstractBacterial physiology and adaptation are influenced by the exopolysaccharides (EPS) they produce. These polymers are indispensable for the assembly of the biofilm extracellular matrix in multiple bacterial species. In a previous study, we described the profound gene expression changes leading to biofilm assembly inB. cereusATCC14579 (CECT148). We found that a genomic region putatively dedicated to the synthesis of a capsular polysaccharide (eps2) was overexpressed in a biofilm cell population compared to in a planktonic population, while we detected no change in the transcript abundance from another genomic region (eps1) also likely to be involved in polysaccharide production. Preliminary biofilm assays suggested a mild role for the products of theeps2region in biofilm formation and no function for the products of theeps1region. The aim of this work was to better define the roles of these two regions inB. cereusmulticellularity. We demonstrate that theeps2region is indeed involved in bacterial adhesion to surfaces, cell-to-cell interaction, cellular aggregation and biofilm formation, while theeps1region appears to be involved in a kind of social bacterial motility. Consistent with these results, we further demonstrate using bacterial-host cell interaction experiments that theeps2region is more relevant to the adhesion to human epithelial cells and the zebrafish intestine, suggesting that this region encodes a bacterial factor that may potentiate gut colonization and enhance pathogenicity against humans.
Acoustic waveguide with virtual soft boundary based on metamaterials
Authors: Liu Guang-Sheng , Zhou Yang , Liu Ming-Hao , Yuan Ying , Zou Xin-Ye , Cheng Jian-Chun 
Published: January 2020

AbstractThe use of acoustic metamaterials with novel phenomena to design acoustic waveguides with special properties has obvious potential application value. Here, we propose a virtual soft boundary (VSB) model with high reflectivity and half cycle phase loss, which consists of an acoustic propagation layer and an acoustic metamaterial layer with tube arrays. Then the waveguide designed by the VSB is presented, and the numerical and experimental results show that it can separate acoustic waves at different frequencies without affecting the continuity and the flow of the medium in the space. The VSB waveguide can enrich the functions of acoustic waveguides and provide more application prospects.
Novel human reovirus isolated from children and its long-term circulation with reassortments
Authors: Yamamoto Seiji P. , Motooka Daisuke , Egawa Kazutaka , Kaida Atsushi , Hirai Yuki , Kubo Hideyuki , Motomura Kazushi , Nakamura Shota , Iritani Nobuhiro 
Published: January 2020

AbstractMammalian orthoreovirus (MRV), also known as reovirus, was discovered in the 1950s and became the first reported segmented double-stranded RNA virus. MRVs have since been found in a variety of animal species, including humans. However, reports on MRV infections are scarce due to the rarity of their symptomatic occurrence. In Japanese surveillance studies, MRVs have been detected as gastrointestinal pathogens since 1981, with a total of 135 records. In Osaka City, Japan, MRV was first isolated in 1994 from a child with meningitis, and then in 2005 and 2014 from children with gastroenteritis. Here, we conducted the first molecular characterization of human MRV isolates from Japan and identified a novel human reovirus strain belonging to MRV type 2, designated the MRV-2 Osaka strain. This strain, with all three isolates classified, is closely related to MRV-2 isolates from sewage in Taiwan and is relatively close to an MRV-2 isolate from a bat in China. Our data suggest that the MRV-2 Osaka strain, which has circulated amongst humans in Japan for at least two decades, has spread internationally.
Cervical carcinomas that overexpress human trophoblast cell-surface marker (Trop-2) are highly sensitive to the antibody-drug conjugate sacituzumab govitecan
Authors: Zeybek Burak , Manzano Aranzazu , Bianchi Anna , Bonazzoli Elena , Bellone Stefania , Buza Natalia , Hui Pei , Lopez Salvatore , Perrone Emanuele , Manara Paola , Zammataro Luca , Altwerger Gary , Han Chanhee , Tymon-Rosario Joan , Menderes Gulden , Ratner Elena , Silasi Dan-Arin , Huang Gloria S. , Azodi Masoud , Schwartz Peter E. , Santin Alessandro 
Published: January 2020

AbstractHuman trophoblast cell-surface marker (Trop-2) is a surface glycoprotein originally identified in human placental tissue and subsequently found to be highly expressed by various types of human epithelial solid tumors. We investigated the efficacy of sacituzumab govitecan, an antibody-drug conjugate (ADC) comprised of a humanized anti- Trop-2 antibody, conjugated with active metabolite of irinotecan (SN-38), on Trop-2 positive cervical cancer cell lines and a xenograft model. Trop-2 expression was evaluated in 147 primary cervical tumors by immunohistochemistry, real-time polymerase chain reaction, and flow cytometry. For in vitro experiments, two Trop-2 positive (CVX-8, ADX-3), and one Trop-2 negative (ADX-2) cell lines were used. A cell line with a strong Trop-2 expression (CVX-8) was used to test in vivo antitumor activity in xenografts models. Out of 147 primary cervical cancers, 113 were squamous cell carcinomas (SCCs), and 34 were adenocarcinoma/adenosquamous carcinomas. Moderate to strong diffuse staining was seen in 95% (108/113) of SCCs, and 81% (29/34) of adenocarcinoma/adenosquamous cancers on immunohistochemistry. Trop-2 positive cell lines were highly sensitive to sacituzumab govitecan in vitro, with IC50 values in the range of 0.18 to 0.26 nM (p = 0.02, and p = 0.04 for CVX-8, and ADX-3, respectively). In xenografts, a significant tumor growth inhibition was seen after twice-weekly intravenous administration of the drug for three weeks (p < 0.0001, and p = 0.001 for sacituzumab govitecan vs naked antibody, and sacituzumab govitecan vs control-ADC, respectively). Overall survival at 90 days was significantly improved in the sacituzumab govitecan group (p = 0.014). In conclusion, sacituzumab govitecan may represent a novel targeted therapy option in cervical cancer patients overexpressing Trop-2.
Conversion of Broad-Spectrum Antimicrobial Peptides into Species-Specific Antimicrobials Capable of Precisely Targeting Pathogenic Bacteria
Authors: Xu Lin , Shao Changxuan , Li Guoyu , Shan Anshan , Chou Shuli , Wang Jiajun , Ma Qingquan , Dong Na 
Published: January 2020

AbstractCurrently, the majority of antibiotics in clinical use have broad activity spectra, killing pathogenic and beneficial microorganisms indiscriminately. The disruption of the ecological balance of normal flora often results in secondary infections or other antibiotic-associated complications. Therefore, targeted antimicrobial therapies capable of specifically eliminating pathogenic bacteria while retaining the protective benefits of a normal microflora would be advantageous. In this study, we successfully constructed a series of Enterococcus faecalis-targeted antimicrobial peptides from wide-spectrum antimicrobial peptide precursors. These peptides are designed based on fusion of the species-specific peptide pheromone cCF10 and modification of the active region of the antimicrobial peptide. The results showed that cCF10-C4 possessed specific antimicrobial activity against E. faecalis and was not active against other types of bacteria tested. The specificity of this hybrid peptide was shown by the absence of antimicrobial effects in the pheromone-substituted derivative. Further studies indicated that cCF10-C4 and its parent peptide C4 exert their activities by damaging cytoplasmic membrane integrity. The present study reveals the application potential of these molecules as “probiotic” antimicrobials for the control of specific bacterial infections, and it also helps to elucidate the design and construction of species-specific antimicrobials with precise targeting specificity.
Spin-orbit torques and their associated effective fields from gigahertz to terahertz
Authors: Guimarães Filipe S. M. , Bouaziz Juba , dos Santos Dias Manuel , Lounis Samir 
Published: January 2020

AbstractTerahertz spintronics offers the prospect of devices which are both faster and more energy-efficient. A promising route to achieve this goal is to exploit current-induced spin-orbit torques. However, the high-frequency properties of these quantities remain unexplored both experimentally and theoretically, within a realistic material-specific approach. Here we investigate the dynamical transverse components of the torques and uncover contributions longitudinal to the magnetic moment capable of changing its magnitude. We show that, while the torques can be drastically altered in the dynamical regime, the effective magnetic fields that accompany them present a frequency-independent behaviour, ranging from the static limit up to the terahertz domain — including the ferromagnetic resonance of the system. The outcomes of this work point to new ways to control magnetic units in next-generation spintronic devices.
Testosterone improves muscle function of the extensor digitorum longus in rats with sepsis
Authors: Wang Jinlong , Wu Tong 
Published: January 2020

Abstract
Among patients with intensive care unit-acquired weakness (ICUAW), skeletal muscle strength often decreases significantly. The present study aimed to explore the effects of testosterone propotionate on skeletal muscle using rat model of sepsis. Male SD rats were randomly divided into experimental group, model control group, sham operation group and blank control group. Rats in experimental group were given testosterone propionate two times a week, 10 mg/kg for 3 weeks. Maximal contraction force, fatigue index and cross-sectional area of the extensor digitorum longus (EDL) were measured. Myosin, IGF-1, p-AKT and p-mTOR levels in EDL were detected by Western blot. Histological changes of the testis and prostate were detected by hematoxylin and eosin staining. We found that maximal contraction force and fatigue index of EDL in experimental group were significantly higher than in model control group. Cross-sectional area of fast MHC muscle fiber of EDL in group was significantly higher than in model control group. The levels of myosin, IGF-1, p-AKT and p-mTOR of EDL in experimental group were significantly higher than in model control group. In addition, no testicle atrophy and prostate hyperplasia were detected in experimental group. In conclusion, these results suggest that testosterone propionate can significantly improve skeletal muscle strength, endurance and volume of septic rats, and the mechanism may be related to the activation of IGF-1/AKT pathway. Moreover, testosterone propionate with short duration does not cause testicular atrophy and prostate hyperplasia in septic rats. Therefore, testosterone propionate is a potential treatment for muscle malfunction in ICUAW patients.
The pro- and anti-cancer effects of oxycodone are associated with epithelial growth factor receptor level in cancer cells
Authors: Yu Yuqin , Li Dapeng , Duan Ji’an , Xu Hongshuang , Li Li , Tan Dengwu , Yan Hong 
Published: January 2020

Abstract
Background: Oxycodone is an opioid medication used for the treatment of pain in cancer patients. However, little is known on the direct effects of oxycodone on cancer cells. Aim: To determine the effects and mechanisms of oxycodone in cancer cells. Materials and Methods: Proliferation, survival and migration assays were performed on multiple types of cancer cells. Epithelial growth factor receptor (EGFR)/ERK/Akt pathway and oxidative stress were investigated after oxycodone treatment. Results: Oxycodone can either stimulate growth and migration without affecting survival in MDA-468 cells or inhibit growth and survival without affecting migration in SKBR3 and Caco2 cells. In addition, oxycodone can either attenuate or stimulate efficacy of chemotherapeutic drugs in cancer, depending on the type of cancer cells and nature of action of oxycodone as single drug alone. Our mechanism studies suggest that the stimulatory and inhibitory effects of oxycodone are associated with EGFR expression levels in cancer cells. In cancer cells with high EGFR level, oxycodone activates EGFR signaling in cancer cells, leading to stimulatory effects in multiple biological activities, and this is dependent on opioid receptor. In cancer cells with low EGFR level, oxycodone induces mitochondria-mediated caspase activity and oxidative stress and damage, leading to cell death. Conclusions: Our work is the first to demonstrate systematic analysis of oxycodone’s effects and mechanism of action in cancer. The activation of EGFR signaling by oxycodone may provide a new guide in the clinical use of oxycodone, in particular for cancer patients with high EGFR levels.
Symptomkontrolle in der Palliativmedizin (ohne Schmerztherapie)
Authors: Wulf Hinnerk , Volberg Christian , Morin Astrid 
Published: January 2020

ZusammenfassungPatienten in palliativer Erkrankungsphase leiden häufig unter einer Vielzahl belastender Symptome mit deutlicher Einschränkung der Lebensqualität. Die Behandlung gestaltet sich hierbei oftmals schwierig. Zum einen, da die Patienten zumeist mehrere Probleme gleichzeitig mitbringen, und zum anderen, weil die notwendigen Medikamente an anderer Stelle Nebenwirkungen hervorrufen können, die ihrerseits wiederum behandelt werden müssen. Im vorliegenden Artikel erläutern wir einen Großteil dieser Symptome und geben Behandlungsempfehlungen anhand der aktuellen Literatur (ausgenommen Schmerztherapie). Im Speziellen ist der Artikel in folgende Unterpunkte gegliedert: Mukositis/Stomatitis, Atemnot, Übelkeit, Obstipation, Angst, Depression, Schwäche/Fatigue, Delir, Schlafstörungen und terminale Unruhe, Pruritus, Pleuraerguss, Aszites. Nur selten kann man in der Arbeit mit Palliativpatienten nach Lehrbuch vorgehen. Man muss improvisieren, Medikamente abseits ihrer Zulassung (Off-Label) gebrauchen oder manchmal auch einfach nur da sein. Der wichtigste Grundsatz in der Arbeit mit Palliativpatienten liegt in der Erhaltung oder Wiederherstellung der Lebensqualität. Unsere Therapie sollte immer an die Bedürfnisse des Patienten angepasst sein und es gilt, die Autonomie des Betroffenen zu wahren.
Blind-eye cannulation as a new method for ERCP training: Can we do more than merely teach?
Authors: Boškoski Ivo , Webster George , Tringali Andrea , Familiari Pietro , Perri Vincenzo , Costamagna Guido 
Published: January 2020

Abstract
Background and study aims Endoscopic retrograde cholangiopancreatography (ERCP) requires extensive hands-on training. Currently in ERCP training there are two very important problems that need attention: lack of standardized commands for communication, and misunderstanding between the trainee and the trainer.
Methods A method of “blind-eye” cannulation was developed with two paired trainees using the Boškoski-Costamagna ERCP Trainer. The trainee who was holding the duodenoscope was blind-folded and the other trainee gave instructions on what maneuvers were necessary to achieve cannulation, under the supervision of a trainer. Before starting cannulation, a standard list of commands was agreed by the operators.
Results The blind-eye method of cannulation teaches the operator trainee to listen and the assistant trainee to teach. Trainees use standardized commands. During the training session the two trainees swapped roles.
Conclusions Currently, we do not have proof that this type of training is useful, therefore, scientific studies are needed for confirmation. However, we believe that this ERCP model may provide an entirely safe means of improving communication and technical proficiency.
EDGE in Roux-en-Y gastric bypass: How does it compare to laparoscopy-assisted and balloon enteroscopy ERCP: a systematic review and meta-analysis
Authors: Dhindsa Banreet Singh , Dhaliwal Amaninder , Mohan Babu P. , Mashiana Harmeet Singh , Girotra Mohit , Singh Shailender , Ohning Gordon , Bhat Ishfaq , Adler Douglas G. 
Published: January 2020

Abstract
Background and study aims Endoscopic ultrasound-directed transgastric ERCP (EDGE) is a new endoscopic procedure to perform ERCP in Roux-en-y gastric bypass (RYGB) patients. The aim of this study was to conduct a systematic review and meta-analysis to evaluate technical success, clinical success and adverse effects of EDGE and compare it to laparoscopic ERCP (LA-ERCP) and balloon ERCP (BE-ERCP).
Patients and methods We conducted a comprehensive search of several databases and conference proceedings including PubMed, EMBASE, Google-Scholar, LILACS, SCOPUS, and Web of Science databases to identify studies reporting on EDGE, LA-ERCP, and BE-ERCP. The primary outcome was to evaluate technical and clinical success of all three procedures and the secondary analysis focused on calculating the pooled rate of all adverse events (AEs), along with the commonly reported AE subtypes.
Results Twenty-four studies on 1268 patients were included in our analysis with the majority of the population being males with mean age 53.72 years. Pooled rates of technical and clinical success with EDGE wer 95.5 % and 95.9 %, with LA-ERCP were 95.3 % and 92.9 % and were BE-ERCP were 71.4 % and 58.7 %, respectively. Pooled rates of all AEs with EDGE were 21.9 %, with LA-ERCP 17.4 % and with BE-ERCP 8.4 %. Stent migration was the most common AE with EDGE with 13.3 % followed by bleeding with 6.6 %.
Conclusion Our meta-analysis demonstrated that the technical and clinical success of EDGE procedure is better than BE-ERCP and comparable to that of LA-ERCP in RYGB patients. EDGE also has a similar safety profile as compared to LA-ERCP but has higher AE rate as compared to BE-ERCP.