bluuebunny/crossref_metadata_2025 huggingface dataset:
Identification of a major locus determining a pigmentation defect in cultivated gilthead seabream (Sparus aurata)
Authors: Bertolini F. , Ribani A. , Capoccioni F. , Buttazzoni L. , Utzeri V. J. , Bovo S. , Schiavo G. , Caggiano M. , Fontanesi L. , Rothschild M. F.
Published: January 2020

The gilthead seabream (Sparus aurata) is an important cultivated species in the Mediterranean area. A major problem for the gilthead seabream aquaculture sector derives from the high frequency of phenotypic abnormalities, including discolorations. In this study, we applied a whole‐genome resequencing approach to identify a genomic region affecting a pigmentation defect that occurred in a cultivated S. aurata population. Two equimolar DNA pools were constructed using DNA extracted from 30 normally coloured and 21 non‐pigmented fish collected among the offspring of the same broodstock nucleus. Whole‐genome resequencing reads from the two DNA pools were aligned to the S. aurata draft genome and variant calling was performed. A whole‐genome heterozygosity scan from single pool sequencing data highlighted a peak of reduced heterozygosity of approximately 5 Mbp on chromosome 6 in the non‐pigmented pool that was not present in the normally coloured pool. The comparison of the non‐pigmented with the normally coloured fish using a whole‐genome FST analysis detected three main regions within the coordinates previously detected with the heterozygosity analysis. The results support the presence of a major locus affecting this discoloration defect in this fish population. The results of this study have practical applications, including the possibility of eliminating this defect from the breeding stock, with direct economic advantages derived from the reduction of discarded fry. Other studies are needed to identify the candidate gene and the causative mutation, which could add information to understand the complex biology of fish pigmentation.
Identification of potential functional variants underlying ovine resistance to gastrointestinal nematode infection by using RNA‐Seq
Authors: Chitneedi P. K. , Arranz J. J. , Suárez‐Vega A. , Martínez‐Valladares M. , Gutiérrez‐Gil B.
Published: January 2020

In dairy sheep flocks from Mediterranean countries, replacement and adult ewes are the animals most affected by gastrointestinal nematode (GIN) infections. In this study, we have exploited the information derived from an RNA‐Seq experiment with the aim of identifying potential causal mutations related to GIN resistance in sheep. Considering the RNA‐Seq samples from 12 ewes previously classified as six resistant and six susceptible animals to experimental infection by Teladorsagia circumcincta, we performed a variant calling analysis pipeline using two different types of software, gatk version 3.7 and Samtools version 1.4. The variants commonly identified by the two packages (high‐quality variants) within two types of target regions – (i) QTL regions previously reported in sheep for parasite resistance based on SNP‐chip or sequencing technology studies and (ii) functional candidate genes selected from gene expression studies related to GIN resistance in sheep – were further characterised to identify mutations with a potential functional impact. Among the genes harbouring these potential functional variants (930 and 553 respectively for the two types of regions), we identified 111 immune‐related genes in the QTL regions and 132 immune‐related genes from the initially selected candidate genes. For these immune‐related genes harbouring potential functional variants, the enrichment analyses performed highlighted significant GO terms related to apoptosis, adhesion and inflammatory response, in relation to the QTL related variants, and significant disease‐related terms such as inflammation, adhesion and necrosis, in relation to the initial candidate gene list. Overall, the study provides a valuable list of potential causal mutations that could be considered as candidate causal mutations in relation to GIN resistance in sheep. Future studies should assess the role of these suggested mutations with the aim of identifying genetic markers that could be directly implemented in sheep breeding programmes considering not only production traits, but also functional traits such as resistance to GIN infections.
Genome‐wide association study to identify genetic loci associated with gastrointestinal nematode resistance in Katahdin sheep
Authors: Becker G. M. , Davenport K. M. , Burke J. M. , Lewis R. M. , Miller J. E. , Morgan J. L. M. , Notter D. R. , Murdoch B. M.
Published: January 2020

Resistance to gastrointestinal nematodes has previously been shown to be a moderately heritable trait in some breeds of sheep, but the mechanisms of resistance are not well understood. Selection for resistance currently relies upon faecal egg counts (FEC), blood packed cell volumes and FAMACHA visual indicator scores of anaemia. Identifying genomic markers associated with disease resistance would potentially improve the selection process and provide a more reliable means of classifying and understanding the biology behind resistant and susceptible sheep. A GWAS was conducted to identify possible genetic loci associated with resistance to Haemonchus contortus in Katahdin sheep. Forty animals were selected from the top and bottom 10% of estimated breeding values for FEC from a total pool of 641 sires and ram lambs. Samples were genotyped using Applied Biosystems™ Axiom™ Ovine Genotyping Array (50K) consisting of 51 572 SNPs. Following quality control, 46 268 SNPs were included in subsequent analyses. Analyses were conducted using a linear regression model in plink v1.90 and a single‐locus mixed model in snp and variation suite. Genome‐wide significance was determined by a Bonferroni correction for multiple testing. Using linear regression, loci on chromosomes 2, 3, 16, 23 and 24 were significantly associated at the genome level with FEC estimated breeding values, and we identified a region on chromosome 2 that was significant using both statistical analyses. We suggest a potential role for the gene DIS3L2 for gastrointestinal nematode resistance in Katahdin sheep, although further research is needed to validate these findings.
Computed tomographic and radiographic morphometric study of cardiac and coelomic dimensions in captive blue‐fronted Amazon parrots (Amazona aestiva, Linnaeus, 1758) with varying body condition scores
Authors: dos Santos Gisele J. , da Silva Jeana P. , Hippólito Alícia G. , Ferro Bárbara S. , Oliveira Elton Luís R. , Okamoto Priscylla Tatiana C. G. , Lourenço Maria Lucia G. , de Vasconcelos Machado Vania Maria , Rahal Sheila C. , Teixeira Carlos R. , Melchert Alessandra
Published: January 2020

This study aimed to assess radiographic and tomographic cardiac parameters, including width and length of the heart, and the ratio of heart width to coelom width of blue‐fronted Amazon parrots (Amazona aestiva) with varying body condition scores. Thirty‐five captive birds were included in the study and were allocated into one of three groups according to their respective body condition score: lean, ideal and obese. No differences were observed among the groups with regard to radiographic and tomographic measurements. Computed tomography enabled better identification of the structures of the cardiovascular system without interference from the overlying structures of the celomatic cavity observed in radiographic images. However, radiographic examinations should still be considered the standard screening method to identify cardiac alterations, such as increased or reduced organ dimensions. Standardizing the techniques and measurements performed in this study may serve as a basis for further research in the field.
The preconception environment and sperm epigenetics
Authors: Marcho Chelsea , Oluwayiose Oladele A. , Pilsner J. Richard
Published: January 2020

Background

Infertility is a common reproductive disorder, with male factor infertility accounting for approximately half of all cases. Taking a paternal perceptive, recent research has shown that sperm epigenetics, such as changes in DNA methylation, histone modification, chromatin structure, and noncoding RNA expression, can impact reproductive and offspring health. Importantly, environmental conditions during the preconception period has been demonstrated to shape sperm epigenetics.

Objectives

To provide an overview on epigenetic modifications that regulate normal gene expression and epigenetic remodeling that occurs during spermatogenesis, and to discuss the epigenetic alterations that may occur to the paternal germline as a consequence of preconception environmental conditions and exposures.

Materials and methods

We examined published literature available on databases (PubMed, Google Scholar, ScienceDirect) focusing on adult male preconception environmental exposures and sperm epigenetics in epidemiologic studies and animal models.

Results

The preconception period is a sensitive developmental window in which a variety of exposures such as toxicants, nutrition, drugs, stress, and exercise, affects sperm epigenetics.

Discussion and Conclusion

Understanding the environmental legacy of the sperm epigenome during spermatogenesis will enhance our understanding of reproductive health and improve reproductive success and offspring well‐being.
Fasting‐ and ghrelin‐induced food intake is regulated by NAMPT in the hypothalamus
Authors: de Guia Roldan M. , Hassing Anna S. , Skov Louise J. , Ratner Cecilia , Plucińska Kaja , Madsen Søren , Diep Thi A. , Dela Cruz Gelo V. , Trammell Samuel A.J. , Sustarsic Elahu G. , Emanuelli Brice , Gillum Matthew P. , Gerhart‐Hines Zach , Holst Birgitte , Treebak Jonas T.
Published: January 2020

Aim

Neurons in the arcuate nucleus of the hypothalamus are involved in regulation of food intake and energy expenditure, and dysregulation of signalling in these neurons promotes development of obesity. The role of the rate‐limiting enzyme in the NAD+ salvage pathway, nicotinamide phosphoribosyltransferase (NAMPT), for regulation energy homeostasis by the hypothalamus has not been extensively studied.

Methods

We determined whether Nampt mRNA or protein levels in the hypothalamus of mice were affected by diet‐induced obesity, by fasting and re‐feeding, and by leptin and ghrelin treatment. Primary hypothalamic neurons were treated with FK866, a selective inhibitor of NAMPT, or rAAV carrying shRNA directed against Nampt, and levels of reactive oxygen species (ROS) and mitochondrial respiration were assessed. Fasting and ghrelin‐induced food intake was measured in mice in metabolic cages after intracerebroventricular (ICV)‐mediated FK866 administration.

Results

NAMPT levels in the hypothalamus were elevated by administration of ghrelin and leptin. In diet‐induced obese mice, both protein and mRNA levels of NAMPT decreased in the hypothalamus. NAMPT inhibition in primary hypothalamic neurons significantly reduced levels of NAD+, increased levels of ROS, and affected the expression of Agrp, Pomc and genes related to mitochondrial function. Finally, ICV‐induced NAMPT inhibition by FK866 did not cause malaise or anhedonia, but completely ablated fasting‐ and ghrelin‐induced increases in food intake.

Conclusion

Our findings indicate that regulation of NAMPT levels in hypothalamic neurons is important for the control of fasting‐ and ghrelin‐induced food intake.
Alterations of Nedd4‐2‐binding capacity in PY‐motif of NaV1.5 channel underlie long QT syndrome and Brugada syndrome
Authors: Wang Ya , Du Yuan , Luo Ling , Hu Peijing , Yang Guodong , Li Tao , Han Xiu , Ma Aiqun , Wang Tingzhong
Published: January 2020

Aims

Pathogenic variants of the SCN5A gene can cause Brugada syndrome (BrS) and long QT syndrome (LQTS), which predispose individuals to potentially fatal ventricular arrhythmias and sudden cardiac death. SCN5A encodes the NaV1.5 protein, the pore forming α‐subunit of the voltage‐dependent cardiac Na+ channel. Using a WW domain, the E3 ubiquitin ligase Nedd4‐2 binds to the PY‐motif ([L/P]PxY) within the C‐terminus of NaV1.5, which results in decreased protein expression and current through NaV1.5 ubiquitination. Here, we investigate the role of E3 ubiquitin ligase Nedd4‐2‐mediated NaV1.5 degradation in the pathological mechanisms of the BrS‐associated variant SCN5A‐p.L1239P and LQTS‐associated variant SCN5A‐p.Y1977N.

Methods and Results

Using a combination of molecular biology, biochemical and electrophysiological approaches, we examined the expression, function and Nedd4‐2 interactions of SCN5A‐p.L1239P and SCN5A‐p.Y1977N. SCN5A‐p.L1239P is characterized as a loss‐of‐function, whereas SCN5A‐p.Y1977N is a gain‐of‐function variant of the NaV1.5 channel. Sequence alignment shows that BrS‐associated SCN5A‐p.L1239P has a new Nedd4‐2‐binding site (from LLxY to LPxY). This new Nedd4‐2‐binding site increases the interaction between NaV1.5 and Nedd4‐2, enhancing ubiquitination and degradation of the NaV1.5 channel. Disruption of the new Nedd4‐2‐binding site of SCN5A‐p.L1239P restores NaV1.5 expression and function. However, the LQTS‐associated SCN5A‐p.Y1977N disrupts the usual Nedd4‐2‐binding site (from PPxY to PPxN). This decreases NaV1.5‐Nedd4‐2 interaction, preventing ubiquitination and degradation of NaV1.5 channels.

Conclusions

Our data suggest that the PY‐motif plays an essential role in modifying the expression/function of NaV1.5 channels through Nedd4‐2‐mediated ubiquitination. Alterations of NaV1.5‐Nedd4‐2 interaction represent a novel pathological mechanism for NaV1.5 channel diseases caused by SCN5A variants.
Overexpression of the histidine triad nucleotide‐binding protein 2 protects cardiac function in the adult mice after acute myocardial infarction
Authors: Fan Mengkang , Chen Zhangwei , Huang Yin , Xia Yan , Chen Ao , Lu Danbo , Wu Yuan , Zhang Ning , Zhang Peipei , Li Su , Chen Jinxiang , Zhang Yingmei , Sun Aijun , Zou Yunzeng , Hu Kai , Qian Juying , Ge Junbo
Published: January 2020

Aim

To explore the role of the histidine triad nucleotide‐binding 2 (HINT2) protein in heart failure.

Methods

Neonatal mouse ventricle myocytes (NMVMs) and myocardial infarction‐induced heart failure mice were used for in vitro or in vivo experiments. Adenovirus (ADV) and adeno‐associated virus serum type 9 (AAV9) vectors were used to regulate HINT2 expression. The expression of HINT2 was determined by quantifying the mRNA and protein levels. Cell survival was analysed using the CCK‐8 kit and TUNEL staining. Mitochondrial function was determined by the mitochondrial membrane potential and oxygen consumption rates. AAV9‐HINT2 was injected 24 h post‐myocardial infarction following which transthoracic echocardiography and histological analyses were performed after 4 weeks. Positron emission tomography tomography‐computed tomography (PET/CT) and targeted metabolomics analyses were used to explore the metabolic status in vivo. NAD levels were measured using a colorimetric kit. Computer‐simulated rigid body molecular docking was performed using AUTODOCK4. Molecule binding kinetics assays were performed using biolayer interferometry.

Results

HINT2 was down‐regulated in NMVMs in hypoxia. ADV‐HINT2‐induced HINT2 overexpression improved NMVM survival after exposure to hypoxia. Mitochondrial function was preserved in the ADV‐HINT2 group under hypoxic conditions. In vivo experiments showed that cardiac function and metabolic status was preserved by HINT2 overexpression. HINT2 overexpression restored mitochondrial NAD levels; this was dependent on nicotinamide mononucleotide (NMN). Using computer‐simulated molecular docking analysis and biolayer interferometry, we observed that HINT2 potentially binds and associates with NMN.

Conclusion

HINT2 overexpression protects cardiac function in adult mice after myocardial infarction by maintaining mitochondrial NAD homeostasis.
Factor VIII: the protein, cloning its gene, synthetic factor and now – 35 years later – gene therapy; what happened in between?
Authors: Ling Gavin , Tuddenham Edward G. D.
Published: January 2020

The foundation of haemophilia A therapy in the last 35 years has been critically dependent on isolation of the Factor VIII (FVIII) protein and discovery of the cDNA sequence of the FVIII gene, published in 1984. Identification of the FVIII sequence resulted in a new era of recombinant concentrates and led to significant improvements in safety, set against the tragedy of widespread HIV and hepatitis infections in haemophilia patients from contaminated plasma‐based products. We chronicle the scientific methods and race leading up to the publication of the FVIII DNA sequence and the legacy that follows through to revolutionary gene therapy treatment in clinical trials today.
Long‐term sustained response to fostamatinib in two patients with chronic refractory immune thrombocytopenia (ITP)
Authors: Lee Eun‐Ju , Izak Marina , Bussel James B.
Published: January 2020

Care of patients with chronic immune thrombocytopenia (ITP) who are refractory to available treatments can be quite challenging. Fostamatinib, an oral Syk inhibitor, is the newest FDA‐approved agent for ITP. Phase 3 clinical trials demonstrated an overall response in 43% of patients treated with fostamatinib and use for two years has been reported. Herein, we report two patients with long histories of ITP without lasting responses to numerous first‐, second‐ and third‐line therapies with prolonged responses to ongoing fostamatinib. This shows that patients unresponsive to other agents may respond to fostamatinib and can have sustained benefit.
Collective directional movement and the perception of social cohesion
Authors: Wilson Stuart , Mansour Jamal K.
Published: January 2020

We argue that perceivers associate collective directional movement – groups moving from one place to the next – with higher levels of social cohesion. Study 1 shows that pairs are rated as being more cohesive when described as engaging in directional movement compared to non‐directional activities. Study 2 replicates this finding using film clips. Study 3 reveals that the proximity of directionally moving dyads is a better predictor of perceived cohesion than behavioural synchrony. Study 4 replicates the original finding and reveals that perceptions of common fate and shared goals both contribute to the effect, with the former having more predictive power than the latter. We suggest that collective directional movement is an invariant part of social environments and is utilized by perceivers to make inferences about social dynamics.
Automated differentiation of benign renal oncocytoma and chromophobe renal cell carcinoma on computed tomography using deep learning
Authors: Baghdadi Amir , Aldhaam Naif A. , Elsayed Ahmed S. , Hussein Ahmed A. , Cavuoto Lora A. , Kauffman Eric , Guru Khurshid A.
Published: January 2020

Objectives

To develop and evaluate the feasibility of an objective method using artificial intelligence (AI) and image processing in a semi‐automated fashion for tumour‐to‐cortex peak early‐phase enhancement ratio (PEER) in order to differentiate CD117(+) oncocytoma from the chromophobe subtype of renal cell carcinoma (ChRCC) using convolutional neural networks (CNNs) on computed tomography imaging.

Methods

The CNN was trained and validated to identify the kidney + tumour areas in images from 192 patients. The tumour type was differentiated through automated measurement of PEER after manual segmentation of tumours. The performance of this diagnostic model was compared with that of manual expert identification and tumour pathology with regard to accuracy, sensitivity and specificity, along with the root‐mean‐square error (RMSE), for the remaining 20 patients with CD117(+) oncocytoma or ChRCC.

Results

The mean ± sd Dice similarity score for segmentation was 0.66 ± 0.14 for the CNN model to identify the kidney + tumour areas. PEER evaluation achieved accuracy of 95% in tumour type classification (100% sensitivity and 89% specificity) compared with the final pathology results (RMSE of 0.15 for PEER ratio).

Conclusions

We have shown that deep learning could help to produce reliable discrimination of CD117(+) benign oncocytoma and malignant ChRCC through PEER measurements obtained by computer vision.
The ProtecT trial: analysis of the patient cohort, baseline risk stratification and disease progression
Authors: Bryant Richard J. , Oxley Jon , Young Grace J. , Lane Janet A. , Metcalfe Chris , Davis Michael , Turner Emma L. , Martin Richard M. , Goepel John R. , Varma Murali , Griffiths David F. , Grigor Ken , Mayer Nick , Warren Anne Y. , Bhattarai Selina , Dormer John , Mason Malcolm , Staffurth John , Walsh Eleanor , Rosario Derek J. , Catto James W.F. , Neal David E. , Donovan Jenny L. , Hamdy Freddie C. ,   for the ProtecT Study Group
Published: January 2020

Objective

To test the hypothesis that the baseline clinico‐pathological features of the men with localized prostate cancer (PCa) included in the ProtecT (Prostate Testing for Cancer and Treatment) trial who progressed (n = 198) at a 10‐year median follow‐up were different from those of men with stable disease (n = 1409).

Patients and Methods

We stratified the study participants at baseline according to risk of progression using clinical disease stage, pathological grade and PSA level, using Cox proportional hazard models.

Results

The findings showed that 34% of participants (n = 505) had intermediate‐ or high‐risk PCa, and 66% (n = 973) had low‐risk PCa. Of 198 participants who progressed, 101 (51%) had baseline International Society of Urological Pathology Grade Group 1, 59 (30%) Grade Group 2, and 38 (19%) Grade Group 3 PCa, compared with 79%, 17% and 5%, respectively, for 1409 participants without progression (P < 0.001). In participants with progression, 38% and 62% had baseline low‐ and intermediate‐/high‐risk disease, compared with 69% and 31% of participants with stable disease (P < 0.001). Treatment received, age (65–69 vs 50–64 years), PSA level, Grade Group, clinical stage, risk group, number of positive cores, tumour length and perineural invasion were associated with time to progression (P ≤ 0.005). Men progressing after surgery (n = 19) were more likely to have a higher Grade Group and pathological stage at surgery, larger tumours, lymph node involvement and positive margins.

Conclusions

We demonstrate that one‐third of the ProtecT cohort consists of people with intermediate‐/high‐risk disease, and the outcomes data at an average of 10 years' follow‐up are generalizable beyond men with low‐risk PCa.
Adreno–melatonin receptor complexes control ion homeostasis and intraocular pressure ‐ their disruption contributes to hypertensive glaucoma
Authors: Alkozi Hanan Awad , Navarro Gemma , Aguinaga David , Reyes‐Resina Irene , Sanchez‐Naves Juan , Pérez de Lara Maria J. , Franco Rafael , Pintor Jesus
Published: January 2020

Background and Purpose

Often, glaucoma presents with elevated eye hydrostatic pressure, which is regulated by endogenous melatonin. Phenylephrine increases cytoplasmic [Ca2+], via α1‐adrenoceptor activation, that is detrimental in glaucoma. The aims of this study were (a) to elucidate the role of melatonin receptors in humour production and intraocular pressure (IOP) maintenance and (b) to identify glaucoma‐relevant melatonin–adrenoceptor interactions.

Experimental Approach

Biophysical and proximity ligation assays were performed to identify interactions in heterologous expression systems, in cell lines and in human eyes. Gs/Gi/Gq signalling was investigated in these systems and in cells producing aqueous humour. IOP was determined in a mice model of glaucoma. Retinography and topically pharmacological treatment were performed in control and in glaucomatous mice.

Key Results

α1‐adreno‐ and melatonin receptors form functional complexes in which the C‐terminal tail of the adrenoceptor plays a role. Remarkably, activation of α1‐adrenoceptors in these complexes did not lead to cytosolic Ca2+ increases, suggesting Gs instead of Gq coupling is involved. The number of these complexes significantly decreased in models of glaucoma and, importantly, in human samples from glaucoma patients. This has led to hypothesize that melatonin, a hypotensive agent, plus blockade of α1‐adrenoceptors could normalize pressure in glaucoma. Remarkably, co‐instillation of melatonin and prazosin, an α1‐adrenoceptor antagonist, resulted in long‐term decreases in IOP in a well‐established animal model of glaucoma.

Conclusions and Implications

The findings are instrumental to understand the physiological function of melatonin in the eye and its potential to address eye pathologies by targeting melatonin receptors and their complexes.
Melatonin up‐regulates bone marrow mesenchymal stem cells osteogenic action but suppresses their mediated osteoclastogenesis via MT2‐inactivated NF‐κB pathway
Authors: Zhou Yi , Wang Chaowei , Si Jinyan , Wang Baixiang , Zhang Denghui , Ding Ding , Zhang Jian , Wang Huiming
Published: January 2020

Background and Purpose

Melatonin is a neurohormone involved in bone homeostasis. Melatonin directs bone remodelling and the role of bone marrow mesenchymal stem cells (BMMSCs) in the regulating melatonin‐mediated bone formation–resorption balance remains undefined.

Experimental Approach

Osteoporosis models were established and bone tissue and serum were collected to test the effects of melatonin on bone homeostasis. Melatonin receptors were knocked down, the NF‐κB signalling pathway and receptor activator of NF‐κB ligand (RANKL) expression were investigated. Communication between bone marrow mesenchymal stem cells and osteoclasts was detected with direct‐contact or indirect‐contact system.

Key Results

Bone loss and microstructure disorder in mice were reversed after melatonin treatment, as a result of anabolic and anti‐resorptive effects. In vitro, a physiological (low) concentration of melatonin promoted the bone marrow mesenchymal stem cells, osteogenic lineage commitment and extracellular mineralization but had no impact on extracellular matrix synthesis. After MT knockdown, especially MT2, the positive effects of melatonin on osteogenesis were attenuated. The canonical NF‐κB signalling pathway was the first discovered downstream signalling pathway after MT receptor activation and was found to be down‐regulated by melatonin during osteogenesis. Melatonin suppressed BMMSC‐mediated osteoclastogenesis by inhibiting RANKL production in BMMSCs and this effect only occurred when BMMSCs and osteoclast precursors were co‐cultured in an indirect‐contact manner.

Conclusion and Implications

Our work suggests that melatonin plays a crucial role in bone balance, significantly accelerates the osteogenic differentiation of bone marrow mesenchymal stem cells by suppressing the MT2‐dependent NF‐κB signalling pathway, and down‐regulates osteoclastogenesis via RANKL paracrine secretion.
Preclinical pharmacological evaluation of the fatty acid amide hydrolase inhibitor BIA 10‐2474
Authors: Bonifácio Maria‐João , Sousa Filipa , Aires Cátia , Loureiro Ana I. , Fernandes‐Lopes Carlos , Pires Nuno M. , Palma Pedro Nuno , Moser Paul , Soares‐da‐Silva Patrício
Published: January 2020

Background and Purpose

In 2016, one person died and four others had mild‐to‐severe neurological symptoms during a phase I trial of the fatty acid amide hydrolase (FAAH) inhibitor BIA 10‐2474.

Experimental Approach

Pharmacodynamic and pharmacokinetic studies were performed with BIA 10‐2474, PF‐04457845 and JNJ‐42165279 using mice, rats and human FAAH expressed in COS cells. Selectivity was evaluated by activity‐based protein profiling (APBB) in rats. BIA 10‐2474 effect in stroke‐prone spontaneously hypertensive rats (SHRSP) was investigated.

Key Results

BIA 10‐2474 was 10‐fold less potent than PF‐04457845 in inhibiting human FAAH in situ but inhibited mouse brain and liver FAAH with ED50 values of 13.5 and 6.2 μg·kg−1, respectively. Plasma and brain BIA 10‐2474 levels were consistent with in situ potency and neither BIA 10‐2474 nor its metabolites accumulated following repeat administration. FAAH and α/β‐hydrolase domain containing 6 were the primary targets of BIA 10‐2474 and, at higher exposure levels, ABHD11, PNPLA6, PLA2G15, PLA2G6 and androgen‐induced protein 1. At 100 mg·kg−1 for 28 days, the level of several lipid species containing arachidonic acid increased. Daily treatment of SHRSP with BIA 10‐2474 did not affect mortality rate or increased the incidence of haemorrhage or oedema in surviving animals.

Conclusions and Implications

BIA 10‐2474 potently inhibits FAAH in vivo, similarly to PF‐04457845 and interacts with a number of lipid processing enzymes, some previously identified in human cells as off‐targets particularly at high levels of exposure. These interactions occurred at doses used in toxicology studies, but the implication of these off‐targets in the clinical trial accident remains unclear.
Pathogenesis and pathophysiology of autosomal dominant sleep‐related hypermotor epilepsy with S284L‐mutant α4 subunit of nicotinic ACh receptor
Authors: Fukuyama Kouji , Fukuzawa Masashi , Shiroyama Takashi , Okada Motohiro
Published: January 2020

Background and Purpose

The mechanisms causing spontaneous epileptic seizures, including carbamazepine‐resistant/zonisamide ‐sensitive seizures and comorbidity in autosomal dominant sleep‐related hypermotor epilepsy (ADSHE) are unclear. This study investigated functional abnormalities in thalamocortical transmission in transgenic rats bearing rat S286L‐mutant Chrna4 (S286L‐TG) of α4 subunit of the nicotinic ACh receptor (nAChR) that corresponds to the human S284L‐mutant CHRNA4.

Experimental Approach

Effects of carbamazepine and zonisamide on epileptic discharges of S286L‐TG rat were measured using telemetry electrocorticogram. Transmission abnormalities of L‐glutamate and GABA in thalamocortical pathway of S286L‐TG rats were investigated using multiprobe microdialysis and ultra‐high‐performance liquid‐chromatography.

Key Results

Epileptic discharges in S286L‐TG rats were reduced by zonisamide but not by carbamazepine, similar to that of S284L‐ADSHE patients. Carbamazepine unaffected functional abnormality in transmission of S286L‐TG rats. However, zonisamide was able to compensate for the attenuated S286L‐mutant nAChR induced GABA release in frontal‐cortex, without affecting attenuated thalamocortical glutamatergic transmission. Excitatory effects of S286L‐mutant nAChR on thalamocortical transmission were attenuated compared with those of wild‐type nAChR. Loss‐of‐function of S286L‐nAChR enhanced transmission in thalamocortical motor pathway by predominantly attenuating GABAergic transmission. However, it attenuated transmission in thalamocortical cognitive pathway by reducing inhibitory GABAergic and excitatory glutamatergic transmission.

Conclusion and Implications

Our results suggest that functional abnormalities of S286L‐nAChR are associated with intra‐frontal and thalamocortical transmission, possibly contributing to the pathogenesis of ADSHE‐seizure and comorbidity of S284L‐ADSHE. Selective compensation of impaired GABAergic transmission by zonisamide (but not by carbamazepine) in frontal cortex may be involved, at least partially, in carbamazepine‐resistant ADSHE‐seizure of S284L‐ADSHE patients.
Terrestrial heat flow and lithospheric thermal structure in the Chagan Depression of the Yingen‐Ejinaqi Basin, north central China
Authors: Zuo Yinhui , Jiang Shu , Wu Shihu , Xu Wei , Zhang Jiong , Feng Renpeng , Yang Meihua , Zhou Yongshui , Santosh M.
Published: January 2020

The Chagan Depression in the Yingen‐Ejinaqi Basin, located at the intersection of the Paleo‐Asian Ocean and the Tethys Ocean domains is an important region to gain insights on terrestrial heat flow, lithospheric thermal structure and deep geodynamic processes. Here, we compute terrestrial heat flow values in the Chagan Depression using a large set of system steady‐state temperature data from four representative wells and rock thermal conductivity. We also estimate the “thermal” lithospheric thickness, mantle heat flow, ratio of mantle heat flow to surface heat flow and Moho temperature to evaluate the regional tectonic framework and deep dynamics. The results show that the heat flow in the Chagan Depression ranges from 66.5 to 69.8 mW/m2, with an average value of 68.3 ± 1.2 mW/m2. The Chagan Depression is characterized by a thin “thermal” lithosphere, high mantle heat flow, and high Moho temperature, corresponding to the lithospheric thermal structure of “cold mantle and hot crust” type. We correlate the formation of the Yingen‐Ejinaqi Basin to the Early Cretaceous and Cenozoic subduction of the western Pacific Plate and the Cenozoic multiple extrusions. Our results provide new insights into the thermal structure and dynamics of the lithospheric evolution in central China.
When Helping Hurts: Children Think Groups That Receive Help Are Less Smart
Authors: Sierksma Jellie , Shutts Kristin
Published: January 2020

Helping has many positive consequences for both helpers and recipients. However, in the present research, we considered a possible downside to receiving help: that it signals a deficiency. We investigated whether young children make inferences about intelligence from observing some groups of people receive help and other groups not. In a novel group paradigm, we show that children (4–6 years) think groups that receive help are less smart (n = 44) but not less nice (n = 45). Children also generalized their inferences about relative intelligence to new group members (n = 55; forced‐choice‐method). These results have implications for understanding how children develop stereotypes about intelligence as well as for educational practices that group children according to their ability.
A Developmental Study of the Self‐Prioritization Effect in Children Between 6 and 10 Years of Age
Authors: Maire Hélène , Brochard Renaud , Zagar Daniel
Published: January 2020

Self‐biases are well described in adults but remain poorly understood in children. Here, we investigated in 6–10 year‐old children (N = 132) the self‐prioritization effect (SPE), a self‐bias which reflects, in adults, the perceptual advantage for stimuli arbitrarily associated with the self as compared to those associated with other persons. We designed a child‐friendly adaptation of a paradigm originally introduced in adults by Sui, He, and Humphreys (2012) in order to test whether the SPE also occurs in children and if so, to determine its evolution with age. A robust SPE was obtained from the age of 6, and this effect was similar‐sized in our four age groups. These findings are discussed with reference to the development of the self during childhood.
Phenotypical and potential functional characteristics of different immune cells expressing CD28H/B7-H5 and their relationship with cancer prognosis
Authors: Zhong C , Lang Q , Yu J , Wu S , Xu F , Tian Y
Published: January 2020

CD28H and B7-H5 have been identified as receptor–ligand pairs in the B7/CD28 family, and have co-stimulatory activity in immune cells. Here, we have systematically reviewed the research reports concerning the CD28H/B7-H5 pathway. It was found that CD28H is mainly expressed in T cells and natural killer (NK) cells with naive and poorly differentiated properties, and repeated antigen stimulation leads to permanent loss of CD28H. In tumors, CD28H is mainly expressed in tissue-resident memory (TRM) lymphocyte T cells, which is associated with improved tumor prognosis. B7-H5 is a ligand for CD28H and is widely expressed in tumor cells. B7-H5 expression is closely related to the prognosis of the tumor. Studies have shown that high expression of B7-H5 in tumor is related to a worse prognosis for lung cancer, osteosarcoma, oral squamous cell carcinoma (OSCC), breast carcinoma, human clear cell renal cell carcinoma (ccRCC), intrahepatic cholangiocarcinoma (ICC), bladder urothelial carcinoma (BUC) and colorectal cancer (CRC), but is associated with a better prognosis for pancreatic ductal adenocarcinoma (PDAC) and glioma. Controversial views exist in studies on gastric cancer prognosis.
Maternal, cord, and three‐year‐old child serum thyroid hormone concentrations in the Health Outcomes and Measures of the Environment study
Authors: Doherty Brett T. , Kosarek Noelle , Hoofnagle Andy N. , Xu Yingying , Zoeller R. Thomas , Yolton Kimberly , Chen Aimin , Lanphear Bruce P. , Braun Joseph M. , Romano Megan E.
Published: January 2020

Purpose

Maternal thyroid function during pregnancy may influence offspring thyroid function, though relations between maternal and child thyroid function are incompletely understood. We sought to characterize relations between maternal, cord and child thyroid hormone concentrations in a population of mother‐child pairs with largely normal thyroid function.

Methods

In a prospective birth cohort, we measured thyroid hormone concentrations in 203 mothers at 16 gestational weeks, 273 newborns and 159 children at 3 years among participants in the Health Outcomes and Measures of the Environment (HOME) Study. We used multivariable linear regression to estimate associations of maternal thyroid hormones during pregnancy with cord serum thyroid hormones and also estimated associations of maternal and cord thyroid hormones with child thyroid‐stimulating hormone (TSH).

Results

Each doubling of maternal TSH was associated with a 16.4% increase of newborn TSH (95% CI: 3.9%, 30.5%), and each doubling of newborn TSH concentrations was associated with a 10.4% increase in child TSH concentrations at 3 years (95% CI: 0.1%, 21.7%). An interquartile range increase in cord FT4 concentrations was associated with an 11.7% decrease in child TSH concentrations at 3 years (95% CI: −20.2%, −2.3%).

Conclusions

We observed relationships between maternal, newborn and child thyroid hormone concentrations in the HOME Study. Our study contributes to understandings of interindividual variability in thyroid function among mother‐child pairs, which may inform future efforts to identify risk factors for thyroid disorders or thyroid‐related health outcomes.
Microstructural disruption of the right inferior fronto‐occipital and inferior longitudinal fasciculus contributes to WMH‐related cognitive impairment
Authors: Chen Hai‐Feng , Huang Li‐Li , Li Hui‐Ya , Qian Yi , Yang Dan , Qing Zhao , Luo Cai‐Mei , Li Meng‐Chun , Zhang Bing , Xu Yun
Published: January 2020

Aims

White matter hyperintensity (WMH) is the most common neuroimaging manifestation of cerebral small vessel disease and is related to cognitive dysfunction or dementia. This study aimed to investigate the mechanism and effective indicators to predict WMH‐related cognitive impairment.

Methods

We recruited 22 healthy controls (HC), 25 cases of WMH with normal cognition (WMH‐NC), and 23 cases of WMH with mild cognitive impairment (WMH‐MCI). All individuals underwent diffusion tensor imaging (DTI) and a standardized neuropsychological assessment. Automated Fiber Quantification was used to extract altered DTI metrics between groups, and partial correlation was performed to assess the associations between WM integrity and cognitive performance. Furthermore, machine learning analyses were performed to determine underlying imaging markers of WMH‐related cognitive impairment.

Results

Our study found that mean diffusivity (MD) values of several fiber bundles including the bilateral anterior thalamic radiation (ATR), the left inferior fronto‐occipital fasciculus (IFOF), the right inferior longitudinal fasciculus (ILF), and the right superior longitudinal fasciculus (SLF) were negatively correlated with memory function, while that of the anterior component of the right IFOF and the posterior and intermediate component of the right ILF showed significant negative correlation with MMSE and episodic memory, respectively. Furthermore, machine learning analyses showed that the accuracy of recognizing WMH‐MCI patients from the WMH populations was up to 80.5% and the intermediate and posterior components of the right ILF and the anterior component of the right IFOF contribute the most.

Conclusions

Changes in the properties of DTI may be the potential mechanism of WMH‐related MCI, especially the right IFOF and the right ILF, which may become imaging markers for predicting WMH‐related cognitive dysfunction.
Hypersensitivity to antibiotics in drug reaction with eosinophilia and systemic symptoms (DRESS) from other culprits
Authors: Santiago Luis G. , Morgado Francisca J. , Baptista Mariana S. , Gonçalo Margarida
Published: January 2020

Background

Antibiotics have been implicated in the reactivation of exanthema and systemic involvement in drug reaction with eosinophilia and systemic symptoms (DRESS); however, it is not clear whether these patients become sensitized to the antibiotic.

Objective

To evaluate if, after DRESS, patients become sensitized to antibiotics.

Methods

We retrospectively reviewed the patch test (PT) data and clinical files of DRESS patients who were administered antibiotics during DRESS from other culprits.

Results

Nine patients out of 17 (53%) were positive to antibiotics in PT: six to the penicillin group and three to cephalosporins (including one patient with additional positivity to vancomycin). Considering the eight patients who were negative to antibiotics in PT, seven were exposed to a fluoroquinolone. Four cases were patch tested again and three remained positive to antibiotics 2 to 5 years thereafter. Two patients with positive PT results had an accidental re‐exposure to antibiotics and developed a maculopapular exanthema without systemic symptoms.

Conclusion

Exposure to antibiotics during DRESS or its prodromal phase could enhance sensitization to antibiotics, as confirmed by a positive PT. Reproducibility of positive PTs to antibiotics after several years and reactivation after re‐exposure support that T‐cell‐mediated hypersensitivity to antibiotics in the setting of DRESS is a specific reaction.
CD44 expression in human skin: High expression in irritant and allergic contact dermatitis and moderate expression in psoriasis lesions in comparison with healthy controls
Authors: Lugović‐Mihić Liborija , Novak‐Bilić Gaby , Vučić Majda , Japundžić Iva , Bukvić Iva
Published: January 2020

Background

Previous research using animal models demonstrated that CD44 expression may contribute to directing inflammatory cells into skin lesions during inflammation development in allergic contact dermatitis (ACD).

Objectives

To examine CD44 expression in patients with ACD and irritant contact dermatitis (ICD), and to compare it to patients with psoriatic lesions and healthy controls’ (HCs) skin.

Methods

This study included 200 patients comprising four groups of 50 each: ACD, ICD, psoriasis vulgaris, and HCs. CD44 expression was determined by immunohistochemical analysis using an optical microscope, and the results were visualized semiquantitatively by determining the percentage of immunoreactive cells in the epidermis, dermis, and on lymphocytes.

Results

The highest CD44 expression was found in ICD, followed by ACD, psoriasis vulgaris, and lastly, the HCs (P < .001). Epidermal CD44 expression was significantly higher in contact dermatoses (especially in ICD) compared with psoriasis and healthy skin (P < .001). Similarly, CD44 expression in the dermis and on lymphocytes was strongest in ICD, although less pronounced than in the epidermis.

Conclusions

Because significantly elevated CD44 expression in ICD might be related to its function in maintaining and preserving the skin barrier in affected patients, further research on disease pathogenesis and new treatment options is needed.
Therapeutic effects of nebulized verapamil on chronic obstructive pulmonary disease: A randomized and double‐blind clinical trial
Authors: Bozorgmehr Rama , Edalatifard Maryam , Safavi Enayat , Rahimi Besharat , Ghorbani Fariba , Abtahi Hamidreza , Amini Shahideh , Pourdowlat Guitti
Published: January 2020

Objectives

In this study, we assessed the clinical effect of inhaled verapamil on hospitalized COPD patients in a randomized and double‐blind study.

Method

COPD patients randomly received 10 mg of inhaled verapamil or 4 cc nebulized distilled water (DW) as placebo.

Results

Twenty patients enrolled in each group with no difference in baseline characteristics. Mean age was 64.95 ± 8.9 and 66.9 ± 10.74 years in verapamil and control group; respectively, (P > 0.05).

The mean dyspnea score was 6.4 ± 1.2 and 6.2 ± 1.8 in the verapamil and control group, respectively and decreased to 4.9 ± 1.3 and 5.7 ± 1.8 after the intervention. The mean change in the verapamil group was significantly higher, (22.43% ± 10.6% vs 8.7% ± 12.1%), P = 0.00.

Unlike the control group, the FEV1 value in the verapamil group significantly increased and reached to 1.17 ± 0.4 L from 1.03 ± 0.4. There was a significant decrease in airway resistance in both groups after intervention. However, neither total lung capacity and residual volume nor forced vital capacity changed significantly. Moreover, oxygen saturation in the verapamil group changed 4.8% ± 2.5% and this improvement in the control group was 1.8 ± 1 (P = 0.00). Smoker subjects, ones with PAP more than 35 mm Hg and obese patients benefit from verapamil.

Conclusion

The beneficial impact of inhaled verapamil on the diminishing of dyspnea score along with its bronchodilatory effect would make this selective calcium blocker agent a therapeutic option in COPD.
The presence of underlying asthma should be investigated in patients diagnosed with ACE inhibitor induced cough
Authors: Yılmaz İnsu , Türk Murat , Baran Ketencioğlu Burcu , Çetinkaya Zeki , Tutar Nuri , Oymak Fatma Sema , Gülmez İnci , Adkinson Newton Franklin
Published: January 2020

Introduction

Why do only some of patients who are prescribed angiotensin converting enzyme inhibitors (ACE‐I) develop cough? The pathogenesis of ACE‐I‐induced cough remains controversial and requires further studies.

Objective

We aim to investigate whether asthma is a contributing cause of ACE‐I‐induced cough.

Methods

Patients attending a cardiology clinic between March 2016 and March 2017 who were diagnosed with ACE‐I induced cough were included in this study. ACE‐I‐induced cough was defined as cough which developed within 4 weeks after initiation of ACE‐I therapy and which improved within 4 weeks after discontinuation of the ACE‐I. Patients who had received ACE‐I treatment for at least 6 months without side effects were included in the study as a control group. Face‐to‐face questionnaires, pulmonary function tests (PFT) and skin prick tests were applied to all the patients. If there was discordance between asthma history and PFT results, a methacholine bronchial provocation test (BPT) was performed.

Results

A total of 43 patients with ACE‐I induce cough were compared with 50 controls. Bronchial hyperreactivity (BHR), rhinitis, atopy and family history of asthma were more frequent in patients with ACE‐I induced cough (P < .001). Patients with ACE‐I‐induced cough had significantly higher incidence of diagnosed asthma [OR = 8.28 (95%CI: 3.26‐21.03) P < .001].

Conclusions

Asthma and an atopic background constitute a substantial risk factor for ACE‐I induced cough. The presence of underlying asthma should be investigated in patients diagnosed with ACE inhibitor induced cough. However, the fact that most asthma patients tolerate ACE‐I therapy, indicates that other cofactors are likely involved.