bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

AbstractAimNeurons 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.MethodsWe 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.ResultsNAMPT 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.ConclusionOur 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

AbstractAimsPathogenic 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 ResultsUsing 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.ConclusionsOur 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

AbstractAimTo explore the role of the histidine triad nucleotide‐binding 2 (HINT2) protein in heart failure.MethodsNeonatal 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.ResultsHINT2 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.ConclusionHINT2 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

SummaryThe 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

SummaryCare 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.
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

ObjectivesTo 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.MethodsThe 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.ResultsThe 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).ConclusionsWe 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

ObjectiveTo 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 MethodsWe 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.ResultsThe 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.ConclusionsWe 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 PurposeOften, 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 ApproachBiophysical 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 Resultsα1‐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 ImplicationsThe 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 PurposeMelatonin 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 ApproachOsteoporosis 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 ResultsBone 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 ImplicationsOur 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 PurposeIn 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 ApproachPharmacodynamic 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 ResultsBIA 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 ImplicationsBIA 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 PurposeThe 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 ApproachEffects 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 ResultsEpileptic 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 ImplicationsOur 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

AbstractThe 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.