bluuebunny/crossref_metadata_2025_split huggingface dataset:
TRPV1 activation alleviates cognitive and synaptic plasticity impairments through inhibiting AMPAR endocytosis in APP23/PS45 mouse model of Alzheimer’s disease
Authors: Du Yehong , Fu Min , Huang Zhilin , Tian Xin , Li Junjie , Pang Yayan , Song Weihong , Tian Wang Yu , Dong Zhifang 
Published: February 2020

AbstractAlzheimer's disease (AD) is one of the most common causes of neurodegenerative diseases in the elderly. The accumulation of amyloid‐β (Aβ) peptides is one of the pathological hallmarks of AD and leads to the impairments of synaptic plasticity and cognitive function. The transient receptor potential vanilloid 1 (TRPV1), a nonselective cation channel, is involved in synaptic plasticity and memory. However, the role of TRPV1 in AD pathogenesis remains largely elusive. Here, we reported that the expression of TRPV1 was decreased in the brain of APP23/PS45 double transgenic AD model mice. Genetic upregulation of TRPV1 by adeno‐associated virus (AAV) inhibited the APP processing and Aβ deposition in AD model mice. Meanwhile, upregulation of TRPV1 ameliorated the deficits of hippocampal CA1 long‐term potentiation (LTP) and spatial learning and memory through inhibiting GluA2‐containing α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptor (AMPAR) endocytosis. Furthermore, pharmacological activation of TRPV1 by capsaicin (1 mg/kg, i.p.), an agonist of TRPV1, dramatically reversed the impairments of hippocampal CA1 LTP and spatial learning and memory in AD model mice. Taken together, these results indicate that TRPV1 activation effectively ameliorates cognitive and synaptic functions through inhibiting AMPAR endocytosis in AD model mice and could be a novel molecule for AD treatment.
Associations between neighborhood‐level factors and opioid‐related mortality: A multi‐level analysis using death certificate data
Authors: Flores Michael William , Lê Cook Benjamin , Mullin Brian , Halperin‐Goldstein Gabriel , Nathan Aparna , Tenso Kertu , Schuman‐Olivier Zev 
Published: February 2020

AbstractAimTo identify associations between opioid‐related mortality and neighborhood‐level risk factors.DesignCross‐sectional study.SettingMassachusetts, USA.ParticipantsUsing 2011–14 Massachusetts death certificate data, we identified opioid‐related (n = 3089) and non‐opioid‐related premature deaths (n = 8729).MeasurementsThe independent variables consisted of four sets of neighborhood‐level factors: (1) psychosocial, (2) economic, (3) built environment and (4) health‐related. At the individual level we included the following compositional factors: age at death, sex, race/ethnicity, marital status, education, veteran status and nativity. The primary outcome of interest was opioid‐related mortality.FindingsMulti‐level models identified number of social associations per 10 000 [odds ratio (OR) = 0.84, P = 0.002, 95% confidence interval (CI) = 0.75–0.94] and number of hospital beds per 10 000 (OR = 0.78, P < 0.001, 95% CI = 0.68–0.88) to be inversely associated with opioid‐related mortality, whereas the percentage living in poverty (OR = 1.01, P = 0.008, 95% CI = 1.00–1.01), food insecurity rate (OR = 1.21, P = 0.002, 95% CI = 1.07–1.37), number of federally qualified health centers (OR = 1.02, P = 0.028, 95% CI = 1.02–1.08) and per‐capita morphine milligram equivalents of hydromorphone (OR = 1.05, P = 0.003, 95% CI = 1.01–1.08) were positively associated with opioid‐related mortality.ConclusionsOpioid‐related deaths between 2011 and 2014 in the state of Massachusetts appear to be positively associated with the percentage living in poverty, food insecurity rate, number of federally qualified health centers and per‐capita morphine milligram equivalents of hydromorphone, but inversely associated with number of social associations per 10 000 and number of hospital beds per 10 000.
Association between alcohol consumption and subclinical femoral atherosclerosis in smoking and non‐smoking men: the AWHS study
Authors: Moreno‐Franco Belén , Pérez‐Esteban Alejandro , Civeira Fernando , Guallar‐Castillón Pilar , Casasnovas José Antonio , Mateo‐Gállego Rocío , Jarauta Estíbaliz , Malo Sara , Laclaustra Martín 
Published: February 2020

AbstractBackground and AimsMany addictive substances, such as tobacco and alcohol, influence atherosclerosis development. Whether or not tobacco's pro‐atherosclerotic effect is influenced by alcohol consumption is unknown. We aimed to estimate the impact of alcohol intake on the presence of subclinical atherosclerosis in femoral arteries in smoking and non‐smoking middle‐aged men.Design, Setting and ParticipantsCross‐sectional analysis of a subset of the Aragon Workers Health Study (AWHS), comprising 2099 men with mean age 50.9 years without previous cardiovascular disease.MeasurementsThe presence of plaques in femoral arteries was assessed by high‐resolution sonography. Self‐reported alcohol consumption over the previous year was measured with a food frequency questionnaire. The sample was divided into four groups according to their daily grams of alcohol consumption ≤ 1 (abstainers), ≥ 2 to < 30, ≥ 30 to < 60 and ≥ 60 g/day. Participants were divided on ever‐smoking (current and former) versus never‐smoking strata in the main analysis.FindingsWe did not find a significant association between the different levels of alcohol intake and the likelihood of developing femoral artery atherosclerosis in never‐smokers. Ever‐smoking was positively associated with femoral atherosclerosis overall [odds ratio (OR) = 3.00; 95% confidence interval (CI) = 2.40, 3.74; P < 0.001] and within each level of alcohol consumption. Atherosclerosis was lower in ever‐smokers who consumed 2 g/day or more but less than 30 g/day with respect to those ever‐smokers who were abstainers (OR = 0.70; 95% CI = 0.49, 0.99; P < 0.05). However, among these ever‐smokers, atherosclerosis prevalence was still higher than among never‐smokers who consumed alcohol in the same amount (2 g/day or more but less than 30 g/day) (OR = 2.73; 95% CI = 2.07, 3.61; P < 0.001).ConclusionsAmong middle‐aged men, moderate alcohol consumption appears to be associated with lower prevalence of femoral artery subclinical atherosclerosis compared with alcohol abstinence only in ever‐smokers.
New genomic features of the polled intersex syndrome variant in goats unraveled by long‐read whole‐genome sequencing
Authors: Simon R. , Lischer H. E. L. , Pieńkowska‐Schelling A. , Keller I. , Häfliger I. M. , Letko A. , Schelling C. , Lühken G. , Drögemüller C. 
Published: February 2020

SummaryIn domestic goats, the polled intersex syndrome (PIS) refers to XX female‐to‐male sex reversal associated with the absence of horn growth (polled). The causal variant was previously reported as a 11.7 kb deletion at approximately 129 Mb on chromosome 1 that affects the transcription of both FOXL2 and several long non‐coding RNAs. In the meantime the presence of different versions of the PIS deletion was postulated and trials to establish genetic testing with the existing molecular genetic information failed. Therefore, we revisited this variant by long‐read whole‐genome sequencing of two genetically female (XX) goats, a PIS‐affected and a horned control. This revealed the presence of a more complex structural variant consisting of a deletion with a total length of 10 159 bp and an inversely inserted approximately 480 kb‐sized duplicated segment of a region located approximately 21 Mb further downstream on chromosome 1 containing two genes, KCNJ15 and ERG. Publicly available short‐read whole‐genome sequencing data, Sanger sequencing of the breakpoints and FISH using BAC clones corresponding to both involved genome regions confirmed this structural variant. A diagnostic PCR was developed for simultaneous genotyping of carriers for this variant and determination of their genetic sex. We showed that the variant allele was present in all 334 genotyped polled goats of diverse breeds and that all analyzed 15 PIS‐affected XX goats were homozygous. Our findings enable for the first time a precise genetic diagnosis for polledness and PIS in goats and add a further genomic feature to the complexity of the PIS phenomenon.
Immune epigenetic age in pregnancy and 1 year after birth: Associations with weight change
Authors: Ross Kharah M. , Carroll Judith , Horvath Steve , Hobel Calvin J. , Coussons‐Read Mary E. , Dunkel Schetter Christine 
Published: February 2020

AbstractProblemEpigenetic age indices are markers of biological aging determined from DNA methylation patterns. Accelerated epigenetic age predicts morbidity and mortality. Women tend to demonstrate slower blood epigenetic aging compared to men, possibly due to female‐specific hormones and reproductive milestones. Pregnancy and the post‐partum period are critical reproductive periods that have not been studied yet with respect to epigenetic aging. The purpose of this paper was to examine whether pregnancy itself and an important pregnancy‐related variable, changes in body mass index (BMI) between pregnancy and the post‐partum period, are associated with epigenetic aging.Method of StudyA pilot sample of 35 women was recruited as part of the Healthy Babies Before Birth (HB3) project. Whole blood samples were collected at mid‐pregnancy and 1 year post‐partum. DNA methylation at both time points was assayed using Infinium 450K and EPIC chips. Epigenetic age indices were calculated using an online calculator.ResultsPaired‐sample t‐tests were used to test differences in epigenetic age indices from pregnancy to 1 year after birth. Over this critical time span, women became younger with respect to phenotypic epigenetic age, GrimAge, DNAm PAI‐1, and epigenetic age indices linked to aging‐related shifts in immune cell populations, known as extrinsic epigenetic age. Post‐partum BMI retention, but not prenatal BMI increases, predicted accelerated epigenetic aging.ConclusionWomen appear to become younger from pregnancy to the post‐partum period based on specific epigenetic age indices. Further, BMI at 1 year after birth that reflects weight retention predicted greater epigenetic aging during this period.
Efficacy and safety of treatment with biologicals (benralizumab, dupilumab and omalizumab) for severe allergic asthma: A systematic review for the EAACI Guidelines ‐ recommendations on the use of biologicals in severe asthma
Authors: Agache Ioana , Rocha Claudio , Beltran Jessica , Song Yang , Posso Margarita , Solà Ivan , Alonso‐Coello Pablo , Akdis Cezmi , Akdis Mubeccel , Canonica Giorgio W. , Casale Thomas , Chivato Tomas , Corren Jonathan , Del Giacco Stefano , Eiwegger Thomas , Firinu Davide , Gern James E. , Hamelmann Eckard , Hanania Nicola , Mäkelä Mika , Martín Irene Hernández , Nair Parameswaran , O'Mahony Liam , Papadopoulos Nikolaos G. , Papi Alberto , Park Hae‐Sim , Pérez de Llano Luis , Quirce Santiago , Sastre Joaquin , Shamji Mohamed , Schwarze Jurgen , Canelo‐Aybar Carlos , Palomares Oscar , Jutel Marek 
Published: February 2020

AbstractAllergic asthma is a frequent asthma phenotype. Both IgE and type 2 cytokines are increased, with some degree of overlap with other phenotypes. Systematic reviews assessed the efficacy and safety of benralizumab, dupilumab and omalizumab (alphabetical order) vs standard of care for patients with uncontrolled severe allergic asthma. PubMed, Embase and Cochrane Library were searched to identify RCTs and health economic evaluations, published in English. Critical and important asthma‐related outcomes were evaluated. The risk of bias and the certainty of the evidence were assessed using GRADE. All three biologicals reduced with high certainty the annualized asthma exacerbation rate: benralizumab incidence rate ratios (IRR) 0.63 (95% CI 0.50 − 0.81); dupilumab IRR 0.58 (95%CI 0.47 − 0.73); and omalizumab IRR 0.56 (95%CI 0.42 − 0.73). Benralizumab and dupilumab improved asthma control with high certainty and omalizumab with moderate certainty; however, none reached the minimal important difference (MID). Both benralizumab and omalizumab improved QoL with high certainty, but only omalizumab reached the MID. Omalizumab enabled ICS dose reduction with high certainty. Benralizumab and omalizumab showed an increase in drug‐related adverse events (AEs) with low to moderate certainty. All three biologicals had moderate certainty for an ICER/QALY value above the willingness to pay threshold. There was high certainty that in children 6‐12 years old omalizumab decreased the annualized exacerbation rate [IRR 0.57 (95%CI 0.45‐0.72)], improved QoL [relative risk 1.43 (95%CI 1.12 −1.83)], reduced ICS [mean difference (MD) −0.45 (95% CI −0.58 to −0.32)] and rescue medication use [ MD −0.41 (95%CI −0.66 to −0.15)].
A prospective study of perinatal and metabolic risk factors for early childhood caries
Authors: Boustedt Katarina , Roswall Josefine , Kjellberg Emma , Twetman Svante , Dahlgren Jovanna 
Published: February 2020

AbstractAimTo study the relationship between early childhood caries and perinatal and metabolic risk factors in a cohort of preschool children.MethodsThe study population consisted of 208 children followed from birth to 6.5 years. We extracted the perinatal factors from medical records and questionnaires and assessed the occurrence of caries at the age of 5 years. Indicators of the metabolic syndrome (waist circumference, blood pressure, fasting insulin, glucose and dyslipidaemia) were recorded at 6.5 years of age.ResultsInfants born moderately to late preterm and infants born small for gestational age were more likely to have early childhood caries at 5 years of age (relative risk 4.2 and 2.3, respectively; P < .05). The presence of metabolic risk factors according to the IDEFICS monitoring levels did not differ between children with or without caries but a statistically significant correlation was found between the fasting glucose values and the number of decayed or filled teeth (r = 0.18; P < .05).ConclusionBeing born preterm or small for gestational age increased the risk of early childhood caries. Preschool children with caries had higher fasting glucose levels but no other signs of the metabolic syndrome.
School bonding and ethos in trajectories of offending: Results from the Belfast Youth Development Study
Authors: Higgins Kathryn , Perra Oliver , Jordan Julie‐Ann , O'Neill Tara , McCann Mark 
Published: February 2020

BackgroundAspects of the school environment, such as school attachment levels, are linked to adolescent offending. Previous research has not clarified whether a school‐ or individual‐level intervention approach to improving pupil school attachment and commitment is most likely to reduce adolescent offending.AimThe present study assessed the impact of individual‐ and school‐level variables on offending behaviour from ages 14–16 years.SampleThe participants were 4,049 young people from 42 mainstream schools who took part in the Belfast Youth Development Study.MethodMultilevel modelling was used to examine the relative influence of individual‐ and school‐level variables on offending behaviour in adolescence.ResultsPupils who had high levels of school commitment and attachment and were involved in fewer fights at age 13 reported lower levels of offending at age 14 years. Differences between schools accounted for 7% of the variation in offending. Lower individual‐level commitment was associated with higher initial levels of offending at age 14 if the school‐level ethos was of higher commitment. Lack of safety at the school level appeared to be detrimental for young people not exposed to socio‐economic deprivation.ConclusionsIndividual‐level targeted interventions are likely to be a more cost‐effective approach of reducing offending behaviour in adolescence. Additional, albeit smaller, reductions in offending levels could be achieved through school‐level interventions in some school types (e.g., deprived areas).
The antiarrhythmic compound efsevin directly modulates voltage‐dependent anion channel 2 by binding to its inner wall and enhancing mitochondrial Ca2+ uptake
Authors: Wilting Fabiola , Kopp Robin , Gurnev Philip A. , Schedel Anna , Dupper Nathan J. , Kwon Ohyun , Nicke Annette , Gudermann Thomas , Schredelseker Johann 
Published: February 2020

Background and PurposeThe synthetic compound efsevin was recently identified to suppress arrhythmogenesis in models of cardiac arrhythmia, making it a promising candidate for antiarrhythmic therapy. Its activity was shown to be dependent on the voltage‐dependent anion channel 2 (VDAC2) in the outer mitochondrial membrane. Here, we investigated the molecular mechanism of the efsevin–VDAC2 interaction.Experimental ApproachTo evaluate the functional interaction of efsevin and VDAC2, we measured currents through recombinant VDAC2 in planar lipid bilayers. Using molecular ligand‐protein docking and mutational analysis, we identified the efsevin binding site on VDAC2. Finally, physiological consequences of the efsevin‐induced modulation of VDAC2 were analysed in HL‐1 cardiomyocytes.Key ResultsIn lipid bilayers, efsevin reduced VDAC2 conductance and shifted the channel's open probability towards less anion‐selective closed states. Efsevin binds to a binding pocket formed by the inner channel wall and the pore‐lining N‐terminal α‐helix. Exchange of amino acids N207, K236 and N238 within this pocket for alanines abolished the channel's efsevin‐responsiveness. Upon heterologous expression in HL‐1 cardiomyocytes, both channels, wild‐type VDAC2 and the efsevin‐insensitive VDAC2AAA restored mitochondrial Ca2+ uptake, but only wild‐type VDAC2 was sensitive to efsevin.Conclusion and ImplicationsIn summary, our data indicate a direct interaction of efsevin with VDAC2 inside the channel pore that leads to modified gating and results in enhanced SR‐mitochondria Ca2+ transfer. This study sheds new light on the function of VDAC2 and provides a basis for structure‐aided chemical optimization of efsevin.
Overview of treatment approaches to osteoporosis
Authors: Langdahl Bente L. 
Published: February 2020

Efficient therapies are available for the treatment of osteoporosis. Anti‐resorptive therapies, including bisphosphonates and denosumab, increase bone mineral density (BMD) and reduce the risk of fractures by 20–70%. Bone‐forming or dual‐action treatments stimulate bone formation and increase BMD more than the anti‐resorptive therapies. Two studies have demonstrated that these treatments are superior to anti‐resorptives in preventing fractures in patients with severe osteoporosis. Bone‐forming or dual‐action treatments should be followed by anti‐resorptive treatment to maintain the fracture risk reduction. The BMD gains seen with bone‐forming and dual‐action treatments are greater in treatment‐naïve patients compared to patients pretreated with anti‐resorptive treatments. However, the antifracture efficacy seems to be preserved. Treatment failure will often lead to switch of treatment from orally to parentally administrated anti‐resorptives treatment or from anti‐resorptive to bone‐forming or dual‐action treatment. Osteoporosis is a chronic condition and therefore needs a long‐term management plan with a personalized approach to treatment.LINKED ARTICLESThis article is part of a themed issue on The molecular pharmacology of bone and cancer‐related bone diseases. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.9/issuetoc
Upregulation of ZNF148 in SDHB‐deficient gastrointestinal stromal tumor potentiates Forkhead box M1‐mediated transcription and promotes tumor cell invasion
Authors: Gao Xiaodong , Ma Chunmin , Sun Xiangwei , Zhao Qin , Fang Yong , Jiang Yuhui , Shen Kuntang , Shen Xian 
Published: February 2020

AbstractSuccinate dehydrogenase (SDH) deficiency is associated with gastrointestinal stromal tumor (GIST) oncogenesis, but the underlying molecular mechanism remains to be further investigated. Here, we show that succinate accumulation induced by SDHB loss of function increased the expression of zinc finger protein 148 (ZNF148, also named ZBP‐89) in GIST cells. Meanwhile, ZNF148 is found to be phosphorylated by ERK at Ser306, and this phosphorylation results in ZNF148 binding to Forkhead box M1 (FOXM1). Through the complex formation at the promoter, ZNF148 facilitates Histone H3 acetylation and FOXM1‐mediated Snail transcription, which eventually promotes cell invasion and tumor growth. The clinical analysis indicates that SDHB deficiency is associated with elevated ZNF148 levels, and ZNF148‐S306 phosphorylation level displays a positive correlation with poor prognosis in GIST patients. These findings illustrate an unidentified molecular mechanism underlying FOXM1‐regulated gene transcription related to GIST cell invasion, which highlights the physiological effects of SDHB deficiency on the invasiveness of GIST.
Expression, mutation, and methylation of cereblon‐pathway genes at pre‐ and post‐lenalidomide treatment in multiple myeloma
Authors: Tachita Takuto , Kinoshita Shiori , Ri Masaki , Aoki Sho , Asano Arisa , Kanamori Takashi , Yoshida Takashi , Totani Haruhito , Ito Asahi , Kusumoto Shigeru , Komatsu Hirokazu , Yamagata Kazufumi , Kubo Kohmei , Tohkin Masahiro , Fukuda Shinsaku , Iida Shinsuke 
Published: February 2020

AbstractCereblon (CRBN) is a target for immunomodulatory drugs. This study investigated the prognostic value of the expression of CRBN‐pathway genes on the clinical relevance of lenalidomide (Len) treatment and evaluated the levels of CRBN‐binding proteins and mutations in these genes after Len treatment. Forty‐eight primary multiple myeloma cells were collected prior to treatment with Len and dexamethasone (Ld) and 25 paired samples were obtained post‐Ld therapy. These tumor cells were used to determine the expression and mutated forms of the CRBN‐pathway genes. Following normalization with CRBN levels, there was a significantly reduced IKZF1/CRBN ratio in samples that responded poorly to Ld therapy. Moreover, patients with low ratios of IKZF1/CRBN showed a significantly shorter progression‐free survival (PFS) and overall survival (OS) than those with higher ratios. However, patients with high ratios of KPNA2/CRBN showed a significantly shorter PFS and OS than patients with lower ratios. Of the 25 paired samples analyzed, most samples showed a reduction in the expression of CRBN and an increase in IKZF1 gene expression. No mutations were observed in CRBN, IKZF1, or CUL4A genes in the post‐Ld samples. In conclusion, a decreased expression of IKZF1 and increased expression of KPNA2 compared to that of CRBN mRNA predicts poor outcomes of Ld therapy.
Novel Abs targeting the N‐terminus of fibroblast growth factor 19 inhibit hepatocellular carcinoma growth without bile‐acid‐related side‐effects
Authors: Liu Huisi , Zheng Sanduo , Hou Xinfeng , Liu Ximing , Du Kaixin , Lv Xueyuan , Li Yulu , Yang Fang , Li Wenhui , Sui Jianhua 
Published: February 2020

AbstractHepatocellular carcinoma (HCC) is a common and particularly fatal form of cancer for which very few drugs are effective. The fibroblast growth factor 19 (FGF19) has been viewed as a driver of HCC development and a potential Ab target for developing novel HCC therapy. However, a previously developed anti‐FGF19 Ab disrupted FGF19’s normal regulatory function and caused severe bile‐acid‐related side‐effects despite of having potent antitumor effects in preclinical models. Here, we developed novel human Abs (G1A8 and HS29) that specifically target the N‐terminus of FGF19. Both Abs inhibited FGF19‐induced HCC cell proliferation in vitro and significantly suppressed HCC tumor growth in mouse models. Importantly, no bile‐acid‐related side effects were observed in preclinical cynomolgus monkeys. Fundamentally, our study demonstrates that it is possible to target FGF19 for anti‐HCC therapies without adversely affecting its normal bile acid regulatory function, and highlights the exciting promise of G1A8 or HS29 as potential therapy for HCC.