bluuebunny/crossref_metadata_2025_split huggingface dataset:
Repository corticotrophin injection exerts direct acute effects on human B cell gene expression distinct from the actions of glucocorticoids
Authors: Benko A L , McAloose C A , Becker P M , Wright D , Sunyer T , Kawasawa Y I , Olsen N J , Kovacs W J 
Published: December 2017

SummaryRepository corticotrophin injection (RCI, H.P Acthar® gel) has been approved for use in the management of multiple autoimmune and inflammatory diseases for more than a half-century, but its mechanism of action is not well understood. We used RNA-Seq methods to define RCI-regulated mRNAs in cultured human B cells under conditions of activation by interleukin (IL)-4 and CD40 ligand. Following IL-4/CD40L activation and RCI treatment we found up-regulation of 115 unique mRNA transcripts and down-regulation of 80 unique mRNAs. The effect on these RNA levels was dose-dependent for RCI and was distinct from changes in mRNA expression induced by treatment with a potent synthetic glucocorticoid. RCI down-regulated mRNAs were observed to include a significant over-representation of genes critical for B cell proliferation under activating conditions. These data confirm that RCI exerts direct effects on human B cells to modulate mRNA expression in specific pathways of importance to B cell function and that, at the molecular level, the effects of RCI are distinct from those exerted by glucocorticoids.
Multidisciplinary management of refractory insulinomas
Authors: Brown Emily , Watkin Daniel , Evans Jonathan , Yip Vincent , Cuthbertson Daniel J. 
Published: December 2017

SummaryInsulinomas are predominantly benign (~90%), pancreatic neuroendocrine tumours characterized by hyperinsulinaemic hypoglycaemia. They usually present as a small (<2 cm), well‐demarcated, solitary nodule that can arise in any part of the organ. Treatment for sporadic insulinomas is generally aimed at curative surgical resection with special consideration in genetic syndromes. Patients with significant hypoglycaemia can pose a difficult management challenge. In isolated cases where the patient is not medically fit for surgery or with metastatic spread, other treatment options are employed. Medical therapy with diazoxide or somatostatin analogues is commonly used first line for symptom control, albeit with variable efficacy. Other medical options are emerging, including newer targeted biological therapies, including everolimus (an mTOR inhibitor), sunitinib (a tyrosine kinase inhibitor) and pasireotide, a multisomatostatin receptor ligand. Pasireotide and everolimus both cause hyperglycaemia by physiological mechanisms synergistic with its antitumour/antiproliferative effects. Minimally invasive treatment modalities such as ethanol ablation are available in selected cases (particularly in patients unfit for surgery), peptide receptor radionuclide therapy (PRRT) can effectively control tumour growth or provide symptomatic benefit in metastatic disease, while cytotoxic chemotherapy can be used in patients with higher‐grade tumours. This review considers the developments in the medical and other nonsurgical management options for cases refractory to standard medical management. Early referral to a dedicated neuroendocrine multidisciplinary team is critical considering the array of medical, oncological, interventional radiological and nuclear medical options. We discuss the evolving armamentarium for insulinomas when standard medical therapy fails.
Retinal pigment epithelium in the pathogenesis of age‐related macular degeneration and photobiomodulation as a potential therapy?
Authors: Ao Jack , Wood John PM , Chidlow Glyn , Gillies Mark C , Casson Robert J 
Published: December 2017

AbstractThe retinal pigment epithelium (RPE) comprises a monolayer of cells located between the neuroretina and the choriocapillaries. The RPE serves several important functions in the eye: formation of the blood‐retinal barrier, protection of the retina from oxidative stress, nutrient delivery and waste disposal, ionic homeostasis, phagocytosis of photoreceptor outer segments, synthesis and release of growth factors, reisomerization of all‐trans‐retinal during the visual cycle, and establishment of ocular immune privilege. Age‐related macular degeneration (AMD) is the leading cause of blindness in developed countries. Dysfunction of the RPE has been associated with the pathogenesis of AMD in relation to increased oxidative stress, mitochondrial destabilization and complement dysregulation. Photobiomodulation or near infrared light therapy which refers to non‐invasive irradiation of tissue with light in the far‐red to near‐infrared light spectrum (630–1000 nm), is an intervention that specifically targets key mechanisms of RPE dysfunction that are implicated in AMD pathogenesis. The current evidence for the efficacy of photobiomodulation in AMD is poor but its safety profile and proposed mechanisms of action motivate further research as a novel therapy for AMD.
Monocarboxylate transporter 1 and the vulnerability of oligodendrocyte lineage cells to metabolic stresses
Authors: Zhou Peng , Guan Teng , Jiang Zhao , Namaka Mike , Huang Qing‐Jun , Kong Ji‐Ming 
Published: December 2017

SummaryAimsOligodendrocytes, especially oligodendrocyte precursor cells, are known to be sensitive to hypoxic and metabolic stresses. Vulnerability of oligodendrocytes is considered a contributing factor to white matter dysfunction. However, little is known about the energy processing characteristics of oligodendrocyte lineage cells under basal and metabolic stress conditions. The aim of this study was to identify the energy requirements and cellular responses of oligodendrocytes at different developmental stages.MethodsWe compared the metabolic stress responses between myelinating oligodendrocytes (OLs) and oligodendrocyte precursor cells (OPCs). Differential regulation of cellular response was also investigated.ResultsWe found that, following cerebral ischemia, monocarboxylate transporter 1 (MCT1) expression was upregulated in the peri‐infarct striatum but not in the cortex of the brain. In vitro ischemia models were used to induce oligodendrocyte stress as well. An increase in MCT1 expression was detected in OPCs after a mild oxygen‐glucose deprivation. Double‐labeled immunohistochemical analysis revealed that OPCs and OLs responded differently to metabolic stresses and that the susceptibility to metabolic stresses of OPCs and OLs was associated with their distinct expression profiles of MCT1.ConclusionTaken together, this study shows that MCT1 plays a role in the responses of OPCs and OLs to metabolic and ischemic stresses and suggests that redistribution of energy substrates is a determinant in white matter injury.
Higher spring temperatures increase food scarcity and limit the current and future distributions of crossbills
Authors: Mezquida Eduardo T. , Svenning Jens‐Christian , Summers Ron W. , Benkman Craig W. 
Published: December 2017

AbstractAimUnderstanding how climate affects species distributions remains a major challenge, with the relative importance of direct physiological effects versus biotic interactions still poorly understood. We focus on three species of resource specialists (crossbill Loxia finches) to assess the role of climate in determining the seasonal availability of their food, the importance of climate and the occurrence of their food plants for explaining their current distributions, and to predict changes in their distributions under future climate change scenarios.LocationEurope.MethodsWe used datasets on the timing of seed fall in European Scots pine Pinus sylvestris forests (where different crossbill species occur) to estimate seed fall phenology and climate data to determine its influence on spatial and temporal variation in the timing of seed fall to provide a link between climate and seed scarcity for crossbills. We used large‐scale datasets on crossbill distribution, cover of the conifers relied on by the three crossbill species and climate variables associated with timing of seed fall, to assess their relative importance for predicting crossbill distributions. We used species distribution modelling to predict changes in their distributions under climate change projections for 2070.ResultsWe found that seed fall occurred 1.5–2 months earlier in southern Europe than in Sweden and Scotland and was associated with variation in spring maximum temperatures and precipitation. These climate variables and area covered with conifers relied on by the crossbills explained much of their observed distributions. Projections under global change scenarios revealed reductions in potential crossbill distributions, especially for parrot crossbills.Main conclusionsRanges of resource specialists are directly influenced by the presence of their food plants, with climate conditions further affecting resource availability and the window of food scarcity indirectly. Future distributions will be determined by tree responses to changing climatic conditions and the impact of climate on seed fall phenology.
Clinical correlates of hypoglycaemia over 4 years in people with type 2 diabetes starting insulin: An analysis from the CREDIT study
Authors: Home Philip , Calvi‐Gries Francoise , Blonde Lawrence , Pilorget Valerie , Berlingieri Joseph , Freemantle Nick 
Published: December 2017

AimTo identify factors associated with documented symptomatic and severe hypoglycaemia over 4 years in people with type 2 diabetes starting insulin therapy.Materials and methodsCREDIT, a prospective international observational study, collected data over 4 years on people starting any insulin in 314 centres; 2729 and 2271 people had hypoglycaemia data during the last 6 months of years 1 and 4, respectively. Multivariable logistic regression was used to select the characteristics associated with documented symptomatic hypoglycaemia, and the model was tested against severe hypoglycaemia.ResultsThe proportions of participants reporting ≥1 non‐severe event were 18.5% and 16.6% in years 1 and 4; the corresponding proportions of those achieving a glycated haemoglobin (HbA1c) concentration <7.0% (<53 mmol/mol) were 24.6% and 18.3%, and 16.5% and 16.2% of those who did not. For severe hypoglycaemia, the proportions were 3.0% and 4.6% of people reaching target vs 1.5% and 1.1% of those not reaching target. Multivariable analysis showed that, for documented symptomatic hypoglycaemia at both years 1 and 4, baseline lower body mass index and more physical activity were predictors, and lower HbA1c was an explanatory variable in the respective year. Models for documented symptomatic hypoglycaemia predicted severe hypoglycaemia. Insulin regimen was a univariate explanatory variable, and was not retained in the multivariable analysis.ConclusionsHypoglycaemia occurred at significant rates, but was stable over 4 years despite increased insulin doses. The association with insulin regimen and with oral agent use declined over that time. Associated predictors and explanatory variables for documented symptomatic hypoglycaemia conformed to clinical impressions and could be extended to severe hypoglycaemia. Better achieved HbA1c was associated with a higher risk of hypoglycaemia.
LH‐21 and abnormal cannabidiol improve β‐cell function in isolated human and mouse islets through GPR55‐dependent and ‐independent signalling
Authors: Ruz‐Maldonado Inmaculada , Pingitore Attilio , Liu Bo , Atanes Patricio , Huang Guo Cai , Baker David , Alonso Francisco José , Bermúdez‐Silva Francisco Javier , Persaud Shanta J. 
Published: December 2017

AimsTo examine the effects of Abn‐CBD (GPR55 agonist) and LH‐21 (CB1 antagonist) on human and mouse islet function, and to determine signalling via GPR55 using islets from GPR55−/− mice.Materials and methodsIslets isolated from human organ donors and mice were incubated in the absence or presence of Abn‐CBD or LH‐21, and insulin secretion, [Ca2+]i, cAMP, apoptosis, β‐cell proliferation and CREB and AKT phosphorylation were examined using standard techniques.ResultsAbn‐CBD potentiated glucose‐stimulated insulin secretion and elevated [Ca2+]i in human islets and islets from both GPR55+/+ and GPR55−/− mice. LH‐21 also increased insulin secretion and [Ca2+]i in human islets and GPR55+/+ mouse islets, but concentrations of LH‐21 up to 0.1 μM were ineffective in islets from GPR55−/− mice. Neither ligand affected basal insulin secretion or islet cAMP levels. Abn‐CBD and LH‐21 reduced cytokine‐induced apoptosis in human islets and GPR55+/+ mouse islets, and these effects were suppressed after GPR55 deletion. They also increased β‐cell proliferation: the effects of Abn‐CBD were preserved in islets from GPR55−/− mice, while those of LH‐21 were abolished. Abn‐CBD and LH‐21 increased AKT phosphorylation in mouse and human islets.ConclusionsThis study showed that Abn‐CBD and LH‐21 improve human and mouse islet β‐cell function and viability. Use of islets from GPR55−/− mice suggests that designation of Abn‐CBD and LH‐21 as a GPR55 agonist and a CB1 antagonist, should be revised.
Plasma proprotein‐convertase‐subtilisin/kexin type 9 (PCSK9) and cardiovascular events in type 2 diabetes
Authors: El Khoury Petra , Roussel Ronan , Fumeron Frederic , Abou‐Khalil Yara , Velho Gilberto , Mohammedi Kamel , Jacob Marie‐Paule , Steg Philippe Gabriel , Potier Louis , Ghaleb Youmna , Elbitar Sandy , Ragot Stephanie , Andreata Francesco , Caligiuri Giusepinna , Hadjadj Samy , Boileau Catherine , Marre Michel , Abifadel Marianne , Varret Mathilde , Hansel Boris 
Published: December 2017

AimTo investigate whether plasma concentrations of proprotein‐convertase‐subtilisin/kexin type 9 (PCSK9) were associated with cardiovascular (CV) events in two cohorts of patients with type 2 diabetes mellitus.MethodsWe considered patients from the DIABHYCAR (n = 3137) and the SURDIAGENE (n = 1468) studies. Baseline plasma PCSK9 concentration was measured using an immunofluorescence assay. In post hoc, but preplanned, analyses we assessed the relationship between PCSK9 and the following endpoints: (1) a combined endpoint of major CV events: CV death, non‐fatal myocardial infarction (MI), stroke and heart failure‐related hospital admission; (2) a composite of all CV events: MI, stroke, heart failure‐related hospital admission, coronary/peripheral angioplasty or bypass, CV death; (3) MI; (4) stroke/transient ischaemic attack (TIA); and (5) CV death.ResultsIn the DIABHYCAR study, plasma PCSK9 tertiles were associated with the incidence of MI, all CV events and stroke/TIA (P for trend <.05). In adjusted Cox analysis, plasma PCSK9 was associated, independently of classic risk factors, with the incidence of major CV events (hazard ratio [HR] for 1‐unit increase of log[PCSK9] 1.28 [95% confidence interval {CI} 1.06‐1.55]), the incidence of MI (HR 1.66 [95% CI 1.05‐2.63]), and the incidence of all CV events (HR 1.22 [95% CI 1.04‐1.44]), but not with CV death. Plasma PCSK9 was not associated with the incidence of CV disease in the participants of the SURDIAGENE study with high CV risk treated with statins and insulin.ConclusionsWe found that PCSK9 was inconsistently associated with CV events in populations with type 2 diabetes. The association may depend on the level of CV risk and the background treatment.
Claims‐based studies of oral glucose‐lowering medications can achieve balance in critical clinical variables only observed in electronic health records
Authors: Patorno Elisabetta , Gopalakrishnan Chandrasekar , Franklin Jessica M. , Brodovicz Kimberly G. , Masso‐Gonzalez Elvira , Bartels Dorothee B. , Liu Jun , Schneeweiss Sebastian 
Published: December 2017

AimTo evaluate the extent to which balance in unmeasured characteristics of patients with type 2 diabetes (T2DM) was achieved in claims data, by comparing against more detailed information from linked electronic health records (EHR) data.MethodsWithin a large US commercial insurance database and using a cohort design, we identified patients with T2DM initiating linagliptin or a comparator agent within class (ie, another dipeptidyl peptidase‐4 inhibitor) or outside class (ie, pioglitazone or a sulphonylurea) between May 2011 and December 2012. We focused on comparators used at a similar stage of diabetes to linagliptin. For each comparison, 1:1 propensity score (PS) matching was used to balance >100 baseline claims‐based characteristics, including proxies of diabetes severity and duration. Additional clinical data from EHR were available for a subset of patients. We assessed representativeness of the claims–EHR‐linked subset, evaluated the balance of claims‐ and EHR‐based covariates before and after PS‐matching via standardized differences (SDs), and quantified the potential bias associated with observed imbalances.ResultsFrom a claims‐based study population of 166 613 patients with T2DM, 7219 (4.3%) patients were linked to their EHR data. Claims‐based characteristics in the EHR‐linked and EHR‐unlinked patients were similar (SD < 0.1), confirming the representativeness of the EHR‐linked subset. The balance of claims‐based and EHR‐based patient characteristics appeared to be reasonable before PS‐matching and generally improved in the PS‐matched population, to be SD < 0.1 for most patient characteristics and SD < 0.2 for select laboratory results and body mass index categories, which was not large enough to cause meaningful confounding.ConclusionIn the context of pharmacoepidemiological research on diabetes therapy, choosing appropriate comparison groups paired with a new‐user design and 1:1 PS matching on many proxies of diabetes severity and duration improves balance in covariates typically unmeasured in administrative claims datasets, to the extent that residual confounding is unlikely.
Silicon‐mediated resistance against specialist insects in sap‐sucking and leaf‐chewing guilds in the Si non‐accumulator collard
Authors: Teixeira Natália C. , Valim Janete Oliveira S. , Campos Wellington G. 
Published: December 2017

AbstractSoil amendment with Silicon (Si) can increase plant resistance against insect herbivores, but the underlying mechanisms remain unclear. The mechanical resistance hypothesis (MRH) states that Si accumulated in epidermal cells directly and passively protects against herbivores by creating a mechanical barrier. The physiological resistance hypothesis (PRH) states that Si enhances resistance by activating plant biochemical and physiological processes. We tested both hypotheses by manipulating Si fertilization of the Si non‐accumulator collard, Brassica oleracea L. cv. acephala (Brassicaceae). Then, we assessed functional and ultrastructural plant responses and the developmental and reproductive performance of the leaf‐chewing larvae of the diamondback moth, Plutella xylostella L. (Lepidoptera: Plutellidae), and the sap‐sucking cabbage aphid, Brevicoryne brassicae L. (Hemiptera: Aphididae). There was a 20% increase in leaf Si content. Silicon deposition in epidermal cells was identified by confocal microscopy and directly coincided with lower performance of P. xylostella, but did not affect B. brassicae. On the other hand, we found no unequivocal evidence that Si‐mediated changes in primary and secondary metabolism improved plant resistance against the insects. Negative mechanical effects of Si on the insects may have masked beneficial effects of increased water, nitrogen, and mineral contents in Si‐treated collards. Silicon did not change leaf contents of hemicellulose, cellulose, and lignin. Although Si‐mediated increases in leaf glucosinolates (GLS) correlated with lower larval performance and higher oviposition preference of P. xylostella, both P. xylostella and B. brassicae are highly specialized in overcoming such secondary metabolites. Thus, mechanical resistance may have impaired P. xylostella, rather than the Si‐mediated increase in GLS. We suggest that the PRH may depend on the degree of insect feeding specialization, so that toxic Si‐mediated defenses may be more efficient against unadapted polyphagous herbivores. For them, a toxic barrier may be added to the mechanical resistance.
Different pre‐scanning instructions induce distinct psychological and resting brain states during functional magnetic resonance imaging
Authors: Kawagoe Toshikazu , Onoda Keiichi , Yamaguchi Shuhei 
Published: December 2017

AbstractResting‐state functional magnetic resonance imaging (rs‐fMRI) is widely used to investigate functional brain network connectivity during rest or when the subject is not performing an explicit task. In the standard procedure, subjects are instructed to ‘let your mind wander’ or ‘think of nothing’. While these instructions appear appropriate to induce a ‘resting‐state’, they could induce distinct psychological and physiological states during the scan. In this study, we investigated whether different instructions affect mental state and functional connectivity (FC) (i.e. induce distinct ‘resting states’) during rs‐fMRI scanning. Thirty healthy subjects were subjected to two rs‐fMRI scans differing only in pre‐scan instructions: think of nothing (TN) and mind‐wandering (MW) conditions. Self‐reports confirmed that subjects spent the majority of the scanning time in the appropriate mental state. Independent component analysis extracted 19 independent components (ICs) of interest and functional network connectivity analyses indicated several conditional differences in FCs among those ICs, especially characterised by stronger FC in the MW condition than in the TN condition, between default mode network and salience/visual/frontal network. Complementary correlation analysis indicated that some of the network FCs were significantly correlated with their self‐reported data on how often they had the TN condition during the scans. The present results provide evidence that the pre‐scan instruction has a significant influence on resting‐state FC and its relationship with mental activities.
Machine learning for decoding listeners’ attention from electroencephalography evoked by continuous speech
Authors: de Taillez Tobias , Kollmeier Birger , Meyer Bernd T. 
Published: December 2017

AbstractPrevious research has shown that it is possible to predict which speaker is attended in a multispeaker scene by analyzing a listener's electroencephalography (EEG) activity. In this study, existing linear models that learn the mapping from neural activity to an attended speech envelope are replaced by a non‐linear neural network (NN). The proposed architecture takes into account the temporal context of the estimated envelope and is evaluated using EEG data obtained from 20 normal‐hearing listeners who focused on one speaker in a two‐speaker setting. The network is optimized with respect to the frequency range and the temporal segmentation of the EEG input, as well as the cost function used to estimate the model parameters. To identify the salient cues involved in auditory attention, a relevance algorithm is applied that highlights the electrode signals most important for attention decoding. In contrast to linear approaches, the NN profits from a wider EEG frequency range (1–32 Hz) and achieves a performance seven times higher than the linear baseline. Relevant EEG activations following the speech stimulus after 170 ms at physiologically plausible locations were found. This was not observed when the model was trained on the unattended speaker. Our findings therefore indicate that non‐linear NNs can provide insight into physiological processes by analyzing EEG activity.