bluuebunny/crossref_metadata_2025_split huggingface dataset:
Loss of Dfg5 glycosylphosphatidylinositol‐anchored membrane protein confers enhanced heat tolerance in Saccharomyces cerevisiae
Authors: Nasution Olviyani , Lee Jaok , Srinivasa Kavitha , Choi In‐Geol , Lee Young Mi , Kim Eunjung , Choi Wonja , Kim Wankee 
Published: October 2014

SummaryThe protein product of Saccharomyces cerevisiae DFG5 gene is a glycosylphosphatidylinositol (GPI)‐anchored plasma membrane protein and a putative glycosidase/glycosyltransferase that links other GPI‐anchored proteins to β‐glucans in the cell wall. Upon exposure to heat (41°C), DFG5 deletion mutant dfg5Δ displayed significantly enhanced heat tolerance as well as lowered level of reactive oxygen species and decreased membrane permeability compared with those in the control (BY4741). Comparative transcriptome profiles of BY4741 and dfg5Δ revealed that 38 and 23 genes were up‐ and down‐regulated in dfg5Δ respectively. Of the 23 down‐regulated genes, 11 of 13 viable deletion mutants were identified to be tolerant to heat, suggesting that the down‐regulation of those genes might have contributed to the enhanced heat tolerance in dfg5Δ. Deletion of DFG5 caused slight activation of mitogen‐activated protein kinases Hog1 in the high‐osmolarity glycerol pathway and Slt2 in the cell wall integrity pathway. Therefore, a model is proposed on the signal transduction pathways associated with deletion of DFG5 upon heat stress.
Treatment and prognostic analysis of patients with leptomeningeal metastases from non‐small cell lung cancer
Authors: Xu Qinghua , Chen Xiu , Qian Danwen , Wang Yongsheng , Meng Shuyan , Liu Hui , Zhou Caicun 
Published: October 2014

AbstractBackgroundLeptomeningeal metastases (LM) from non‐small cell lung cancer (NSCLC) are associated with poor prognosis and optimal treatment for this subgroup of NSCLC patients is controversial. The purpose of this study is to evaluate treatment options and prognostic factors of NSCLC patients with LM.MethodsWe retrospectively analyzed data of 108 patients who had been diagnosed with LM from NSCLC between May 2006 and August 2013.ResultsThe median survival time (MST) of the 108 patients was 5.3 months, and the one‐year survival rate was 23.7%. Forty‐nine patients received whole brain radiotherapy (WBRT) and the MST of patients who received WBRT and those who did not were 6.4 and 4.3 months, respectively. Forty‐two patients were treated with epidermal growth factor receptor‐tyrosine kinase inhibitors (EGFR‐TKIs) after being diagnosed with LM. These patients had prolonged survival (11.1 vs. 4.4 months). Patients who received concomitant WBRT and EGFR‐TKIs had the longest MST (12.3 months). Eastern Cooperative Oncology Group performance status, whether patients received WBRT, and/or EGFR‐TKIs were independent prognostic factors for patients with LM from NSCLC.ConclusionWBRT, EGFR‐TKIs or combined therapy, could lead to better clinical outcomes for NSCLC patients with LM. EGFR‐TKIs plus WBRT has the potential to be the standard strategy for LM in NSCLC patients.
A method for calculating minimum biodiversity offset multipliers accounting for time discounting, additionality and permanence
Authors: Laitila Jussi , Moilanen Atte , Pouzols Federico M. 
Published: October 2014

Summary
Biodiversity offsetting, which means compensation for ecological and environmental damage caused by development activity, has recently been gaining strong political support around the world. One common criticism levelled at offsets is that they exchange certain and almost immediate losses for uncertain future gains. In the case of restoration offsets, gains may be realized after a time delay of decades, and with considerable uncertainty.
Here we focus on offset multipliers, which are ratios between damaged and compensated amounts (areas) of biodiversity. Multipliers have the attraction of being an easily understandable way of deciding the amount of offsetting needed. On the other hand, exact values of multipliers are very difficult to compute in practice if at all possible.
We introduce a mathematical method for deriving minimum levels for offset multipliers under the assumption that offsetting gains must compensate for the losses (no net loss offsetting). We calculate absolute minimum multipliers that arise from time discounting and delayed emergence of offsetting gains for a one‐dimensional measure of biodiversity. Despite the highly simplified model, we show that even the absolute minimum multipliers may easily be quite large, in the order of dozens, and theoretically arbitrarily large, contradicting the relatively low multipliers found in literature and in practice.
While our results inform policy makers about realistic minimal offsetting requirements, they also challenge many current policies and show the importance of rigorous models for computing (minimum) offset multipliers. The strength of the presented method is that it requires minimal underlying information. We include a supplementary spreadsheet tool for calculating multipliers to facilitate application.
Recent advances and future directions in targeting the secretory apparatus in multiple myeloma
Authors: Auner Holger W. , Cenci Simone 
Published: October 2014

SummaryMultiple myeloma is a genetically heterogeneous tumour of transformed plasma cells, terminally differentiated effectors of the B cell lineage specialized in producing large amounts of immunoglobulins. The uniquely well‐developed secretory apparatus that equips normal and transformed plasma cells with the capacity for high‐level protein secretion constitutes a distinctive therapeutic target. In this review we discuss how fundamental cellular processes, such as the unfolded protein response (UPR), endoplasmic reticulum (ER)‐associated degradation and autophagy, maintain intracellular protein homeostasis (proteostasis) and regulate plasma cell ontogeny and malignancy. We summarize our current understanding of the cellular effects of proteasome inhibitors and the molecular bases of resistance to them. Furthermore, we discuss how improvements in our understanding of the secretory apparatus and of the complex interactions between intracellular protein synthesis and degradation pathways can disclose novel drug targets for multiple myeloma, defining a paradigm of general interest for cancer biology and disorders of altered proteostasis.
CardiacNOsignalling in the metabolic syndrome
Authors: Pechánová O , Varga Z V , Cebová M , Giricz Z , Pacher P , Ferdinandy P 
Published: October 2014

It is well documented that metabolic syndrome (i.e. a group of risk factors, such as abdominal obesity, elevated blood pressure, elevated fasting plasma glucose, high serum triglycerides and low cholesterol level in high‐density lipoprotein), which raises the risk for heart disease and diabetes, is associated with increased reactive oxygen and nitrogen species (ROS/RNS) generation.ROS/RNScan modulate cardiacNOsignalling and trigger various adaptive changes inNOS and antioxidant enzyme expressions/activities. While initially these changes may represent protective mechanisms in metabolic syndrome, later with more prolonged oxidative, nitrosative and nitrative stress, these are often exhausted, eventually favouring myocardialRNSgeneration and decreasedNObioavailability. The increased oxidative and nitrative stress also impairs theNO‐soluble guanylate cyclase (sGC) signalling pathway, limiting the ability ofNOto exert its fundamental signalling roles in the heart. EnhancedROS/RNSgeneration in the presence of risk factors also facilitates activation of redox‐dependent transcriptional factors such asNF‐κB, promoting myocardial expression of various pro‐inflammatory mediators, and eventually the development of cardiac dysfunction and remodelling. While the dysregulation ofNOsignalling may interfere with the therapeutic efficacy of conventional drugs used in the management of metabolic syndrome, the modulation ofNOsignalling may also be responsible for the therapeutic benefits of already proven or recently developed treatment approaches, such asACEinhibitors, certain β‐blockers, andsGCactivators. Better understanding of the above‐mentioned pathological processes may ultimately lead to more successful therapeutic approaches to overcome metabolic syndrome and its pathological consequences in cardiacNOsignalling.Linked ArticlesThis article is part of a themed section on Pharmacology of the Gasotransmitters. To view the other articles in this section visithttp://dx.doi.org/10.1111/bph.2015.172.issue-6
Kv11.1 (hERG)‐induced cardiotoxicity: a molecular insight from a binding kinetics study of prototypical Kv11.1 (hERG) inhibitors
Authors: Yu Z , IJzerman A P , Heitman L H 
Published: October 2014

Background and PurposeDrug‐induced arrhythmia due to blockade of the Kv11.1 channel (also known as the hERG K+ channel) is a frequent side effect. Previous studies have primarily focused on equilibrium parameters, i.e. affinity or potency, of drug candidates at the channel. The aim of this study was to determine the kinetics of the interaction with the channel for a number of known Kv11.1 blockers and to explore a possible correlation with the affinity or physicochemical properties of these compounds.Experimental ApproachThe affinity and kinetic parameters of 15 prototypical Kv11.1 inhibitors were evaluated in a number of [3H]‐dofetilide binding assays. The lipophilicity (logKW‐C8) and membrane partitioning (logKW‐IAM) of these compounds were determined by means of HPLC analysis.Key ResultsA novel [3H]‐dofetilide competition association assay was set up and validated, which allowed us to determine the binding kinetics of the Kv11.1 blockers used in this study. Interestingly, the compounds' affinities (Ki values) were correlated to their association rates rather than dissociation rates. Overall lipophilicity or membrane partitioning of the compounds were not correlated to their affinity or rate constants for the channel.Conclusions and ImplicationsA compound's affinity for the Kv11.1 channel is determined by its rate of association with the channel, while overall lipophilicity and membrane affinity are not. In more general terms, our findings provide novel insights into the mechanism of action for a compound's activity at the Kv11.1 channel. This may help to elucidate how Kv11.1‐induced cardiotoxicity is governed and how it can be circumvented in the future.
The effects of microRNA on the absorption, distribution, metabolism and excretion of drugs
Authors: He Y , Chevillet J R , Liu G , Kim T K , Wang K 
Published: October 2014

The importance of genetic factors (e.g. sequence variation) in the absorption, distribution, metabolism, excretion (ADME) and overall efficacy of therapeutic agents is well established. Our ability to identify, interpret and utilize these factors is the subject of much clinical investigation and therapeutic development. However, drug ADME and efficacy are also heavily influenced by epigenetic factors such as DNA/histone methylation and non‐coding RNAs [especially microRNAs (miRNAs)]. Results from studies using tools, such as in silico miRNA target prediction, in vitro functional assays, nucleic acid profiling/sequencing and high‐throughput proteomics, are rapidly expanding our knowledge of these factors and their effects on drug metabolism. Although these studies reveal a complex regulation of drug ADME, an increased understanding of the molecular interplay between the genome, epigenome and transcriptome has the potential to provide practically useful strategies to facilitate drug development, optimize therapeutic efficacy, circumvent adverse effects, yield novel diagnostics and ultimately become an integral component of personalized medicine.Linked ArticlesThis article is part of a themed section on Epigenetics and Therapy. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue‐11
Molecular mechanisms governing different pharmacokinetics of ginsenosides and potential for ginsenoside‐perpetrated herb–drug interactions on OATP1B3
Authors: Jiang Rongrong , Dong Jiajia , Li Xiuxue , Du Feifei , Jia Weiwei , Xu Fang , Wang Fengqing , Yang Junling , Niu Wei , Li Chuan 
Published: October 2014

Background and PurposeGinsenosides are bioactive saponins derived from Panax notoginseng roots (Sanqi) and ginseng. Here, the molecular mechanisms governing differential pharmacokinetics of 20(S)‐protopanaxatriol‐type ginsenoside Rg1, ginsenoside Re and notoginsenoside R1 and 20(S)‐protopanaxadiol‐type ginsenosides Rb1, Rc and Rd were elucidated.Experimental ApproachInteractions of ginsenosides with human and rat hepatobiliary transporters were characterized at the cellular and vesicular levels. A rifampin‐based inhibition study in rats evaluated the in vivo role of organic anion‐transporting polypeptide (Oatp)1b2. Plasma protein binding was assessed by equilibrium dialysis. Drug–drug interaction indices were calculated to estimate potential for clinically relevant ginsenoside‐mediated interactions due to inhibition of human OATP1Bs.Key ResultsAll the ginsenosides were bound to human OATP1B3 and rat Oatp1b2 but only the 20(S)‐protopanaxatriol‐type ginsenosides were transported. Human multidrug resistance‐associated protein (MRP)2/breast cancer resistance protein (BCRP)/bile salt export pump (BSEP)/multidrug resistance protein‐1 and rat Mrp2/Bcrp/Bsep also mediated the transport of the 20(S)‐protopanaxatriol‐type ginsenosides. Glomerular‐filtration‐based renal excretion of the 20(S)‐protopanaxatriol‐type ginsenosides was greater than that of the 20(S)‐protopanaxadiol‐type counterparts due to differences in plasma protein binding. Rifampin‐impaired hepatobiliary excretion of the 20(S)‐protopanaxatriol‐type ginsenosides was effectively compensated by the renal excretion in rats. The 20(S)‐protopanaxadiol‐type ginsenosides were potent inhibitors of OATP1B3.Conclusion and ImplicationsDifferences in hepatobiliary and in renal excretory clearances caused markedly different systemic exposure and different elimination kinetics between the two types of ginsenosides. Caution should be exercised with the long‐circulating 20(S)‐protopanaxadiol‐type ginsenosides as they could induce hepatobiliary herb–drug interactions, particularly when patients receive long‐term therapies with high‐dose i.v. Sanqi or ginseng extracts.
Support and monitoring of families after child abuse detection based on parental characteristics at the Emergency Department
Authors: Diderich H. M. , Pannebakker F. D. , Dechesne M. , Buitendijk S. E. , Oudesluys‐Murphy A. M. 
Published: October 2014

AbstractBackgroundThe ‘Hague Protocol’ enables professionals at the adult Emergency Department (ED) to detect child abuse based on three parental characteristics: (i) suicide attempt or self‐harm, (ii) domestic violence or (iii) substance abuse, and to refer them to the Reporting Centre for Child Abuse and Neglect (RCCAN). This study investigates what had happened to the families three months after this referral.MethodED referrals based on parental characteristics (N = 100) in which child abuse was confirmed after investigation by the RCCAN were analysed. Information was collected regarding type of child abuse, reason for reporting, duration of problems prior to the ED referral, previous involvement of support services or other agencies, re‐occurrence of the problems and outcome of the RCCAN monitoring according to professionals and the families.ResultsOf the 100 referred cases, 68 families were already known to the RCCAN, the police or family support services, prior to the ED referral. Of the 99 cases where information was available, existing support was continued or intensified in 31, a Child Protection Services (CPS) report had to be made in 24, new support was organized for 27 cases and in 17 cases support was not necessary, because the domestic problems were already resolved. Even though the RCCAN is mandated to monitor all referred families after three months, 31 cases which were referred internally were not followed up.ConclusionBefore referral by the ED two thirds of these families were already known to organizations. Monitoring may help provide a better, more sustained service and prevent and resolve domestic problems. A national database could help to link data and to streamline care for victims and families. We recommend a Randomized Controlled Trial to test the effectiveness of this Protocol in combination with the outcomes of the provided family support.
Suspected flunixin poisoning of a wild Eurasian Griffon Vulture from Spain
Authors: Zorrilla Irene , Martinez Rosa , Taggart Mark A. , Richards Ngaio 
Published: October 2014

AbstractExposure to residues of the nonsteroidal anti‐inflammatory drug (NSAID) diclofenac present in livestock carcasses has caused extensive declines in 3 Gyps vulture species across Asia. The carcass of a wild Eurasian Griffon Vulture (Gyps fulvus) was found in 2012 on an Andalucian (Spain) game hunting reserve and examined forensically. The bird had severe visceral gout, a finding consistent with Gyps vultures from Asia that have been poisoned by diclofenac. Liver and kidney samples from this Eurasian Griffon Vulture contained elevated flunixin (an NSAID) levels (median = 2.70 and 6.50 mg/kg, respectively). This is the first reported case of a wild vulture being exposed to and apparently killed by an NSAID outside Asia. It is also the first reported instance of mortality in the wild resulting from environmental exposure to an NSAID other than diclofenac.Caso de Sospecha de Envenenamiento por Flunixin de un Buitre Leonado en España
Children's Developing Intuitions About the Truth Conditions and Implications of Novel Generics Versus Quantified Statements
Authors: Brandone Amanda C. , Gelman Susan A. , Hedglen Jenna 
Published: October 2014

AbstractGeneric statements express generalizations about categories and present a unique semantic profile that is distinct from quantified statements. This paper reports two studies examining the development of children's intuitions about the semantics of generics and how they differ from statements quantified byall,most, andsome. Results reveal that, like adults, preschoolers (a) recognize that generics have flexible truth conditions and are capable of representing a wide range of prevalence levels; and (b) interpret novel generics as having near‐universal prevalence implications. Results further show that by age 4, children are beginning to differentiate the meaning of generics and quantified statements; however, even 7‐ to 11‐year‐olds are not adultlike in their intuitions about the meaning ofmost‐quantified statements. Overall, these studies suggest that by preschool, children interpret generics in much the same way that adults do; however, mastery of the semantics of quantified statements follows a more protracted course.
Is Probabilistic Evidence a Source of Knowledge?
Authors: Friedman Ori , Turri John 
Published: October 2014

AbstractWe report a series of experiments examining whether people ascribe knowledge for true beliefs based on probabilistic evidence. Participants were less likely to ascribe knowledge for beliefs based on probabilistic evidence than for beliefs based on perceptual evidence (Experiments 1 and 2A) or testimony providing causal information (Experiment 2B). Denial of knowledge for beliefs based on probabilistic evidence did not arise because participants viewed such beliefs as unjustified, nor because such beliefs leave open the possibility of error. These findings rule out traditional philosophical accounts for why probabilistic evidence does not produce knowledge. The experiments instead suggest that people deny knowledge because they distrust drawing conclusions about an individual based on reasoning about the population to which it belongs, a tendency previously identified by “judgment and decision making” researchers. Consistent with this, participants were more willing to ascribe knowledge for beliefs based on probabilistic evidence that is specific to a particular case (Experiments 3A and 3B).
Sensitization, pathologic, and imaging findings comparing symptomatic and quiescent failed renal allografts
Authors: Singh Pooja , Feld Rick I. , Colombe Beth W. , Farber John L. , Herman Jay H. , Gulati Rakesh , Maley Warren R. , Frank Adam M. 
Published: October 2014

AbstractLate allograft failure (LAF) is a common cause of end stage renal disease. These patients face interrelated challenges regarding immunosuppression management, risk of graft intolerance syndrome (GIS), and sensitization. This retrospective study analyzes sensitization, pathology, imaging, and transfusion requirements in 33 LAFs presenting either with GIS (22) or grafts remaining quiescent (11). All patients underwent immunosuppression weaning to discontinuation at LAF. Profound increases in sensitization were noted for all groups and occurred in the GIS group prior to transplant nephrectomy (TxN). Patients with GIS experienced a major upswing in sensitization at, or before the time of their symptomatic presentation. For both GIS and quiescent grafts, sensitization appeared to be closely linked to immunosuppression withdrawal. Most transfusion naïve patients became highly sensitized. Fourteen patients in the GIS group underwent TxN which revealed grade II acute cellular rejection or worse, with grade 3 chronic active T‐cell‐mediated rejection. Blinded comparisons of computed tomography scan of GIS group revealed swollen allografts with fluid collections compared with the quiescent allografts (QAs), which were shrunken and atrophic. The renal volume on imaging and weight of explants nearly matched. Future studies should focus on interventions to avoid sensitization and GIS.
Behavioural thermoregulation and bioenergetics of riverine smallmouth bass associated with ambient cold‐period thermal refuge
Authors: Westhoff Jacob T. , Paukert Craig , Ettinger‐Dietzel Sarah , Dodd Hope , Siepker Michael 
Published: October 2014

AbstractSmallmouth bass in thermally heterogeneous streams may behaviourally thermoregulate during the cold period (i.e., groundwater temperature greater than river water temperature) by inhabiting warm areas in the stream that result from high groundwater influence or springs. Our objectives were to determine movement of smallmouth bass (Micropterus dolomieu) that use thermal refuge and project differences in growth and consumption among smallmouth bass exhibiting different thermal‐use patterns. We implanted radio transmitters in 29 smallmouth bass captured in Alley Spring on the Jacks Fork River, Missouri, USA, during the winter of 2012. Additionally, temperature archival tags were implanted in a subset of nine fish. Fish were tracked using radio telemetry monthly from January 2012 through January of 2013. The greatest upstream movement was 42.5 km, and the greatest downstream movement was 22.2 km. Most radio tagged fish (69%) departed Alley Spring when daily maximum river water temperature first exceeded that of the spring (14 °C) and during increased river discharge. Bioenergetic modelling predicted that a 350 g migrating smallmouth bass that used cold‐period thermal refuge would grow 16% slower at the same consumption level as a fish that did not seek thermal refuge. Contrary to the bioenergetics models, extrapolation of growth scope results suggested migrating fish grow 29% more than fish using areas of stream with little groundwater influence. Our results contradict previous findings that smallmouth bass are relatively sedentary, provide information about potential cues for migratory behaviour, and give insight to managers regarding use and growth of smallmouth bass in thermally heterogeneous river systems.