bluuebunny/crossref_metadata_2025 huggingface dataset:
High expression of programmed cell death 1 ligand 1 in lung adenocarcinoma is a poor prognostic factor particularly in smokers and wild‐type epidermal growth‐factor receptor cases
Authors: Mori Shohei , Motoi Noriko , Ninomiya Hironori , Matsuura Yosuke , Nakao Masayuki , Mun Mingyon , Okumura Sakae , Nishio Makoto , Morikawa Toshiaki , Ishikawa Yuichi
Published: December 2016

A clinical implication of programmed cell death 1 ligand 1 (PD‐L1) expression in lung adenocarcinoma has not been well established. We evaluated PD‐L1 expression immunohistochemically on 296 surgically resected lung adenocarcinomas to investigate a clinical implication of PD‐L1 expression especially in terms of smoking history and epidermal growth‐factor receptor (EGFR) mutation status. Patients were classified into high‐ and low‐PD‐L1 expression groups. The high‐expression group (n = 107) showed a significantly higher proportion of smokers and poor differentiation compared with the low‐expression group (n = 189). Survival analysis showed that the prognosis of the high‐expression group was worse in overall survival than that of the low‐expression group (3‐year overall survival 85 vs. 94%, P = 0.005). Stratified survival analyses showed that the prognoses of the high‐expression group were worse than those of the low‐expression group in both strata of smokers and wild‐type EGFR (P = 0.009 and P = 0.007, respectively). We found that high PD‐L1 expression was a poor prognostic factor in the smokers or the patients with wild‐type EGFR, whereas it was not the case in those who never smoked or those with EGFR mutation, implying the importance of adenocarcinoma driver mutations and etiology.
Desiccation‐induced changes in photochemical processes of photosynthesis and spectral reflectance in Nostoc commune (Cyanobacteria, Nostocales) colonies from polar regions
Authors: Trnková Kateřina , Barták Miloš
Published: December 2016

Cyanobacterium Nostoc commune is a species highly resistant against desiccation. In this study, we investigated changes in photochemical processes of photosynthesis and spectral reflectance indices during controlled desiccation of the colonies from Antarctica. In a dehydration process, water potential (WP) reached −3 MPa and values of potential (F
v/F
m) and effective quantum yields (ΦPSII) of photosystem II were kept to high value until 90% of water was lost from the colony, and these values decreased rapidly by further loss of water. This indicates that the colony loses water mostly from the exopolysaccharidic envelope, not from cells during the initial part of dehydration (relative water content, RWC = 100–10%). Other suggestions of inhibition of photosynthetic processes after 90% loss of water were the increase of the chlorophyll fluorescence parameter F
p/F
s. The F
m′ was higher than F
m in hydrated colonies because of state transition which change energy distribution between PS I and PS II, but decreased to same level as F
m in dehydrated colonies. The Normalized Difference Vegetation Index (NDVI) and Photochemical Reflectance Index (PRI) showed concave‐ and convex‐curvilinear relationship with RWC, respectively. The changes of NDVI values were, however, statistically insignificant. PRI values were predominantly below 0 because of phycobiliprotein involvement. These results were compared with the same species in the Arctic region. This is, according to our best knowledge, the first measurement of changes in spectral reflectance indices during desiccation of cyanobacteria.
Antimicrobial activity of the acidophilic eukaryotic microalga Coccomyxa onubensis
Authors: Navarro Francisco , Forján Eduardo , Vázquez María , Toimil Alberto , Montero Zaida , Ruiz‐Domínguez María del C. , Garbayo Inés , Castaño Miguel Á. , Vílchez Carlos , Vega José M.
Published: December 2016

Extremophilic microalgae are unexplored as a source of pharmaceuticals despite the fact that its biomass can be produced at large scale with low risk of contamination. A significant amount of antimicrobial activity was produced by extracts obtained from the eukaryotic acidophilic microalgae Coccomyxa onubensis in non‐polar solvents, such as hexane, diethyl ether, and chloroform or in weakly polar solvents, such as dichloromethane, against Gram‐negative and Gram‐positive bacteria, and also the yeast Candida albicans. The most effective activity was shown by chloroform extract against Escherichia coli S, Salmonella enterica, and Proteus mirabilis; hexane extract against P. mirabilis, Sa. enterica, and Ca. albicans; dichloromethane extract against Sa. enterica or diethyl ether extract against E. coli S and the Gram‐positive Staphylococcus aureus MB. The lowest minimum inhibitory concentration values were recorded against E. coli S (305 μg mL −1) and P. mirabilis (153 μg mL −1) (using chloroform extract) and against P. mirabilis (106 μg mL−1) (using hexane extract). Fatty acids, but not carotenoids, seem to be involved in the antimicrobial activity of this microalga. However, further biochemical and biotechnological studies must be conducted in order to characterize and purify the bioactive principles from Co. onubensis for assessing its potential as a pharmaceutical source and feasibility of production.
Biomarker Detection and Categorization in Ribonucleic Acid Sequencing Meta-Analysis Using Bayesian Hierarchical Models
Authors: Ma Tianzhou , Liang Faming , Tseng George C.
Published: December 2016

Meta-analysis combining multiple transcriptomic studies increases statistical power and accuracy in detecting differentially expressed genes. As the next-generation sequencing experiments become mature and affordable, increasing numbers of ribonucleic acid sequencing (‘RNA-seq’) data sets are becoming available in the public domain. Count-data-based technology provides better experimental accuracy, reproducibility and ability to detect low expressed genes. A naive approach to combine multiple RNA-seq studies is to apply differential analysis tools such as edgeR and DESeq to each study and then to combine the summary statistics of p-values or effect sizes by conventional meta-analysis methods. Such a two-stage approach loses statistical power, especially for genes with short length or low expression abundance. We propose a full Bayesian hierarchical model (namely, BayesMetaSeq) for RNA-seq meta-analysis by modelling count data, integrating information across genes and across studies, and modelling potentially heterogeneous differential signals across studies via latent variables. A Dirichlet process mixture prior is further applied on the latent variables to provide categorization of detected biomarkers according to their differential expression patterns across studies, facilitating improved interpretation and biological hypothesis generation. Simulations and a real application on multiple brain region human immunodeficiency virus type 1 transgenic rats demonstrate improved sensitivity, accuracy and biological findings of the method.
Posttraumatic Stress Disorder Symptom Clusters and the Interpersonal Theory of Suicide in a Large Military Sample
Authors: Pennings Stephanie M. , Finn Joseph , Houtsma Claire , Green Bradley A. , Anestis Michael D.
Published: December 2016

Prior studies examining posttraumatic stress disorder (PTSD) symptom clusters and the components of the interpersonal theory of suicide (ITS) have yielded mixed results, likely stemming in part from the use of divergent samples and measurement techniques. This study aimed to expand on these findings by utilizing a large military sample, gold standard ITS measures, and multiple PTSD factor structures. Utilizing a sample of 935 military personnel, hierarchical multiple regression analyses were used to test the association between PTSD symptom clusters and the ITS variables. Additionally, we tested for indirect effects of PTSD symptom clusters on suicidal ideation through thwarted belongingness, conditional on levels of perceived burdensomeness. Results indicated that numbing symptoms are positively associated with both perceived burdensomeness and thwarted belongingness and hyperarousal symptoms (dysphoric arousal in the 5‐factor model) are positively associated with thwarted belongingness. Results also indicated that hyperarousal symptoms (anxious arousal in the 5‐factor model) were positively associated with fearlessness about death. The positive association between PTSD symptom clusters and suicidal ideation was inconsistent and modest, with mixed support for the ITS model. Overall, these results provide further clarity regarding the association between specific PTSD symptom clusters and suicide risk factors.
Are Suicide Note Writers Representative of All Suicides? Analysis of the National Violent Death Reporting System
Authors: Stack Steven , Rockett Ian R. H.
Published: December 2016

While suicide notes can offer insights into the causes of suicide and clues for prevention, there is disagreement regarding the degree to which note leavers are representative of the general population of suicides. Previous relevant research on the United States is marked by a series of limitations: small local samples, an over focus on demographic constructs, and lack of multivariable analysis. This study uses a large national sample, a wide range of predictor variables, and multivariable statistical techniques to estimate more reliable similarities and differences between note leavers and other suicides. All data are taken from the National Violent Death Reporting System, which covers 17 states. A total of 9,048 note writers were compared to 21,522 other suicides in terms of 39 variables. In both bivariable (32/39 variables) and multivariable analyses (30/39 variables), note leavers differed from other suicides in most demographic variables, stressful life events, psychiatric issues, and methods of suicide. The national evidence suggests that caution be exercised in generalizing patterns found among writers of suicide notes to suicides in general. This is the first analysis of suicide notes using US data on the issue.
From Community Cancer to Common Entertainment: The Dynamics of Lottery Legalization in Massachusetts
Authors: Wetzel Christopher , Luciano Kimberly
Published: December 2016

To theorize the process by which behaviors once regarded as deviant become normalized, this article analyzes the legalization of a state‐run lottery in the American state of Massachusetts. Lotteries are an important case to study the dynamism of socially constructed problems as well as the creation of gaming markets because they raise moral, social, and economic concerns associated with all types of gaming with the added dimension of having the state government serving as regulator and proprietor of the wagering. Drawing on newspaper articles and archival records, this article examines mobilization around failed efforts to establish a lottery in Massachusetts in the 1930s and 1950s, followed by the successful legalization of a lottery in the 1970s. Highlighting meaning making collective struggles over the lottery in variable circumstances illuminates the processes by which the perceptions of proprietors of operations, patrons of the games, and the distribution of proceeds shift, ultimately turning what was once an illegal enterprise into a socially accepted state institution.
Concession and Secession: Constitutional Bargaining Failure in Post‐Communist Czechoslovakia
Authors: Basta Karlo , Bustikova Lenka
Published: December 2016

This article explains the dissolution of Czechoslovak federation. It shows that the breakdown in bargaining between Slovakia and the federal center in Prague resulted from the federal institutional framework, differences in fiscal policy preferences and elite patronage incentives to monopolize the spoils of state property sell‐offs. Relatively less developed minority regions often seek greater autonomy in order to redress their economic backwardness through interventionist economic and social policies. Due to its veto powers, Slovakia was able to block central legislation, setting the stage for the divorce. At the same time, the federal government in the center was committed to a laissez‐faire strategy of governance, which precluded any significant accommodation of the periphery. (Mostly) Czech politicians understood that yielding to Slovak claims would threaten to undercut their pro‐market strategy and diminish Prague's exclusive access to the spoils of market reforms. In terms of the bargaining model, the center was not dependent on the periphery, which possessed a credible exit option. In fact, the periphery was perceived as a hindrance to the center's ability to pursue its fiscal goals and a fast economic transition, and as limiting Prague's exclusive access to a nascent revolving door between the upper echelons in politics and business.
A combination method of hydrofluoric acid, oxalate and NaOH‐EDTA extractions to determine phosphorus species in soil by 31P‐NMR spectroscopy
Authors: Kobayashi K. , Takamoto A. , Hashimoto Y.
Published: December 2016

The objective of this study was to investigate the applicability of selective extraction methods in combination with solution phosphorus‐31 (31P) nuclear magnetic resonance (NMR) for the determination of organic phosphorus (Po) species in soil. Inositol hexakisphosphates (IHP) and glucose 6‐phosphate (GP) were identified in the soil. IHP adsorbed to both soil organic matter (SOM) and short‐range order (SRO) minerals, whereas GP adsorbed only to SOM. These results suggest that Po hosting phases are different depending on Po species.
Phylogeny of the tribe Naupactini (Coleoptera: Curculionidae) based on morphological characters
Authors: LANTERI ANALIA A. , DEL RIO MARIA G.
Published: December 2016

Naupactini (Curculionidae: Entiminae) is a primarily Neotropical tribe of broad‐nosed weevils with its highest genus and species diversity in South America. Despite several taxonomic contributions published during the last decades, the evolutionary history of Naupactini remains poorly understood. We present the first comprehensive phylogenetic analysis for this tribe based on a data matrix of 100 adult morphological characters scored for 70 species, representing 55 genera of Naupactini (ingroup) and four outgroups belonging to the entimine tribes Otiorhynchini, Entimini, Eustylini and Tanymecini. According to the most parsimonious tree Artipus does not belong to Naupactini; the genera with flat and broad antennae, formerly assigned to other entimine tribes, form a monophyletic group (Saurops (Curiades (Aptolemus (Platyomus)))) related to the clade (Megalostylus (Megalostylodes (Chamaelops Wagneriella))); and the genera distributed along the high Andes, Paramos and Puna form a natural group (Asymmathetes (Amphideritus (Leschenius (Amitrus (Obrieniolus (Melanocyphus Trichocyphus)))))), nested within a larger clade that includes Pantomorus, Naupactus and allied genera. Atrichonotus, Hoplopactus, Mimographus and Naupactus are not recovered as monophyletic. In order to address the taxonomic implications of our phylogenetic analysis, we propose the following nomenclatural changes: to transfer Artipus from Naupactini to Geonemini, to revalidate the genera Mimographopsis (type species M. viridicans), and to revalidate the genus Floresianus (type species F. sordidus). The evolution of selected characters is discussed.

This published work has been registered in ZooBank, http://zoobank.org/urn:lsid:zoobank.org:pub:C8AA4388‐A2F0‐4E2D‐889A‐500BEA5A9DE1.
A novel HLA‐A*24 allele, A*24:02:61, confirmed in a Chinese individual
Authors: Liu X.‐H. , Chi X.‐Y. , Feng Z.‐H. , Hu B. , Jiao S.‐X.
Published: December 2016

A novel HLA‐A*24 allele, A*24:02:61, confirmed in a Chinese individual.
Limited HLA sequence variation outside of antigen recognition domain exons of 360 10 of 10 matched unrelated hematopoietic stem cell transplant donor‐recipient pairs
Authors: Hou L. , Vierra‐Green C. , Lazaro A. , Brady C. , Haagenson M. , Spellman S. , Hurley C. K.
Published: December 2016

Traditional DNA‐based typing focuses primarily on interrogating the exons of human leukocyte antigen (HLA) genes that form the antigen recognition domain (ARD). The relevance of mismatching donor and recipient for HLA variation outside the ARD on hematopoietic stem cell transplantation (HSCT) outcomes is unknown. This study was designed to evaluate the frequency of variation outside the ARD in 10 of 10 (HLA‐A, ‐B, ‐C, ‐DRB1, ‐DQB1) matched unrelated donor transplant pairs (n = 360). Next‐generation DNA sequencing was used to characterize both HLA exons and introns for HLA‐A, ‐B, ‐C alleles; exons 2, 3 and the intervening intron for HLA‐DRB1 and exons only for HLA‐DQA1 and ‐DQB1. Over 97% of alleles at each locus were matched for their nucleotide sequence outside of the ARD exons. Of the 4320 allele comparisons overall, only 17 allele pairs were mismatched for non‐ARD exons, 41 for noncoding regions and 9 for ARD exons. The observed variation between donor and recipient usually involved a single nucleotide difference (88% of mismatches); 88% of the non‐ARD exon variants impacted the amino acid sequence. The impact of amino acid sequence variation caused by substitutions in exons outside ARD regions in D–R pairs will be difficult to assess in HSCT outcome studies because these mismatches do not occur very frequently.
Schmidtz on Moral Recognition Rules: A Critique
Authors: Besch Thomas M.
Published: December 2016

David Schmidtz's reconstruction of morality advances Hart‐type recognition rules for a “personal” and an “interpersonal” strand of morality. I argue that his view does not succeed for reasons owed both to the way in which Schmidtz construes of the task of reconstructing morality and the content of the moral recognition rules that he proposes. For Schmidtz, this task must be approached from a Hart‐type “internal” perspective, but this leaves his reconstruction with an unresolved problem of parochiality. He reconstructs morality as a pursuit of the aim of the flourishing of individuals as reflectively rational agents. However, while it is plausible to see reflective rationality as a good, it does not seem to be a morally fundamental good. Ways to instantiate or pursue it depend for their moral value on other, more fundamental moral values that are beyond the normative space mapped by Schmidtz's moral recognition rules.
Coxiella burnetii (Q fever) prevalence in associated populations of humans and small ruminants in The Gambia
Authors: Bok Jeroen , Hogerwerf Lenny , Germeraad Eveline A. , Roest Hendrik I. J. , Faye‐Joof Tisbeh , Jeng Momodou , Nwakanma Davis , Secka Arss , Stegeman Arjan , Goossens Bart , Wegmüller Rita , van der Sande Marianne A. B. , van der Hoek Wim , Secka Ousman
Published: December 2016

Objectives

To simultaneously estimate the prevalence of antibodies against Coxiella burnetii (Q fever) among adults and small ruminants, and C. burnetii shedding prevalence among small ruminants in households in the Kiang West district of The Gambia, and to assess associated risk factors.

Methods

Sera of 599 adults and 615 small ruminants from 125 compounds within 12 villages were tested for antibodies against C. burnetii using ELISA. Vaginal swabs and milk samples of 155 small ruminants were tested using PCR to investigate shedding of C. burnetii.

Results

A total of 3.8–9.7% of adults, depending on ELISA test cut‐off, and 24.9% of small ruminants in Kiang West were seropositive. Having at least one seropositive animal in one's compound was a risk factor for human seropositivity (OR: 3.35, 95% CI: 1.09–14.44). A grazing area within a village was a risk factor for seropositivity in small ruminants (OR: 2.07, 95% CI: 1.26–3.50); others were having lambed (OR: 2.75, 95% CI: 1.37–5.76) and older age of the animals (OR: 2.75, 95% CI: 1.37–5.76 for 1–3 years and OR 5.84, 95% CI: 3.10–11.64 for >3 years); 57.4% of sampled small ruminants were shedding C. burnetii.

Conclusion

Coxiella burnetii infection is endemic among both humans and small ruminants in this area of The Gambia. Human and animal exposure to C. burnetii were related at compound level. Further research into the clinical relevance of C. burnetii infection in West Africa is needed.
The C‐terminal tails of heterotrimeric kinesin‐2 motor subunits directly bind to α‐tubulin1: Possible implications for cilia‐specific tubulin entry
Authors: Girotra Mukul , Srivastava Shalini , Kulkarni Anuttama , Barbora Ayan , Bobra Kratika , Ghosal Debnath , Devan Pavithra , Aher Amol , Jain Akanksha , Panda Dulal , Ray Krishanu
Published: December 2016

The assembly of microtubule‐based cytoskeleton propels the cilia and flagella growth. Previous studies have indicated that the kinesin‐2 family motors transport tubulin into the cilia through intraflagellar transport. Here, we report a direct interaction between the C‐terminal tail fragments of heterotrimeric kinesin‐2 and α‐tubulin1 isoforms in vitro. Blot overlay screen, affinity purification from tissue extracts, cosedimentation with subtilisin‐treated microtubule and LC‐ESI‐MS/MS characterization of the tail‐fragment‐associated tubulin identified an association between the tail domains and α‐tubulin1A/D isotype. The interaction was confirmed by Forster's resonance energy transfer assay in tissue‐cultured cells. The overexpression of the recombinant tails in NIH3T3 cells affected the primary cilia growth, which was rescued by coexpression of a α‐tubulin1 transgene. Furthermore, fluorescent recovery after photobleach analysis in the olfactory cilia of Drosophila indicated that tubulin is transported in a non‐particulate form requiring kinesin‐2. These results provide additional new insight into the mechanisms underlying selective tubulin isoform enrichment in the cilia.
Mitochondrial protein import in trypanosomes: Expect the unexpected
Authors: Harsman Anke , Schneider André
Published: December 2016

Mitochondria have many different functions, the most important one of which is oxidative phosphorylation. They originated from an endosymbiotic event between a bacterium and an archaeal host cell. It was the evolution of a protein import system that marked the boundary between the endosymbiotic ancestor of the mitochondrion and a true organelle that is under the control of the nucleus. In present day mitochondria more than 95% of all proteins are imported from the cytosol in a proces mediated by hetero‐oligomeric protein complexes in the outer and inner mitochondrial membranes. In this review we compare mitochondrial protein import in the best studied model system yeast and the parasitic protozoan Trypanosoma brucei. The 2 organisms are phylogenetically only remotely related. Despite the fact that mitochondrial protein import has the same function in both species, only very few subunits of their import machineries are conserved. Moreover, while yeast has 2 inner membrane protein translocases, one specialized for presequence‐containing and one for mitochondrial carrier proteins, T. brucei has a single inner membrane translocase only, that mediates import of both types of substrates. The evolutionary implications of these findings are discussed.
Poor stem cell harvest may not always be related to poor mobilization: lessons gained from a mobilization study in patients with β‐thalassemia major
Authors: Constantinou Varnavas C. , Bouinta Asimina , Karponi Garyfalia , Zervou Fani , Papayanni Penelope‐Georgia , Stamatoyannopoulos George , Anagnostopoulos Achilles , Yannaki Evangelia
Published: December 2016

BACKGROUND

Hematopoietic stem cell mobilization and leukapheresis in adult patients with β‐thalassemia have recently been optimized in the context of clinical trials for obtaining hematopoietic stem cells for thalassemia gene therapy. In some patients, however, the yield of cluster of differentiation 34‐positive (CD34+) cells was poor despite successful mobilization, and a modification of apheresis settings was mandatory for harvest rescue.

STUDY DESIGN AND METHODS

Data were analyzed from 20 adult patients with β‐thalassemia who were enrolled in a clinical trial of optimizing mobilization strategies for stem cell gene therapy. The aim of this post‐hoc analysis was to assess how certain hematological and/or clinical parameters may correlate with low collection efficiency in the presence of adequate numbers of circulating stem cells after pharmacological mobilization and standard leukapheresis procedures.

RESULTS

Among 19 patients who achieved optimal mobilization with Plerixafor, four who underwent splenectomy demonstrated disproportionately poor CD34+ cell harvests, as determined by their circulating CD34+ cell counts after mobilization. All four patients who underwent splenectomy presented at baseline and before first apheresis with lymphocytosis resulting in lymphocyte/neutrophil ratios well above 1 and marked reticulocytosis compared with patients who achieved optimal mobilization/CD34+ cell harvest. Such unexpected expansion of specific cell populations disrupted the normal cell layer separation and necessitated modification of the apheresis settings to rescue the harvests.

CONCLUSIONS

By close examination of certain hematological and/or clinical parameters before leukapheresis, patients who, despite adequate mobilization, are at risk for poor CD34+ cell harvests may be identified, and harvest failure can be prevented by adjusting the apheresis settings.
Customizing anticoagulation strategies during leukapheresis to limit citrate exposure
Authors: McMannes J. L. , Hershberger J. , Parker D. M. , De Reys S. , Loos T. , Hematti P.
Published: December 2016

Background and Objectives

Leukapheresis has become a standard practice to collect CD34+ haematopoietic progenitor cells (HPC) from peripheral blood. Hypocalcemic toxicity (hypocalcaemia) is the most common complication during leukapheresis associated with citrate‐based anticoagulation (AC) infusion. This report describes a new approach to limit citrate exposure by increasing the inlet:AC ratio while maintaining original inlet flow rates on the device in order to decrease the AC infusion rate.

Materials and Methods

A retrospective analysis was performed on 63 autologous and 29 allogeneic HPC collections. Procedures were started at a conservative inlet:AC ratio of 12:1 with gradual ratio ramping (RR) during the procedure, or at an inlet:AC ratio of 13:1 or higher (HIR), with constant inlet flow rates. The clinical decision to change the ratio was based on platelet counts and concomitant medications, such as systemic anticoagulants. Symptoms of citrate toxicity were treated by calcium supplementation.

Results

Customization of AC management with RR or HIR was performed in 91 of 92 procedures with a final inlet:AC ratio of 13:1–20:1, under careful supervision for platelet clumping episodes. Notably, 33 procedures were completed in individuals chronically treated with aspirin and/or warfarin. Citrate infusion gradually decreased with higher inlet:AC ratios, without affecting procedure time. The HIR strategy resulted in significantly smaller AC infusion volumes compared to RR, and lower frequency of calcium administration. CD34+ collection efficiency was not influenced by increasing inlet:AC ratios.

Conclusion

Customization of the inlet:AC ratio while maintaining a constant, stable inlet flow rate is effective in limiting citrate exposure during leukapheresis.
Activation of protease‐activated receptor 2 mediates cutaneous vasodilatation but not sweating: roles of nitric oxide synthase and cyclo‐oxygenase
Authors: Fujii Naoto , McNeely Brendan D. , Zhang Sarah Y. , Abdellaoui Yasmine C. , Danquah Mercy O. , Kenny Glen P.
Published: December 2016

New Findings

What is the central question of this study?

Protease‐activated receptor 2 (PAR2) is located in the endothelial cells of skin vessels and eccrine sweat glands. However, a functional role of PAR2 in the control of cutaneous blood flow and sweating remains to be assessed in humans in vivo.

What is the main finding and its importance?

Our results demonstrate that in normothermic resting humans in vivo, activation of PAR2 elicits cutaneous vasodilatation partly through nitric oxide synthase‐dependent mechanisms, but does not mediate sweating. These results provide important new insights into the physiological significance of PAR2 in human skin.

Protease‐activated receptor 2 (PAR2) is present in human skin, including keratinocytes, endothelial cells of skin microvessels and eccrine sweat glands. However, whether PAR2 contributes functionally to the regulation of cutaneous blood flow and sweating remains entirely unclear in humans in vivo. We hypothesized that activation of PAR2 directly stimulates cutaneous vasodilatation and sweating via actions of nitric oxide synthase (NOS) and cyclo‐oxygenase (COX). In 12 physically active young men (29 ± 5 years old), cutaneous vascular conductance (CVC) and sweat rate were measured at four intradermal microdialysis forearm skin sites that were treated with the following: (i) lactated Ringer's solution (control); (ii) 10 mm NG‐nitro‐l‐arginine (NOS inhibitor); (iii) 10 mm ketorolac (COX inhibitor); or (iv) a combination of both inhibitors. At all sites, a PAR2 agonist (SLIGKV‐NH2) was co‐administered in a dose‐dependent fashion (0.06, 0.18, 0.55, 1.66 and 5 mm, each for 25 min). The highest dose of SLIGKV‐NH2 (5 mm) increased CVC from baseline at the control site (P ≤ 0.05). This increase in CVC associated with PAR2 activation was attenuated by NOS inhibition regardless of the presence or absence of simultaneous COX inhibition (both P ≤ 0.05). However, COX inhibition alone did not affect the PAR2‐mediated increase in CVC (P > 0.05). No increase in sweat rate was measured at any administered dose of SLIGKV‐NH2 (all P > 0.05). We show that in normothermic resting humans in vivo, PAR2 activation does not increase sweat rate, whereas it does modulate cutaneous vasodilatation through NOS‐dependent mechanisms.
High‐fat diet induces protein kinase A and G‐protein receptor kinase phosphorylation of β2‐adrenergic receptor and impairs cardiac adrenergic reserve in animal hearts
Authors: Fu Qin , Hu Yuting , Wang Qingtong , Liu Yongming , Li Ning , Xu Bing , Kim Sungjin , Chiamvimonvat Nipavan , Xiang Yang K.
Published: December 2016

Key points

Patients with diabetes show a blunted cardiac inotropic response to β‐adrenergic stimulation despite normal cardiac contractile reserve.

Acute insulin stimulation impairs β‐adrenergically induced contractile function in isolated cardiomyocytes and Langendorff‐perfused hearts.

In this study, we aimed to examine the potential effects of hyperinsulinaemia associated with high‐fat diet (HFD) feeding on the cardiac β2‐adrenergic receptor signalling and the impacts on cardiac contractile function.

We showed that 8 weeks of HFD feeding leads to reductions in cardiac functional reserve in response to β‐adrenergic stimulation without significant alteration of cardiac structure and function, which is associated with significant changes in β2‐adrenergic receptor phosphorylation at protein kinase A and G‐protein receptor kinase sites in the myocardium.

The results suggest that clinical intervention might be applied to subjects in early diabetes without cardiac symptoms to prevent further cardiac complications.

Patients with diabetes display reduced exercise capability and impaired cardiac contractile reserve in response to adrenergic stimulation. We have recently uncovered an insulin receptor and adrenergic receptor signal network in the heart. The aim of this study was to understand the impacts of high‐fat diet (HFD) on the insulin–adrenergic receptor signal network in hearts. After 8 weeks of HFD feeding, mice exhibited diabetes, with elevated insulin and glucose concentrations associated with body weight gain. Mice fed an HFD had normal cardiac structure and function. However, the HFD‐fed mice displayed a significant elevation of phosphorylation of the β2‐adrenergic receptor (β2AR) at both the protein kinase A site serine 261/262 and the G‐protein‐coupled receptor kinase site serine 355/356 and impaired adrenergic reserve when compared with mice fed on normal chow. Isolated myocytes from HFD‐fed mice also displayed a reduced contractile response to adrenergic stimulation when compared with those of control mice fed normal chow. Genetic deletion of the β2AR led to a normalized adrenergic response and preserved cardiac contractile reserve in HFD‐fed mice. Together, these data indicate that HFD promotes phosphorylation of the β2AR, contributing to impairment of cardiac contractile reserve before cardiac structural and functional remodelling, suggesting that early intervention in the insulin–adrenergic signalling network might be effective in prevention of cardiac complications in diabetes.
The quantal catecholamine release from mouse chromaffin cells challenged with repeated ACh pulses is regulated by the mitochondrial Na+/Ca2+ exchanger
Authors: López‐Gil Angela , Nanclares Carmen , Méndez‐López Iago , Martínez‐Ramírez Carmen , de los Rios Cristóbal , Padín‐Nogueira J. Fernando , Montero Mayte , Gandía Luis , García Antonio G.
Published: December 2016

Key points

Upon repeated application of short ACh pulses to C57BL6J mouse chromaffin cells, the amperometrically monitored secretory responses promptly decayed to a steady‐state level of around 25% of the initial response. A subsequent K+ pulse, however, overcame such decay. These data suggest that mouse chromaffin cells have a ready release‐vesicle pool that is selectively recruited by the physiological neurotransmitter ACh.

The ACh‐sensitive vesicle pool is refilled and maintained by the rate of Ca2+ delivery from mitochondria to the cytosol, through the mitochondrial Na+/Ca2+ exchanger (mNCX). ITH12662, a novel blocker of the mNCX, prevented the decay of secretion elicited by ACh pulses and delayed the rate of [Ca2+]c clearance.

This regulatory pathway may be physiologically relevant in situations of prolonged stressful conflicts where a sustained catecholamine release is regulated by mitochondrial Ca2+ circulation through the mNCX, which couples respiration and ATP synthesis to long‐term stimulation of chromaffin cells by endogenously released ACh.

Using caged‐Ca2+ photorelease or paired depolarising pulses in voltage‐clamped chromaffin cells (CCs), various pools of secretory vesicles with different readiness to undergo exocytosis have been identified. Whether these pools are present in unclamped CCs challenged with ACh, the physiological neurotransmitter at the splanchnic nerve‐CC synapse, is unknown. We have explored here whether an ACh‐sensitive ready‐release vesicle pool (ASP) is present in C57BL6J mouse chromaffin cells (MCCs). Single cells were fast perfused with a Tyrode solution at 37°C, and challenged with 12 sequential ACh pulses (100 μm, 2 s, every 30 s) plus a K+ pulse given at the end (75 mm K+). After the first 2–3 ACh pulses the amperometrically monitored secretory responses promptly decayed to a steady‐state level of around 25% of the initial response. The last K+ pulse, however, overcame such decay. Repeated ACh pulses to voltage‐clamped cells elicited non‐desensitising nicotinic currents. Also, the [Ca2+]c transients elicited by repeated ACh pulses that were superimposed on a stable baseline elevation did not undergo decay. The novel blocker of the mitochondrial Na+/Ca2+ exchanger (mNCX) ITH12662 prevented the decay of secretion elicited by ACh pulses and delayed the rate of [Ca2+]c clearance. The experiments are compatible with the idea that C57BL6J MCCs have an ASP vesicle pool that is selectively recruited by the physiological neurotransmitter ACh and is regulated by the rate of Ca2+ delivery from mitochondria to the cytosol, through the mNCX.
The role of competing knowledge structures in undermining learning: Newton's second and third laws
Authors: Low David J. , Wilson Kate F.
Published: December 2016

We investigate the development of student understanding of Newton's laws using a pre-instruction test (the Force Concept Inventory), followed by a series of post-instruction tests and interviews. While some students' somewhat naive, pre-existing models of Newton's third law are largely eliminated following a semester of teaching, we find that a particular inconsistent model is highly resilient to, and may even be strengthened by, instruction. If test items contain words that cue students to think of Newton's second law, then students are more likely to apply a “net force” approach to solving problems, even if it is inappropriate to do so. Additional instruction, reinforcing physical concepts in multiple settings and from multiple sources, appears to help students develop a more connected and consistent level of understanding. We recommend explicitly encouraging students to check their work for consistency with physical principles, along with the standard checks for dimensionality and order of magnitude, to encourage reflective and rigorous problem solving.
Comment on “Why does a ball fall?: A new visualization for Einstein's model of gravity” [Am. J. Phys. 84, 396–402 (2016)]
Authors: Rȩbilas Krzysztof
Published: December 2016

A simple analytical approach that allows us to recover Newtonian physics from Schwarzschild's metric is proposed. The method elucidates why the tiny modification of the metric due to gravity entails a significant change of motion of a freely falling body.
Cellular uptake and dynamics of unlabeled freestanding silicon nanowires
Authors: Zimmerman John F. , Parameswaran Ramya , Murray Graeme , Wang Yucai , Burke Michael , Tian Bozhi
Published: December 2016

Cells naturally “eat” nanowires, paving way for intracellular sensing devices and photoresponsive therapies.
A novel Rab10-EHBP1-EHD2 complex essential for the autophagic engulfment of lipid droplets
Authors: Li Zhipeng , Schulze Ryan J. , Weller Shaun G. , Krueger Eugene W. , Schott Micah B. , Zhang Xiaodong , Casey Carol A. , Liu Jun , Stöckli Jacqueline , James David E. , McNiven Mark A.
Published: December 2016

A novel protein complex facilitates lipid droplet autophagy.
Ocean heat drives rapid basal melt of the Totten Ice Shelf
Authors: Rintoul Stephen Rich , Silvano Alessandro , Pena-Molino Beatriz , van Wijk Esmee , Rosenberg Mark , Greenbaum Jamin Stevens , Blankenship Donald D.
Published: December 2016

Inflow of warm water drives rapid melt of the Totten Ice Shelf, demonstrating that this sector of East Antarctica is exposed to ocean heat.
General and programmable synthesis of hybrid liposome/metal nanoparticles
Authors: Lee Jin-Ho , Shin Yonghee , Lee Wooju , Whang Keumrai , Kim Dongchoul , Lee Luke P. , Choi Jeong-Woo , Kang Taewook
Published: December 2016

Programmable liposomes are designed to selectively produce various liposome-nanoparticle hybrids.
Human lymphoid organ dendritic cell identity is predominantly dictated by ontogeny, not tissue microenvironment
Authors: Heidkamp Gordon F. , Sander Jil , Lehmann Christian H. K. , Heger Lukas , Eissing Nathalie , Baranska Anna , Lühr Jennifer J. , Hoffmann Alana , Reimer Katharina C. , Lux Anja , Söder Stephan , Hartmann Arndt , Zenk Johannes , Ulas Thomas , McGovern Naomi , Alexiou Christoph , Spriewald Bernd , Mackensen Andreas , Schuler Gerold , Schauf Burkhard , Forster Anja , Repp Roland , Fasching Peter A. , Purbojo Ariawan , Cesnjevar Robert , Ullrich Evelyn , Ginhoux Florent , Schlitzer Andreas , Nimmerjahn Falk , Schultze Joachim L. , Dudziak Diana
Published: December 2016

Transcriptional identity of human dendritic cell subsets is mainly dictated by ontogeny rather than by signals derived from the cells’ final tissue microenvironment.
The How Project: understanding contextual challenges to global surgical care provision in low-resource settings
Authors: Raykar Nakul P , Yorlets Rachel R , Liu Charles , Goldman Roberta , Greenberg Sarah L M , Kotagal Meera , Farmer Paul E , Meara John G , Roy Nobhojit , Gillies Rowan D
Published: December 2016

Introduction

5 billion people around the world do not have access to safe, affordable, timely surgical care. This series of qualitative interviews was launched by TheLancetCommission on Global Surgery (LCoGS) with the aim of understanding the contextual challenges—the specific circumstances—faced by surgical care providers in low-resource settings who care for impoverished patients, and how those providers overcome these challenges.

Methods

From January 2014 to February 2015, 20 LCoGS collaborators conducted semistructured interviews with 148 surgical providers in low-resource settings in 21 countries. Stratified purposive sampling was used to include both rural and urban providers, and reputational case selection identified individuals. Interviewers were trained with an implementation manual. Following immersion into de-identified texts from completed interviews, topical coding and further analysis of coded texts was completed by an independent analyst with periodic validation from a second analyst.

Results

Providers described substantial financial, geographic and cultural barriers to patient access. Rural surgical teams reported a lack of a trained workforce and insufficient infrastructure, equipment, supplies and banked blood. Urban providers face overcrowding, exacerbated by minimal clinical and administrative support, and limited interhospital care coordination. Many providers across contexts identified national health policies that do not reflect the realities of resource-poor settings. Some findings were region-specific, such as weak patient–provider relationships and unreliable supply chains. In all settings, surgical teams have created workarounds to deliver care despite the challenges.

Discussion

While some differences exist between countries, the barriers to safe surgery and anaesthesia are overall consistent and resource-dependent. Efforts to advance and expand global surgery must address these commonalities, while local policymakers can tailor responses to key contextual differences.
How did rapid scale-up of HIV services impact on workplace and interpersonal trust in Zambian primary health centres: a case-based health systems analysis
Authors: Topp Stephanie M , Chipukuma Julien M
Published: December 2016

Background

In sub-Saharan Africa, large amounts of funding continue to be directed towards HIV-specific care and treatment, often with claims of ‘health system strengthening’ effect. Such claims rarely account for the impact on human relationships and decisions that are core to functional health systems. This research examined how establishment of externally funded HIV services influenced trusting relationships in Zambian health centres.

Methods

An in-depth, multicase study included four health centres selected for urban, peri-urban and rural characteristics. Case data included healthcare worker (HCW) interviews (60); patient interviews (180); direct observation of facility operations (2 weeks/centre) and key informant interviews (14) which were recorded and transcribed verbatim. Thematic analysis adopted inductive and deductive coding guided by a framework incorporating concepts of workplace trust, patient–provider trust, intrinsic and extrinsic motivation.

Results

HIV service scale-up impacted trust in positive and negative ways. Investment in HIV-specific infrastructure, supplies and quality assurance mechanisms strengthened workplace trust, HCW motivation and patient–provider trust in HIV departments in the short-term. In the health centres more broadly and over time, however, non-governmental organisation-led investment and support of HIV departments reinforced HCW's perceptions of the government as uninterested or unable to provide a quality work environment. Exacerbating existing perceptions of systemic workplace inequity and nepotism, uneven distribution of personal and professional opportunities related to HIV service establishment contributed to interdepartmental antagonism and reinforced workplace practices designed to protect individual HCW's interests.

Conclusions

Findings illustrate long-term negative effects of the vertical HIV resourcing and support structures which failed to address and sometimes exacerbated HCW (dis)trust with their own government and supervisors. The short-term and long-term effects of weakened workplace trust on HCWs' motivation and performance signal the importance of understanding how such relationships play a role in generating virtuous or perverse cycles of actor interactions, with implications for service outcomes.
CRE and SRE mediate LPA-induced CCN1 transcription in mouse aortic smooth muscle cells
Authors: Dou Quanlin , Hao Feng , Sun Longsheng , Xu Xuemin , Cui Mei-Zhen
Published: December 2016

Lysophosphatidic acid (LPA), one component of oxidized low-density lipoprotein (ox-LDL), is a potent bioactive phospholipid. Our recent data reveal that LPA induces matricellular protein CCN1 (also known as Cyr61) expression in aortic smooth muscle cells (SMCs) and that CCN1 bridges LPA and integrin signaling pathways leading to SMC migration. Whether and how LPA regulates the transcriptional machinery of the CCN1 gene are unknown. In this study, we found that LPA markedly induces CCN1 mRNA expression in SMCs. Using deleting mutation and reporter gene strategies, we demonstrated regions from –2038 to –1787 and from –101 to +63 of the CCN1 promoter contain the essential regulatory elements. The serum response element (SRE) and cyclic AMP-response element (CRE) are located in these regions. LPA induced time-dependent phosphorylation of serum response factor (SRF) and CRE-binding protein (CREB) in mouse SMCs. Luciferase assays of a series of deleted, mutated CCN1 promoter-reporter gene constructs and dominant negative construct revealed the distal SRE and the proximal CRE in the CCN1 promoter are required for LPA-induced CCN1 gene expression. Our results imply that elevated LPA levels may trigger SMC migration and exacerbate restenosis and atherosclerotic lesions through the induced CCN1, which communicates with a set of plasma membrane proteins and intracellular kinases.
Influence of oxygen partial pressure on the metastable copper oxide thin films
Authors: Geçici Birol , Korkmaz Şadan , Özen Soner , Şenay Volkan , Pat Suat
Published: December 2016

Paramelaconite (Cu4O3) is a metastable copper oxide. Metastable copper oxide thin films were deposited on glass substrates by reactive RF magnetron sputtering in argon (Ar) and oxygen (O2) gas mixture atmospheres. Ar/O2 gas ratios in the sputtering ambient were chosen as 1/1 and 1/9. The surface and optical properties were determined by X-ray diffractometer (XRD), atomic force microscope (AFM) and UV-Vis spectrophotometer. The XRD patterns of the samples exhibited single strong diffraction peaks at 35.39[Formula: see text] and 35.49[Formula: see text], corresponding to the (202) peak of Cu4O3. The mean thickness values were measured as 100 nm and 80 nm for the films deposited at 1/1 and 1/9 Ar/O2 gas ratios, respectively. The samples showed low transmittance and high absorbance in the high frequency region.