bluuebunny/crossref_metadata_2025 huggingface dataset:
Blockage of melanocortin‐4 receptors by intranasal HS014 attenuates single prolonged stress‐triggered changes in several brain regions
Authors: Serova Lidia I. , Laukova Marcela , Alaluf Lishay G. , Sabban Esther L.
Published: August 2014

Melanocortin receptor four (MC4R) is implicated in regulation of stress‐related functions. We previously demonstrated that intranasal infusion of MC4R antagonist HS014, shortly before single prolonged stress (SPS) animal model of post‐traumatic stress disorder, lessened the development of anxiety‐ and depression‐like behavior depending on the dose. Here, we evaluated effects of HS014 on SPS‐elicited changes in hypothalamic‐pituitary‐adrenal axis and expression of several genes of interest in mediobasal hypothalamus, hippocampus, and locus coeruleus. Rats were given intranasal infusion of HS014 (3.5 ng or 100 μg) and 30 min later subjected to SPS stressors. Short‐term responses of HS014 rats in comparison with vehicle‐treated, evident 30 min following SPS stressors, included smaller rise in plasma corticosterone (100 μg HS014), absence of induction of corticotrophin‐releasing hormone mRNA in mediobasal hypothalamus and of mRNA for tyrosine hydroxylase and dopamine‐β hydroxylase in locus coeruleus. Long‐term responses found 7 days after SPS stressors, included lower induction corticotrophin‐releasing hormone mRNA levels in the mediobasal hypothalamus without effect on mRNAs for the glucocorticoid receptor (GR) and FK506‐binding protein 51 (FKBP5), a component of GR co‐chaperone complex; and no induction of GR protein in ventral hippocampus. Thus, antagonism of MC4R prior to SPS attenuates development of several abnormalities in gene expression in regions implicated in post‐traumatic stress disorder.

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Blockade of brain melanocortine receptor 4 (MC4R) with intranasal infusion of the MC4R antagonist HS014 to rats prior to single prolonged stress (SPS) leads to faster termination of stress responses (30 min later) and prevents or attenuates SPS‐triggered abnormal gene expression related to post‐traumatic stress disorder (7 days later). Targeting of brain MC4R is a promising strategy to protect HPA axis, LC‐NE (locus coeruleus‐norepinephrine) systems and hippocampus from overstimulation.
The effects of different light–dark cycles on the metabolism of the diazotrophic, unicellular cyanobacteria Cyanothece sp. ATCC 51142, and Cyanothecesp. PCC 7822
Authors: Arshad Sarah , Mishra Sujata , Sherman Louis A.
Published: August 2014

The diazotrophic unicellular cyanobacterium Cyanothece sp. ATCC 51142 demonstrates circadian patterns in nitrogenase activity, H2 production and glycogen storage when grown under nitrogen‐fixing, 12:12 light:dark (L:D) conditions. In this study, we grew Cyanothece sp. ATCC 51142, and another strain in this genus, Cyanothece sp. PCC 7822, under long‐day (16:8 L:D) and short‐day (8:16 L:D) nitrogen‐fixing conditions to determine if they continued to display circadian rhythms. Both strains demonstrated similar circadian patterns for all three metabolic parameters when grown under long‐day conditions. However, the strains responded differently to short‐day growth conditions. Cyanothece sp. ATCC 51142 retained reasonable circadian patterns under 8:16 L:D conditions, whereas Cyanothece sp. PCC 7822 had quite damped patterns without a clear circadian pattern. In particular, glycogen storage changed very little throughout the day and we ascribe this to the difference in the type of glycogen granules in Cyanothece sp. PCC 7822 which has small β‐granules, compared to the large, starch‐like granules in Cyanothece sp. ATCC 51142. The results suggested that both mechanistic and regulatory processes play a role in establishing the basis for these metabolic oscillations.
The dynamics of sexual phase in the marine diatom Pseudo‐nitzschia multistriata (Bacillariophyceae)
Authors: Scalco Eleonora , Stec Krzysztof , Iudicone Daniele , Ferrante Maria Immacolata , Montresor Marina
Published: August 2014

Sexual reproduction represents a fundamental phase in the life cycle of diatoms, linked to both the production of genotypic diversity and the formation of large‐sized initial cells. Only cells below a certain size threshold can be sexualized, but various environmental factors can modulate the success of sexual reproduction. We investigated the role of cell density and physiological conditions of parental strains in affecting the success and timing of sexual reproduction in the marine heterothallic diatom Pseudo‐nitzschia multistriata. We also studied the dynamics of the sexual phase in still conditions allowing cell sedimentation and in gently mixed conditions that keep cells in suspension. Our results showed that successful sexual reproduction can only be achieved when crossing parental strains in the exponential growth phase. Evidence was provided for the fact that sexual reproduction is a density‐dependent event and requires a threshold cell concentration to start, although this might vary considerably amongst strains. Moreover, the onset of the sexual phase was coupled to a marked reduction in growth of the vegetative parental cells. The crosses carried out in physically mixed conditions produced a significantly reduced number of sexual stages as compared to crosses in still conditions, showing that mixing impairs sexualization. The results of our experiments suggest that the signaling that triggers the sexual phase is favored when cells can accumulate, reducing the distance between them and facilitating contacts and/or the perception of chemical cues. Information on the progression of the sexual phase in laboratory conditions help understanding the conditions at which sex occurs in the natural environment.
Examining the effects of sleep delay on depressed males and females and healthy controls
Authors: Goldschmied Jennifer R. , Cheng Philip , Armitage Roseanne , Deldin Patricia J.
Published: August 2014

Individuals with major depressive disorder typically exhibit sleep electroencephalograpy abnormalities which have been shown to vary by sex. Recent research has shown that depressed males display deficits in slow wave sleep and delta electroencephalograph (EEG) activity that are not apparent in depressed females. This may suggest that males and females with depression vary with respect to their homeostatic regulation of sleep. Utilizing archival data, the present study examined the effects of a 3‐h sleep delay, which represents a mild sleep challenge, on slow wave activity in healthy controls and individuals with depression. All participants slept in the laboratory for three sequential nights. On the third night in the laboratory, the participants' bedtime was delayed by 3 h. Slow wave activity was calculated utilizing power spectral analysis and compared across groups. Following the sleep delay, males with depression exhibited the lowest slow wave activity compared to all other groups. These results may suggest that males with depression are at a greater risk for homeostatic dysregulation than females, and may require specialized intervention.
Overall sleep status and high sensitivity C‐reactive protein: a prospective study in Japanese factory workers
Authors: Nakamura Koshi , Sakurai Masaru , Miura Katsuyuki , Morikawa Yuko , Nagasawa Shin‐Ya , Ishizaki Masao , Kido Teruhiko , Naruse Yuchi , Nakashima Motoko , Nogawa Kazuhiro , Suwazono Yasushi , Nakagawa Hideaki
Published: August 2014

We investigated the relation between overall sleep status based on the modified Pittsburgh Sleep Quality Index (PSQI) global score and subsequent changes in serum high‐sensitivity C‐reactive protein (hsCRP) in a population of Japanese factory workers, who were predominantly female. A total of 991 Japanese with inflammation classified as low cardiovascular risk (baseline hsCRP < 1.0 mg L−1) were grouped according to the presence or absence of unfavourable sleep, defined as a modified PSQI global score > 5.5 points. The subsequent changes in hsCRP after 3 years were then compared in the two groups. Analysis of covariance incorporating log‐transformed baseline hsCRP, age, sex, lifestyle and physical and biochemical profiles was used to compare the geometric means of hsCRP at year 3 in each sleep status group. A logistic regression model incorporating the same variables was used to calculate the odds ratios for development of inflammation with a medium‐to‐high cardiovascular risk (hsCRP at year 3 ≥ 1.0 mg L−1) comparing the presence or absence of unfavourable sleep habits. The multivariate‐adjusted geometric mean of hsCRP at year 3 was significantly higher in subjects with unfavourable sleep habits compared with those with a normal pattern (0.275 versus 0.242 mg L−1). The multivariate‐adjusted odds ratio for developing increased and potentially pathogenic levels of inflammation due to unfavourable sleep was 2.08 (95% confidence interval = 1.29–3.35). There was a significant linear trend for the development of increased inflammation across the modified PSQI global scores (P = 0.04). Unfavourable sleep is associated with activation of low‐grade systemic inflammation.
Losses from Horizontal Merger: an Extension to a Successive Oligopoly Model with Product Differentiation
Authors: Fauli‐Oller Ramon , Mesa‐Sánchez Borja
Published: August 2014

This paper generalizes the model of Salant et al. (1983; Quarterly Journal of Economics, Vol. 98, pp. 185–199) to a successive oligopoly model with product differentiation. Upstream firms produce differentiated goods, retailers compete in quantities, and supply contracts are linear. We show that if retailers buy from all producers, downstream mergers do not affect wholesale prices. Our result replicates that of Salant's, where mergers are not profitable unless the size of the merged firm exceeds 80 per cent of the industry. This result is robust to the type of competition.
“Securing the Rational Foundations of Human Living:” The Pedagogical Nature of Human Law in St. Thomas Aquinas
Authors: Jones Brian
Published: August 2014

Every form of government, whether by its action or inaction, encourages certain forms of behavior and discourages others. The moral well being of a society necessitates its consideration of civil law's legitimate role in shaping moral character. In this paper, I will attepmt to argue that the Thomistic account of civil law is not merely negative, but entails a positive pedagogy that seeks to nurture the moral virtue of its citizens, for both the viciously inclined and those who are already good. Furthermore, Aquinas’ theory of the common good is such that its role is not merely limited, i.e., through establishing some form of civic tranquility and providing basic goods of the material or economic order with little worry of the moral habits thus cultivated.

The treatment of Thomas’ teaching on human law will not be fully exhausted in this paper. However, from examining the texts from the Summa Theologiae and the De Regno, it will appear evident that St. Thomas has provided a concise and intelligent framework for seeing and actualizing the necessary relationship between human law and moral virtue.
Evaluating NIR vascular imaging to support intravenous cannulation in awake children difficult to cannulate; a randomized clinical trial
Authors: de Graaff Jurgen C. , Cuper Natascha J. , van Dijk Atty T.H. , Timmers‐Raaijmaakers Brigitte C.M.S. , van der Werff Désirée B.M. , Kalkman Cor J.
Published: August 2014

Background

Recently, various near‐infrared vascular imaging devices aimed at facilitating peripheral intravenous cannulation (PIC) were introduced, all claiming to increase success rate of PIC. We evaluated the clinical utility of a near‐infrared vascular imaging device (VascuLuminator®) in pediatric patients who were referred to the anesthesiologist because of difficult cannulation.

Methods

There were 226 consecutive children referred to pediatric anesthesiologists by the treating pediatrician of the in‐ and outpatient clinic, because of difficulties with intravenous cannulation, were included in this cluster randomized clinical trial. The presence and use of the near‐infrared vascular imaging device for PIC was randomized in clusters of 1 week. Success at first attempt (Fisher exact test) and time to successful cannulation (Log‐rank test) were assessed to evaluate differences between groups.

Results

Success at first attempt in the group with the VascuLuminator® (59%) was not significantly different from the control group (54%, P = 0.41), neither was the median time to successful cannulation: 246 s and 300 s, respectively (P = 0.54).

Conclusions

Visualization of blood vessels with near‐infrared light and with near‐infrared vascular imaging device did not improve success of PIC in pediatric patients who are known difficult to cannulate.
Genetic analysis of salt tolerance at seedling and reproductive stages in rice (Oryza sativa)
Authors: Mohammadi Reza , Mendioro Merlyn S. , Diaz Genaleen Q. , Gregorio Glenn B. , Singh Rakesh K.
Published: August 2014

Salinity is a major abiotic stress that limits rice production across rice areas as high‐yielding modern rice varieties are generally sensitive to salt stress. The study was conducted to deduce heritability and combining ability estimates of rice for various morphological and physiological traits using a 7 × 7 full‐diallel‐cross analysis at seedling and reproductive stages. The salinity stress treatment was 12 dS m−1 at the seedling stage and 8 dS m−1 at the reproductive stage. Diallel analysis revealed high for salinity tolerance scores and shoot height, moderate for shoot dry weight and root dry weight and low for Na+ and K+ concentrations and K+/Na+ ratio. The low‐to‐moderate narrow‐sense heritability for number of panicles, number of fertile spikelets, grain weight, spikelet fertility and K+/Na+ ratio suggests a large breeding population and delayed selection for tolerance until later generations. Significant maternal effects indicate that selection of the female parent is very important for desired trait development. The results of this study confirmed that salinity tolerance at the seedling and reproductive stages is regulated by a different set of genes that could be pyramided using different donors to enhance the level of tolerance.
Utilizing intraspecific variation in phenotypic plasticity to bolster agricultural and forest productivity under climate change
Authors: ASPINWALL MICHAEL J. , LOIK MICHAEL E. , RESCO DE DIOS VICTOR , TJOELKER MARK G. , PAYTON PAXTON R. , TISSUE DAVID T.
Published: August 2014

Climate change threatens the ability of agriculture and forestry to meet growing global demands for food, fibre and wood products. Information gathered from genotype‐by‐environment interactions (G × E), which demonstrate intraspecific variation in phenotypic plasticity (the ability of a genotype to alter its phenotype in response to environmental change), may prove important for bolstering agricultural and forest productivity under climate change. Nonetheless, very few studies have explicitly quantified genotype plasticity–productivity relationships in agriculture or forestry. Here, we conceptualize the importance of intraspecific variation in agricultural and forest species plasticity, and discuss the physiological and genetic factors contributing to intraspecific variation in phenotypic plasticity. Our discussion highlights the need for an integrated understanding of the mechanisms of G × E, more extensive assessments of genotypic responses to climate change under field conditions, and explicit testing of genotype plasticity–productivity relationships. Ultimately, further investigation of intraspecific variation in phenotypic plasticity in agriculture and forestry may prove important for identifying genotypes capable of increasing or sustaining productivity under more extreme climatic conditions.
Effects of water stress on the development of banana xanthomonas wilt disease
Authors: Ochola D. , Ocimati W. , Tinzaara W. , Blomme G. , Karamura E. B.
Published: August 2014

Water quantity and distribution plays a significant role in determining the productivity of crops and the outcome of many host–pathogen interactions in natural plant populations. In the present study, tissue culture plants of the East African highland banana cultivar Mbwazirume were established in a screenhouse to mimic drought conditions in the field and so investigate the effects of water stress on the development of banana xanthomonas wilt (BXW) caused by the bacterium Xanthomonas campestris pv. musacearum (Xcm). In the absence of host resistance, all inoculated banana plants succumbed to Xcm infection and symptoms were expressed, on average, 14 days post‐inoculation (dpi). Water stress effects were significant (P < 0·05) for disease incubation period, and significant (P < 0·001) for incidence and severity. Data revealed that BXW development is hastened by the combined effect of water stress before and after inoculation compared to when plants are stressed only before inoculation or maintained stress‐free (SF). A twofold increase in evaluated disease parameters suggests that both timing of infection and duration of exposure to water stress are important in determining the shortened resident phase of Xcm to multiply and rapidly spread in the vascular tissues of the banana. This study has shown that water‐stressed banana plants are physiologically weak and hence more vulnerable to Xcm infections. This may be of relevance to the effect of future climate change on banana production.
Effect of Mulligan's and Kinesio knee taping on adolescent ballet dancers knee and hip biomechanics during landing
Authors: Hendry D. , Campbell A. , Ng L. , Grisbrook T. L. , Hopper D. M.
Published: August 2014

Taping is often used to manage the high rate of knee injuries in ballet dancers; however, little is known about the effect of taping on lower‐limb biomechanics during ballet landings in the turnout position. This study investigated the effects of Kinesiotape (KT), Mulligan's tape (MT) and no tape (NT) on knee and hip kinetics during landing in three turnout positions. The effect of taping on the esthetic execution of ballet jumps was also assessed. Eighteen pain‐free 12–15‐year‐old female ballet dancers performed ballet jumps in three turnout positions, under the three knee taping conditions. A Vicon Motion Analysis system (Vicon Oxford, Oxford, UK) and Advanced Mechanical Technology, Inc. (Watertown, Massa chusetts, USA) force plate collected lower‐limb mechanics. The results demonstrated that MT significantly reduced peak posterior knee shear forces (P = 0.025) and peak posterior (P = 0.005), medial (P = 0.022) and lateral (P = 0.014) hip shear forces compared with NT when landing in first position. KT had no effect on knee or hip forces. No significant differences existed between taping conditions in all landing positions for the esthetic measures. MT was able to reduce knee and the hip forces without affecting the esthetic performance of ballet jumps, which may have implications for preventing and managing knee injuries in ballet dancers.
Full length KIR3DS1*0130110 allele isolated by SBT
Authors: Yindom L.‐M. , Wang L. , Dong T. , Rowland‐Jones S. L.
Published: August 2014

KIR3DS1*0130110 differs from KIR3DS1*0130101 with two nucleotide substitutions at positions 7322 (G > T) and 12617 (C > A), respectively.
Starch synthase 4 is located in the thylakoid membrane and interacts with plastoglobule‐associated proteins in Arabidopsis
Authors: Gámez‐Arjona Francisco M. , Raynaud Sandy , Ragel Paula , Mérida Ángel
Published: August 2014

Starch synthesis requires the formation of a primer that can be subsequently elongated and branched. How this primer is produced, however, remains unknown. The control of the number of starch granules produced per chloroplast is also a matter of debate. We previously showed starch synthase 4 (SS4) to be involved in both processes, although the mechanisms involved are yet to be fully characterised. The present work shows that SS4 displays a specific localization different from other starch synthases. Thus, this protein is located in specific areas of the thylakoid membrane and interacts with the proteins fibrillin 1a (FBN1a) and 1b (FBN1b), which are mainly located in plastoglobules. SS4 would seem to be associated with plastoglobules attached to the thylakoids (or to that portion of the thylakoids where plastoglobules have originated), forming a complex that includes the FBN1s and other as‐yet unidentified proteins. The present results also indicate that the localization pattern of SS4, and its interactions with the FBN1 proteins, are mediated through its N‐terminal region, which contains two long coiled‐coil motifs. The localization of SS4 in specific areas of the thylakoid membrane suggests that starch granules are originated at specific regions of the chloroplast.
Manipulation of flavour and aroma compound sequestration and release using a glycosyltransferase with specificity for terpene alcohols
Authors: Yauk Yar‐Khing , Ged Claire , Wang Mindy Y. , Matich Adam J. , Tessarotto Lydie , Cooney Janine M. , Chervin Christian , Atkinson Ross G.
Published: August 2014

Glycosides are an important potential source of aroma and flavour compounds for release as volatiles in flowers and fruit. The production of glycosides is catalysed by UDP‐glycosyltransferases (UGTs) that mediate the transfer of an activated nucleotide sugar to acceptor aglycones. A screen of UGTs expressed in kiwifruit (Actinidia deliciosa) identified the gene AdGT4 which was highly expressed in floral tissues and whose expression increased during fruit ripening. Recombinant AdGT4 enzyme glycosylated a range of terpenes and primary alcohols found as glycosides in ripe kiwifruit. Two of the enzyme's preferred alcohol aglycones, hexanol and (Z)‐hex‐3‐enol, contribute strongly to the ‘grassy‐green’ aroma notes of ripe kiwifruit and other fruit including tomato and olive. Transient over‐expression of AdGT4 in tobacco leaves showed that enzyme was able to glycosylate geraniol and octan‐3‐ol in planta whilst transient expression of an RNAi construct in Actinidia eriantha fruit reduced accumulation of a range of terpene glycosides. Stable over‐expression of AdGT4 in transgenic petunia resulted in increased sequestration of hexanol and other alcohols in the flowers. Transgenic tomato fruit stably over‐expressing AdGT4 showed changes in both the sequestration and release of a range of alcohols including 3‐methylbutanol, hexanol and geraniol. Sequestration occurred at all stages of fruit ripening. Ripe fruit sequestering high levels of glycosides were identified as having a less intense, earthier aroma in a sensory trial. These results demonstrate the importance of UGTs in sequestering key volatile compounds in planta and suggest a future approach to enhancing aromas and flavours in flowers and during fruit ripening.
Constructing supersingular elliptic curves with a given endomorphism ring
Authors: Chevyrev Ilya , Galbraith Steven D.
Published: August 2014

Let $\def \xmlpi #1{}\def \mathsfbi #1{\boldsymbol {\mathsf {#1}}}\let \le =\leqslant \let \leq =\leqslant \let \ge =\geqslant \let \geq =\geqslant \def \Pr {\mathit {Pr}}\def \Fr {\mathit {Fr}}\def \Rey {\mathit {Re}}\mathcal{O}$ be a maximal order in the quaternion algebra $B_p$ over $\mathbb{Q}$ ramified at $p$ and $\infty $. The paper is about the computational problem: construct a supersingular elliptic curve $E$ over $\mathbb{F}_p$ such that ${\rm End}(E) \cong \mathcal{O}$. We present an algorithm that solves this problem by taking gcds of the reductions modulo $p$ of Hilbert class polynomials.

New theoretical results are required to determine the complexity of our algorithm. Our main result is that, under certain conditions on a rank three sublattice $\mathcal{O}^T$ of $\mathcal{O}$, the order $\mathcal{O}$ is effectively characterized by the three successive minima and two other short vectors of $\mathcal{O}^T\! .$ The desired conditions turn out to hold whenever the $j$-invariant $j(E)$, of the elliptic curve with ${\rm End}(E) \cong \mathcal{O}$, lies in $\mathbb{F}_p$. We can then prove that our algorithm terminates with running time $O(p^{1+\varepsilon })$ under the aforementioned conditions.

As a further application we present an algorithm to simultaneously match all maximal order types with their associated $j$-invariants. Our algorithm has running time $O(p^{2.5 + \varepsilon })$ operations and is more efficient than Cerviño’s algorithm for the same problem.
Constructing abelian surfaces for cryptography via Rosenhain invariants
Authors: Costello Craig , Deines-Schartz Alyson , Lauter Kristin , Yang Tonghai
Published: August 2014

This paper presents an algorithm to construct cryptographically strong genus $\def \xmlpi #1{}\def \mathsfbi #1{\boldsymbol {\mathsf {#1}}}\let \le =\leqslant \let \leq =\leqslant \let \ge =\geqslant \let \geq =\geqslant \def \Pr {\mathit {Pr}}\def \Fr {\mathit {Fr}}\def \Rey {\mathit {Re}}2$ curves and their Kummer surfaces via Rosenhain invariants and related Kummer parameters. The most common version of the complex multiplication (CM) algorithm for constructing cryptographic curves in genus 2 relies on the well-studied Igusa invariants and Mestre’s algorithm for reconstructing the curve. On the other hand, the Rosenhain invariants typically have much smaller height, so computing them requires less precision, and in addition, the Rosenhain model for the curve can be written down directly given the Rosenhain invariants. Similarly, the parameters for a Kummer surface can be expressed directly in terms of rational functions of theta constants. CM-values of these functions are algebraic numbers, and when computed to high enough precision, LLL can recognize their minimal polynomials. Motivated by fast cryptography on Kummer surfaces, we investigate a variant of the CM method for computing cryptographically strong Rosenhain models of curves (as well as their associated Kummer surfaces) and use it to generate several example curves at different security levels that are suitable for use in cryptography.
Intestinal regulation of urinary sodium excretion and the pathophysiology of diabetic kidney disease: a focus on glucagon‐like peptide 1 and dipeptidyl peptidase 4
Authors: Vallon Volker , Docherty Neil G.
Published: August 2014

New Findings

What is the topic of this review?

This review describes how hyperglycaemia and attendant increases in proximal tubular growth and sodium reclamation form the mechanistic basis for the tubular hypothesis of hyperfiltration and nephropathy in the kidneys of patients with diabetes. The review highlights how signals arising from the gastrointestinal tract may be capable of modulating this response and how pharmacological enhancement of these signals may ameliorate the progression of diabetic kidney disease.

What advances does it highlight?

The review highlights the potential of glucagon‐like peptide 1 analogues, glucagon‐like peptide 1 receptor agonists and dipeptidyl peptidase 4 inhibitors to exercise renoprotective effects in diabetes independent of their classical effects on endocrine pancreas.

The tubular hypothesis of glomerular filtration and nephropathy in diabetes is a pathophysiological concept that assigns a critical role to the tubular system, including proximal tubular hyper‐reabsorption and growth, which is relevant for early glomerular hyperfiltration and later chronic kidney disease. Here we focus on how harnessing the bioactivity of hormones released from the gut may ameliorate the early effects of diabetes on the kidney in part by attenuating proximal tubular hyper‐reabsorption and growth. The endogenous tone of the glucagon‐like peptide 1 (GLP‐1)/GLP‐1 receptor (GLP‐1R) system and its pharmacological activation are nephroprotective in diabetes independent of changes in blood glucose. This is associated with suppression of increases in kidney weight and glomerular hyperfiltration, which may reflect, at least in part, its inhibitory effects on tubular hyper‐reabsorption and growth. Inhibition of dipeptidyl peptidase 4 (DPP‐4) is also nephroprotective independent of changes in blood glucose and involves GLP‐1/GLP‐1R‐dependent and ‐independent mechanisms. The GLP‐1R agonist exendin‐4 induces natriuresis via activation of the GLP‐1R. In contrast, DPP4 inhibition increases circulating GLP‐1, but drives a GLP‐1R‐independent natriuretic response, implying a role for other DPP‐4 substrates. The extent to which the intrarenal DPP‐4/GLP‐1 receptor system contributes to all these changes remains to be established, as does the direct impact of the system on renal inflammation.
Targeting cellular drivers and counter‐regulators of hyperglycaemia‐ and transforming growth factor‐β1‐associated profibrotic responses in diabetic kidney disease
Authors: Docherty Neil G. , Murphy Madeline , Martin Finian , Brennan Eoin P. , Godson Catherine
Published: August 2014

New Findings

What is the topic of this review?

Through reference to specific lines of investigation, this review sets out the case for how understanding the drivers and endogenous counter‐regulators of inflammatory and fibrotic responses can identify novel targets for inhibition or mimicry in diabetic kidney disease.

What advances does it highlight?

The review highlights the potential of induced in high glucose‐1 (IHG‐1) and induced in high glucose‐2 (IHG‐2/Grem1) to act as drugable targets in transforming growth factor‐β superfamily signalling in diabetic kidney disease. It also describes the preclinical evidence base for the fibrosupressant effects of the resolvent lipoxin series of eicosanoids in diabetic kidney disease, highlighting the role of a novel and specific microRNA‐based effect on transforming growth factor‐β1 signalling.

Diabetic kidney disease occurs in >30% of patients with type 2 diabetes mellitus and is characterized at source by a maladaptive response in the renal parenchyma to exposure to a glucotoxic–lipotoxic diabetic milieu that courses coincident with hypertension. The consequence of these maladaptive responses is progressive renal injury, which is exacerbated by the development of a chronic inflammatory infiltrate associated with the development of tubulointerstitial fibrosis. The evolution of tubulointerstitial fibrosis is correlated with the loss of functional renal mass and descent towards renal failure. Transforming growth factor‐β1 (TGF‐β1) is a recognized mediator of the profibrotic response of mesangial cells and renal tubular epithelial cells to hyperglycaemia. While euglycaemia remains the goal in the treatment of type 2 diabetes mellitus, the prevention, arrest and reversal of microvascular complications, such as diabetic kidney disease, may be assisted by pharmacological modulation of the effectors of glucotoxicity, such as TGF‐β1. This review focuses on describing how, through reductionist in vitro experimentation focusing on TGF‐β1‐related responses to hyperglycaemia, we have identified induced in high glucose‐1 (IHG‐1), induced in high glucose‐2 (IHG‐2/Grem1) and the lipoxin‐inducible microRNA let‐7c as potential targets for harnessing new therapeutic approaches to limit the bioactivity of TGF‐β1 in diabetic kidney disease.
Improvements in the metabolic milieu following Roux‐en‐Y gastric bypass and the arrest of diabetic kidney disease
Authors: Docherty Neil G. , le Roux Carel W.
Published: August 2014

New Findings

What is the topic of this review?

This review outlines the indications for use of Roux‐en‐Y gastric bypass as a bariatric and metabolic procedure, addressing the evidence and proposed mechanisms for improvements in the metabolic milieu and blood pressure control. Evidence to date supportive of a role for Roux‐en‐Y gastric bypass in the arrest of diabetic kidney disease follows with a perspective on mechanisms involved and their potential to be replicated in the non‐surgical setting.

What advances does it highlight?

The review highlights evidence supportive of the potential efficacy of Roux‐en‐Y gastric bypass in preventing progression of early diabetic kidney disease in patients with obesity and type 2 diabetes.

Roux‐en‐Y gastric bypass (RYGB) is an efficacious intervention for morbid obesity and has a diabetes‐remitting effect in patients with obesity and type 2 diabetes mellitus, which occurs prior to significant weight loss. Roux‐en‐Y gastric bypass is also associated with early and sustained reductions in the risk factor profile for the progression of diabetic complications. Attention is therefore now being placed on RYGB as a metabolic intervention with the capacity to yield therapeutic benefit in relation to the progression of diabetic complications, such as diabetic kidney disease. As alterations in gut anatomy following RYGB coincide with attendant shifts in downstream enteroendocrine signals with direct and indirect resolutionary effects on the kidney, the concept of an endocrine gut–kidney axis post‐RYGB is growing. With the model of a gut–kidney axis in mind, this article summarizes emerging data on the effects of RYGB on risk factors for diabetic kidney disease (hyperglycaemia, dyslipidaemia and hypertension), highlighting a potential role for glucagon‐like peptide 1 in risk factor reduction.
Advanced onset of puberty after metformin therapy in swine with thrifty genotype
Authors: Astiz S. , Gonzalez‐Bulnes A. , Astiz I. , Barbero A. , Perez‐Solana M.L. , Garcia‐Real I.
Published: August 2014

New Findings

What is the central question of this study?

What is the effect of prepuberal metformin therapy and lifestyle in an obese swine model (Iberian gilts) with thrifty genotype on patterns of growth, fattening, metabolic status and attainment of puberty?

What is the main finding and its importance?

An obesogenic diet had deleterious effects on corpulence, adiposity and metabolic parameters. These features were favourably modulated by adequate lifestyle and metformin treatment, which favoured muscle deposition. However, metformin advanced the onset of puberty, which would be a negative effect. This provides a warning about the use of metformin, without further studies, in girls from ethnicities with thrifty genotype.

The prevention and treatment of obesity in children is based on adequate nutrition and exercise plus antihyperglycaemic drugs. Currently, the incidence of childhood obesity is aggravated in ethnicities with thrifty genotype, but there is no available information on the effects of metformin therapy. The relative effects of lifestyle and metformin on patterns of growth, fattening, metabolic status and attainment of puberty were assessed in females of an obese swine model (Iberian gilts), allocated to three experimental groups (group A, obesogenic diet and scarce exercise; group DE, adequate diet and opportunity for exercise; and group DEM, adequate diet and opportunity for exercise plus metformin). Group A evidenced high weight, corpulence and adiposity, high plasma triglycerides and impairments of glucose regulation predisposing to insulin resistance. These features were favourably modulated by adequate lifestyle (group DE), and these effects were strengthened by metformin treatment (group DEM), which induced an improvement in body development by favouring muscle deposition. However, contrary to expectations, metformin advanced the onset of puberty. Metformin treatments would have positive effects on growth patterns, adiposity and metabolic features of young females from ethnicities with thrifty genotype or developing leptin resistance, but a negative effect by advancing the attainment of puberty. This study provides a warning regarding the use of metformin, without further studies, in girls from these ethnicities.
ON‐pathway‐dominant glycinergic regulation of cholinergic amacrine cells in the mouse retina
Authors: Ishii Toshiyuki , Kaneda Makoto
Published: August 2014

Key points

Starburst amacrine cells (SACs) in the retina play a key role for the formation of direction selectivity and considered a good model of neural computation.

Although SACs distribute in both ON‐ and OFF‐pathway, only the physiological properties of SACs in ON‐pathway have been well characterized.

As the physiological properties of SACs in the OFF‐pathway were not well known, in this study, we directly compared the inputs of SACs in ON‐ and OFF‐pathways.

Here we report a novel finding that glycinergic inputs onto SACs were ON‐pathway dominant, while glutamatergic inputs were equivalent between ON‐ and OFF‐pathway.

Our results suggest that fully defining the physiological properties of SACs in both ON‐ and OFF‐pathway will be critical to understanding and modelling direction selectivity in the retina.

Direction selectivity in the retina has been studied as a model of dendritic computation of neural circuits. Starburst amacrine cells (SACs) have been examined as a model system of dendritic computation as they play a pivotal role in the formation of direction selectivity. Because the difference of anatomical location inside the retina made ON‐SACs an easier target to record, the biophysical properties of ON‐SACs have been used to predict those of OFF‐SACs. In this study, we systematically compared the responses of ON‐ and OFF‐SACs to the two principal neurotransmitters, glycine and glutamate. We found that responses to glycine were significantly larger in ON‐SACs than in OFF‐SACs. In contrast, ON‐ and OFF‐SACs responded similarly to glutamate. The amplitude of glycine responses in ON‐SACs increased after eye opening and the largest amplitude was observed at postnatal day 28. On the other hand, no increase in the amplitude of glycine responses in OFF‐SACs was observed until postnatal day 28. Glycine‐evoked currents were inhibited by the application of strychnine. Glutamate‐evoked currents were mimicked by the application of AMPA or kainite, and responses to N‐methyl‐d‐aspartate were observed in the absence of Mg2+ block. Glutamate‐evoked currents produced an increase in the frequency of GABAergic inhibitory postsynaptic currents. Our results suggest that signal processing in ON‐SACs cannot be directly used to understand the properties of OFF‐SACs. Therefore fully defining the physiological properties of OFF‐SACs will be critical to understanding and modelling direction selectivity in the retina.
Increased cardiac output, not pulmonary artery systolic pressure, increases intrapulmonary shunt in healthy humans breathing room air and 40% O2
Authors: Elliott Jonathan E. , Duke Joseph W. , Hawn Jerold A. , Halliwill John R. , Lovering Andrew T.
Published: August 2014

Key points

The contribution of blood flow through intrapulmonary arteriovenous anastomoses (IPAVAs) to pulmonary gas exchange efficiency remains unknown and controversial.

Intravenous infusion of adrenaline (epinephrine) increases blood flow through IPAVAs detected by the transpulmonary passage of saline contrast and breathing 40% O2 minimizes potential contributions from ventilation‐to‐perfusion inequality and diffusion limitation.

Pulmonary gas exchange efficiency was impaired to the same degree, and the transpulmonary passage of saline contrast was not different, in humans at rest during the intravenous infusion of adrenaline before and after atropine when breathing room air and 40% O2.

Cardiac output increased to the same degree during intravenous infusion of adrenaline before and after atropine, but pulmonary artery systolic pressure only increased significantly before atropine.

These data demonstrate that blood flow through IPAVAs contributes to pulmonary gas exchange efficiency and that blood flow through IPAVAs is predominantly mediated by increases in cardiac output rather than increases in pulmonary artery systolic pressure.

Blood flow through intrapulmonary arteriovenous anastomoses (IPAVAs) has been demonstrated to increase in healthy humans during a variety of conditions; however, whether or not this blood flow represents a source of venous admixture (/) that impairs pulmonary gas exchange efficiency (i.e. increases the alveolar‐to‐arterial difference (A–aDO2)) remains controversial and unknown. We hypothesized that blood flow through IPAVAs does provide a source of /. To test this, blood flow through IPAVAs was increased in healthy humans at rest breathing room air and 40% O2: (1) during intravenous adrenaline (epinephrine) infusion at 320 ng kg−1 min−1 (320 ADR), and (2) with vagal blockade (2 mg atropine), before and during intravenous adrenaline infusion at 80 ng kg−1 min−1 (ATR + 80 ADR). When breathing room air the A–aDO2 increased by 6 ± 2 mmHg during 320 ADR and by 5 ± 2 mmHg during ATR + 80 ADR, and the change in calculated / was +2% in both conditions. When breathing 40% O2, which minimizes contributions from diffusion limitation and alveolar ventilation‐to‐perfusion inequality, the A–aDO2 increased by 12 ± 7 mmHg during 320 ADR, and by 9 ± 6 mmHg during ATR + 80 ADR, and the change in calculated / was +2% in both conditions. During 320 ADR cardiac output () and pulmonary artery systolic pressure (PASP) were significantly increased; however, during ATR + 80 ADR only was significantly increased, yet blood flow through IPAVAs as detected with saline contrast echocardiography was not different between conditions. Accordingly, we suggest that blood flow through IPAVAs provides a source of intrapulmonary shunt, and is mediated primarily by increases in rather than PASP.
Direct inhibition of hypothalamic proopiomelanocortin neurons by dynorphin A is mediated by the μ‐opioid receptor
Authors: Pennock Reagan L. , Hentges Shane T.
Published: August 2014

Key points

Dynorphin A inhibits anorexigenic hypothalamic proopiomelanocortin neurons by activating a potassium conductance.

Although dynorphin A is considered selective for κ‐opioid receptors, the present data show that the dynorphin A‐induced potassium conductance is reversed by a μ‐opioid receptor‐selective antagonist and is absent in mice lacking functional μ‐opioid receptors.

Thus, μ‐opioid receptors mediate the inhibition of proopiomelanocortin neurons caused by dynorphin A, consistent with other studies showing that κ‐opioid receptor‐selective agonists and antagonists can act at the μ‐opioid receptor when used at sufficiently high concentrations.

The results indicate that if dynorphin A inhibits proopiomelanocortin neurons to increase food intake, it does so either by activating μ‐opioid receptors on these neurons or by inhibiting κ‐opioid receptors located in the presynaptic compartment of proopiomelanocortin neurons.

It has recently been shown that dynorphin A (Dyn A), an endogenous agonist of the κ‐opioid receptor (KOR), directly inhibits proopiomelanocortin (POMC) neurons in the hypothalamus through activation of G‐protein‐coupled inwardly rectifying K+ channels (GIRKs). This effect has been proposed to be mediated by the putative κ2‐opioid receptor (KOR‐2), and has been suggested as a possible mechanism for the orexigenic actions of KOR agonists. Using whole‐cell voltage clamp recordings in brain slice preparations, the present study demonstrates that Dyn A (1 or 5 μm) induces an outward current in POMC neurons that is reversed by the highly selective μ‐opioid receptor (MOR) antagonist CTAP and is absent in mice lacking MORs. Additionally, the KOR‐2‐selective agonist GR89696 binds MORs on POMC neurons but fails to induce an outward current. Similar to Dyn A, the KOR‐selective antagonist nor‐binaltorphimine (nor‐BNI) lacked specificity when used at sufficiently high concentrations. Maximal concentrations of the MOR‐selective agonist DAMGO induced outward currents in POMC neurons that were completely reversed by a relatively high concentration of nor‐BNI. Experiments using a half‐maximal concentration of DAMGO demonstrate that nor‐BNI must be used at concentrations <100 nm to avoid non‐specific actions of the antagonist at MORs located on POMC neurons. These data suggest that direct inhibition of POMC neurons by Dyn A is mediated through the MOR, not the KOR‐2, which is consistent with previous studies demonstrating that Dyn A can act at the μ‐opioid receptor (MOR) when present in high concentrations.
Fine spatiotemporal activity in contracting myometrium revealed by motion‐corrected calcium imaging
Authors: Loftus Fiona C. , Shmygol Anatoly , Richardson Magnus J. E.
Published: August 2014

Key points

Calcium indicator fluorescence imaging is a key tool for investigating the physiological mechanisms that initiate and regulate myometrial contractions. However, inhomogeneous tissue motion severely limits the effective spatial resolution of measurable calcium activity.

We present an image analysis method that locally tracks contractions to produce a complete description of tissue‐wide motion. This renders calcium signals measurable at the micrometre scale. Additionally, the method simultaneously extracts kinematics of the motion that will inform biomechanical models of contracting myometrium.

The method is demonstrated on calcium‐imaging datasets of contracting myometrium. Using the method, we observed significant heterogeneity in calcium activity and identified a characteristic length scale of 40–50 μm below which tissue motion remains locally homogeneous.

We provide freely available and modifiable code to process datasets affected by motion artefacts. The method has potential application to in vivo neuron imaging, as well as to calcium imaging of other smooth muscle tissue.

Successful childbirth depends on the occurrence of precisely coordinated uterine contractions during labour. Calcium indicator fluorescence imaging is one of the main techniques for investigating the mechanisms governing this physiological process and its pathologies. The effective spatiotemporal resolution of calcium signals is, however, limited by the motion of contracting tissue: structures of interest in the order of microns can move over a hundred times their width during a contraction. The simultaneous changes in local intensity and tissue configuration make motion tracking a non‐trivial problem in image analysis and confound many of the standard techniques. This paper presents a method that tracks local motion throughout the tissue and allows for the almost complete removal of motion artefacts. This provides a stabilized calcium signal down to a pixel resolution, which, for the data examined, is in the order of a few microns. As a byproduct of image stabilization, a complete kinematic description of the contraction–relaxation cycle is also obtained. This contains novel information about the mechanical response of the tissue, such as the identification of a characteristic length scale, in the order of 40–50 μm, below which tissue motion is homogeneous. Applied to our data, we illustrate that the method allows for analyses of calcium dynamics in contracting myometrium in unprecedented spatiotemporal detail. Additionally, we use the kinematics of tissue motion to compare calcium signals at the subcellular level and local contractile motion. The computer code used is provided in a freely modifiable form and has potential applicability to in vivo calcium imaging of neural tissue, as well as other smooth muscle tissue.