bluuebunny/crossref_metadata_2025 huggingface dataset:
The red macroalgae Asparagopsis taxiformis is a potent natural antimethanogenic that reduces methane production during in vitro fermentation with rumen fluid
Authors: Kinley Robert D. , de Nys Rocky , Vucko Matthew J. , Machado Lorenna , Tomkins Nigel W.
Published: February 2016

Livestock feed modification is a viable method for reducing methane emissions from ruminant livestock. Ruminant enteric methane is responsible approximately to 10% of greenhouse gas emissions in Australia. Some species of macroalgae have antimethanogenic activity on in vitro fermentation. This study used in vitro fermentation with rumen inoculum to characterise increasing inclusion rates of the red macroalga Asparagopsis taxiformis on enteric methane production and digestive efficiency throughout 72-h fermentations. At dose levels ≤1% of substrate organic matter there was minimal effect on gas and methane production. However, inclusion ≥2% reduced gas and eliminated methane production in the fermentations indicating a minimum inhibitory dose level. There was no negative impact on substrate digestibility for macroalgae inclusion ≤5%, however, a significant reduction was observed with 10% inclusion. Total volatile fatty acids were not significantly affected with 2% inclusion and the acetate levels were reduced in favour of increased propionate and, to a lesser extent, butyrate which increased linearly with increasing dose levels. A barrier to commercialisation of Asparagopsis is the mass production of this specific macroalgal biomass at a scale to provide supplementation to livestock. Another area requiring characterisation is the most appropriate method for processing (dehydration) and feeding to livestock in systems with variable feed quality and content. The in vitro assessment method used here clearly demonstrated that Asparagopsis can inhibit methanogenesis at very low inclusion levels whereas the effect in vivo has yet to be confirmed.
Effects of tea seed saponin supplementation on physiological changes associated with blood methane concentration in tropical Brahman cattle
Authors: Ramírez-Restrepo C. A. , O'Neill C. J. , López-Villalobos N. , Padmanabha J. , Wang J. K. , McSweeney C.
Published: February 2016

A 59-day experiment compared the effects of increasing tea seed (Camellia sinensis L.) saponin (TSS) supplementation on dry matter intake (DMI), liveweight (LW), rumen fermentation, methanogenesis, blood biochemistry and animal tolerance. Six, 10, 15, 20, 25 and 30 g of powder TSS were dissolved during 5, 7, 4, 3, 3 and 2 days, respectively, and infused into the rumen of four rumen-cannulated Brahman steers (234 ± 13.6 kg LW; least-squares means ± s.e.m.) or mixed in the basal diet [BD: 0.15 Rhodes grass (Chloris gayana) hay plus a high-grain feed (0.85)] of two non-cannulated (253 ± 19.3 kg) steers. Overall, DMI was not affected, by the sequential infusion of TSS (5.3 ± 0.15 kg) or addition to the BD (5.4 ± 0.18 kg), but relative to all diets, 6 g of TSS supplementation reduced DMI (P < 0.05), while the administration above 30 g of the supplement was associated with significantly (P < 0.001) reduced DMI, scours and bloat disorders. Clinical symptoms disappeared 8 days after withdrawal of the supplement. LW increased with time (P < 0.05) and the final LW was similar for cannulated (258 ± 13.6 kg) and non-cannulated (276 ± 19.3 kg) steers. Saponin supplementation reduced total volatile fatty acid (VFA) concentration (P < 0.05), modified pattern of individual molar VFA concentrations and moderately increased ruminal pH (P < 0.05). Cannulated and non-cannulated steers fed the BD had similar daily (g) methane or yield (CH4 g/kg DMI) emissions while in respiratory chambers. However, compared with cannulated (8.0 ± 1.20 ng/mL) animals, the addition of 30 g of TSS in the BD increased (P < 0.01) blood CH4 concentration in non-cannulated (15.6 ± 1.74 ng/mL) animals. Diets supplemented with 30 g of TSS were associated with higher chloride (P < 0.01) and alkaline phosphatase (P < 0.05) blood concentrations, and lower serum concentrations of potassium and urea nitrogen (P < 0.01), iron and total lipase (P < 0.05), than was the BD. It was concluded that higher levels of TSS supplement may evoke physiological changes in the animal. However, the potential CH4 mitigation effect of this form of saponin in tropical cattle needs further investigation, alongside the derived response of the rumen microbial ecology to the tested range of supplementation.
Milk mid-infrared spectra enable prediction of lactation-stage-dependent methane emissions of dairy cattle within routine population-scale milk recording schemes
Authors: Vanlierde Amélie , Vanrobays Marie-Laure , Gengler Nicolas , Dardenne Pierre , Froidmont Eric , Soyeurt Hélène , McParland Sinead , Lewis Eva , Deighton Matthew H. , Mathot Michaël , Dehareng Frédéric
Published: February 2016

Mitigating the proportion of energy intake lost as methane could improve the sustainability and profitability of dairy production. As widespread measurement of methane emissions is precluded by current in vivo methods, the development of an easily measured proxy is desirable. An equation has been developed to predict methane from the mid-infrared (MIR) spectra of milk within routine milk-recording programs. The main goals of this study were to improve the prediction equation for methane emissions from milk MIR spectra and to illustrate its already available usefulness as a high throughput phenotypic screening tool. A total of 532 methane measurements considered as reference data (430 ± 129 g of methane/day) linked with milk MIR spectra were obtained from 165 cows using the SF6 technique. A first derivative was applied to the MIR spectra. Constant (P0), linear (P1) and quadratic (P2) modified Legendre polynomials were computed from each cows stage of lactation (days in milk), at the day of SF6 methane measurement. The calibration model was developed using a modified partial least-squares regression on first derivative MIR data points × P0, first derivative MIR data points × P1, and first derivative MIR data points × P2 as variables. The MIR-predicted methane emissions (g/day) showed a calibration coefficient of determination of 0.74, a cross-validation coefficient of determination of 0.70 and a standard error of calibration of 66 g/day. When applied to milk MIR spectra recorded in the Walloon Region of Belgium (≈2 000 000 records), this equation was useful to study lactational, annual, seasonal, and regional methane emissions. We conclude that milk MIR spectra has potential to be used to conduct high throughput screening of lactating dairy cattle for methane emissions. The data generated enable monitoring of methane emissions and production characteristics across and within herds. Milk MIR spectra could now be used for widespread screening of dairy herds in order to develop management and genetic selection tools to reduce methane emissions.
Gas emissions from dairy barnyards
Authors: Powell J. M. , Vadas P. A.
Published: February 2016

Dairy cattle spend considerable time in outside barnyards. Nine barnyards were constructed to examine impacts of surface materials (bark, sand, soil) and timing of cattle corralling (before and after 3–14-day corralling periods) on fluxes of carbon dioxide (CO2), methane (CH4), ammonia (NH3), nitrous oxide (N2O) and CO2 equivalents (CO2eq). Surface, year, and surface*year interactions accounted for 64%, 6% and 16% of CO2 flux variability. Average CO2 flux from bark (2552 mg/m2.h) was 3.1–3.9 times greater than from sand or soil, especially after bark replenishment. Timing, year, timing*year and surface*year accounted for 40%, 17%, 14%, and 17% of CH4 variability. Average CH4 flux after corralling (10.6 mg/m2.h) was 3.8 times greater than before corralling, and 5.2 times greater the year following bark replenishment. Timing accounted for 67% of NH3 variability. After corralling, NH3 fluxes (1622 µg/m2.h) were 95 times greater than before corralling. Timing, surface, surface*timing and timing*year accounted for 33%, 10%, 24% and 13% of N2O variability. Average N2O flux after corralling (2252 µg/m2.h) was 3.7 times greater than before corralling. Surface and surface*year accounted for 71% and 16% of CO2eq variability. Average CO2eq flux from bark (3188 mg/m2.h) was 2.5–3.0 times greater than sand or soil. Greatest CO2eq flux occurred the year after bark replenishment. Tradeoffs between gas emissions, nutrient runoff and leaching, and cow comfort and health need to be assessed more fully before recommending beneficial practices for barnyard surface type and management.
In vitro methane and gas production characteristics of Eragrostis trichopophora substrate supplemented with different browse foliage
Authors: Hassen Abubeker , Theart Jacobus Johannes Francois , Adriaan van Niekerk Willem , Adejoro Festus Adeyemi , Gemeda Belete Shenkute
Published: February 2016

An in vitro gas production study was conducted to evaluate the potential of six browse species (high, medium and low condensed tannin concentrations) collected from the Kalahari Desert as antimethanogenic additives to an Eragrostis trichopophora-based substrate. The browse species studied were Acacia luederitzii, Monechma incanum, Acacia erioloba, Acacia haematoxylon, Olea europaea and Acacia mellifera. The edible forage dry matter of the browse species were incubated with Eragrostis trichopophora in a 30 : 70 (w/w) ratio by adding 40 mL of a buffered rumen fluid at 39°C for 48 h. Gas and methane production at different time intervals after incubation were determined whereas the volatile fatty acids concentration was evaluated after 48 h. Acacia luederitzii and M. incanum foliage decreased methane production by more than 50%, but simultaneously decreased digestibility, and rumen fermentation parameters such as volatile fatty acids concentration. Tannin extracts from A. luederitzii could possibly be used as a dietary alternative to reduce methane production; however, there is a need to determine an optimum level of inclusion that may not compromise the efficiency of rumen fermentation and overall digestibility of the diet.
Disentangling the effect of sheep urine patch size and nitrogen loading rate on cumulative N2O emissions
Authors: Marsden Karina A. , Jones Davey L. , Chadwick David R.
Published: February 2016

Ruminant urine nitrogen (N) concentration and volume are important parameters influencing the size and N loading rate of urine patches deposited to soil. Such parameters can influence N cycling and emissions of the greenhouse gas, nitrous oxide (N2O) from grazed grassland, yet, there is limited information on the effect of these parameters within typical ranges reported for sheep. We used an automated, high-frequency gas monitoring system to investigate N2O emissions from varying urine N application rates and patch sizes under field conditions. Using artificial sheep urine, we manipulated urine N concentration to provide two urine N application rates (4 and 16 g N/L; equivalent to 200 and 800 kg N/ha). We investigated the effect of urine patch size with equal N application rates (4 × 125 cm2 vs 500 cm2, at 200 and 800 kg N/ha) and the effect of patch size with unequal N application rates, but the same total amount of N applied (62.5 mL over 125 cm2 at 800 kg N/ha and 250 mL over 500 cm2 at 200 kg N/ha). Cumulative emissions of N2O generally increased with N loading rate, whether applied as one large urine patch or four smaller ones. Cumulative N2O emissions increased when the N was applied in four smaller urine patches compared with one large patch; this difference was significant at 800 kg N/ha, but not at 200 kg N/ha. When the total amount of N applied was held constant (1 g of N), the amount of N2O released was similar when urine was applied as a high N concentration small patch (800 kg N/ha) compared with a low N concentration large patch (200 kg N/ha). Urine N2O emission factors in this study were, on average, 10 times lower than the IPCC default of 1% for sheep excreta. This research clearly demonstrates that the chemical and physical nature of the urine patch influences N2O emissions, yet further research is required to gather more data on typical sheep urine volumes (individual and daily), urination frequency, urine N concentrations and the typical volumes of soil influenced by urine deposition, to provide more accurate estimates of emissions from sheep grazed pastures.
Acidification with sulfur of the separated solid fraction of raw and co-digested pig slurry: effect on greenhouse gas and ammonia emissions during storage
Authors: Gioelli F. , Dinuccio E. , Cuk D. , Rollè L. , Balsari P.
Published: February 2016

A study was performed to assess: (1) the feasibility to acidify the separated solid fraction of raw and co-digested pig slurry by using a powdery sulfur-based product; and (2) the effect of this acidification method on greenhouse gases and ammonia emissions during manure storage. Samples of raw and co-digested pig slurry were collected at two commercial farms and mechanically separated by a laboratory-scale screw press device. The sulfur powder (80% concentration) was added to the obtained separated solid fractions at three application rates: 0.5%, 1% and 2% (w/w). Carbon dioxide, methane, nitrous oxide and ammonia emissions were afterwards measured during storage of the acidified samples and compared with those measured from untreated samples (Control). Gaseous emissions were determined with dynamic chamber method by Infrared Photoacoustic Detection. Gaseous losses were monitored along 30 and 60 days of storage time for raw solid fraction and digested solid fraction, respectively. The addition of the tested sulfur powder to solid fractions showed to be a reliable and effective method to acidify raw and co-digested solid fractions. Results showed a significant reduction of both greenhouse gases and ammonia emission regardless of the separated solid fraction type. The highest sulfur application rate (2% w/w) led to a reduction of up to 78% of greenhouse gas emission and 65% of ammonia losses from raw separated solid fraction when compared with the Control. Similar results were achieved from the co-digested solid fraction, with emission reduction of up to 67% for ammonia and 61% for greenhouse gas.
Cellular softening mediates leukocyte demargination and trafficking, thereby increasing clinical blood counts
Authors: Fay Meredith E. , Myers David R. , Kumar Amit , Turbyfield Cory T. , Byler Rebecca , Crawford Kaci , Mannino Robert G. , Laohapant Alvin , Tyburski Erika A. , Sakurai Yumiko , Rosenbluth Michael J. , Switz Neil A. , Sulchek Todd A. , Graham Michael D. , Lam Wilbur A.
Published: February 2016

Significance

Clinical hematologists have long known that antiinflammatory glucocorticoids such as dexamethasone and blood pressure-supporting catecholamines such as epinephrine cause leukocytes to demarginate from the vascular wall and microvasculature into the main circulation, significantly elevating the effective white blood cell count. Canonically, this has been attributed to down-regulation of adhesion molecules such as selectins, but we show that a purely mechanical phenomenon caused by leukocyte softening plays a major role as well. Our work provides an answer to an old hematological problem and reveals a mechanism in which the immune system simply alters leukocyte stiffness to regulate leukocyte trafficking. This has clinically relevant implications for the inflammatory process overall as well as for hematopoietic stem cell mobilization and homing.
Measuring the value of groundwater and other forms of natural capital
Authors: Fenichel Eli P. , Abbott Joshua K. , Bayham Jude , Boone Whitney , Haacker Erin M. K. , Pfeiffer Lisa
Published: February 2016

Significance

Economists have long argued, with recent acceptance from the science and policy community, that natural resources are capital assets. Pricing of natural capital has remained elusive, with the result that its value is often ignored, and expenditures on conservation are treated as costs rather than investments. This neglect stems from a lack of a valuation framework to enable apples to apples comparisons with traditional forms of capital. We develop such an approach and demonstrate it on Kansas’ groundwater stock. Between 1996 and 2005, groundwater withdrawal reduced Kansas’ wealth approximately $110 million per year. Wealth lost through groundwater depletion in Kansas is large, but in a range where offsetting investments may be feasible.
Cockroaches traverse crevices, crawl rapidly in confined spaces, and inspire a soft, legged robot
Authors: Jayaram Kaushik , Full Robert J.
Published: February 2016

Significance

Cockroaches intrude everywhere by exploiting their soft-bodied, shape-changing ability. We discovered that cockroaches traversed horizontal crevices smaller than a quarter of their height in less than a second by compressing their bodies’ compliant exoskeletons in half. Once inside vertically confined spaces, cockroaches still locomoted rapidly at 20 body lengths per second using an unexplored mode of locomotion—body-friction legged crawling. Using materials tests, we found that the compressive forces cockroaches experience when traversing the smallest crevices were 300 times body weight. Cockroaches withstood forces nearly 900 times body weight without injury, explaining their robustness to compression. Cockroach exoskeletons provided inspiration for a soft, legged search-and-rescue robot that may penetrate rubble generated by tornados, earthquakes, or explosions.
Isotopic evidence for primordial molecular cloud material in metal-rich carbonaceous chondrites
Authors: Van Kooten Elishevah M. M. E. , Wielandt Daniel , Schiller Martin , Nagashima Kazuhide , Thomen Aurélien , Larsen Kirsten K. , Olsen Mia B. , Nordlund Åke , Krot Alexander N. , Bizzarro Martin
Published: February 2016

Significance

Comets are pristine, volatile-rich objects formed beyond the orbits of the gas giants and, thus, thought to preserve a record of the primordial molecular cloud material parental to our Solar System. We use magnesium and chromium isotopes to show that a class of pristine chondrites, the metal-rich carbonaceous chondrites, has a signature distinct from most inner Solar System planets and asteroids. This signature is consistent with that predicted for unprocessed primordial molecular cloud material, suggesting that—similar to comets—metal-rich carbonaceous chondrites are samples of asteroids that accreted in the outer Solar System. Therefore, these objects may provide a direct window into the formation history of the outer Solar System.
Warning signals are under positive frequency-dependent selection in nature
Authors: Chouteau Mathieu , Arias Mónica , Joron Mathieu
Published: February 2016

Significance

Warning coloration and defensive mimicry are textbook examples of antipredator strategies under frequency-dependent selection (FDS), where predators avoid defended prey that are common but attack rarer ones. Whether the efficiency of mimicry truly derives from positive FDS remains unverified, yet assessing FDS is essential for understanding the diversity of warning signals observed. Using wing patterns found in natural communities of toxic butterflies, we demonstrate that warning signals are under strong, nonlinear, positive FDS. Predator knowledge is saturated and protection is optimal only for a few superabundant prey types. Most warning signals fall below optimal protection, limited by their local abundance. This potential for improved protection may explain the extraordinary efficiency of selection to drive convergence in morphology and life history in mimetic prey.
Aberrant activation of canonical Notch1 signaling in the mouse uterus decreases
progesterone receptor
by hypermethylation and leads to infertility
Authors: Su Ren-Wei , Strug Michael R. , Jeong Jae-Wook , Miele Lucio , Fazleabas Asgerally T.
Published: February 2016

Significance

These studies show a physiological role for Notch signaling in female reproduction. The fact that both loss and gain of function of Notch signaling result in the impairment of early pregnancy identifies Notch1 signaling as a critical regulator of endometrial function. We also provide the first evidence, to our knowledge, that Notch signaling can regulate methylation of exon 1 of the progesterone receptor (
Pgr
) gene through its target PU.1, which provides novel insight into the role of Notch in steroid hormone regulation. This mechanism also provides an opportunity for future studies in identifying the cause of progesterone resistance in gynecological pathologies in women, such as endometriosis and adenomyosis, in which the hypermethylation of
Pgr
has been reported.
Adaptive methylation regulation ofp53pathway in sympatric speciation of blind mole rats,Spalax
Authors: Zhao Yang , Tang Jia-Wei , Yang Zhi , Cao Yi-Bin , Ren Ji-Long , Ben-Abu Yuval , Li Kexin , Chen Xue-Qun , Du Ji-Zeng , Nevo Eviatar
Published: February 2016

Significance

p53has been shown to play important roles in environmental adaptive evolution. Here we show that p53 and its target genes express differentially between two abutting populations of the blind mole ratSpalax galiliduring its sympatric speciation caused by sharply divergent abutting ecologies of chalk and basalt. Remarkably, the differential expression ofp53is due to differing methylation on sites –1446, –1204, and –1086 of thep53promoter, which plays a key role in regulating the binding of several transcription factors including Cut-Like Homeobox 1, paired box 4 (Pax 4), Pax 6, and activator protein 1. Different expressions ofS. galili p53selectively changed adaptive cell-cycle arrest. This article provides evidence supporting the sympatric speciation ofS. galili, demonstrating the importance of epigenetic modifications in adaptive evolution.
Effective treatment of steatosis and steatohepatitis by fibroblast growth factor 1 in mouse models of nonalcoholic fatty liver disease
Authors: Liu Weilin , Struik Dicky , Nies Vera J. M. , Jurdzinski Angelika , Harkema Liesbeth , de Bruin Alain , Verkade Henkjan J. , Downes Michael , Evans Ronald M. , van Zutphen Tim , Jonker Johan W.
Published: February 2016

Significance

Fibroblast growth factor 1 (FGF1) is critical for adipose tissue remodeling under conditions of dietary stress. Pharmacological treatment with recombinant FGF1 (rFGF1) has potent glucose-lowering, insulin-sensitizing, and antisteatotic effects in hyperglycemic mouse models, but the mechanism is largely unknown. Here we characterize the effects of rFGF1 on nonalcoholic liver disease in two etiologically different mouse models. Strong antisteatotic effects of rFGF1 were observed in
ob/ob
mice but not in choline-deficient mice, suggesting that rFGF1 exerts its antisteatotic effect via processes specifically impaired in choline-deficient mice, such as lipid oxidation and lipoprotein secretion. In contrast, hepatic inflammation and alanine aminotransferase levels were reduced in both models, indicating that these effects are independent of the antisteatotic properties of rFGF1.
Time-coded neurotransmitter release at excitatory and inhibitory synapses
Authors: Rodrigues Serafim , Desroches Mathieu , Krupa Martin , Cortes Jesus M. , Sejnowski Terrence J. , Ali Afia B.
Published: February 2016

Significance

Neurotransmitter exocytosis and short-term synaptic plasticity (STSP) regulate large-scale brain electrical activity. This study is the first, to our knowledge, proposing a multiple-time-scale model that bridges between the microscopic and mesoscopic scales. It is parsimonious, yet with enough descriptive power to express, on the one hand, the interactions between the SNARE and Sec1/Munc18 (SM) protein complexes mediating all forms of neurotransmitter release and STSP and, on the other hand, the electrical activity required for neuronal communication. A key finding is the discovery of a mathematical structure, termed activity-induced transcritical canard, which quantifies and explains delayed and irregular exocytosis. This structure also provides a previously unidentified way to understand delayed and irregular processes sensitive to initial conditions across various biology processes.
Self-targeting of TNF-releasing cancer cells in preclinical models of primary and metastatic tumors
Authors: Dondossola Eleonora , Dobroff Andrey S. , Marchiò Serena , Cardó-Vila Marina , Hosoya Hitomi , Libutti Steven K. , Corti Angelo , Sidman Richard L. , Arap Wadih , Pasqualini Renata
Published: February 2016

Significance

A recent paradigm shift has established “tumor cell seeding” as an intriguing biological phenomenon in cancer biology. However, the clinical implications of a bidirectional flow of cancer cells remains largely unexplored. We show that systemic administration of TNF-expressing cancer cells reduces growth of both primary tumors and metastatic colonies defined here as “tumor self-targeting.” Our findings support a provocative concept in which circulating tumor cells genetically manipulated ex vivo and readministered into the circulating bloodstream may indeed serve as tumor-targeted cellular vectors in preclinical settings and could potentially open a field of translational investigation.
A glutamate/aspartate switch controls product specificity in a protein arginine methyltransferase
Authors: Debler Erik W. , Jain Kanishk , Warmack Rebeccah A. , Feng You , Clarke Steven G. , Blobel Günter , Stavropoulos Pete
Published: February 2016

Significance

Posttranslational modifications in proteins profoundly modulate their function, and enzymes that generate these modifications therefore have key regulatory roles in a wide array of biological processes. Protein arginine methyltransferases (PRMTs) attach methyl group(s) to arginines and differ in their product specificity, as they form either monomethyl arginine (MMA), asymmetric dimethylarginine (ADMA), or symmetric dimethylarginine (SDMA), each of which relays specific biological signals. Although the members of the PRMT family are structurally highly homologous, the precise molecular basis of their product specificity has not been determined. Based on our structure of
Tb
PRMT7, which explicitly forms MMA, we identified a glutamate residue as a key determinant of its product specificity, and we were able to engineer a
Tb
PRMT7 mutant capable of ADMA formation.
Anti-myostatin antibody increases muscle mass and strength and improves insulin sensitivity in old mice
Authors: Camporez João-Paulo G. , Petersen Max C. , Abudukadier Abulizi , Moreira Gabriela V. , Jurczak Michael J. , Friedman Glenn , Haqq Christopher M. , Petersen Kitt Falk , Shulman Gerald I.
Published: February 2016

Significance

Sarcopenia, or aging-associated muscle atrophy, increases the risk of falls and fractures and is associated with metabolic disease. Because skeletal muscle is a major contributor to glucose handling after a meal, sarcopenia has significant effects on whole-body glucose metabolism. Despite the high prevalence and potentially devastating consequences of sarcopenia, no effective therapies are available. Here, we show that treatment of mice with an anti-myostatin antibody for just 4 wk increased muscle mass and strength in both young and old mice. In old mice, this increase in muscle mass was accompanied by an improvement in muscle insulin sensitivity. These data provide support for myostatin inhibition as a potential therapeutic strategy for aging-associated sarcopenia and insulin resistance.
Iontophoretic device delivery for the localized treatment of pancreatic ductal adenocarcinoma
Authors: Byrne James D. , Jajja Mohammad R. N. , Schorzman Allison N. , Keeler Amanda W. , Luft J. Christopher , Zamboni William C. , DeSimone Joseph M. , Yeh Jen Jen
Published: February 2016

Significance

Drug delivery to pancreatic tumors is impaired by a unique desmoplastic response and poor tumor vascularization. A drug delivery device capable of overcoming these barriers could provide substantial benefit for patients with pancreatic cancer. In this study, we show that local iontophoretic delivery of folinic acid (leucovorin), fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX) resulted in better tumor response and tolerability compared with i.v. FOLFIRINOX. Given the low systemic exposure of FOLFIRINOX using iontophoretic delivery, it may be possible to use in combination with systemic delivery to treat micrometastatic disease. Local iontophoretic delivery of cytotoxic agents should be considered as a neoadjuvant approach to improve resection rates and outcome in patients with localized and locally advanced pancreatic cancer.
Plakophilin-2 loss promotes TGF-β1/p38 MAPK-dependent fibrotic gene expression in cardiomyocytes
Authors: Dubash Adi D. , Kam Chen Y. , Aguado Brian A. , Patel Dipal M. , Delmar Mario , Shea Lonnie D. , Green Kathleen J.
Published: February 2016

Members of the desmosome protein family are integral components of the cardiac area composita, a mixed junctional complex responsible for electromechanical coupling between cardiomyocytes. In this study, we provide evidence that loss of the desmosomal armadillo protein Plakophilin-2 (PKP2) in cardiomyocytes elevates transforming growth factor β1 (TGF-β1) and p38 mitogen-activated protein kinase (MAPK) signaling, which together coordinate a transcriptional program that results in increased expression of profibrotic genes. Importantly, we demonstrate that expression of Desmoplakin (DP) is lost upon PKP2 knockdown and that restoration of DP expression rescues the activation of this TGF-β1/p38 MAPK transcriptional cascade. Tissues from PKP2 heterozygous and DP conditional knockout mouse models also exhibit elevated TGF-β1/p38 MAPK signaling and induction of fibrotic gene expression in vivo. These data therefore identify PKP2 and DP as central players in coordination of desmosome-dependent TGF-β1/p38 MAPK signaling in cardiomyocytes, pathways known to play a role in different types of cardiac disease, such as arrhythmogenic or hypertrophic cardiomyopathy.
Metabolic regulation of mitochondrial dynamics
Authors: Mishra Prashant , Chan David C.
Published: February 2016

Mitochondria are renowned for their central bioenergetic role in eukaryotic cells, where they act as powerhouses to generate adenosine triphosphate from oxidation of nutrients. At the same time, these organelles are highly dynamic and undergo fusion, fission, transport, and degradation. Each of these dynamic processes is critical for maintaining a healthy mitochondrial population. Given the central metabolic function of mitochondria, it is not surprising that mitochondrial dynamics and bioenergetics reciprocally influence each other. We review the dynamic properties of mitochondria, with an emphasis on how these processes respond to cellular signaling events and how they affect metabolism.
Integrin β3 inhibition is a therapeutic strategy for supravalvular aortic stenosis
Authors: Misra Ashish , Sheikh Abdul Q. , Kumar Abhishek , Luo Jiesi , Zhang Jiasheng , Hinton Robert B. , Smoot Leslie , Kaplan Paige , Urban Zsolt , Qyang Yibing , Tellides George , Greif Daniel M.
Published: February 2016

The aorta is the largest artery in the body, yet processes underlying aortic pathology are poorly understood. The arterial media consists of circumferential layers of elastic lamellae and smooth muscle cells (SMCs), and many arterial diseases are characterized by defective lamellae and excess SMCs; however, a mechanism linking these pathological features is lacking. In this study, we use lineage and genetic analysis, pharmacological inhibition, explant cultures, and induced pluripotent stem cells (iPSCs) to investigate supravalvular aortic stenosis (SVAS) patients and/or elastin mutant mice that model SVAS. These experiments demonstrate that multiple preexisting SMCs give rise to excess aortic SMCs in elastin mutants, and these SMCs are hyperproliferative and dedifferentiated. In addition, SVAS iPSC-derived SMCs and the aortic media of elastin mutant mice and SVAS patients have enhanced integrin β3 levels, activation, and downstream signaling, resulting in SMC misalignment and hyperproliferation. Reduced β3 gene dosage in elastin-null mice mitigates pathological aortic muscularization, SMC misorientation, and lumen loss and extends survival, which is unprecedented. Finally, pharmacological β3 inhibition in elastin mutant mice and explants attenuates aortic hypermuscularization and stenosis. Thus, integrin β3–mediated signaling in SMCs links elastin deficiency and pathological stenosis, and inhibiting this pathway is an attractive therapeutic strategy for SVAS.
On the optimum processing conditions of Pb(ZrxTi1−x)O3: revealing the mechanisms to increase the piezoelectric coefficients up to 1100 pm V−1
Authors: Zeibekis M , Vertsioti G , Stamopoulos D
Published: February 2016

The ferroelectric compound family Pb(Zr
x
Ti1−x
)O3 (PZT) is one of the most investigated and widely used piezoelectric materials. Optimization of the piezoelectric coefficients is observed for x ~ 0.52 (Pb(Zr0.52Ti0.48)O3) and is further promoted by the increase of grain size (GS). However, in some cases the piezoelectric properties of Pb(Zr0.52Ti0.48)O3 deteriorate upon processing due to the decrease of density, ρ, that is mostly ascribed to the appearance of byproduct phases. In the present study we discuss the influence of the processing conditions on the piezoelectric properties for polycrystalline Pb(Zr0.52Ti0.48)O3, specifically focusing on the sintering temperature, 1100 °C  ⩽  T
sin  ⩽  1250 °C. To this end, we use atomic force microscopy (AFM), Archimedes’ method, x-ray diffraction (XRD) and a newly introduced local technique, based on a conventional optical microscope, which is further developed here to accommodate non-clamped specimens. The data obtained via this technique in the regime of relatively high electric fields evidence that the absolute piezoelectric coefficients, |d

zi
| (i  =  x, y) show a non-monotonic behavior with an unexpectedly high maximum value |d

zi
| ~ 1100 pm V−1 at T
sin  =  1180 °C. These features are accompanied by a progressive increase of coercivity, reaching maximum value E
C,i
~ 4.5–5.0 kV cm−1 (i  =  x, y) at T
sin  =  1250 °C. To explain these findings, the |d
zi
| coefficients are compared with the microstructure and compositional information, coming from AFM, Archimedes’ method and XRD data. We conclude that the significantly high |d

zi
| values observed for samples prepared at T
sin  =  1180 °C are motivated by the increase of mean GS, , while for T
sin  >  1180 °C the decrease of density, ρ, ascribed to the appearance of byproduct phases, dominates and deteriorates |d

zi
|. These experimental results on |d

zi
|(T
sin) are reliably reproduced by a phenomenological model with reasonable assumptions for    (T
sin) and ρ(T
sin). The unexpectedly high piezoelectric coefficients, |d

zi
| ~ 1100 pm V−1, reported here for the first time, are provocative and call for utilization of the introduced approach in the investigation of the respective properties of other compounds.
Spin polarisation using gate voltage through a Rashba barrier in graphene
Authors: Wu Xiuqiang
Published: February 2016

Gate-tunable spin-resolved scattering through a Rashba spin–orbit (SO) coupling graphene barrier is considered theoretically by using a mode-matching method. In this structure, we investigate the dependence of the tunnelling transmission probability on the spin orientation of the incident electron. It is found that the difference of the transmission probability for opposite spin orientations exhibits considerable incident-angle-dependent features when both gate voltage and Rashba SO coupling in the barrier region are present. The difference is adjustable by the gate voltage. More specifically, we find that the sign of spin polarisation of conductance can switch from positive to negative by adjusting the electric potential at any Rashba SO coupling. These results can provide an efficient way to design graphene spintronic devices without the need for ferromagnets.
Observation of the intrinsic rotation in KSTAR Ohmic L-mode plasmas
Authors: Na D.H. , Na Yong-Su , Lee S.G. , Angioni C. , Yang S.M. , Kim H.-S. , Hahm T.S. , Ko W.H. , Jhang H. , Lee W.J.
Published: February 2016

Two types of experiments were carried out to conduct an intrinsic rotation study in KSTAR. The first was a density ramp-up experiment without neutral beam injection, and the second was an experiment with beam blip technique. In these experiments, some characteristics of the intrinsic rotation were observed in the KSTAR Ohmic L-mode plasmas including: (i) a non-monotonic dependence of the core intrinsic rotation, called U-curve behaviour, with respect to the electron density and the collisionality related to the gradient of the toroidal rotation profile; and (ii) the behaviour of the anchor point in the intrinsic rotation profile for which the region exhibits a roughly flat shape and stays at nearly the same value even if the gradient of the toroidal rotation changes significantly in the core region. The location of the anchor point seems to be related to the q profile, and the toroidal rotation at the anchor point changes with the plasma operation parameters. These observations in the KSTAR Ohmic L-mode plasmas seem to be related to the rotation reversal phenomenon. A transport analysis was performed for the beam blip experiments in order to evaluate the intrinsic torque so that the U-curve behaviour can be further understood. The first results of the transport analysis in the KSTAR Ohmic L-mode plasmas show a correlation of the momentum fluxes and the intrinsic torques with the electron density and the collisionality. The rough magnitude and profiles of the intrinsic torque was experimentally obtained, and their possible mechanism is briefly discussed.
New insights into the generalized Rutherford equation for nonlinear neoclassical tearing mode growth from 2D reduced MHD simulations
Authors: Westerhof E. , de Blank H.J. , Pratt J.
Published: February 2016

Two dimensional reduced MHD simulations of neoclassical tearing mode growth and suppression by ECCD are performed. The perturbation of the bootstrap current density and the EC drive current density perturbation are assumed to be functions of the perturbed flux surfaces. In the case of ECCD, this implies that the applied power is flux surface averaged to obtain the EC driven current density distribution. The results are consistent with predictions from the generalized Rutherford equation using common expressions for

and

. These expressions are commonly perceived to describe only the effect on the tearing mode growth of the helical component of the respective current perturbation acting through the modification of Ohm’s law. Our results show that they describe in addition the effect of the poloidally averaged current density perturbation which acts through modification of the tearing mode stability index. Except for modulated ECCD, the largest contribution to the mode growth comes from this poloidally averaged current density perturbation.
From Curious to Pragmatically Curious: Comment on “From Hopeless to Curious? Thoughts on Hausman's ‘Dubious to Hopeless’ Critique of Contingent Valuation”
Authors: Desvousges William , Mathews Kristy , Train Kenneth
Published: February 2016

This article extends the discussion introduced in this journal by Haab et al. (2013), who critique a 2012 article on contingent valuation (CV) by Hausman. We agree with Haab et al. “that the intellectual debate over [CV] is ongoing and that plenty of work remains to be done for the truly curious researcher” (593). However, our paper illuminates the limitations of current approaches to guide future research.
Genetics of autoimmune diseases: perspectives from genome-wide association studies
Authors: Kochi Yuta
Published: February 2016

Genome-wide association studies (GWASs) for autoimmune diseases (ADs) have identified many risk loci and have provided insights into the etiology of each disease. Some of these loci, such as PTPN22 , IL23R and STAT4 , are shared among different ADs, and the combination of risk loci may determine an individual’s susceptibility for a disease. The majority of GWAS loci are expression quantitative trait loci (eQTLs), where disease-causing variants regulate expression of neighboring (or sometimes distant) genes. Because the eQTL effects are often cell type-specific, the incorporation of epigenetic data from disease-related cell types and tissues is expected to refine the identification of causal variants. The cumulative eQTL effects in multiple genes may influence the activity or fate of immune cells, which in turn may affect the function of the immune system in individuals. In this paper, I review the etiology of ADs by focusing on important immune cells (T h 1 cells, T h 17 cells and regulatory T cells), important pathways (antigen-receptor signaling and type I interferon signaling) and relevant genes identified in GWASs.
Systemic Cytokine Levels Do Not Predict CD4+ T-Cell Recovery After Suppressive Combination Antiretroviral Therapy in Chronic Human Immunodeficiency Virus Infection
Authors: Norris Philip J. , Zhang Jinbing , Worlock Andrew , Nair Sangeetha V. , Anastos Kathryn , Minkoff Howard L. , Villacres Maria C. , Young Mary , Greenblatt Ruth M. , Desai Seema , Landay Alan L. , Gange Stephen J. , Nugent C. Thomas , Golub Elizabeth T. , Keating Sheila M. ,   the Women's Interagency HIV Study, Anastos Kathryn , Minkoff Howard , Gustafson Deborah , Cohen Mardge , French Audrey , Young Mary , Greenblatt Ruth , Aouizerat Bradley , Tien Phyllis , Gange Stephen , Golub Elizabeth , Milam Joel
Published: February 2016

Background.  Subjects on suppressive combination antiretroviral therapy (cART) who do not achieve robust reconstitution of CD4+ T cells face higher risk of complications and death. We studied participants in the Women's Interagency HIV Study with good (immunological responder [IR]) or poor (immunological nonresponder [INR]) CD4+ T-cell recovery after suppressive cART (n = 50 per group) to determine whether cytokine levels or low-level viral load correlated with INR status.

Methods.  A baseline sample prior to viral control and 2 subsequent samples 1 and 2 years after viral control were tested. Serum levels of 30 cytokines were measured at each time point, and low-level human immunodeficiency virus (HIV) viral load and anti-HIV antibody levels were measured 2 years after viral suppression.

Results.  There were minimal differences in cytokine levels between IR and INR subjects. At baseline, macrophage inflammatory protein-3β levels were higher in IR subjects; after 1 year of suppressive cART, soluble vascular endothelial growth factor-R3 levels were higher in IR subjects; and after 2 years of suppressive cART, interferon gamma-induced protein 10 levels were higher in INR subjects. Very low-level HIV viral load and anti-HIV antibody levels did not differ between IR and INR subjects.

Conclusions.  These results imply that targeting residual viral replication might not be the optimum therapeutic approach for INR subjects.
Quaternary Lidocaine Derivative QX-314 Activates and Permeates Human TRPV1 and TRPA1 to Produce Inhibition of Sodium Channels and Cytotoxicity
Authors: Stueber Thomas , Eberhardt Mirjam J. , Hadamitzky Christoph , Jangra Annette , Schenk Stefan , Dick Felicia , Stoetzer Carsten , Kistner Katrin , Reeh Peter W. , Binshtok Alexander M. , Leffler Andreas
Published: February 2016

AbstractAbstract

In cells expression human TRPV1 and TRPA1 channels, QX-314 activates both channels and enters the cell to inhibit sodium currents. In these cells, QX-314 produces cytotoxicity by a mechanism dependent on TRPV1 channels.

Background

The relatively membrane-impermeable lidocaine derivative QX-314 has been reported to permeate the ion channels transient receptor potential vanilloid 1 (TRPV1) and transient receptor potential cation channel, subfamily A, member 1 (TRPA1) to induce a selective inhibition of sensory neurons. This approach is effective in rodents, but it also seems to be associated with neurotoxicity. The authors examined whether the human isoforms of TRPV1 and TRPA1 allow intracellular entry of QX-314 to mediate sodium channel inhibition and cytotoxicity.

Methods

Human embryonic kidney 293 (HEK-293) cells expressing wild-type or mutant human (h) TRPV1 or TRPA1 constructs as well as the sodium channel Nav1.7 were investigated by means of patch clamp and ratiometric calcium imaging. Cytotoxicity was examined by flow cytometry.

Results

Activation of hTRPA1 by carvacrol and hTRPV1 by capsaicin produced a QX-314–independent reduction of sodium current amplitudes. However, permeation of QX-314 through hTRPV1 or hTRPA1 was evident by a concentration-dependent, use-dependent inhibition of Nav1.7 activated at 10 Hz. Five and 30 mM QX-314 activated hTRPV1 via mechanisms involving the intracellular vanilloid-binding domain and hTRPA1 via unknown mechanisms independent of intracellular cysteins. Expression of hTRPV1, but not hTRPA1, was associated with a QX-314–induced cytotoxicity (viable cells 48 ± 5% after 30 mM QX-314) that was ameliorated by the TRPV1 antagonist 4-(3-chloro-2-pyridinyl)-N-[4-(1,1-dimethylethyl)phenyl]-1-piperazinecarboxamide (viable cells 81 ± 5%).

Conclusions

The study data demonstrate that QX-314 directly activates and permeates the human isoforms of TRPV1 and TRPA1 to induce inhibition of sodium channels, but also a TRPV1-dependent cytotoxicity. These results warrant further validation of this approach in more intact preparations and may be valuable for the development of this concept into clinical practice.
Depressive symptoms in midlife: the role of reproductive stage
Authors: Almeida Osvaldo P. , Marsh Kylie , Flicker Leon , Hickey Martha , Sim Moira , Ford Andrew
Published: February 2016

Objective:

The aim of the study was to determine the prevalence of depression among community-dwelling women in the premenopause, menopausal transition (MT), and postmenopause stage. We also sought to clarify the direct and indirect contribution of menopausal status on the risk of depression.

Methods:

Cross-sectional survey of 1,612 women aged 45 to 55 years living in the Perth metropolitan region, who were recruited using a random sample of the electoral roll (voting is compulsory in Australia), was conducted. Women with clinically significant symptoms of depression had Patient Health Questionnaire (PHQ-9) scores of at least 10, and those with major depression, reported symptoms consistent with Diagnostic and Statistical Manual of Mental Disorders, 5th ed (DSM-5), criteria. We used past and current gynecological and reproductive data to classify women as premenopausal, undergoing the MT, and postmenopausal. Other study measures included age, place of birth, education, marital status, drinking habit, number of children, medical illnesses, and history of premenstrual syndrome, postnatal depression, and past depression or anxiety. We investigated the direct and indirect effect of reproductive status with mediation/modulation analysis.

Results:

Among the women included in the survey, 8.2%, 11.5%, and 13.0% of women in premenopause, MT, and postmenopause had PHQ-9 at least 10, whereas major depression was present in 2.2%, 3.4%, and 3.6% of them. Reproductive status did not affect the prevalence of major depression, but more postmenopausal than premenopausal women had PHQ-9 score equal to or greater than 10 (P = 0.013). Compared with premenopausal women, MT was associated with a direct odds ratio (OR) 1.35 (95% confidence interval [CI] = 0.90, 2.01) and indirect OR 1.08 (95% CI = 0.92, 1.26) for PHQ-9 at least 10. Similarly, the direct and indirect effect of the postmenopause on the odds of PHQ-9 at least 10 was OR 1.31 (95% CI = 0.87, 1.98) and OR 1.29 (95% CI = 1.10, 1.52).

Conclusions:

The slight, but not significant, excess of depressive symptoms during MT and early postmenopause cannot be attributed to a direct effect of reproductive status.