bluuebunny/crossref_metadata_2025 huggingface dataset:
X-ray burst ignition location on the surface of accreting X-ray pulsars: can bursts preferentially ignite at the hotspot?
Authors: Goodwin A J , Heger A , Chambers F R N , Watts A L , Cavecchi Y
Published: June 2021

Hotspots on the surface of accreting neutron stars have been directly observed via pulsations in the light curves of X-ray pulsars. They are thought to occur due to magnetic channelling of the accreted fuel to the neutron star magnetic poles. Some X-ray pulsars exhibit burst oscillations during Type I thermonuclear X-ray bursts that are thought to be caused by asymmetries in the burning. In rapidly rotating neutron stars, it has been shown that the lower gravity at the equator can lead to preferential ignition of X-ray bursts at this location. These models, however, do not include the effect of accretion hotspots at the the neutron star surface. There are two accreting neutron star sources in which burst oscillations have been observed to track exactly the neutron star spin period. We analyse whether this could be due to the X-ray bursts igniting at the magnetic pole of the neutron star, because of heating in the accreted layers under the hotspot causing ignition conditions to be reached earlier. We investigate heat transport in the accreted layers using a 2D model and study the prevalence of heating down to the ignition depth of X-ray bursts for different hotspot temperatures and sizes. We perform calculations for accretion at the pole and at the equator, and infer that ignition could occur away from the equator at the magnetic pole for hotspots with temperature $T_{\mathrm{HS}}\gtrsim 1\times 10^8\, \mathrm{K}$. However, current observations have not identified such high temperatures in accretion-powered X-ray pulsars.
Prospects of high redshift constraints on dark energy models with the Ep, i − Eiso correlation in long gamma ray bursts
Authors: Demianski M , Piedipalumbo E , Sawant D , Amati L
Published: June 2021

So far large and different data sets revealed the accelerated expansion rate of the Universe, which is usually explained in terms of dark energy. The nature of dark energy is not yet known, and several models have been introduced: a non-zero cosmological constant, a potential energy of some scalar field, effects related to the non-homogeneous distribution of matter, or effects due to alternative theories of gravity. Recently, a tension with the flat ΛCDM model has been discovered using a high-redshift Hubble diagram of supernovae, quasars, and gamma-ray bursts (GRB). Here we use the Union2 type Ia supernovae and GRB Hubble diagram, and a set of direct measurements of the Hubble parameter to explore different dark energy models. We use the Chevallier–Polarski–Linder parametrization of the dark energy equation of state, a minimally coupled quintessence scalar field, and, finally, we consider models with dark energy at early times. We perform a statistical analysis based on the Markov chain Monte Carlo method, and explore the probability distributions of the cosmological parameters for each of the competing models. We apply the Akaike Information Criterion to compare these models: our analysis indicates that an evolving dark energy, described by a scalar field with exponential potential seems to be favoured by observational data.
DeepMerge – II. Building robust deep learning algorithms for merging galaxy identification across domains
Authors: Ćiprijanović A , Kafkes D , Downey K , Jenkins S , Perdue G N , Madireddy S , Johnston T , Snyder G F , Nord B
Published: June 2021

In astronomy, neural networks are often trained on simulation data with the prospect of being used on telescope observations. Unfortunately, training a model on simulation data and then applying it to instrument data leads to a substantial and potentially even detrimental decrease in model accuracy on the new target data set. Simulated and instrument data represent different data domains, and for an algorithm to work in both, domain-invariant learning is necessary. Here, we employ domain adaptation techniques – Maximum Mean Discrepancy as an additional transfer loss and Domain Adversarial Neural Networks – and demonstrate their viability to extract domain-invariant features within the astronomical context of classifying merging and non-merging galaxies. Additionally, we explore the use of Fisher loss and entropy minimization to enforce better in-domain class discriminability. We show that the addition of each domain adaptation technique improves the performance of a classifier when compared to conventional deep learning algorithms. We demonstrate this on two examples: between two Illustris-1 simulated data sets of distant merging galaxies, and between Illustris-1 simulated data of nearby merging galaxies and observed data from the Sloan Digital Sky Survey. The use of domain adaptation techniques in our experiments leads to an increase of target domain classification accuracy of up to ${\sim }20{{\ \rm per\ cent}}$. With further development, these techniques will allow astronomers to successfully implement neural network models trained on simulation data to efficiently detect and study astrophysical objects in current and future large-scale astronomical surveys.
Searching for Saturn’s X-rays during a rare Jupiter Magnetotail crossing using Chandra
Authors: Weigt D M , Dunn W R , Jackman C M , Kraft R , Branduardi-Raymont G , Nichols J D , Wibisono A D , Vogt M F , Gladstone G R
Published: June 2021

Every 19 yr, Saturn passes through Jupiter’s ‘flapping’ magnetotail. Here, we report Chandra X-ray observations of Saturn planned to coincide with this rare planetary alignment and to analyse Saturn’s magnetospheric response when transitioning to this unique parameter space. We analyse three Director’s Discretionary Time (DDT) observations from the High Resolution Camera (HRC-I) on-board Chandra, taken on 2020 November 19, 21, and 23 with the aim to find auroral and/or disc emissions. We infer the conditions in the kronian system by looking at coincident soft X-ray solar flux data from the Geostationary Operational Environmental Satellite (GOES) and Hubble Space Telescope (HST) observations of Saturn’s ultraviolet (UV) auroral emissions. The large Saturn–Sun–Earth angle during this time would mean that most flares from the Earth-facing side of the Sun would not have impacted Saturn. We find no significant detection of Saturn’s disc or auroral emissions in any of our observations. We calculate the 3σ upper band energy flux of Saturn during this time to be 0.9–3.04 × 10−14 erg cm−2 s−1 which agrees with fluxes found from previous modelled spectra of the disc emissions. We conclude by discussing the implications of this non-detection and how it is imperative that the next fleet of X-ray telescope (such as Athena and the Lynx mission concept) continue to observe Saturn with their improved spatial and spectral resolution and very enhanced sensitivity to help us finally solve the mysteries behind Saturn’s apparently elusive X-ray aurora.
The major mechanism to drive turbulence in star-forming galaxies
Authors: Yu Xiaoling , Bian Fuyan , Krumholz Mark R , Shi Yong , Li Songlin , Chen Jianhang
Published: June 2021

Two competing models, gravitational instability-driven transport and stellar feedback, have been proposed to interpret the high velocity dispersions observed in high-redshift galaxies. We study the major mechanisms to drive the turbulence in star-forming galaxies using a sample of galaxies from the xCOLD GASS survey, selected based on their star formation rate (SFR) and gas fraction to be in the regime that can best distinguish between the proposed models. We perform Wide Field Spectrograph integral field spectroscopic observations to measure the intrinsic gas velocity dispersions, circular velocities, and orbital periods in these galaxies. Comparing the relation between the SFR, velocity dispersion, and gas fraction with predictions of these two theoretical models, we find that our results are most consistent with a model that includes both transport and feedback as drivers of turbulence in the interstellar medium. By contrast, a model where stellar feedback alone drives turbulence under-predicts the observed velocity dispersion in our galaxies, and does not reproduce the observed trend with gas fraction. These observations therefore support the idea that gravitational instability makes a substantial contribution to turbulence in high-redshift and high-SFR galaxies.
‘Conducting his own Campaigns’: Evelyn Waugh and Propaganda
Authors: Woodward Guy
Published: June 2021

This essay examines Evelyn Waugh as practitioner and critic in the field of wartime propaganda. In 1941, Waugh produced a fictitious account of a British Commando raid on German territory in North Africa for publication in Britain and the United States, an episode which reveals his skill as a propagandist, but also prompts scrutiny of his contacts with British propaganda agencies and agents and of the effect of propaganda on his writings. Waugh’s interwar fiction exhibits a sophisticated understanding of the evolving and growing power of modern propaganda, but the novels also anticipate the public relations and psychological warfare campaigns of the Second World War, specifically those carried out by the Political Warfare Executive (PWE), a secret service established in 1941 to produce and coordinate propaganda to enemy and occupied Europe. Waugh’s proximity to the PWE is suggested by a dense network of social and professional connections, and is further indicated by a series of references to the PWE and its work which I have uncovered in his fiction. Allusions to covert propaganda in Put Out More Flags and the Sword of Honour trilogy betray Waugh’s understanding of the PWE’s operations, but also provide a critique of the corrosive and unforeseen effects of information warfare waged by the secret state and offer a productive means of re-examining his much-noted anxieties regarding modernity and mid-century political change.
Risky Matching
Authors: Chade Hector , Lindenlaub Ilse
Published: June 2021

We develop a model where risk-averse workers can costly invest in their skills before matching with heterogenous firms. At the investment stage, workers face multiple sources of risk. They are uncertain about how skilled they will turn out and also about their income shock realizations at the time of employment. We analyse the equilibria of two versions of the model that depend on when uncertainty resolves, which determines the available risk-sharing possibilities between workers and firms. We provide a thorough analysis of equilibrium comparative statics regarding changes in risk, worker and firm heterogeneity, and technology. We derive conditions on the match output function and risk attitudes under which these shifts lead to more investment and show how this affects matching and wages. To illustrate the applied relevance of our theory, we provide a stylized quantitative assessment of the model and analyse the sources (risk, heterogeneity, or technology) of rising U.S. wage inequality. We find that changes in risk were the most important driver behind the surge in inequality, followed by technological change. We show that these conclusions are significantly altered if one neglects the key feature of our model, which is that educational investment is endogenous.
J. SAINSBURY PLC v FROMAGERIES BEL SA
Authors:   Chancery Division (Intellectual Property List)
Published: June 2021

H1 Trade marks – Invalidation proceedings – Shape mark with dimension and colour limitations – Assessment of essential characteristics - Colours – Graphical representation - Requirement of clarity and precision - Whether limitation to “the colour red” sufficient – Whether graphical representation and written description inconsistent - Appeal to High Court – Admission of additional evidence on appeal – Relevance of other registrations with similar limitations
Anterior Cingulate Cortex and Ventral Tegmental Area Activity During Cost–Benefit Decision-Making Following Maternal Immune Activation
Authors: Croy Eloise , Elston Thomas W , Bilkey David K
Published: June 2021

Schizophrenia is associated with deficits in memory, behavioral flexibility, and motivation, which can result in difficulties in decision-making. The anterior cingulate cortex (ACC) and ventral tegmental area (VTA) are two brain regions that are involved in decision-making, and display dysfunction in schizophrenia. We investigated ACC and VTA activity in the maternal immune activation (MIA) model of a schizophrenia risk factor. Control and MIA rats completed a cost–benefit decision-making task in a continuous T-maze, choosing between a high cost and high reward (HCHR), and a low cost and low reward (LCLR), option. A choice reversal occurred halfway through each session. Single unit activity in the ACC and local field potentials (LFPs) in the VTA were monitored. Overall, MIA and control rats made a similar proportion of HCHR and LCLR choices across the whole recording session, suggesting similar levels of motivation. However, MIA rats made different decisions than controls during periods of increased uncertainty. This appeared to reflect memory deficits and behavioral inflexibility. MIA animals displayed an increase in ACC activity associated with cost, an increase in synchrony of ACC neurons to the VTA theta oscillation, and a decrease in coherence in the delta frequency between the ACC and VTA. These changes suggest that MIA animals may be biased towards focusing on the cost rather than the benefits of the task, a change also seen in schizophrenia. Here, however, the MIA animals may be able to increase motivation to maintain behavior despite this change.
Phylogenetic analysis of HIV-1 shows frequent cross-country transmission and local population expansions
Authors: Bennedbæk Marc , Zhukova Anna , Tang Man-Hung Eric , Bennet Jaclyn , Munderi Paula , Ruxrungtham Kiat , Gisslen Magnus , Worobey Michael , Lundgren Jens D , Marvig Rasmus L
Published: June 2021

Understanding of pandemics depends on the characterization of pathogen collections from well-defined and demographically diverse cohorts. Since its emergence in Congo almost a century ago, Human Immunodeficiency Virus Type 1 (HIV-1) has geographically spread and genetically diversified into distinct viral subtypes. Phylogenetic analysis can be used to reconstruct the ancestry of the virus to better understand the origin and distribution of subtypes. We sequenced two 3.6-kb amplicons of HIV-1 genomes from 3,197 participants in a clinical trial with consistent and uniform sampling at sites across 35 countries and analyzed our data with another 2,632 genomes that comprehensively reflect the HIV-1 genetic diversity. We used maximum likelihood phylogenetic analysis coupled with geographical information to infer the state of ancestors. The majority of our sequenced genomes (n = 2,501) were either pure subtypes (A–D, F, and G) or CRF01_AE. The diversity and distribution of subtypes across geographical regions differed; USA showed the most homogenous subtype population, whereas African samples were most diverse. We delineated transmission of the four most prevalent subtypes in our dataset (A, B, C, and CRF01_AE), and our results suggest both continuous and frequent transmission of HIV-1 over country borders, as well as single transmission events being the seed of endemic population expansions. Overall, we show that coupling of genetic and geographical information of HIV-1 can be used to understand the origin and spread of pandemic pathogens.
All stressed out: physical tension drives mesenchymal‐to‐epithelial transition in heart progenitor cells
Authors: Davidson Lance , Jackson Timothy R , Kim Hye Young
Published: June 2021

Proper heart formation involves coordinated movements by endoderm and mesenchymal heart progenitor cells (HPCs). Bilateral populations of HPCs begin these movements as mesenchymal cells but transition to epithelial before they form the ventral heart trough. Originating from the lateral plate mesoderm in the frog Xenopus laevis HPCs first localize aPKC to a putative apical surface then assemble apical junctions rich in ZO‐1 well in advance of reaching the ventral midline. Ex vivo and intra vital imaging reveals that cells undergoing MET exhibit stereotypical changes in collective migration and traction forces. This “phase‐transition” supports observations in chicken and zebrafish and suggest that mesenchymal HPCs are initially carried to the midline by endoderm but complete their movements as epithelia via traction‐mediated migration. To understand the role of mechanics in the spatial and temporal control of this mesenchymal‐to‐epithelial transition (MET) we carried out a biomechanical analysis of the heart forming region (HFR). Time‐lapse imaging of the HFR reveals a complex pattern of shape change, first contracting in the anterior‐posterior direction then elongating. Strain maps from this analysis combined with biomechanical measurements of tissue compliance with microaspiration reveal MET coincides with peak levels of tissue stress in the HFR suggesting mechanical cues from the microenvironment are responsible for inducing MET in the HPCs. To test such a role for tissue stress we took three different approaches to modulating mechanics: 1) overexpression of constitutive active Rho‐GEF, 2) incubation with activators and inhibitors of cell contractility, and 3) exogenously applied strain. Overexpression of contractility by targeted mRNA injections revealed that MET could be driven non‐cell autonomously by stiffening endoderm. Transient disruptions in MET with small molecule inhibitors and activators of contractility revealed decreased contractility could inhibit while increased contractility could precociously induce MET. Finally, using only physical means to strain the HFR we were also able to induce early MET. Each of these three perturbations of the mechanical microenvironment resulted in specific defects in the architecture of the larval heart which manifest in defects in cardiac output. Thus, using biophysical and cell biological methods we identified endogenous changes in the mechanical microenvironment in the heart forming region (HFR) that appear to drive HPCs into a mesenchymal‐to‐epithelial transition and how lesions in that regulation impact heart structure and function.

Support or Funding Information

National Science Foundation (CBET‐1547790), National Institutes of Health (R01HD044750; R56HL13495) and the Cardiovascular Bioengineering Training Program (NIH NHLBI T32 HL076124).
Mechanistic pathways to unusual outcomes in reactions of iron‐dependent oxygenases
Authors: Bollinger J. Martin , Krebs Carsten
Published: June 2021

Non‐heme‐iron (NH‐Fe) enzymes activate O2 for an array of biomedically, agriculturally, and environmentally important oxidation reactions. Our past decade's work has characterized iron(IV)‐oxo (ferryl) complexes in several such NH‐Fe enzymes.1 In all such systems that transform aliphatic carbon centers, the ferryl complexes generate substrate radicals by abstracting hydrogen (H•),2–6 leading to formation of new C–O,2–4 C–Cl/Br,5,6 or C–S bonds.1 Motivated by our success in rationalizing the divergent outcomes of the NH‐Fe‐ and 2‐ (oxo)glutarate‐dependent aliphatic hydroxylases and halogenases,7 we now seek both to exploit the ferryl manifold for novel, unnatural carbon‐functionalization reactions8 and to explain the structural and mechanistic bases for several other natural reaction types – including 1,3‐dehydrogenation of an alcohol to epoxide,9 stereo‐inversion of a chiral carbon,10 and desaturation and cleavage of C–C bonds – that are initiated by ferryl complexes in other NH‐Fe enzymes. Insight obtained will inform development of new biocatalytic synthetic routes and combinatorial design of new antibiotic and anticancer drugs.

Support or Funding Information

National Institutes of Health GM118812, GM113106, and GM069657; National Science Foundation CHE‐0724084 and MCB‐0642058.
Energy restriction upregulates circulating myomiR expression in vivo and in vitro
Authors: Margolis Lee M , Rivas Dontato A , Pasiakos Stefan M , McClung James P , Ceglia Lisa , Fielding Roger A
Published: June 2021

Energy restriction (ER)‐induced weightloss attenuates the rate of protein synthesis, which over time can result inreductions in skeletal muscle mass. Recently, changes in the expression of circulating muscle‐specific microRNA (c‐myomiR)have been suggested to reflect rates of protein synthesis. However, whether an increased expression ofc‐myomiR are associated with lower rates of protein synthesis remains undefined. The present investigation sought to determine whether ER influences c‐myomiR expression, and if changes in c‐myomiR are associated with rates of protein synthesis both in vivo (humans) and in vitro (cultured myocytes). Sixteen older (64 ± 2 yrs) overweight (28.5 ±1.2 kg·m−2) males enrolled in this 35‐day controlled feedingtrial. A 7‐day weight maintenance (WM)period was followed by 28 days of 30% ER; whole‐body protein turnover (15N‐glycine)and c‐myomiR (miR‐1–3p, miR‐133a‐3p, miR‐133b, miR‐206) expression was assessed by RT‐qPCR at the conclusions of WM and ER. Participants lost 4.4 ± 0.3 kg body mass during ER (P < 0.05). Overall, ER upregulated c‐myomiR expression compared to WM (P < 0.05). Expression ofc‐myomiR was inversely associated (r= −0.700, P < 0.05) with whole‐body protein synthesis after ER. Similarly, assessing the expression of c‐myomiR obtained from media that C2C12myotubes were cultured; ER increased c‐myomiR expression by 2.9 ± 0.1 fold and lowered the protein synthesis rate by 2.1 ±0.2 fold compared to control. Corroboration of in vitro and in vivo findings indicates that increased expressions of c‐myomiR maybe noninvasive markers reflective of ER‐induced reductions in the rate protein synthesis.

Support or Funding Information

This material is based on the work supported by the U.S. Department of Agriculture(USDA), under agreement No. 58‐1950‐4‐003 and the US Army Medical Research and Material Command. Any opinions, findings, conclusions, or recommendations expressed in this publication are those of the authors and do not necessarily reflect the view of the USDA. Mention of trade names or commercial products in this publication is solely for the purpose of providing specific information and does not imply recommendation or endorsement by the USDA. The study was also supported by the Boston Claude D. Pepper Center Older American Independence Centers (OAIC;1P30AG031679). L.M.M is supported by T32NIDDK training grant # 5T32DK062032‐23. D.A.R. is supported by NIA K01 award # KAG047247A‐A1.
Serum 24,25‐dihydroxyvitamin D Is Suppressed Across Pregnancy In Adolescents with Low Vitamin D Status
Authors: Best Cora M. , Pressman Eva K. , Cooper Elizabeth , Queenan Ruth Anne , O'Brien Kimberly O.
Published: June 2021

Background

Low maternal serum 25(OH)D has been associated with preeclampsia, low birth weight, and offspring bone health. Serum concentrations of the hormone 1,25(OH)2D (calcitriol) rise in pregnancy, yet the importance of calcitriol and parathyroid hormone (PTH) to calcium homeostasis during pregnancy is uncertain. Possible alterations in serum 24,25(OH)2D, the catabolite of 25(OH)D, remain largely unexplored across gestation, and assessment of 24,25(OH)2D could improve understanding of pregnancy adaptations in vitamin D metabolism.

Methods

We supplemented 79 pregnant adolescents at risk of vitamin D inadequacy with 2000 International Units (IU) or 200 IU of vitamin D3 daily and sought to determine how the serum 25(OH)D response related to circulating calcitriol, 24,25(OH)2D, and PTH. Serum was collected at study entry, midway through the study, and delivery. We measured serum 25(OH)D, calcitriol, and 24,25(OH)2D by LC‐MS/MS and PTH by immunoassay. We used pre‐post and longitudinal analyses to assess change in serum markers.

Results

At study entry (18 ± 5 wk gestation, mean ± sd), serum 25(OH)D was 25 ± 9 ng/ml, and it changed 0.5 ± 10 ng/ml between entry and delivery. Calcitriol was elevated above non‐pregnant levels at entry and peaked in the 3rd trimester. Calcitriol and 25(OH)D were weakly correlated at delivery, yet baseline and change in 25(OH)D did not predict calcitriol concentrations across pregnancy. In contrast, serum 24,25(OH)2D and 25(OH)D were highly correlated throughout pregnancy (r≥0.85, p<0.001), but change in 24,25(OH)2D relative to that of 25(OH)D varied by baseline vitamin D status. When serum 25(OH)D increased any amount over pregnancy, the increase in 24,25(OH)2D was attenuated in teens with baseline 25(OH)D <20 ng/ml (n=27) vs. ≥20 ng/ml (n=52). Change in 24,25(OH)2D was related to change in serum calcium (r=0.40, p=0.001). Change in the 1,25(OH)2D/24,25(OH)2D ratio was positively related to change in serum PTH (r=0.30, p=0.02), a hormone that elevates 1,25(OH)2D and suppresses the renal 24‐hydroxylase in the non‐pregnant state. Those with baseline 25(OH)D <20 ng/ml drove this association of 1,25(OH)2D/24,25(OH)2D and PTH (p=0.01).

Conclusions

Our results imply that production of 24,25(OH)2D across pregnancy is suppressed/constrained when 25(OH)D supply is limited, perhaps to preserve 25(OH)D and adequate production of calcitriol. Serum 24,25(OH)2D and vitamin D metabolite ratios may be useful indicators of vitamin D and calcium homeostasis during pregnancy.

Support or Funding Information

This research was supported by USDA grant 2011‐03424 and NIH award T32‐DK007158. Content does not represent the official views of the NIH.
Impact of Maternal Obesity and High Fat Diet during Pregnancy and Lactation on Offspring Body Weight, Immune Function, and Resistance to Influenza Infection
Authors: Guo Weimin , Wu Dayong , Li Lijun , Smith Donald E. , Meydani Simin Nikbin
Published: June 2021

Studies have suggested that obesity is associated with immune dysfunction and higher risk of infection. Maternal obesity is thought to affect body weight which may in turn alter immune function in offspring. However, the relative contribution of maternal factors (maternal obesity versus high fat diet during pregnancy and lactation) to the changes in body weight, immune function, and response to infection in the offspring is not well‐understood. To address this, we fed outbred 1‐mo old female CD‐1 mice a high fat (HF, 45%) diet or a low fat (LF, 10%) control diet to induce obesity. After 5‐mo on the respective diets, mice fed the high fat diet had considerable variation in weight gain. Thus, based on body weight, we further divided the mice in the HF group into two sub‐groups: obesity‐prone (high fat obese, HF‐O) and obesity‐resistant (high fat lean, HF‐L) groups. This provided us with the opportunity to separate the impact of obesity from that of high fat diet during pregnancy. Dams in all 3 groups (LF, HF‐O, HF‐L) were mated with 3‐mo old male CD1 mice fed a standard chow diet. All dams continued to be fed their respective diet during pregnancy and lactation. The offspring born to LF, HF‐L, and HF‐O dams were fed standard chow and monitored for their body weight. At 10‐mo of age, they were infected with influenza virus (A/Puerto Rico/8/34) and then monitored daily for symptoms until day 8 post‐infection when they were euthanized and tissues collected for analysis. Results showed that while offspring in all groups exhibited post‐infection weight loss, offspring of HF‐L group had the most weight loss. Further, both male and female offspring born to HF‐L dams had significantly more severe lung pathology compared to those born to HF‐O dams. In addition, female offspring born to HF‐O dams had significantly higher CD3 or CD3/CD28‐stimulated lymphocyte proliferation than those born to LF dams, and also had significantly lower % cytotoxic T cells (CD8+ cells) than those born to LF dams and HF‐L dams. Percentage of total T cells (CD3+), helper T cells (CD4+), and regulatory T cells (CD4+CD25+) in spleen were significantly lower in the male offspring of HF‐O dams compared with the male offspring of HF‐L dams. Taken together our results showed that maternal obesity, independent of high fat diet, influences immune response and resistance to influenza infection. Contrary to our expectation, offspring born to obese mothers had less pathology and weight loss and better T cell function following influenza infection. While the underlying mechanisms of varied resistance to influenza infection are not completely understood, our results suggest that they might be, at least in part, related to differences in T cell profile and function.

Support or Funding Information

Supported by the USDA under contract #58‐1950‐4‐003
Both paternal exercise and healthy diet are required to protect offspring from high fat diet‐induced obesity and type 2 diabetes risk in mice
Authors: Claycombe Kate J , Krout Danielle , Garcia Rolando , Roemmich James
Published: June 2021

Objective

Paternal eating and physical activity behaviors peri‐conception may influence offspring obesity and type 2 diabetes (T2D) risk. A recent study showed that paternal exercise increased offspring susceptibility to obesity when the offspring consumed a high fat (HF) diet. However, it is not yet known how paternal HF diet and paternal exercise interact to alter offspring adiposity and T2D risk.

Method

Three week old male C57BL/6J mice were fed a control normal fat (NF) diet (16% fat) or a HF diet (45% fat) and provided voluntary wheel running exercise or cage activity (sedentary) for 3 months prior to mating with NF diet‐fed dams. After weaning, male offspring were fed NF or HF diet for 3 months.

Results

Compared to offspring born from cage‐active fathers fed a NF diet, offspring of cage‐active fathers fed a HF diet had decreased body weights at postnatal days 5, 12, and 21 as well as increased insulin resistance at 5 months of age. Paternal HF diet‐induced changes in offspring body weights early in post‐natal life and insulin resistance in adulthood were abolished when fathers exercised. In addition, paternal exercise prevented postnatal HF diet‐induced body and adipose tissue weight increases in offspring at 5 months of age, but only when fathers were fed NF diets.

Conclusion

These findings suggest that paternal exercise reduces risk for adiposity and insulin resistance in offspring exposed to a HF diet, but only when fathers consumed a NF diet and exercised. A paternal NF diet alone, without paternal exercise, did not protect HF diet‐induced body and adipose tissue weight gains in offspring. Future studies will determine physiological mechanisms underlying beneficial effects of combined exercise and diet through paternal lineage.

Support or Funding Information

This work was supported by USDA Agricultural Research Service Project #3062‐51000‐052‐00D.
Alveolar Macrophage Heterogeneity As A Driver Of Age‐Related Responses To Influenza A Infection
Authors: McQuattie‐Pimentel Alexandra Cristina , Chen Ching‐I , Reyfman Paul , Morales‐Nebreda Luisa , Walter James , Chi Monica , Ridge Karen , Perlman Harris , Budinger GR Scott , Misharin Alexander
Published: June 2021

Rationale

Seasonal influenza A virus infection causes at least 20,000–50,000 deaths in the United States each year and causes disproportionate morbidity and mortality in older individuals. We and others have found similarly disproportionate mortality in aged mice infected with influenza A. An important role for alveolar macrophages in the response to influenza A infection is recognized. Strategies to therapeutically target alveolar macrophages during lung injury have considered that they are a single population of monocyte‐derived cells. This paradigm has been challenged by studies that identified tissue‐resident alveolar macrophages (TR‐AM) as highly specialized cells that populate the lung shortly after birth and persist over the lifespan.

Methods

We aged bone marrow chimeric C57Bl/6 (CD45.1 donor into CD45.2 host) mice generated with thoracic shielding followed by busulfan depletion of the remaining bone marrow. The resulting chimeric mice (>99% donor monocytes in blood, >99 % recipient in tissue resident alveolar macrophages), were treated with influenza A (A/WSN/33) virus, or bleomycin.

Results

Severe injury early in life alters the alveolar macrophage landscape during aging. We treated shielded‐bone‐marrow chimeric mice with influenza A or bleomycin and measured the ratio between Mo‐AM and TR‐AM 10 months later. We found that TR‐AM were remarkably stable, constituting >95% of alveolar macrophages in naïve mice at 14 months of age. In contrast, in mice infected with influenza A (A/WSN/33) virus, 100pfu at 8 weeks post bone marrow transfer (4 months of age), approximately 50% of the alveolar macrophages were monocyte‐derived 10 months later. To determine whether this finding was unique to influenza A, we treated a separate cohort of shielded‐bone‐marrow chimeric mice with bleomycin and obtained similar results. Next, we sought to determine whether the differences in gene expression between TR‐AM and Mo‐AM we observed during injury and fibrosis persisted over the lifespan. Ten months after bleomycin treatment or influenza A infection, TR‐AM and Mo‐AM were not disgtinguishable by flow cytometry. A comparison of the transcriptomes of TR‐AM and Mo‐AM 10 months after bleomycin administration revealed only 101 differentially expressed genes.

Conclusion

This finding suggests that a severe injury early in life can permanently reshape the alveolar macrophage landscape with respect to its developmental origins. If monocyte‐derived alveolar macrophages differ in their response to challenge, this might explain some of the age‐related susceptibility to influenza A infection.

Support or Funding Information

AG049665, HL071643, ES013995, The Veterans Administration, DOD W81XWH‐15‐1‐0215
What Do People Eat When They Don't Eat Meat? An Evaluation of Dietary Quality Using the National Health and Nutrition Examination Survey (NHANES), 2007–2012
Authors: Conrad Zach , Karlsen Micaela , Chui Kenneth , Jahns Lisa
Published: June 2021

Objective

To compare diet quality scores between adult non‐meat eaters and meat eaters, and to compare the consumption of diet components across quintiles of diet quality.

Design

Cross‐sectional analysis. Healthy Eating Index‐2010 (HEI‐2010) and Alternative Healthy Eating Index‐2010 (AHEI‐2010) were used to assess mean diet quality. Differences in consumption of diet components between quintiles of diet quality were tested using post hoc Wald tests.

Setting

The National Health and Nutrition Examination Survey (NHANES), 2007–2012.

Subjects

The sample consisted of 16,688 respondents ≥20 y, including 281 individuals that reported not consuming meat, fowl, or seafood on two non‐consecutive days of dietary recall. Dietary data were obtained from one dietary recall per individual.

Results

Non‐meat eaters had substantially greater HEI‐2010 and AHEI‐2010 scores compared to meat eaters (P<0.05). Among non‐meat eaters, mean consumption across HEI‐2010 quintiles demonstrated different (P<0.05) amounts of empty calories, whole fruit, and plant proteins. Mean consumption across AHEI‐2010 quintiles demonstrated different (P<0.05) amounts of nuts and legumes, vegetables, and polyunsaturated fatty acids.

Conclusions

Public health messages targeted at vegetarians and others who may choose to eat meat‐free on certain days should emphasize decreased consumption of empty calories, and increased consumption of whole grains, plant proteins, nuts and legumes, and vegetables as a way to improve overall dietary quality.

Support or Funding Information

USDA 3062‐51000–51‐00D
The Role of Scleraxis in Intestinal Fibroblasts
Authors: Johnson Charles , Nillas Andrea , Reaves Titus A.
Published: June 2021

Scleraxis is a transcription factor in the BHLH family originally shown to regulate the development of embryonic tissue into tendon and bone—suggesting a link to collagen production and release. Recently, scleraxis has been shown to play a role in the development cardiac fibrosis. Organ fibrosis typically follows inflammation and involves over activation of myofibroblasts (activated fibroblasts that express α‐smooth muscle actin). Intestinal fibrosis is a somewhat common complication of Inflammatory Bowel Disease (IBD), which primarily includes Crohn's Disease (CD) and Ulcerative Colitis (UC). Intestinal fibrosis is characterized by dysregulated and excessive production of collagen from fibroblasts that results in excessive contraction in the intestine, intestinal stricture and bowel obstruction. Interestingly, approximately 20–25% of IBD patients will develop fibrosis. We hypothesize that scleraxis is expressed by intestinal fibroblasts and can modify the activation of such fibroblasts. Transfection (siRNA) studies show that when scleraxis is reduced in fibroblasts there is an increase in intestinal fibroblast attachment to fibrinogen (CD11b ligand). While exposure of fibroblasts to cytokines does not appear to regulate its expression, scleraxis expression is increased in IBD intestines. Immuno‐purification studies reveal that scleraxis may have a physical link to CD11b suggesting that they may have similar signaling pathways. These results highlight scleraxis as a target molecule in the treatment of diseases involving the over‐activation of fibroblasts.

Support or Funding Information

5T35DK007431‐32 and and National Science Foundation RII
GPCRs in Pulmonary Arterial Smooth Muscle Cells as Novel Targets in Pulmonary Arterial Hypertension
Authors: Gorr Matthew W , Sriram Krishna , Insel Paul A
Published: June 2021

Pulmonary arterial hypertension (PAH) is a progressive disease that can eventually result in right heart failure and premature death. The pulmonary arterial tree in PAH narrows and limits the blood supply to the lungs, due predominately to the hyperproliferation and hyperconstriction of pulmonary artery smooth muscle cells (PASMCs). Current therapies for PAH have limited long‐term benefits (in particular, on mortality) and multiple side‐effects, including systemic hypotension. Thus, new means to target PASMCs has the potential to improve therapy for PAH. To this end, we have assessed mRNA expression of G‐protein coupled receptors (GPCRs) using Taq‐man GPCR arrays and RNA‐seq from PASMCs acquired from patients (n=4) with PAH and healthy control subjects (n=4). GPCR array analysis revealed that 91 GPCRs were expressed on average across all samples with most them shared amongst replicates (82 in control and 76 in PAH samples). Thirty‐one GPCRs, including 13 orphan GPCRs (without known physiologic agonists) were highly expressed (average delta cycle threshold < 20) across all samples. In PAH‐PASMCs, 27 and 40 GPCRs were >2‐fold more highly or lower expressed, respectively, than in control‐PASMCs. RNA‐seq analysis confirmed these results. Initial studies indicate enhanced functional activity (proliferation and signaling) of at least one of the more highly expressed GPCRs. Together, these results suggest that newly recognized, more highly expressed GPCRs in PAH‐PASMCs are potential therapeutic targets for this disease. Although further work is needed to validate such GPCRs, we propose that the use of unbiased strategies to identify GPCRs in PASMCs can provide a novel way to discover potential drivers of pathophysiology and therapeutic targets for PAH and other diseases.

Support or Funding Information

Supported by Department of Defense (W81XWH‐14‐1‐0372) and the National Institutes of Health (5T32HL007444‐33)
Single cardiac myocytes from the left and right ventricles respond similarly to isoproterenol and omecamtiv mecarbil
Authors: Buckley Tori Dawn , Isaac Joslyn , Campbell Kenneth S.
Published: June 2021

The left and right cardiac ventricles develop from different embryonic structures and generate different systolic pressures in vivo (left ventricle ~120 mm Hg, right ventricle, ~25 mm Hg). Some patients also develop chamber‐specific hypertrophy. We measured the contractile properties of cells isolated from the left and right ventricles of rat hearts and tested how they responded to omecamtiv mecarbil and isoproterenol. Based on data from ongoing experiments using human samples in our laboratory, our hypothesis was that cells from the left and right ventricles would exhibit similar contractile effects. Cells were isolated from 3 to 6 month old female Sprague Dawley rats by enzymatic digestion. Shortening profiles and calcium transients were measured at 32°C using video microscopy and Fura2‐AM fluorescence respectively. Statistical tests were performed using linear mixed models. A total of ~150 cells were analyzed using isoproterenol concentrations ranging from 0 to 1.0 μM and omecamtiv mecarbil concentrations ranging from 0 to 10.0 μM. We measured 22 parameters quantifying various aspects of the Ca2+ transients and shortening profiles (e.g. time to peak, amplitude, etc.) Although some statistical tests produced p values less than 0.05 for region, no systematic differences were observed between cells from the left and right ventricles. Our conservative interpretation is that single cardiac myocytes from the left and right ventricles have similar contractile properties. The different pressures generated by the two ventricles probably reflect differences in chamber structure and wall thickness as opposed to differences in the contractile properties of the myocytes themselves.

Support or Funding Information

AHA GRNT2546003, NSF 1538754, NIH TR000117, APS STRIDE, APS UGSRF, HL115473.
Nutrient sensing and mitochondrial coenzyme Q biosynthesis: Are they connected by a phosphatase?
Authors: Awad Agape M. , Venkataramanan Srivats , Nag Anish , Bradley Michelle C. , Galivanche Anoop R. , Johnson Tracy L. , Clarke Catherine F.
Published: June 2021

Coenzyme Q (also termed ubiquinone or Q) is an electron carrier in the mitochondrial respiratory chain that functions as an essential component in energy metabolism processes. Q transfers electrons from NADH and succinate to cytochrome c, a heme protein, and also serves as a vital lipid soluble antioxidant. Sufficient de novo Q biosynthesis is crucial for human health. Saccharomyces cerevisiae (baker's yeast) serves as an excellent model for studies on Q because of its powerful molecular genetics and the functional identity of yeast and human COQ genes in Q biosynthesis and function. Coenzyme Q biosynthesis in S. cerevisiae (which makes Q6 with six isoprene units, versus Q10 in humans with ten isoprene units) takes place in the mitochondria and, currently, thirteen known mitochondrial proteins are responsible for facilitating this process—Coq1‐Coq11, Yah1 (ferredoxin), and Arh1 (ferredoxin reductase). Many of the proteins necessary for the biosynthesis of Q6 associate in a high molecular weight complex (termed the “CoQ‐Synthome”) that localizes in the inner mitochondrial membrane. Previous work indicated that the stability of the Q biosynthetic complex relied on the presence of Coq8, the putative kinase of the system. In addition, several Coq polypeptides are phosphorylated in a Coq8‐dependent manner, including Coq3, Coq5, and Coq7, and potentially Coq6. Thus, the role of phosphorylation, as it pertains to Q biosynthesis and regulation, may provide novel information as to how the CoQ‐synthome is regulated. Additionally, intriguing links have been discovered that relate Coq polypeptides and phosphorylation status with nutrient availability and regulatory genes. Hence, our objectives are to investigate these links further and discover new information related to regulation by phosphorylation of the CoQ‐Synthome. Such studies will aid our understanding and treatment of multiple diseases caused by CoQ‐deficiencies and will provide novel insight in longevity and issues related to aging in humans. This research was supported by NSF MCB‐1330803.

Support or Funding Information

NSF MCB‐1330803
Mangenese superoxide dismutase (MnSOD) promotes stem‐like cell phenotypes in breast cancer
Authors: He Chenxia , Hart Peter , Fricano Kristine , Vargas Micaela , Thieraud Kraig , de Abreu Andre Luelsdorf , Bonini Marcelo
Published: June 2021

It is becoming increasingly clear that a small subpopulation of cells within tumors displaying stem cell characteristics drive tumor resistance to therapy, recurrence and metastasis. These cells are generally referred to as cancer stem cells (CSC). Reactive oxygen species (ROS) are active signaling metabolites produced in mitochondria and to a significance extent serve as determinants of cellular reprogramming to stemness. In our study we found that a primary ROS detoxifying enzyme MnSOD is dysregulated in breast cancer and that higher levels of MnSOD expression are associated with lowest survival odds in patients with tumors displaying a MnSODhigh molecular signature. In primary breast tumor cell line MCF7, overexpression of MnSOD leads to higher expression of stemness markers (Oct4, Sox2 and Nanog), increased stem cell population, and upregulation of cancer stem cell regulator hypoxia‐induced factor HIF2α transcription factor. Also, MCF7 cells which are amongst the least invasive breast cancer cell lines show significantly enhanced colony forming capacity and invasiveness ex vivo, and metastatic potential in mice. Silencing of HIF2α reversed the effect of MnSOD ectopic expression in MCF7. Altogether our results indicate that there is a MnSODhigh/HIF2α phenotype in breast cancer that displays stem‐like cell characteristics which may be involved in treatment resistance and metastatic recurrence in a subgroup of patients displaying MnSODhigh tumors.

Support or Funding Information

This research supported by the U.S. Department of Defense (ARO #61758‐LS) to M.G.B, the NCRR/NIH (S10RR027848) to M.G.B.