bluuebunny/crossref_metadata_2025_split huggingface dataset:
Machine-learning enhanced photometric analysis of the extremely bright GRB 210822A
Authors: Angulo-Valdez Camila , Becerra Rosa L , Pereyra Margarita , Garcia-Cifuentes Keneth , Vargas Felipe , Watson Alan M , De Colle Fabio , Fraija Nissim , Butler Nathaniel R , Dainotti Maria G , Dichiara Simone , Lee William H , Troja Eleonora , Bloom Joshua S , González J Jesús , Kutyrev Alexander S , Prochaska J Xavier , Ramirez-Ruiz Enrico , Richer Michael G 
Published: November 2023

ABSTRACT
We present analytical and numerical models of the bright long GRB 210822A at z = 1.736. The intrinsic extreme brightness exhibited in the optical, which is very similar to other bright GRBs (e.g. GRBs 080319B, 130427A, 160625A 190114C, and 221009A), makes GRB 210822A an ideal case for studying the evolution of this particular kind of GRB. We use optical data from the RATIR instrument starting at T + 315.9 s, with publicly available optical data from other ground-based observatories, as well as Swift/UVOT, and X-ray data from the Swift/XRT instrument. The temporal profiles and spectral properties during the late stages align consistently with the conventional forward shock model, complemented by a reverse shock element that dominates optical emissions during the initial phases (T &lt; 300 s). Furthermore, we observe a break at T = 80 000 s that we interpreted as evidence of a jet break, which constrains the opening angle to be about θj = (3–5) degrees. Finally, we apply a machine-learning technique to model the multiwavelength light curve of GRB 210822A using the afterglowpy library. We estimate the angle of sight θobs = (6.4 ± 0.1) × 10−1 degrees, the energy E0 = (7.9 ± 1.6) × 1053 erg, the electron index p = 2.54 ± 0.10, the thermal energy fraction in electrons ϵe = (4.63 ± 0.91) × 10−5 and in the magnetic field ϵB = (8.66 ± 1.01) × 10−6, the efficiency χ = 0.89 ± 0.01, and the density of the surrounding medium n0 = 0.85 ± 0.01 cm−3.
A new star formation recipe for magnetohydrodynamics simulations of galaxy formation
Authors: Girma Eden , Teyssier Romain 
Published: November 2023

ABSTRACT
Star formation has been observed to occur at globally low yet locally varying efficiencies. As such, accurate capture of star formation in numerical simulations requires mechanisms that can replicate both its smaller scale variations and larger scale properties. Magnetic fields are thought to play an essential role within the turbulent interstellar medium (ISM) and affect molecular cloud collapse. However, it remains to be fully explored how a magnetized model of star formation might influence galaxy evolution. We present a new model for a sub-grid star formation recipe that depends on the magnetic field. We run isolated disc galaxy simulations to assess its impact on the regulation of star formation using the code ramses. Building upon existing numerical methods, our model derives the star formation efficiency from local properties of the sub-grid magnetized ISM turbulence, assuming a constant Alfvén speed at sub-parsec scales. Compared to its non-magnetized counterpart, our star formation model suppresses the initial starburst by a factor of 2 while regulating star formation later on to a nearly constant rate of ∼1 M⊙ yr−1. Differences also arise in the local Schmidt law with a shallower power-law index for the magnetized star formation model. Our results encourage further examination into the notion that magnetic fields are likely to play a non-trivial role in our understanding of star and galaxy formation.
New Antibiotics For The Post‐Antibiotic Era
Authors: Mobashery Shahriar 
Published: November 2023

β‐Lactam antibiotics are the most important antibiotics targetting the bacterial cell wall. However, their utility has been compormised due to broad resistance by bacteria to these antibiotics. Yet, their targets, penicillin‐binding proteins (PBPs) still remain important targets for antibiotics. The importance of PBPs, especially the high‐molcular‐mass variants, is due to their critical functions in biosynhesis of bacterial cell wall. But equally important, these proteins decorate the surface of the plasma membrane, hence access by antibiotics is often less of a problem than is for the cytoplasmic targets. I will describe an in silico search for novel classes of antibiotics carried out with the X‐ray structure of the PBP2a from methicillin‐resistant Staphylococcus aureus (MRSA). MRSA is a global scourge, infections by which afflicate 100,000 individuals annually in the USA alone. A significant proportion of these cases leads to mortality. Resistance to β‐lactam antibiotics in these organisms is overencompassing, including penicillins, cephalosporins, carbapenems, among others. I will describe discovery of the oxadiazole and quinazolinone classes of antibacterials, which target PBPs in MRSA. The lead compounds were elaborated synthetically into a library of several hundred members, which were screened for antibacterial activity. Both classes of antibiotics target bacterial cell‐wall biosynthesis, they exhibit favorable pharmacokinetic properties, they are efficacious in rodent models of MRSA infection and they are orally bioavailable. Both classes of compounds hold great promise in addressing clinical needs in treating infections by MRSA.Support or Funding InformationNIH
Evidence for female specific changes in the sympathetic nervous system in post‐infarction heart failure
Authors: Pinkham Maximilian I , Pyner Susan , Shenton Fiona C , Whalley Gillian , Habecker Beth , Woodward Bill , Guild Sarah‐Jane I , Barrett Carolyn J 
Published: November 2023

The development and progression of post‐myocardial infarction (MI) heart failure is, in part, driven by adverse changes in the sympathetic nervous system (SNS). Clinically, females, compared to males, typically have a worse outcome post‐MI. The aim of these experiments was to characterize changes in the SNS in females and males. All experiments were performed in ovary‐intact female and male Wistar rats. Following MI or sham‐MI surgery, heart failure developed over a 6–8 week period at which time left ventricular (LV) function was assessed before and following the acute infusion of metoprolol, under chloralose‐urethane anesthesia. Following the terminal experiment, brain and heart tissue were collected and processed for histochemical and molecular analyses. Post‐MI, LV function was significantly reduced in both males and females which was associated with cardiomyocyte hypertrophy and increased collagen deposition. The acute infusion of metoprolol decreased arterial pressure significantly less in females with MI (−9±2 mmHg) compared to female sham‐MI group (−21±8 mmHg, P<0.05) and male MI group (−23±3 mmHg, P<0.05). In animals with post‐infarction heart failure, metoprolol decreased cardiac output similarly in males (−33±8 ml/min) and females (−31±7 ml/min); however females responded by significantly increasing total peripheral resistance (TPR) whereas TPR was unchanged in males. In a subset of animals with post‐infarction heart failure, renal sympathetic nerve activity responses to a decrease in arterial pressure were augmented in females but not in males and arterial baroreceptor denervation abolished this response. Compared to sham MI group, LV noradrenaline (NA) tissue content was decreased in males with MI (4.6±0.2 vs. 2.7±0.4 pmol/mg, P<0.05) but was unaltered in females with MI (4.3±0.4 pmol/mg). Post‐infarction heart failure resulted in reduced nNOS levels in the paraventricular nucleus (PVN) in both males and females with MI whereas super oxide dismutase levels were decreased only in males, not females. cFOS levels in the PVN were increased in females with post‐infarction heart failure but decreased in males, possibly related to an augmented baroreflex response in female MI group following the metoprolol mediated decrease in cardiac output. The current findings show that ovary‐intact female rats have similar changes in cardiac function and remodelling in post‐infarction heart failure as males; however there are sex differences in the regulation of the SNS. In particular, these findings suggest sex differences in post‐infarction heart failure particularly in relation to the autonomic regulation of arterial pressure.Support or Funding InformationThis work was supported by grants from the University of Auckland Research and Development Fund and The National Heart Foundation of New Zealand
Moderately High Salt Intake does not Raise Blood Pressure but does Activate Peripheral Immune Cells with the Capacity to Raise Blood Pressure
Authors: ZUBCEVIC Jasenka , Ahmari Niousha , Diaz Devon , Malphurs Wendi , Redlitz Conrad M , Andrade Marry Ann , Toney Glenn M 
Published: November 2023

INTRODUCTIONArterial hypertension (HTN) is often salt sensitive and accompanied by renin‐angiotensin (RAS) and immune system activation. For example, activated T cells contribute significantly to Angiotensin II (Ang II)‐dependent HTN. In a salt‐sensitive model, rats fed a moderately high salt diet (2% NaCl) experience neuroadaptations that increase excitability of PVN sympathetic control neurons without developing overt HTN. Dietary salt is also linked with autoimmune diseases (e.g., psoriatic arthritis, lupus, etc.) that are often co‐morbid with HTN and associated with T cell‐dependent interleukin 17 (IL17) signaling. Here, we hypothesized that elevated dietary salt will increase IL17 expression in T lymphocytes and contribute to the salt‐sensitivity of arterial HTN, possibly by priming of the pre‐sympathetic circuitry.METHODSAdult Sprague‐Dawley rats were placed on either a normal (0.4% NaCl) or high salt (2% NaCl) diet for two weeks. Blood and bone marrow (BM) were collected to determine levels of CD4+IL17+ T lymphocytes by FACS. Additionally, adult C57BL/6‐Il17atm1Bcgen/J mice (Jax Labs), with constitutive expression of EGFP as a marker of IL17a activity, were subjected to a similar experimental protocol. Blood pressures (BP) were measured once a week by tail cuff. Whole body fluorescence imaging was performed in all mice to detect group differences in the levels of IL17a. BM was collected both from normal and high salt fed mice, and fluorescence sorting separated IL17+ from IL17‐cells. Adoptive transfer was performed by injecting the same number of harvested cells via tail vein into separate groups of naïve C57BL6/J adult mice (n=6/group). BP was measured twice a week for two weeks following the adoptive transfer.RESULTSIn rats, high salt intake increased expression of IL17a in BM, but not in circulating CD4+ T cells. There was no change in the total CD4+ T cell population. In mice, whole body fluorescence revealed a ~12% increase of IL17 reporter fluorescence selectively in the head region in the high salt group. We observed a significant increase of systolic BP (113±6 to 135±3 mm Hg; P<0.05) within one week of adoptive transfer of IL17a+ BM cells from the high salt group.CONCLUSIONA moderately high salt diet is not sufficient to raise BP in the whole animal. Nevertheless, it does activate a population of IL17‐expressing immune cells which alone are capable of raising BP. We speculate that suppression of endogenous RAS by high salt intake might offset or otherwise preclude the pro‐HTN effects of immune cell activation.Support or Funding InformationAHA14SDG18300010&UFCVM (JZ); NIH HL102310 (GMT)
Phospholamban is a Potential Regulator of Skeletal Muscle and Whole‐Body Metabolism
Authors: Gamu Daniel , Mazereeuw Symon , Tupling A. Russell 
Published: November 2023

Phospholamban (PLN) is a known inhibitor of the sarco(endo)plasmic reticulum Ca2+‐ATPase (SERCA) pump and modulator of muscular contractility. We have previously shown that the PLN homologue, sarcolipin, is an uncoupler of SERCA function, increasing the energy demand of skeletal muscle to pump Ca2+. Here, we sought to determine whether PLN has a similar effect on SERCA energetics and metabolism. To examine this, SERCA function and whole‐body metabolic rate were measured in PLN knock‐out mice and wild‐type (WT) littermates (n = 5–6/group). Ca2+‐dependent ATPase activity was measured in left ventricle (LV) and soleus (SOL) homogenates in both the absence (i.e. presence of the Ca2+ ionophore A23187) and presence (i.e. no ionophore) of a Ca2+ gradient. The ionophore ratio, an indication of membrane leak, was calculated by dividing maximal activity in the presence of ionophore by that without. Indirect calorimetry was also used to measure whole‐body metabolic rate. In the presence of ionophore, maximal SERCA activity was 25% and 33% greater with PLN ablation in LV (P < 0.05) and SOL (P < 0.01), respectively, while no differences were found in the absence of ionophore in either LV (P = 0.82) or SOL (P = 0.11). The LV ionophore ratio was 22% lower in WT mice (P < 0.05), suggesting that the presence of PLN is associated with membrane leak. While not statistically significant (P = 0.21), the SOL ionophore ratio was 11% lower in WT mice. Lastly, whole‐body energy expenditure tended (P = 0.07) to be lower with PLN ablation. Together, these findings suggest that PLN may alter SERCA pumping energetics and whole‐body metabolic rate.Support or Funding InformationCanadian Institutes for Health Research
IL‐15 Promotes Mitochondrial Activity Through an ERK1/2‐PPARδ Signaling Axis in C2C12 Skeletal Muscle Cells
Authors: Abbott Marcia J , Krolopp James E , Nakamoto Ty 
Published: November 2023

Myokines are specialized factors that are secreted from skeletal muscle (SKM). Many myokines have been shown to increase in circulation following exercise. In particular, interleukin‐15 (IL‐15) is one such myokine and its expression and secretion is induced with exercise. It has been postulated that IL‐15 induces SKM mitochondrial activity, via activation of PPARδ. However, the direct downstream mediators linking IL‐15 to PPARδ activity have yet to be elucidated. Here we aimed to identify the direct downstream signaling molecules of IL‐15 and their roles in mediating mitochondrial activity in SKM. The SKM cell line, C2C12, was cultured and cells were induced to differentiate into mature myotubes. Upon induction of differentiation, C2C12 cells were treated every other day, for 6 days, with vehicle (DMSO), IL‐15 (100 ng/ml), a PPARδ inhibitor (GSK), or IL‐15 + GSK. Western blotting and qPCR analysis were performed to verify inhibition of PPARδ. To assess mitochondrial activity, cells were stained with Mitotracker, fixed, and imaged at the end of the 6 day protocol. Additional short term experiments were performed on fully differentiated cells that were treated with or without IL‐15 (100 ng/ml) for 24 hours. Subsequently, proteins were extracted and western blotting was performed to assess phosphorylation levels of potential downstream signals of IL‐15 (Jak1, Akt, Akt substrates, and ERK1/2). Additionally, following the 24 hour protocol proteins were extracted and ERK1/2 was immunoprecipitated and western blotting procedures were performed to determine potential PPARδ interaction. PPARδ protein and mRNA expression were increased with IL‐15 treatment and these effects were abolished with GSK. Further, IL‐15 stimulated mitochondrial activity, as indicated by increases in Mitoctracker staining, and IL‐15 + GSK blunted these effects. IL‐15 treatment, for 24 hours, had no effect on phosphorylation or total protein expression of Jak1, Akt, or Akt substrates. However, ERK1/2 phosphorylation was increased with IL‐15, without a concomitant increase in total ERK1/2 expression levels. Moreover, when ERK1/2 was immunoprecipitated, there were higher levels of PPARδ interaction with ERK1/2 (34%; P<0.05), in the IL‐15 treated cells when compared to cells without IL‐15 treatment. Taken together, IL‐15 mediated increases in mitochondrial activity are dependent on PPARδ activity. Here we show, for the first time, that IL‐15 activates ERK1/2 in C2C12 SKM cells. Further, our data indicate that IL‐15 induces interaction between ERK1/2 and PPARδ. Overall, it is clear that IL‐15 acts to regulate mitochondrial activity via an ERK1/2‐PPARδ signaling axis in SKM cells.Support or Funding InformationCrean College of Health and Behavioral Sciences, Chapman University, Start‐Up Funding
Regulation of Metabolism by Estrogen Receptor Alpha
Authors: Archer Ashley E. , Rogers Robert S. , Wheatley Joshua L. , White Kathleen , Rumi M.A. Karim , Soares Michael J. , Geiger Paige C. 
Published: November 2023

Postmenopausal estrogen deficiency increases the risk for metabolic syndrome, obesity, and type 2 diabetes. Estrogen treatment improves metabolic function in postmenopausal women, and estrogen receptor α (ERα) is thought to be the primary player in these protective metabolic effects. However, the mechanisms behind ERα regulation of metabolic function have not been elucidated. The purpose of this study was to investigate the impact of ERα loss on whole body and skeletal muscle oxidative capacity in a rat model. 14 wk‐old female Wildtype (WT) and ERα knockout (ERα−/−) rats were exercised to exhaustion and one week later a glucose tolerance test was performed. At sacrifice, body weight and adipose tissue depot weights (subcutaneous, retroperitoneal and periuterine) were measured. Adipocyte cell size and mitochondrial protein content were assessed by immunohistochemistry and western blot, respectively. Intramuscular triglyceride storage was also assessed. ERα deficient rats had increased body weight and subcutaneous adipose tissue mass compared with WT rats. Although there was no increase in retroperitoneal adipose tissue mass, adipocyte size was increased in ERα deficient rats. HOMA‐IR values were also increased in ERα−/− animals indicating increased insulin resistance. ERα deficiency also decreased exercise time to exhaustion when compared with WT rats. Mitochondrial proteins Complex IV and peroxisome proliferator‐activated receptor gamma coactivator 1‐alpha (PGC1α) were significantly decreased and intramuscular triglyceride storage was increased in skeletal muscles from ERα deficient rats. Our data demonstrate the potential regulatory role of ERα to enhance oxidative capacity and improve energy metabolism both systemically and in skeletal muscle. Pharmacological activation of ERα could be an effective strategy for the prevention and treatment of metabolic dysfunction. Selective estrogen receptor modulators currently used as treatment for various postmenopausal symptoms may have the potential to restore metabolic function in postmenopausal women and improve quality of life.Support or Funding InformationThis research was supported in part by an NIH grant (R01 AG031575) and the IRHRM Pilot grant.
Acute Expression of PGC‐1α Isoforms in Skeletal Muscle of Postmenopausal Women following Resistance Exercise
Authors: Kiwata Jacqueline L. , Tuzon Creighton , Rice Judd C. , Schroeder E. Todd , Dieli‐Conwright Christina M. 
Published: November 2023

PGC‐1α4, an isoform of the transcriptional coactivator PGC‐1α, has been postulated to regulate skeletal muscle hypertrophy through modulation of anabolic and catabolic gene expression. While resting levels of PGC‐1α4 mRNA expression were found to increase in skeletal muscle of healthy adults after a resistance training program, the acute effect of resistance exercise (RE) on PGC‐1α4 expression in a population prone to progressive muscle loss, such as postmenopausal women, has not been investigated. We sought to determine whether high‐intensity eccentric RE altered mRNA expression of PGC‐1α isoforms including total PGC‐1α, PGC‐1α4 and a regulator of muscle oxidative changes, PGC‐1α1, in postmenopausal women. Further we examined whether PGC‐1α isoforms were associated with changes in anabolic gene expression of IGF‐1Ea, IGF‐1Eb, and IGF‐1Ec (MGF), and catabolic gene expression of myostatin, FOXO3A, MAFbx and MuRF1. Nine postmenopausal women (57.9 ± 3.2 yr) performed 10 sets of 10 maximal eccentric repetitions of single‐leg extension on an isokinetic dynamometer with 20 second rest periods between sets. Muscle biopsies were obtained from the vastus lateralis of the exercised leg before and 4 hours after the RE bout with mRNA expression determined by RT‐qPCR. No significant changes in the mRNA expression of PGC‐1α total, PGC‐1α1, PGC‐1α4, IGF‐1Eb or MGF were observed following acute eccentric RE (P > 0.05). However, expression of IGF‐1Ea significantly increased following RE (P < 0.05). No significant correlations were found between PGC‐1α and IGF‐1 isoforms, although PGC‐1α4 mRNA expression was associated with reduced expression of the catabolic gene myostatin (R = −0.88, P < 0.01) and increased expression of the catabolic gene MuRF1 (R = 0.78, P < 0.05). Thus, our data demonstrate an attenuated response of PGC‐1α isoforms to an acute bout of maximal eccentric exercise with short rest periods in postmenopausal women, with no association to changes in muscle growth factors involved with myogenic activity.Support or Funding InformationThe Clinical Exercise Research Center at the University of Southern California and NIH NCRR GCRC M0I RR000043 provided funds for this project.
The Correlation Between Tfeb and PGC‐1α in Skeletal Muscle
Authors: Erlich Avigail T , Vainshtein Anna , Hood David 
Published: November 2023

Muscle health is strongly dependent on the maintenance of functional mitochondria for the provision of ATP through oxidative phosphorylation. The mitochondrial pool is governed by two competing processes: mitochondrial biogenesis and autophagy (mitophagy). Peroxisome proliferator‐activated receptor gamma coactivator 1‐alpha (PGC‐1α) is the master regulator of mitochondrial biogenesis, while transcription factor EB (Tfeb) regulates lysosomal biogenesis and is required for autophagy. Since the two processes are strongly linked, we sought to study their ability to regulate one another. The purpose of this study was to further elucidate the relationship between Tfeb and PGC‐1α by investigating Tfeb family members, as well as its transcription factors and downstream targets. Protein levels of Tfeb were reduced by 70% in whole body PGC‐1α KO mice compared to their WT counterparts. In contrast, muscle‐specific overexpression of PGC‐1α resulted in a 25% increase in Tfeb protein expression. Tfe3, a family member of Tfeb, was reduced by 50% in PGC‐1α KO mice. Despite this similar reduction in Tfeb and Tfe3 in KO animals, there were no significant changes observed in YY1, a transcription factor upstream of Tfeb that may regulate Tfeb expression. Since Tfeb is involved in lysosomal biogenesis, markers of chaperone‐mediated autophagy, were measured in the PGC‐1α WT and KO mice in order to see if they were affected by PGC‐1α‐mediated Tfeb downregulation. However, no changes were observed in Hsc70 or Lamp‐2A between the two genotypes. Our findings confirm the positive correlation between the two master regulators of biogenesis and autophagy, PGC‐1α and Tfeb. PGC‐1α does not seem to have an effect on markers of chaperone‐mediated autophagy, despite its regulation of Tfeb expression. Thus, it is probable that this correlation is working to promote other forms of autophagy, as well as mitochondrial biogenesis, in order regulate the turnover of the mitochondrial network.Support or Funding InformationSupported by NSERC