bluuebunny/crossref_metadata_2025_split huggingface dataset:
Thiamine Insufficiency Induced Hypoxia‐Inducible Factor 1‐α (HIF‐1α) Regulates Alzheimer’s Disease‐Like Neuropathology
Authors: Valle Maria Luisa , Zastre Jason 
Published: April 2020

Vitamin B1 (thiamine) insufficiency (TI) promotes debilitating neurotoxicity that frequently accompanies the most prevalent and devastating age‐related neurodegenerative disorder, Alzheimer’s disease (AD). Age related decline in thiamine levels highly correlates with a deterioration in cognitive function and a potential biomarker for AD diagnosis. Congruent with established AD pathology, TI promotes cerebral energy hypometabolism, inflammation, oxidative stress, and plaque formation. Yet despite progress into the relationship between reduced thiamine levels and the neuropathology of AD, mechanistic insight into how chronic thiamine insufficiency promotes AD‐like pathology is lacking. Our previous work has shown that TI stabilizes Hypoxia Inducible Factor‐1α (HIF‐1α), the main transcription factor involved in hypoxic stress, through an oxygen independent mechanism (pseudo‐hypoxia). After cerebral ischemia, HIF‐1α has been shown to potentiate the amyloidogenic cascade via direct transcriptional activation of β‐secretase‐1 (BACE‐1). BACE‐1 cleaves the Amyloid Precursor Protein (APP) into 99‐residue membrane‐associated fragments (C99) involved in the generation of β‐amyloid peptides. Therefore, HIF‐1α may be a critical link between thiamine insufficiency and AD pathophysiology. Treatment with the thiamine antagonist Pyrithiamine (PT) activated HIF‐1α and enhanced the levels of BACE‐1 and C99 fragments in mouse hippocampal neuronal cells (HT22). In association with the increased expression, BACE‐1 activity was also enhanced. Supplementation of the Prolyl Hydroxylase (PHD) activator Octyl‐α‐ketoglutarate, attenuated HIF‐1α activation and reduced expression and activity levels of BACE‐1. This suggests that TIinduced HIF‐1α activation may occur through a pseudo‐hypoxic mechanism via PHDs inhibition. Additionally, pharmacological inhibition of HIF‐1α via YC‐1 or by a Dominant Negative HIF‐1α construct decreased BACE‐1 expression and activity, confirming that the BACE‐1 increase was HIF‐1α dependent. Overall, these findings suggest that HIF‐1α may be a key transcriptional regulator in TI mediated AD‐like neuropathology.Support or Funding InformationDepartment funding
Effects of Oligosaccharide Supplementation on Intestinal Morphology and Enteric Glial Cell Marker Expression in a Neonatal Pig Model
Authors: Shapiro Lindsey D. , Ziegler Amanda , Odle Jack , Van Landeghem Laurianne , Blikslager Anthony 
Published: April 2020

We have shown that oligosaccharide supplementation can modulate the gut flora in neonates, and the microbiome is known to drive the maturation of the enteric glial cell (EGC) network postnatally. Here, we test the effects of dietary oligosaccharides on postnatal changes in the EGC network and intestinal morphology in a neonatal pig model.After suckling colostrum for 24‐hours, one‐day‐old pigs were grouped onto one of three formula‐based diets: control, high oligosaccharide (1:1 mixture of galactooligosaccharide and polydextrose, 8g/L), or low oligosaccharide (4g/L). Small intestine and colon samples were collected at 1‐ 7‐ 14‐ and 21‐ days‐of‐age for western blot and histological analysis. Preliminary histological results indicate a trend toward a decreased small intestinal villus length in the high oligosaccharide group at 7‐days‐of‐age, indicative of accelerated intestinal maturity. Expression of the EGC marker glial fibrillary acidic protein is increased in the small intestinal mucosa at 7‐ and 14‐days‐of‐age in the high oligosaccharide group based on a preliminary western blot (n=1). Following ongoing work to assess crypt morphology and quantify additional EGC markers S100B, PLP‐1, Sox10 in the small intestine and colon, we expect to find increased mucosal expression of EGC markers earlier in postnatal development in the high oligosaccharide group, as well as histological changes consistent with enhanced rates of gut maturation in pigs fed a high oligosaccharide diet. Understanding how dietary inputs drive intestinal development postnatally may improve practices for managing optimal gut heath early in life.Support or Funding InformationNIH K01 OD 028207, NIH P30 DK 034987, NIH‐NICHD R01 HD095876, USDA‐NIFA VMCG‐0065
Cerebrovascular carbon dioxide reactivity is influenced by sex despite comparable hemodynamic and respiratory chemosensitivity in young fit individuals
Authors: Drapeau Audrey , Imhoff Sarah , Labrecque Lawrence , Paquette Myriam , Le Blanc Olivier , Malenfant Simon , Brassard Patrice 
Published: April 2020

Cerebral blood flow (CBF) is generally higher in women compared to men at rest. Although accumulating evidence supports sex differences in CBF regulation, findings remain contradictory for dynamic cerebral autoregulation (dCA) and cerebrovascular reactivity to carbon dioxide (CVRCO2). Cardiorespiratory fitness represents an indicator of cardiovascular health. However, we have recently reported that dCA is reduced in young fit men compared to controls, and that dCA is attenuated in young fit women compared to fit men. However, the influence of sex on CVRCO2 in these young fit individuals remains misunderstood. The aim of this study was to examine the influence of sex on CVRCO2 in young fit individuals. Changes in middle cerebral artery mean blood velocity (MCAvmean; transcranial doppler), mean arterial pressure (MAP; photoplethysmography), heart rate (HR; ECG) and pulmonary ventilation (spirometer) were measured in 29 young fit individuals (women n=10, men n=19), in response to changes in end‐tidal partial pressure of carbon dioxide (PETCO2; gas analyzer) during the modified Duffin hyperoxic rebreathing test. Women were tested in the early follicular phase. CVRCO2, as well as hemodynamic and ventilatory chemosensitivity, were characterized using linear regressions on the rebreathing portion of the test after the determined ventilatory recruitment threshold. While age was not different between groups (26 ± 6 vs. 27 ± 5 years, P = 0.92), height: (1.64 ± 0.06 vs. 1.77 ± 0.08 m; P < 0.0001), body weight (60 ± 6 vs. 72 ± 10 kg; P = 0.0009) and maximal oxygen uptake (48.4 ± 3.8 vs. 57.9 ± 6.8 mL−1kg−1min−1; P < 0.0001) were lower in women. At rest, MCAvmean (72 ± 8 cm/s vs. 62 ± 11 cm/s; P = 0.02) and HR (73 ± 8 vs. 64 ± 11 bpm; P = 0.02) were higher in women, whereas MAP was not different between groups (100 ± 19 vs. 97 ± 10 mm Hg; P = 0.73). CVRCO2 was higher in women compared to men, both in absolute (1.59 ± 0.78 vs. 0.35 ± 1.51 cm/s/mm Hg, P = 0.01) and normalized terms (2.19 ± 0.97 vs. 0.54 ± 2.41 %/mm Hg, P = 0.02). Hemodynamic and respiratory chemosensitivity responses during CO2 rebreathing were not different between groups (all P > 0.05). These results indicate that the cerebrovasculature of young fit women is more sensitive to CO2 than men despite comparable hemodynamic and ventilatory chemosensitivity responses.Support or Funding InformationS.I., L.L. and S.M. have been supported by a doctoral training scholarship from the Fonds de recherche du Québec ‐ Santé (FRQS)
Mitochondrial fatty acid synthesis: not just another way to make fatty acids
Authors: Nowinski Sara M. , Solmonson Ashley D. , Rusin Scott F. , Bensard Claire , Bott Alex J. , Morgan Jeffrey T. , Fogarty Sarah , Lettlova Sandra , Berg Jordan A. , Gygi Steven P. , Winge Dennis R. , Deberardinis Ralph , Rutter Jared P. 
Published: April 2020

Mitochondria are often dubbed “the powerhouse of the cell,” however this gross over‐simplification has arguably led to a paucity of knowledge concerning the many other functions of these incredibly diverse organelles. Fatty acid synthesis (FAS) is an essential cellular process, but it is a little‐known fact even among mitochondrial experts that eukaryotes actually harbor two distinct FAS systems – one in the cytoplasm, and one in the mitochondria. Although mitochondrial FAS (mtFAS) was discovered decades ago, its function(s) in mammals are still unclear. One well known product of the pathway is lipoic acid, an important lipid co‐factor for several mitochondrial dehydrogenases, however we now appreciate that mtFAS plays a far wider role in mitochondrial physiology. Here we show that while mtFAS does not directly contribute to the synthesis of structural lipids like PS, it instead is required for the production of lipids that facilitate assembly and stability of the mitochondrial electron transport chain (ETC). This novel regulatory role of mtFAS occurs via physical interaction of the acyl carrier protein and a family of late‐stage ETC assembly factors known as the LYR proteins. Notably, this effect is separate from lipoic acid production, as Lipt1 knockouts do not display the same strong ETC depletion phenotype. Proteomics and metabolomics data provide intriguing insights into the consequences of mtFAS depletion, and highlight promising future directions towards further understanding the role of this pathway in cellular metabolism.Support or Funding InformationThis work was supported partially by grants from the NIH (GM115174 and GM115129 to JR and GM97645 to SPG) and the Nora Eccles Treadwell Foundation (to JR), as well as HHMI (JR). Support for SMN was also provided by UMDF and ACS postdoctoral fellowships.
An investigation of the pro‐inflammatory effects of wood smoke on human lung airway epithelial cells.
Authors: Enright Sarenna , Jones Shannon 
Published: April 2020

Over two‐fifths of the world’s population uses solid biomass fuels such as animal dung, plastic, rubber or wood for the purpose of cooking and the heating of their homes. In some instances, especially in underdeveloped regions of the world, biomass smoke exposure can disproportionately impact women and children of color, as they are more than likely to be performing cooking duties and being exposed to this type indoor air pollution. Poor ventilation of homes can also contribute to poorer health outcomes associated with biomass smoke exposure. These individuals exposed to biomass smoke and particulate matter are also more likely to be suffer from negative health outcomes such as repeated, acute lower respiratory infections (ALRI) and asthma. The mechanisms by which biomass smoke exposure contributes to these pathologies of the lung remain largely unknown. The purpose of this research was to determine the general effects of woodsmoke on lung airway epithelial cells (A549). In this project, we are modeling the effects biomass smoke exposure using solubilized wood smoke. Biomass smoke is believed to have a significant impact on the innate immune system and the epithelial cells than line airways. To determine the pro‐inflammatory effects of woodsmoke, we used the polymerase chain reaction (PCR) to assess the expression of many pro‐inflammatory genes. Results thus far show that treated A549 cells displayed an increase in COX‐2 expression with increasing concentrations of woodsmoke. This induction of iNOS, TGF‐beta, and HO‐1 gene expression was also observed. The cytotoxicity of woodsmoke on A549 cells was also assessed using the lactate dehydrogenase assay (LDH) assay. Future studies are aimed at determining the impact of woodsmoke on cytokine secretion in A549 cells and whether smoke exposure is capable of inducing oxidative stress in these cells.Support or Funding InformationUniversity of Richmond’s Integrated and Inclusive Science Program
Identification of Candidate Genes Involved in the Survival of Drosophila in Extreme O2 Environments
Authors: Stobdan Tsering , Zhao Huiwen W. , Zhou Dan , Iranmehr Arya , Lu-Bo Ying , Bafna Vineet , Haddad Gabriel G. 
Published: April 2020

The origin and evolution of life forms depended by and large on O2 availability over thousands of years. The mechanism of the adaptation process under strong selection pressure, however, is subject to some debate. For instance, it could be mediated by extant mutations or cryptic genetic variation that yield a fitness advantage in the new environment, or by mutations that arise de novo. For sexually reproducing organisms, multiple favored variants can also be acquired on a single haplotype via recombination to alleviate the effect of clonal interference and accelerate adaptation. It is however difficult to directly observe evolution in action. In the current study, we have identified the genomic intervals under selection in the high and low O2‐adapted Drosophila melanogaster. The adapted Drosophila melanogaster constitutes flies that could complete its life cycle in 90% and 4% O2 environments respectively, which otherwise is lethal for the naive flies. We used UAS‐RNAi x daGal4 system to functionally validate the role of specific genes of the top selected genomic interval. The top interval selected under high O2 environment consisted of 32 genes that includes four non‐protein‐coding genes. RNAi lines were available for 15 genes (15/28) that were evenly scattered across this interval. The high O2 tolerance assay indicate >98% eclosion rate in the adapted flies. Four genes i.e., CG15472, Klf15, CG2861 and CG42594, depicts a relatively higher number of pupation compared to the controls (12±0.6 to 14±2.5 versus <7 pupae counts per vial. The average pupae eclosed was higher for two of the genes, CG15472 and CG42594, although these numbers were significantly lower than the adapted flies. The percentage eclosion rate was significantly higher for CG15472 ‐(91.4 ±16.7%), which is close to the 98% eclosion seen in the adapted flies. Similarly, we have identified intervals under selection in the low O2 adapted flies. Remarkably, there was higher proportion of genes from the Notch signaling pathway in these selected intervals. Our results so far indicate that CG15472 from the top selected interval is one of the important gene playing critical role in the successful adaptation of flies to high O2 environment. Similarly, the Notch signaling pathway has an important role in the successful adaptation of flies to extremely low O2.Support or Funding InformationNIH grant (R01 HL127403‐02, R21NS101652‐01) to GGH. NSF grant (NSF‐DBI‐1458557, NSF‐IIS‐1318386) and NIH (1R01GM114362) to VB and AA.
Anatomical and histological observations on a musk ox brain (Ovibos moschatus)
Authors: Ackermans Nicole L. 
Published: April 2020

Musk oxen are large tundra‐dwelling bovids that, when in rut, can strike heads at speeds around 30 mph. The wide base of their large horns armor their skull against such impacts, although it is unknown if they sustain brain trauma. There is no literature describing concussion, or other adverse repercussions of severe cranial contact in musk oxen. Our research explores the brain and skull anatomy of combative bovids, specifically focusing on whether these animals sustain brain injury after head‐butting, and if not, what features most likely provide protection. Achieving a better understanding of how these extreme animals may avoid brain injury will provide insight to develop strategies for the reduction of traumatic brain injury in humans.An archived brain of an adult male musk ox was used in this preliminary study. It had been collected after humane euthanasia and preserved in formalin following a goring injury in the wild where it had been observed clashing heads with another musk ox bull in the moments before its death. The brain was MR scanned and examined histologically for evidence of traumatic brain injury. The right hemisphere was fixed in paraformaldehyde (4%, buffered) and prepared using a variety of exploratory histological protocols, to investigate abnormalities in neurons, microglia, astrocytes, and blood vessels. Specifically, Tau protein, a biomarker found in the cerebrospinal fluid and in neurodegenerative lesions, was used to detect any brain trauma‐related cellular consequence of chronic or acute head clashing. Preliminary histological results indicate no apparent abnormalities. A high‐resolution 7‐T MRI scan additionally revealed no abnormal neuropathological changes. This brain being a single sample does not allow us to make sweeping assumptions. However, these preliminary investigations lead us to believe that musk oxen do not appear to suffer from chronic or acute brain trauma after head clashing. A more in‐depth exploration with a larger sample size is proposed to better understand the combination of anatomical structures contributing to brain protection in these animals.Support or Funding InformationNLA is a fellow of the Swiss National Science Foundation
GLP‐1 Induces a Shift in Primary Carbon Metabolites in Late‐fasted Northern Elephant Seals
Authors: Dhillon Jaapna , Viscarra Jose A. , Fiehn Oliver , Ortiz Rudy M. 
Published: April 2020

Insulin resistance has been suggested to be an adaptive response to food deprivation since it promotes the preservation of glucose and oxidation of fat. However, the insulin resistance‐like conditions that fasting mammals experience may result from reduced pancreatic sensitivity to glucose/capacity to secrete insulin. Glucagon‐like peptide 1 (GLP‐1) is a gastrointestinal hormone that enhances postprandial glucose‐stimulated insulin secretion. To better assess the effects of GLP‐1 on the metabolism of primary carbon metabolites associated with late‐fasting induced insulin resistance, we dose‐dependently infused late‐fasted seals (naturally adapted to prolonged fasting) with low (10 pM/kg; n=3) or high (100 pM/kg; n=4) GLP‐1 immediately following a glucose bolus (0.5g/kg), using glucose without GLP‐1 as control (n=5). The plasma metabolome was measured from samples collected at 5 time points just prior to and during the infusions and areas under the curve (AUC) were calculated.The median AUC fold changes between the GLP‐1‐treated (low and high doses combined) and control group were analyzed using ChemRICH which is a chemical similarity enrichment analysis software for metabolomics datasets that uses medical subject headings and Tanimoto substructure chemical similarity coefficients to cluster metabolites into non‐overlapping chemical groups. Statistically significant p‐values for clusters were obtained by self‐contained Kolmogorov–Smirnov tests. ChemRich mapped 149 of the identified metabolites to 23 nonoverlapping chemical classes, of which 2 were found to be significantly different between the GLP‐1‐treated and control group (false discovery rate adjusted P value < 0.05). Treatment with GLP‐1 infusions was associated with altered Kreb Cycle activity represented by increased levels of tricarboxylic acids, and reduced levels of carbocyclic acids (benzoic acid being a key compound). Hence, GLP‐1 infusion induced a shift in primary carbon metabolites in a model of fasting‐induced insulin resistance.Support or Funding InformationThis work was supported by grants: NIH NHLBI HL091767, NIH NHLBI HL091767‐S1, NIH NHLBI K02HL103787, NIH NHLBI R01HL09176, and NIH U24 DK097154.
Structure of sympathetic input to interscapular brown adipose tissue in the mouse
Authors: Muenzberg-Gruening Heike , Huesing Clara , Gummadi Sanjeev , Zhang Rui , Lee Nathan , Qualls-Creekmore Emily , Yu Sangho , Morrison Chistopher D. , Burk David , Berthoud Hans Rudolph , Neuhuber Winfried 
Published: April 2020

Interscapular brown adipose tissue (iBAT) is under sympathetic and sensory nerve control. We recently identified the stellate and thoracic sympathetic chain ganglia T1‐T5 as the main origins of sympathetic input to iBAT in adult male and female mice. Previous studies reported that iBAT receives sympathetic innervation from five intercostal nerves; even though intercostal nerves (which originate from ventral rami) are typically known to provide innervation to lateral, ventral body tissues. Furthermore, we were unable to find literature with detailed anatomical studies. Here, we used a reporter mouse model that expresses tdTomato in tyrosine hydroxylase expressing neurons (TH‐tomato mice) in all sympathetic nerve fibers to facilitate dissection and imaging of sympathetic nerves to iBAT. Our data clarifies that iBAT receives sympathetic input via dorsal rami, which combine sensory and sympathetic fibers. This is consistent with the role of dorsal rami to innervate dorsal body structures, while intercostal nerves (traveling along the ribs) provide innervation to lateral and ventral body structures in mammals. Furthermore, we performed whole mount and paraffin embedded anatomical studies of TH (as surrogate for sympathetic nerves) to understand the anatomy and structure of sympathetic iBAT innervation. We found that fine sympathetic nerve fibers branch off the dorsal rami emanating from T1‐T4 to enter the BAT pad, and from there further branch to form axonal varicosities. Meanwhile, the dorsal rami continue to innervate vasculature and skin. We further established a novel tool to quantify axonal varicosities across entire adipose tissue depots using the IMARIS spot detection tool. This allowed us to visualize the extensive variation of axonal varicose density within the entire iBAT depot with dense varicosities adjacent to brown adipocytes, but sparse varicosities adjacent to white adipocytes. We also analyzed the axonal varicosities in inguinal white adipose tissue and found denser varicosities associated with beige islands that were significantly increased after 7day cold exposure (10°C). Finally, we use UCP1‐reporter mice and whole mount iBAT staining of TH to verify that dense axonal varicosities overlap with UCP1‐positive tissue, while UCP1‐negative tissue shows sparse axonal varicosities. The dynamic and anatomically distinct regulation of sympathetic axonal varicose density is likely due to distinct neurotrophic interaction of brown and white adipocytes with sympathetic neurons. Our data clarify the structure of sympathetic innervation to the iBAT in the mouse and highlights the benefits to study endorgans like entire adipose depots in an anatomically defined manner.Support or Funding InformationGrant support: NIH 4OT2 OD23864‐01