bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of hypohydration and altitude exposure on skin blood flow responses to local heating
Authors: Castellani John , Alinovi Martha , Charkoudian Nisha
Published: June 2021

It is unknown whether hypohydration (HYPO) or hypobaric hypoxia alter skin blood flow (SkBF) responses to local heating. We hypothesized that HYPO (4% of body weight) and acute altitude (ALT, 3,048 m) would decrease forearm SkBF responses to local heating and that ALT‐HYPO together would result in a further decline. Four healthy young men (23 ± 6 years, 175 ± 5 cm, 74 ± 5 kg) completed 4 trials each: a) sea‐level–euhydrated (SL‐ EUH); b) SL‐HYPO; c) ALT‐EUH; and d) ALT‐HYPO. Local thermal control of cutaneous vascular conductance (CVC) was assessed by local heating to 42°C for 30 min. CVC was calculated as laser‐Doppler flow/mean arterial pressure and analyzed for initial peak (~2–4 min after onset of warming), and plateau (last 3–5 min of warming). Initial peak CVC values were 1107 ± 593, 673 ± 273, 619 ± 241 and 784 ± 440 % of baseline for SL‐EUH, SL‐HYPO, ALT‐EUH, and ALT‐HYPO, respectively. Plateau CVC values were 1585 ± 797, 1340 ± 609, 962 ± 396 and 1082 ± 869 % of baseline. There were no significant influences of HYPO or ALT (P > 0.05 for all), although HYPO and ALT reduced initial peak SkBF by 29–44% and plateau SkBF by 15–39%. Based on these pilot data, 14–18 subjects would be required to give 80% power to detect statistical differences in initial peak and plateau SkBF responses during local heating as a result of hypohydration and altitude exposure.

The opinions contained herein are not official and do not reflect Army/DOD views
Epinephrine opens intrapulmonary arteriovenous anastomoses in healthy humans at rest
Authors: Laurie Steven , Elliott Jonathan E. , Lovering Andrew T.
Published: June 2021

During exercise or while breathing hypoxic gas mixtures large diameter intrapulmonary arteriovenous anastomoses (IPAVA) open and can be detected with saline contrast echocardiography (SCE). The mechanisms regulating these vessels remain unknown, but both of these conditions activate the sympathetic nervous system and increase plasma catecholamine concentrations. We hypothesized that exogenously increasing the plasma epinephrine concentration would open IPAVA. Using SCE, we studied 5 subjects at rest, before and after continuous infusions of epinephrine at 20, 40, 80, 160, and 320 ng/kg/min for 3 min each. Cardiac output (Q) and pulmonary artery systolic pressure (PASP) were measured using ultrasound. Bubble scores (0–5) increased in a dose‐dependent fashion in all subjects to a max score ranging from 2–4. Q and PASP doubled at the highest infusion rate. After a 30 min break, epinephrine infusions were repeated while subjects breathed 100% O2 and bubble scores did not increase despite similar increases in cardiac output and PASP. These data demonstrate that during exercise or when breathing hypoxic gas mixtures the sympathetically‐mediated release of epinephrine may directly open IPAVA independent of changes in cardiac output or PASP. Mechanisms responsible for hyperoxia‐mediated closure remain elusive.

Support: Eugene Evonuk Graduate Fellowship in Exercise & Environmental Physiology
Zn2+ has biphasic effects on KCNQ1/KCNE3 K+ channels
Authors: Duffey Michael E , Mongiardo Krystin , Hallman Jason , Crane Jokn K
Published: June 2021

Basolateral membrane K+ channels composed of KCNQ1 and the KCNE3 ancillary subunit play a critical role in epithelial tissue anion secretion by establishing electrical driving force. We are studying the effects on these channels of an inhibitor of intestinal secretion, Zn2+. When we used 8‐(4‐chlorophenylthio)‐cAMP (500 μM) to activate short circuit current (Isc) across human colonic T84 cell monolayers, Zn2+ (2 mM zinc acetate) in the serosal bath transiently increased Isc from 21±6 to 97±12 μA/cm2, followed by inhibition to 9±4 μA/cm2 (N=4). When cAMP‐mediated K+ currents were measured using whole cell voltage clamp in isolated T84 cells exposed to VIP (200 nM), Zn2+(2 mM) caused a 487±47 pA increase in current followed by a 568±66 pA decline (N=3). To directly measure the effects of Zn2+, we co‐expressed KCNQ1 and KCNE3 in Xenopus oocytes and determined current‐voltage relationships. Zn2+ (2mM) rapidly increased KCNQ1/KCNE3 currents from 1.9±0.7 to 4.6±1.2 μA (at +30 mV), then slowly inhibited the currents to 0.8±0.3 μA (N=4). To determine mechanism, we exposed oocytes to 5 mM glutathione before Zn2+ (2mM), and Zn2+ did not activate KCNQ1/KCNE3 currents (N=3). Rather, currents were inhibited to near zero values. These results suggest that Zn2+ activates KCNQ1/KCNE3 K+ channels via a thiol‐mediated mechanism, possibly at cysteine residues, while the mechanism of inhibition is unknown. (Supported by NIH AI 081528)
Stearidonic acid‐enriched soybean oil improved metabolic and omega‐3 profile in obese Zucker rats
Authors: Davis Jeremy E , Casey John M , Krul Elaine S , Butteiger Dustie N , Goldstein Daniel A , banz William J
Published: June 2021

Dietary intake of omega‐3 PUFA (i.e. EPA and DHA) is associated with a reduced risk of obesity‐related comorbidities. However, the consumption of marine‐based omega‐3 PUFA remains minimal. To address this disparity, a novel soybean was developed to produce oil high in stearidonic acid (SDA), which is readily converted to EPA by elongation. The objective of this study was to determine the impact of soybean (SB) oil enriched with SDA (SDA‐SB) on the metabolic profile in male lean (LZR) and obese Zucker (OZR) rats. For this, rodents were provided isocaloric and isonitrogenous diets containing conventional SB, SDA‐SB, flaxseed (FLAX), or menhaden (FISH) oil for 12 weeks. At termination, there was no significant effect of diet on body weight, energy intake, liver weight, or glucose homeostasis. However, OZR rats fed SDA‐SB or FISH oil exhibited 10 to 25% lower serum concentrations of cholesterol and TG (diet*genotype, p<0.0001), as well as hepatic fat content (diet*genotype, p<0.0001) compared to SB and FLAX groups. The omega‐3 index (sum of EPA and DHA in RBC membranes) was also over 2.0‐, 2.4‐ and 4.0‐fold greater with FLAX, SDA‐SB, or FISH treatment vs. SB oil (5.29, 6.19, 11.42 vs. 2.85; diet effect, p<0.0001), respectively. Collectively, these data indicate that SDA‐SB may be a viable plant‐based source of omega‐3 PUFA that like FISH oil, may offer protection from obesity‐associated pathologies.
IMMUNOLOGIC DYSREGULATION AND MICRONUTRIENT DEFICIENCIES ASSOCIATED WITH RISK OF INTRAPARTUM HEPATITIS E INFECTIONS IN PREGNANT BANGLADESHI WOMEN
Authors: Labrique Alain Bernard , Klein Sabra , Kmush Brittany , Ali Hasmot , Engle Ronald , Schulze Kerry , Purcell Robert , West Keith P , Nelson Kenrad E
Published: June 2021

Hepatitis E is the leading cause of acute hepatitis globally, causing death (15–40%CFR) in pregnant women. We analyzed serial sera from two prospective cohorts totaling 110,473 pregnancies from Bangladesh, between 2001–2007(A) and 2007–2010(B). We tested anti‐HEV IgG status twice in pregnancy and at 3 months postpartum. From 1,127 specimens in cohort A, 63 women seroconverted‐ an incidence of 56 per 1000 person‐years. In cohort B, in 1100 women, 40 seroconverters revealed a lower incidence of 46 per 1000 person‐years. Cytokine and micronutrient analysis across pregnancy compared host risk factors and immunologic trajectories between seroconverters and age‐, parity‐ and GA‐matched controls using multiplex Th1/Th2 cytokine assays. Seroconverters (98% after 3rd trimester) had higher concentrations of IFN‐gamma, IL‐2, IL‐12, IL‐8, IL‐4, IL‐5, IL‐10, and TNF‐alpha than controls during the 1st trimester and 3 months postpartum (p<0.05), long before their infections occurred, suggesting immunologic dysregulation associated with risk of future infection. Future cases also had lower circulating Zn at pregnancy onset (749±113 versus 814±151 μg/L, p=0.03), perhaps increasing HEV susceptibility through compromised gut immunity. VitD and Cu levels were also lower. Differences in Zn, Hb, and VitD at the outset of pregnancy may predispose women to HEV infection through immunomodulation. Supported by NIH/NIAID.
Maternal low protein diet and postnatal high fat diet increases adipose imprinted gene expression
Authors: Claycombe Kate J , Uthus Eric O , Johnson William Thomas
Published: June 2021

Maternal and postnatal diet can alter Igf2 gene expression and DNA methylation. To test whether maternal low protein and postnatal high fat (HF) diet result in alteration in Igf2 expression and obesity, we fed obese‐prone Sprague‐Dawley rats 8% (LP) or 20% (NP) protein for 3 wk prior to breeding and through pregnancy and lactation. At weaning, male offspring were placed on 10% (NE) or 45% (HE) fat, thus, giving 4 groups (LP‐NE, NP‐NE, LP‐HE, NP‐HE). At 12 wk, LP‐HE rats had the greatest increase in body wt (14‐fold) and adipose tissue mass (27‐fold). LP‐HE rats also had the greatest increase in Igf2 expression (~7.5‐ fold increase) in subcutaneous adipose tissue (ScAT) while no difference was found in the visceral adipose tissue (VisAT). To determine whether DNA methylation may be involved, we measured the methylation status of the Igf2 imprinting control region but found no differences. Because mitochondria play a central role in regulating energy metabolism, we tested whether mitochondrial (mt) copy number is altered with increased calories from HF diet. Results showed that LP‐HE rats had the lowest mt copy number in ScAT (1.4 fold‐change relative NP‐NE) while no difference was found in VisAT. These data demonstrate that maternal low protein and postnatal HF diet results in greater propensity to develop obesity by increased adipose tissue mass, increased ScAT Igf2 expression, and reduced ScAT mt copy numbers.
Low dietary protein intake during pregnancy differentially affects mitochondrial copy number in stromal vascular cells from subcutaneous versus visceral adipose tissue in the offspring
Authors: Johnson Tom , Uthus Eric O , Claycombe Kate J
Published: June 2021

The present study examined the influence of protein intake during pregnancy on mitochondrial metabolism in stromal vascular cells from subcutaneous (SVSu) and visceral (SVVi) adipose tissue of offspring fed a high fat diet. Obese‐prone Sprague‐Dawley rats were fed diets containing either 8% or 20% protein throughout pregnancy and lactation. Male weanling offspring were fed diets with 20% protein and and either 10% fat (NF) or 45% fat (HF) for 12 wks. The mitochondrial copy number showed a 5X increase in SVCu in offspring fed HE whose dams were fed normal protein compared to a 1.5X increase in offspring in offspring fed HE but whose dams were fed low protein. Neither pre‐ nor postnatal diets influenced mitochondrial number in SVVi. This finding suggests that prenatal protein intake and postnatal fat intake may differentially affect mitochondrial metabolism in SVSu versus SVVi. Although dietary treatments did not affect cellular respiration as measured with a Seahorse XF24 Analyzer with 5 mM glucose and 1mM pyruvate using cultured cells, SVSu exhibited lower maximum O2 consumption and lower reserve respiratory capacity than SVVi. Lower reserve capacity suggests that SVSu in offspring may not be able to sufficiently respond metabolically to HE diets and adapt by increasing mitochondrial biogenesis. Low prenatal protein intake during pregnancy may impair this adaptation in the offspring.
Neuropeptide Y stimulates VEGF production and secretion and promotes angiogenesis in murine and human breast cancer
Authors: Medeiros Philip John , Jackson Dwayne Neville
Published: June 2021

The functional impact of NPY on breast cancer progression has been a question of growing interest. Our group has reported augmented mitogenic and migratory effects of NPY on breast cancer cells, however the anigogenic potential of NPY remains to be examined in models of breast cancer. In the current study we hypothesized that NPY promotes angiogenesis by stimulating the production and secretion of vascular endothelial growth factor (VEGF) from cancer cells. Endothelial tube formation assays (human umbilical vein endothelial cells: HUVEC) were conducted using control and NPY treated (10−11M to 10−7M for 24‐hr) conditioned media (CM) from 4T1 and MDA‐MB‐231 breast cancer cells. Compared to control, there was a concentration‐dependent increase in the number of endothelial tube branch‐points (BP) and endothelial cell networks (EN) in HUVEC exposed to NPY CM. The CM from 10−8 M NPY treatment induced the greatest angiogenic response, which resulted in a 2‐fold & 5‐fold increase in number of BP (4T1 and MDA‐MB‐231 resp.) and 3‐ fold & 21‐fold increase in EN (4T1 and MDA‐MB‐231 resp.). Congruently, NPY treatment caused a 108% increase in VEGF expression in cancer cells and a 65% increase in VEGF secretion. These data support our ongoing in vivo studies showing a correlation between NPY availability and tumor angiogenesis; thus, highlighting an additional pathological implication of NPY in breast cancer. NSERC & CBCF.
Dissecting the fetal development of cystic fibrosis tracheal abnormalities
Authors: Meyerholz David K. , Stoltz David A. , McCray Paul B. , Welsh Michael J.
Published: June 2021

Cystic fibrosis (CF) is a genetic condition that leads to chronic lung disease, the principal cause of mortality. It had been presumed that CF neonatal lungs are normal at birth, but we recently showed that tracheas from human infants and pigs with CF have structural defects including reduced caliber and circularity. To identify primary and secondary features related to development of these changes we studied fetal tracheas (d82‐83 gestational age, ~70% of gestation) from non‐CF and CF pigs. CF trachea lumen circumference and area were reduced (P<0.001 each), while trachea circularity was similar to non‐CF fetal pigs. Trachealis smooth muscle area (normalized to trachea size) was similar between groups, but fetal CF pigs had higher incidence of altered smooth muscle bundles (P<0.001). We examined the submucosal glands, which were composed of uncommon ducts invading from the surface epithelium into the subjacent tissue with a lack of acinus differentiation. Unlike hypoplastic submucosal glands seen in newborn CF pigs, fetal CF pig submucosal gland area (normalized to trachea size) was similar to non‐CF fetal pigs. Our results suggest that fetal CF pig trachea has structural defects including altered smooth muscle morphology, but submucosal glands are not likely a primary contributor to these CF tracheal defects. Earlier fetal studies are needed to better address the pathogenesis of tracheal abnormalities in CF.
Methionine Adenosyltransferase 2A Positively Regulates Bcl‐2 Expression in a Ubiquitin‐Conjugating Enzyme 9‐Dependent Manner
Authors: Tomasi Maria Lauda , Lu Shelly C.
Published: June 2021

BACKGROUND & AIMS

Ubiquitin‐conjugating enzyme 9 (Ubc9) is required for sumoylation and inhibits apoptosis via Bcl‐2 expression by unknown mechanism. Ubc9 and Bcl‐2 expression is up‐regulated in several malignancies. S‐adenosylmethionine (SAMe) is the methyl donor synthesized by methionine adenosyltransferase (MAT). MATII, encoded by MAT2A, is overexpressed in liver and colon cancers. SAMe decreases MAT2A expression and is pro‐apoptotic in cancer cells. Here we investigated whether MAT2A's effect on apoptosis may involve Bcl‐2 and Ubc9.

METHODS

Our studies used human colon and liver cancer cell lines RKO and Huh‐7, respectively. Gene and protein expression, Bcl2 promoter activity and protein binding were measured.

RESULTS

SAMe and its metabolite methylthioadenosine (MTA) treatment lowered Bcl‐2 expression at mRNA and protein levels by 55–80%. Knockdown of Ubc9 lowered MAT2A protein (but not mRNA) levels by 25%. Knockdown of MAT2A reduced Bcl‐2 mRNA level and Bcl‐2 promoter activity by 50–65%, while MAT2A overexpression doubled Bcl2 promoter activity in both cell types. Chip assay showed that MATII could physically interact with Bcl‐2 promoter in an Ubc9‐dependent manner.

CONCLUSIONS

MATII binds to the Bcl‐2 promoter region and this requires Ubc9. Ubc9's protective effect on apoptosis may be mediated at least in part by enhancing MATII expression, which in turn positively maintains Bcl‐2 expression.

This work was supported by NIH grants R01DK51719, R01AT1576 and R01AT004896 (SC Lu), and F32AA020150 (ML Tomasi). Huh‐7 and RKO cells were provided by the Cell Culture Core of the USC Research Center for Liver Diseases (P30DK48522).
Pharmacological evaluation of IMMP, a new immunomodulator drug, in chronic liver damage in rat
Authors: Rodríguez-Fragoso Lourdes , Martínez Ulises Osuna , Esparza Jorge Reyes
Published: June 2021

The aim of this study was to evaluate effect of IMMP (Immunomodulator metallopeptide), a new immunomodulatory drug, in the serum levels of ALT and production in the liver of IL‐6, TGF‐β1 and collagen in chronic liver damage (CLD) induced in rat by porcine serum (PS) administration. 32 Wistar rats (120 g) were, divided into 4 experimental groups (n=8): 1. Control (PBS 0.5 mL 3 times per week for 8 weeks), 2. IMMP (50 ng/kg 3 times per week for the last 4 weeks), 3. CLD (PS 373 mg/kg twice per week for 8 weeks), 4. CLD+IMMP (doses mentioned above). At the end of the 8th week the rats were sacrificed using CO2 chamber. ALT was evaluated in blood samples, in liver the expression of IL‐6 and TGF‐β1 were done by immunohistochemistry and collagen quantification was performed by hidroxyproline. Animals with CLD had an increase in ALT (2.0‐fold) and collagen (4.6‐fold) levels as compared with control (P<0.05), a huge expression of IL‐6 and TGF‐β1 was observed in hepatocytes around the collagen fibers that were forming regeneration nodules. Rats with CLD and treatment with IMMP had a reduction of ALT (37.7%) and collagen (63.1%) in comparison with CLD group (p<0.05). The expression of IL‐6 and TGF‐β1 was reduced and no regeneration nodules were seen. In conclusion, the treatment with IMMP reduced liver damage (ALT), inflammatory (IL‐6) and fibrosis (TGF‐β1 and collagen) parameters in animals with chronic liver damage by PS administration.
Mesenchymal stem cell niches in tooth growth and repair
Authors: Sharpe Paul
Published: June 2021

When teeth are damaged to the extent that the pulp tissue is exposed, a natural repair process is activated to prevent infection. Mesenchymal stem cells (MSCs) located in the pulp are mobilised to proliferate, migrate to the site and damage and differentiate into specialised cells (odontoblasts) that repair the dentine.

In rodent incisor teeth, a specialised MSC niche is located at the cervical end of the tooth to provide a source of cells to replace those lost during the continuous growth of these specialised teeth. These cells are also mobilised following damage and can be observed migrating towards the site of damage. In addition damage also induces a pericyte‐MSC response where pericytes are stimulated to proliferate and can be seen differentiating into odontoblasts at the site of damage (Feng et al 2011). During feeding, the pulp at the tips of the incisors becomes exposed and a third MSC niche can be identified that acts to rapidly mineralise the pulp to prevent blood loss and infection. Interestingly this same niche can also been found at the tips of molar teeth that do not grow continuously in rodents or humans. The continuously‐growing rodent incisor thus has three separate MSC niches, involved in homeostasis and repair. Non‐growing teeth (as found in humans) have two MSC niches involved only in repair.

The ease with which MSCs can be obtained from teeth makes them a highly attractive source for all therapeutic applications requiring MSCs and numerous dental pulp cell banks are in operation. The multiple niches in the rodent incisor make this organ an attractive model system to study the molecular and structural properties of MSCs and their niches and the molecules involved in the processes of mobilisation during tissue repair.
Combining Ultrasound and Gross Anatomic Dissection in Teaching 3‐D anatomy: Effectiveness in a first year medical course curriculum
Authors: Yee Alyssa Mae , Hwang Jiye , Pagano Anthony S , Marquez Samuel
Published: June 2021

The practice of exposing medical students to different imaging modalities has been advanced by the wave of curriculum reform sweeping the nation. Cross‐sectional imaging has taken up a central role in diagnostic medicine, particularly with CT imaging and now, more recently, Ultrasound (US) technology. Exposing students to US imaging lectures without careful coordination of in‐lab serial dissection has, however, been met with mixed reviews. This study reports on the use of serial dissection activities on three donor bodies combined with US technology on live subjects (n=3). Six distinct diarthrodal joints were targeted: 1) shoulder, elbow, wrist, hip, knee, and ankle. Each joint was approached from different perspectives, each noting tissue depths. The shoulder was dissected in the anterior, posterior, lateral and superior orientation. Measures on US and dissections were from epidermis to: dermis, superficial fascia, muscle, deep fascia, superficial joint surface and joint capsule. Results showed no statistically significant (p<0.05) differences between the two approaches, confirming the accuracy of US. One notable qualitative result was the impression felt by students that combining traditional dissection activities with US improved understanding of contiguous structures in 3‐D space. Many felt that their learning experience was greatly enriched by the use of a new imaging modality tool.

Grant Funding Source: none
The role of microenvironment in the regenerative potential of neural stem cells after spinal cord injury
Authors: Karimi Soheila
Published: June 2021

Spinal cord injury (SCI) results in permanent loss of myelin forming oligodendrocytes that significantly contribute to white matter degeneration. Despite the existence of multipotent neural precursor cells (NPCs) inside the spinal cord, replacement of oligodendrocytes is severely limited after SCI. Interestingly, NPCs mainly contribute to oligodendrocyte turnover in the normal spinal cord; however, in SCI activated NPCs predominantly differentiate into astrocytes and contribute to scar formation. To date, we have only a poor understanding of the extracellular events that modulate NPCs in their post‐SCI niche. After SCI, local microenvironment undergoes profound modifications that limit the regenerative capacities of NPCs. Optimizing the SCI microenvironment is therefore critical not only to promote NPCs cell replacement, but also to attenuate the otherwise non‐constructive effects of NPCs activation after SCI. We have recently identified several mechanisms that influence the behaviour of NPCs after SCI. Our data suggest a role for the matrix molecules chondroitin sulfate proteoglycans (CSPGs) in limiting the activation and differentiation of NPCs after SCI. We also show that the inadequate oligodendrocyte cell replacement in SCI may be attributed to the impaired expression of neureglulin‐1/ErbB signalling in the spinal cord. This talk will discuss our recent research findings in these areas
Oligosaccharides as Recognition Molecules – A coming of age
Authors: Kornfeld Stuart
Published: June 2021

Most membrane and secreted proteins as well as lysosomal acid hydrolases contain covalently‐linked oligosaccharides that exhibit a vast array of structures. We now recognize that these oligosaccharides participate in numerous biologic processes ranging from folding of nascent glycoproteins to trafficking of lymphocytes in the circulation. The requirement for proper glycosylation is underscored by the growing list of human diseases that result from defects in glycan assembly.

Our early work focused on the structural analysis of Asn‐linked glycans and their biosynthesis. We then turned to the study of a specific glycosylation event that serves to target acid hydrolases to lysosomes, i.e. the formation of mannose 6‐ phosphate residues on the Asn‐linked glycans of these enzymes. We have investigated the unique two‐step pathway for the biosynthesis of this marker and explored how the first enzyme in this process distinguishes acid hydrolases from non‐lysosomal glycoproteins, a critical step in the sorting process. This led to studies of the two Man‐6‐P receptors that bind the Man‐6‐P determinant and deliver the hydrolases to lysosomes. This pathway serves as a valuable model for studies of intracellular protein trafficking. Analysis of mouse models of lysosomal storage disorders caused by the failure to synthesize the Man‐6‐P recognition marker is providing insight into the pathophysiology of these disorders.
The heparan sulfate 3‐O‐sulfotransferase hst‐3.2 is required for neural development in C. elegans
Authors: Buelow Hannes Erich , Tecle Eillen , Diaz-Balzac Carlos A , Richard Magali , Bessereau Jean-Louis
Published: June 2021

Heparan sulfates (HS) are extracellular sugars that modulate protein‐protein interactions by way of their covalent modification patterns and are important for neural development. The rarest of all HS modifications are HS 3‐O‐sulfates which have been identified as part of modification patterns that bind proteins with high affinity in vitro. Yet, their in vivo functions have remained largely elusive. We show that hst‐3.2, a gene involved in introducing the HS 3‐Osulfate modification, is required for the establishment of select neural circuits in C. elegans. Animals that lack hst‐3.2 show neuroanatomical and behavioral defects in the mechanosensory and defecation motor circuits. Transgenic rescue and expression studies suggest that hst‐3.2 functions cell non‐autonomously. Genetically, hst‐3.2 acts in parallel with rpm‐1, a member of the conserved PHR proteins that are required autonomously for presynaptic differentiation. Moreover, loss of function phenotypes of hst‐3.2 are suppressed by mutations in HS genes. Thus, hst‐3.2 may unexpectedly act to negatively regulate HS function during neural development.
Relation of Whole Grain Intake to Risk of Type 2 Diabetes, Cardiovascular Disease and Weight Gain: A Systematic Review and Meta‐Analysis
Authors: Chacko Sara , Ye Eva Qing , Chou Elizabeth L , Kugizaki Matthew , Liu Simin
Published: June 2021

Background

Whole grain intake is routinely recommended for prevention of vascular disease, however current literature lacks a comprehensive and quantitative review of potential benefits.

Purpose

Systematically examine longitudinal studies investigating whole‐grain and fiber intake in relation to risk of type 2 diabetes (T2D), cardiovascular disease (CVD), weight gain, and metabolic risk factors.

Study Selection

45 prospective cohort studies and 17 randomized‐controlled trials were identified between 1966‐December 2010 in CINAHL, EMBASE and PUBMED using a standardized protocol.

Data Synthesis

Compared to never/rare consumers, those who consumed an average of 3 servings/day of whole grains had a ~26% lower risk of T2D [RR=0.74 (0.70, 0.79)], ~14% lower risk of CVD [RR=0.86 (0.83, 0.89)] and ~49% lower risk of weight gain [RR=0.51 (0.39, 0.67)]. In randomized settings, mean differences of fasting glucose [−0.28 mmol/L(−0.48, −0.09)], total cholesterol [−0.99 mmol/L (−1.49, −0.49)], low‐density lipoprotein cholesterol [−1.10 mmol/L (−1.68, −0.51)], and systolic blood pressure [−0.34, ( −0.57, −0.11)] were significantly lower after whole grain interventions than after control diets.

Conclusion

Whole‐grain intake may have beneficial effects for vascular disease prevention. Potential mechanisms require further investigation in large intervention trials.
Sweeteners in the US food supply and the role of fruit juice concentrates (FJC)
Authors: Ng Shu Wen , Slining Meghan M , Popkin Barry M
Published: June 2021

Added sugars measurements defined by the USDA and estimated in MPED exclude fruit juice concentrate (FJC) as a sweetener, and have not been created since NHANES 2003/04. This study utilizes full ingredient list and nutrition facts panel (NFP) data from Gladson Nutrition Database, and nationally representative food purchases from Nielsen Homescan 2005–2009. Of the 85,452 uniquely formulated foods purchased between 2005–2009 representing >400,000 items in the marketplace, 75% contain sweeteners (73.3% nutritive, 1.3% non‐nutritive). 7% contain FJC (not reconstituted) as a sweetener, and 2% contain reconstituted fruit juice. FJC as a sweetener is used in 13% of granola or energy bars, 12% of baby food, 17% of salad dressings and dips, 18% of sweets, 11% of ready‐to‐eat cereals, 16% of yogurts, 30% caloric sugar‐ and 16% of diet‐sweetened beverages. Among uniquely formulated products, those containing FJC as the only sweetener have a mean of 21g total sugar/100g, which is not statistically different from the 23g total sugar in products sweetened only by other nutritive sweeteners. However, when total sugar/100g is weighted by volume purchased, we found that foods purchased in 2007–2008 containing FJC as the only sweetener had significantly higher total sugars than those sweetened by other nutritive sweeteners only (20.1–20.3g vs. 15.9–16.1g, p>0.05). Our study poses a challenge toward monitoring what is consumed in the US by discussing the need to improve added sugar measures and require added sugars in NFP labeling regulations. Funding for this research is from the Robert Wood Johnson Foundation (Grant 68793) and the National Institutes of Health (R01 HL104580).
Comparison of coconut water and a carbohydrate/electrolyte sport drink on measures of hydration and physical performance in exercise‐trained men
Authors: Kalman Douglas S , Feldman Samantha , Martino Elaine , Krieger Diane R
Published: June 2021

Sport drinks are ubiquitous in the fitness & sporting world. Most are artificially flavored CHO‐electrolyte beverages. Recently, attention has been given to coconut water, a natural alternative to manufactured sport drinks. We compared coconut water & a CHO‐electrolyte drink on measures of hydration & physical performance in exercise‐trained men (26.6±5.7 yrs). After a 60‐min bout of dehydrating treadmill exercise, 12 men received bottled water (BW), pure coconut water (VitaCoco®: CW), coconut water from concentrate (CWC), or a CHO‐electrolyte drink (SD) [20 oz/lb lost during the dehydration] on 4 occasions (separated by at least 5 days) in a random order, single blind, X‐over design. Hydration status (body mass, fluid retention, plasma Osm, urine SG) & performance (treadmill TTE; assessed after rehydration) were determined during the recovery period. Subjective measures of thirst/bloatedness/refreshed/stomach upset & tiredness were determined using a 5‐point VAS. Subjects lost ~1.7 kg (~2% of body mass) during the dehydrating exercise & regained this amount in a similar manner across all conditions. No differences were noted between CW, CWC, or SD for BM, FL Ret or pOsm (p>0.05). No significant difference was noted for TTE (p>0.05) between BW (11.9±5.9 min), CW (12.3±5.8 min), CWC (11.9±6.0 min) & SD (12.8±4.9 min). In general, subjects reported feeling more bloated & experienced greater stomach upset with the CW & CWC conditions. All beverages are capable of promoting rehydration. Little difference is noted b/w the 4 tested conditions for hydration or exercise effects as tested in a sample of young, healthy men. Additional study inclusive of a more demanding dehydration protocol, possibly utilizing a “no beverage” control condition, & a sport specific exercise performance test, may more specifically determine the efficacy of these beverages on enhancing hydration and performance following dehydrating exercise.
Entamoeba histolytica induces a robust acute inflammatory response with increased colonic permeability and altered tight junction proteins in Muc2−/− mice
Authors: Kissoon-Singh Vanessa , Moreau France , Chadee Kris
Published: June 2021

The intestinal MUC2 mucus layer is the first line of innate host defense against pathogens. Mice deficient in Muc2 spontaneously develop colitis and are more susceptible to DSS induced injury. The colonic parasite Entamoeba histolytica (Eh) exploit the mucus layer by binding of the parasite Gal/GalNAc lectin to mucin oligosaccharides to facilitate colonization leading to infectious disease in humans. In this study we investigated the innate host defenses in Muc2−/− mice challenged with virulent Eh in a colonic loop model of infection. Eh induced a time dependent robust secretory response in Muc2−/− mice associated with increased pathology and leakage of serum albumin (p<0.01). The acute inflammation was dominated by elevated IFN‐γ and TNF‐α protein secretion. Surprisingly, Eh caused an increased expression of the pore forming tight junction protein claudin‐2 and a corresponding decreased expression of claudin‐4 and occludin (p<0.05). In the absence of Muc2, Eh elicits a robust acute inflammatory response and expression of TJ proteins leading to increased intestinal permeability emphasizing the role of Muc2 in luminal and epithelial barrier functions.
Mechanistic role for α3β1/CD151 and the neutrophilic fungal response to β‐Glucan
Authors: Johnson Courtney M , Byrd Angel , Reichner Jonathan
Published: June 2021

Polymorphonuclear leukocytes (PMNs) mediate host defense against fungal pathogens, such as C. albicans, through CR3 recognition of the fungal PAMP β‐glucan. β‐glucan is known to increase adhesion, chemotaxis, respiratory burst in PMNs via CR3. Since the PMN response to mycotic infections occurs within afflicted tissues, cells encounter extracellular matrix components which may regulate cell effector functions. Indeed, we found homotypic aggregations of neutrophils exposed to fibronectin and β‐glucan; but not to either one alone. In studies to determine the integrin mediated mechanism of homotypic aggregation, we discovered a role for αMβ1 and the TMF, CD151, in the formation of aggregates. Use of a mAbs against α3β1 attenuated aggregate formation. Use of TS151R Ab against CD151 at its α3β1 binding epitope led to smaller aggregates. These findings suggest a novel role for α3β1, a prototypical laminin receptor, in fungal defense involving CR3. The hypothesis resulting from these findings is that there is an integrin cross talk pathway through which β‐glucan ligation at the lectin site of CR3 activates α3β1.
Inflammasome Activation Triggered by the Cysteine Proteases of Entamoeba histolytica
Authors: Mortimer Leanne Marie , Moreau France , Chadee Kris
Published: June 2021

Entamoeba histolytica (Eh) is an enteric dwelling parasite that invades the epithelial barrier and instigates devastating diseases, collectively called amebiasis. A fundamental question of Eh‐host interactions is how the parasite activates host defenses. Inflammasomes are a family of cytosolic sensors that form in response to infectious or cellular injury and trigger innate responses by activating caspase‐1, which in turn regulates cleavage and activation of potent pro‐inflammatory cytokines, such as IL‐1β and IL‐18. We hypothesized an inflammasome is involved in innate detection of Eh. THP‐1 macrophages were stimulated with live Eh and Western blotting and ELISA were used to detect caspase‐1 and IL‐1β activation. Eh activated the NLRP3 inflammasome in a dose‐ and time‐dependent manner: inhibition of K+ efflux, reactive oxygen species and caspase‐1 with specific inhibitor YVAD, abrogated inflammasome activation. We identified Eh cysteine protease 5 as the microbial ligand that triggered the inflammasome through PI3KIγ‐dependent signaling. This is the first pathogen cysteine protease shown to activate the NLRP3 inflammasome. This work was funded by NSERC.
A longitudinal study of food insecurity among low income families in Toronto
Authors: Loopstra-Masters Rachel , Tarasuk Valerie
Published: June 2021

Most studies of food insecurity in Canada have been cross‐sectional, yielding little insight into the chronicity or dynamics of food insecurity. Objectives of this study were to examine the experiences of food insecurity among low income families over a two‐year period and identify factors that mitigate or exacerbate severity of food insecurity. In 2006, data on household food security, demographics, and resources were collected from 485 low income, tenant families in Toronto recruited by door‐to‐door sampling in high poverty neighbourhoods. One year later, 76% were re‐interviewed. Working with an analytic sample of 361, fixed and random effects regression models were run to examine factors associated with severity of food insecurity, using a continuous scale based on the Household Food Security Survey Module. Of 290 families who were food insecure at baseline, 86% remained food insecure at follow‐up and 32% experienced more severe insecurity. Lower income, receipt of welfare, lack of employment, less education and lone motherhood were related to more severe food insecurity. Loss of employment or transition onto welfare was associated with an increase in severity of food insecurity. While changes in source of income were associated with shifts in severity, most families remained food insecure, highlighting the static nature of poverty in this group and corresponding chronic food insecurity. Funded by CIHR.
Epigenomic Implications of Antisense Transcription
Authors: Wahlestedt Claes
Published: June 2021

Much of the mammalian genome is transcribed into non‐coding RNAs of different categories. This lecture will primarily be concerned with natural antisense transcripts (NATs) most of which are long noncoding RNAs. NATs are found in most gene loci and regulate gene expression through several distinct mechanisms including chromatin modifications. Inhibition/perturbation of endogenous NATs by modified oligonucleotides called AntagoNATs, in vitro or in vivo, reveals concordant or discordant regulation and results in down‐ or up‐regulation of conventional (protein‐coding) gene expression, respectively. Evidence will be presented that AntagoNATs can potently induce locus‐specific and reversible modulation of gene expression associated with alterations in chromatin marks.
Tissue Interactions that Regulate Facial Morphogenesis
Authors: Marcucio Ralph , Young Nathan , Hu Diane , Hallgrimsson Benedikt
Published: June 2021

Molecular signaling among the forebrain, neural crest mesenchyme, and facial ectoderm regulate morphogenesis of the upper jaw. The forebrain and neural crest mesenchyme regulate expression of Sonic Hedgehog in the Frontonasal Ectodermal Zone (FEZ), which controls proximodistal extension and dorsoventral polarity of the upper jaw. The FEZ is highly conserved among vertebrates, but the spatial pattern of Shh expression is varied and highly correlated with the shape of the facial primordia in the developing upper jaw. In birds Shh expression spans the entire Frontonasal Process, while in mammals (human and mouse) Shh is restricted to lateral domains associated with the Median Nasal Processes. These expression patterns appear to result from molecular signals, including SHH itself, from the forebrain. From these observations we predicted that the signaling axis among the brain, mesenchyme, and ectoderm could be used to generate variation during evolutionary and disease processes. We have tested this by modulating SHH signaling in the brain of chick embryos to varying degrees and assessing facial shape using 3‐dimensional morphometrics and multivariate statistical analyses. This perturbation produced embryos with continuous phenotypic variation. The shape outcomes were highly correlated with SHH signaling, cell proliferation rates, and the organization of the FEZ in treated embryos. Further, these results revealed that phenotypic variation may result from non‐linear mechanisms by which signaling pathways operate. For instance, when the SHH pathway was blocked maximally, a highly penetrant phenotype resulted, while at lower levels of blockade the phenotypes rapidly returned to more normal shapes. Thus, large phenotypic variation was generated by small changes in receptor activation over certain ligand concentrations.
Intrinsic and extrinsic control of the balance between stem cell self‐renewal and differentiation
Authors: Xie Ting
Published: June 2021

Stem cells in adult tissues have the capacity to self‐renew and generate differentiated progeny that replenish lost or damaged cells. Drosophila ovarian germline stem cells (GSCs) are an effective system for studying relationships between the niche and stem cells because of well defined stem cells and niche and availability of versatile genetic tools. Our previous studies have revealed how extrinsic niche signals and intrinsic factors to work together to control GSC self‐renewal. Niche cells use BMP signaling to control GSC self‐renewal by repressing differentiation, and E‐cadherin to anchor GSCs for long‐term self‐renewal. We have recently identified intrinsic factor Lis1 for its requirement for facilitating BMP signaling and E‐cadherin‐mediated cell adhesion and thereby GSC self‐renewal. In addition, we and others have shown that somatic escort cells are maintained by self‐duplication and play an important role in the regulation of germ cell differentiation. Recently, we have shown that H3K9 trimethylase Eggless is required in escort cells for controlling germ cell differentiation and in GSCs themselves for self‐renewal. Thus, the balance between stem cell self‐renewal and differentiation is controlled by concerted actions of extrinsic signals and intrinsic factors. Recently, we have applied this knowledge to convert adult fibroblasts into neural progenitor cells using a combination of lineage‐specific factors and growth factors.
Rescue of Stalled Replication Forks by the DNA Translocase FANCM
Authors: Constantinou Angelos , Basbous Jihane , Luke-Glaser Sarah , Gari Kerstin
Published: June 2021

Fanconi anemia (FA) is a chromosomal instability syndrome that manifests with congenital abnormalities, bone marrow failure and cancer predisposition. To date, fourteen FA genes have been identified and implicated in a ubiquitin signaling pathway, in S phase checkpoint activation, in lesion bypass and in DNA double‐strand break (DSB) repair by homologous recombination.

FANCM is a DNA translocase that acts as a molecular scaffold involved in multiple DNA damage signaling and processing reactions. FANCM interacts with : 1) the checkpoint protein HCLK2 to facilitate DNA damage signaling; 2) with the Bloom's complex at stalled forks; 3) and with the FA ubiquitin ligase complex, promoting its recruitment to chromatin and the monoubiquitination of FANCD2 and FANCI.

Our biochemical studies revealed that FANCM binds and translocates the branch point of DNA structures that mimic replication and repair intermediates, suggesting that FANCM may remodel replication intermediates to promote recovery. Using a molecular combing approach, we have observed that FANCM facilitates the restart of replication forks stalled by DNA topoisomerase I inhibitors. Our recent efforts have focused on studying the role new DNA damage response proteins that interact with FANCM.

Research support: ARC Association pour la Recherche sur le Cancer, ANR Agence Nationale de la Recherche, SNSF Swiss National Science Foundation.
Harnessing Genetic Dependencies In Cancer Therapy
Authors: Ashworth Alan
Published: June 2021

Many tumours harbour defects in their ability to maintain genomic integrity. This contributes to the mutational burden and likely fosters pathogenesis. We have been exploring therapeutic strategies to exploit these defects. We have used a synthetic lethal approach to target the defect in DNA repair by homologous recombination in tumours with a BRCA1 or BRCA2 mutation. This strategy using PARP inhibitors is showing considerable promise in the clinic. Here, I will describe the approach as well recent work defining determinants of sensitivity and resistance to PARP inhibitors. The application of the synthetic lethal approach to other cancer types will also be discussed. In addition, we have been using high‐ and medium‐ throughput RNAi screens to uncover new therapeutic targets for cancer as well as biomarkers of patients who might respond to specific treatments. In particular I will discuss the integration of genomic, gene expression and RNAi data to generate functional maps of cancers.
Development of a simple in vitro digestion model suitable for multi‐nutrient food systems
Authors: Garcia-Campayo Vicenta M , Ross Keri , Ayeni Philip , Bonnema Angela , Berger Alvin
Published: June 2021

In vitro digestion models screen kinetics of digestion of nutrients, as alternatives to in vivo testing. Most models digest only one type of macronutrient. We developed a batch in vitro digestion model for ranking digestion of all macronutrients alone, mixed, or as whole food. Ingredients are sequentially agitated with saliva, gastric, and duodenal/bile solutions at 37°C for up to 72 h. Ingredients are characterized by: primary structure (PS), physical form (PF), and controlled architecture (CA). We selected ingredients of known digestibility and predicted their rate (slow/fast) and extent (complete/incomplete) of digestion.

Selected rate examples

Nutrient: Concept
Digestibility

PS
CHO: High Amylose (Amy) slows digestion  Proteins: Native structure
Waxy corn starch (CS) > common CS>50%Amy CS  Casein≈Whey≈Soy>Pea>Rice

PF
CHO:Gelatinization increases digestion  Proteins: Processing  Lipids: Higher melting point (MP) slows digestion
Gelatinized CS >Native 50% Amy CS  Native Soy>Freeze dried soy  Olive oil >high MP solid fats

CA
Whole food: Processing
Bread Whole wheat (WW) flour >Raw WW flour

The model is suitable for digestion of mixed macronutrients and appropriately ranks their rate/extent of digestion on basis of PS, PF, and CA. Applications include slowed digestion as a satiety marker, and enhanced digestibility for clinical/animal husbandry use. Comparative studies in pigs are ongoing. Funded by Cargill Inc.
A novel student‐centered nutrition medicine education model
Authors: Lenders Carine M , Gorman Kathy , Peace Kaitlin
Published: June 2021

Background

For more than a decade, national surveys have reported that most common deaths in the United States are preventable and related to nutrition. As a result, physicians have been urged to counsel their patients but with minimal improvement in nutrition medicine education in US medical schools.

Objective

To partner with various BU communities and enhance medical students’ knowledge, attitudes, and counseling skills in nutrition medicine.

Intervention

We developed a novel student–centered model of nutrition medicine education that focuses on student mentored extra‐curricular activities to develop, evaluate, and sustain nutrition medicine. Using the NAA nutrition objectives from NIH and AAMC CurrMit software to evaluate nutrition content in the curriculum, we found that three‐quarter of pre‐clerkship objectives were met.

Conclusions

These findings are encouraging. We further plan to conduct program evaluations, administer surveys to students and faculty, and partner with national groups to improve population wellness and services. Support from the New Balance Foundation.