bluuebunny/crossref_metadata_2025 huggingface dataset:
How Anatomical “Artifacts” are Leading to Novel Treatments for Osteoporosis
Authors: Burr David
Published: June 2021

One approach to preventing bone loss in postmenopausal osteoporosis is to suppress bone remodeling. However, bone remodeling is also used to repair microscopic bone damage that occurs as a consequence of skeletal loading. Suppressing bone loss by suppressing bone remodeling will allow microdamage to accumulate and raise the risk for fracture rather than lowering it. Selective estrogen receptor modulators (SERMs) are mild suppressors of bone remodeling, but reduce fracture risk nearly as much as more potent inhibitors. The mechanism for this has been unclear, but recently, using 3D ultrashort echo time MRI of devitalized bone we discovered that the SERM raloxifene increases water content in the bound water fraction of bone. Atomic force microscopy shows swelling of the collagen fibrils, and synchrotron wide and small angle X‐ray scattering shows that the localization of water between the collagen fibril and the mineral in bone allows these phases of bone to slide along one another to reduce stress and delay fracture. Interestingly, the process by which raloxifene increases water in the bound fraction is purely physical and does not require living cells. These results open avenues to engineering of new compounds that do not act through cellular processes, but specifically target the mineral and collagen interface to increase hydration and energy absorption and reduce fracture risk.
Through a Camera Lucida, Darkly: The State and Future of Anatomical Education
Authors: Dalley Art
Published: June 2021

The teaching of anatomy, as an educational activity and as a career, continues to evolve, and in so doing has realized some progress and benefits while creating new, seemingly increasingly formidable challenges. New resources and technologies continue to develop and improve, new and improved facilities for teaching, learning and application are being built, body donation and enrollments continue to increase as the student base broadens, and clinical relevance and integration is well established. Yet didactic and laboratory hours and course content continue to be reduced within the professional curriculum, many students appear to be less invested, and the training and supply of anatomy teachers with desired qualifications is at an all‐time low‐‐at a time while many experienced anatomists are retiring or retired. Integrated and interdisciplinary curricula and new teaching methodology require faculty development which may or may not be effectively provided by the institutions demanding it. Currently, in the US at least, there are few programs to train gross anatomists, and no formal training programs available to transform gross anatomists into “clinical anatomists.” This presentation will consider current dichotomies facing anatomy as an educational discipline and vocation, and their potential for shaping the future. It will conclude by considering some potential means of influencing or adapting to the outcome, with hopes of stimulating more discussion and pro‐activity.
Gut Microbiota, Low‐Grade Inflammation, and Metabolic Syndrome
Authors: Gewirtz Andrew
Published: June 2021

The intestinal tract is inhabited by a large diverse community of bacteria collectively referred to as the gut microbiota. Alterations in gut microbiota composition are associated with a variety of disease states including obesity, diabetes, and inflammatory bowel disease (IBD). Transplant of microbiota from diseased persons (or mice) to germfree mice transfers some aspects of disease phenotype, indicating that altered microbiota plays a role in disease manifestation. There are myriad potential mechanisms by which alterations in gut microbiota might promote disease including increasing energy harvest, production of toxic metabolites, and molecular mimicry of host proteins. However, our research indicates that an overarching mechanism by which an aberrant microbiota negatively impacts health is by driving chronic inflammation. More specifically, we hypothesize that the histopathologically‐evident gut inflammation that defines IBD is a severe but relatively rare outcome of an altered host‐microbiota relationship while a much more common consequence of such disturbances is “low‐grade” inflammation, characterized by elevated proinflammatory gene expression, that associates with, and may promote, metabolic syndrome. In this context, a variety of chronic inflammatory diseases may stem from inability of the mucosal immune system to properly manage a stable healthy relationship with the gut microbiota. While one's ability to manage their gut microbiota is dictated in part by genetics, it can be markedly influenced by the composition of the microbiota one inherits from their early environment. Moreover, the host‐microbiota relationship can be perturbed by instigator bacteria or dietary components, which may prove to play a role in promoting chronic inflammatory disease states.
Intakes of key dietary indicators among children 2‐8 years participating in the Children's Healthy Living (CHL) Program
Authors: Boushey C , Yonemori K , Novotny R , Fialkowski M , Wilkens L , Nigg C , Leon Guerrero R , Bersamin A , Kim J , Johnson K
Published: June 2021

Studies evaluating dietary intakes of children in Alaska, Hawaii, Commonwealth of the Northern Mariana Islands, and Guam are limited. The CHL program is addressing this gap as part of a community trial to prevent childhood obesity. Intervention targets are intakes of fruit (FRT), vegetables (VEG), water, and sugar‐sweetened beverages (SSB) among children 2‐8y. Our objective is to present preliminary data regarding CHL targets using an age‐ and sex‐stratified random sample (n=318) from baseline data. Parents completed 2‐d dietary records which were analyzed with Pacific Tracker 3. The sample was composed of 54% boys, 60% 2‐5y, and 40% 6‐8y. Mean VEG intake was 0.58 cups (sd 1.4) and 8% of children met the 蠅1.5 cups/d of the My Daily Food Plan (MDFP) recommendation. Mean FRT consumption was 0.98 cups (sd 1.1) with 42% meeting the MDFP of 蠅 1 cup. Mean intake of water/d among girls 2‐5y and 6‐8y was 1.5 cups and 1.4 cups, respectively (similar to NHANES, 2‐5y, 1.3 cups and 6‐11y, 1.8 cups). Boys' water intake was 1.5 cups/d for 2‐5y and 2.4 cups/d for 6‐8y compared to NHANES of 1.3 and 1.9 cups, respectively. 68% of children consumed SSB, the most common being sweetened tea. Among those consuming SSB, the mean intake was 2.75 cups/d (sd 3.3) and 40% drank over 2 cups/d. There were no significant differences in any of the targets by sex, age, or jurisdiction. These data support the efforts of the CHL program to improve intakes of FRT and VEG among children in the Pacific region along with reducing consumption of SSB.
Level of Dietary Adherence to WCRF/AICR Recommendations among 81,079 Adventist Health Study‐2 Participants
Authors: Le Lap , Sirirat Rawiwan , Jaceldo‐Siegl Karen
Published: June 2021

Background

More than 50 years of Adventist research on diet and disease risk, diet has been quantified by nutrients, food groups, and dietary patterns. An alternative and novel approach is the index‐based scoring method to evaluate overall diet quality.

Objective

Our objective is to assess the degree of dietary adherence to the WCRF/AICR recommendations among the Adventist Health Study‐2 (AHS‐2) population, a cohort with unique and wide range of dietary patterns.

Method

The score is based on the operationalization of multiple dietary and lifestyle components recommended by the World Cancer Research Fund / American Institute of Cancer Research (WCRF/AICR), using data from AHS‐2 comprehensive questionnaires.

Results

Among 81,079 study participants, 48% are non‐vegetarians, 6% are semi‐vegetarians, 10% are pesco‐vegetarians, 29% are lacto‐ovo‐vegetarians, and 8% are vegans. The average WCRF/AICR score in this population is 8.81 (SD, 1.70), ranging from 1.50 to 16.0, respectively. Vegans scored on average 2 points higher than non‐vegetarians. When stratified by gender and race, females consistently scored higher than males, and non‐blacks scored higher than blacks across all levels of dietary patterns.

Conclusions

Overall, females have better diet quality than their male counterparts. Non‐blacks consistently have better diet quality than blacks. Similarly, vegans have better diet quality than non‐vegetarians irrespective of gender and race/ethnicity.
Do Changes in Body Composition Contribute to Decline in Muscle Strength? The BACH/Bone Study
Authors: Bartali Benedetta , Dagincourt Nicholas , Curto Teresa , Araujo Andre
Published: June 2021

Background

Decline in muscle strength is a risk factor for dependence and disability in older persons. The role of changes in body composition on muscle strength decline is unclear. The aim of this study was to examine the relationship between changes in lean and fat mass on decline in muscle strength in a racially diverse population of men.

Methods

This study included 692 black, Hispanic, and white men aged 30‐80y participating to the baseline and 8‐y follow‐up assessments of the population‐based longitudinal Boston Area Community Health/Bone Survey. Fat and lean mass were measured by dual‐energy x‐ray absorptiometry, and muscle strength by hand dynamometer. Multivariable linear regression models were used to determine the marginal mean change in muscle strength according to decline in fat or lean mass.

Results

There was a significant difference in change in muscle strength in men who declined in fat mass during 8‐y follow‐up compared to those who did not decline (p=.009; mean change for no decline= ‐.06; 95%CI:‐.24,0.12; mean change for decline: ‐.47, 95%CI:‐.72,‐.22). Differences in muscle strength were not statistically significant for decline in lean mass (p=.26; mean change for no decline=‐.17; 95% CI: ‐.38, .04; mean change for decline=‐.34; 95% CI: ‐.55,‐.12). The results did not substantially change after mutual adjustment for fat mass and lean mass at baseline

Conclusions

In men, decline in fat mass contributes to decline in muscle strength independently of lean mass. These results suggest that adipose tissue‐related factors (e.g. endocrine function) may play a role on muscle strength decline in middle‐aged and older men.
“I Try to Keep That Sugar Down” Homebound Older Adults with Type 2 Diabetes Mellitus: Barriers to Self‐Management
Authors: Bustillos CPT Brenda , Sharkey Joseph
Published: June 2021

With the population of older Americans on the rise, the burden of chronic health conditions, functional decline, and diminished independence place an unprecedented strain on the resources of individuals, family members, caregivers, and healthcare systems. Diabetes Mellitus (DM) affects older adults at higher rates, notably within the most vulnerable subgroups of the population including women, minorities, those in poverty, and the homebound. Following a telephone screening process, in‐depth interviews were conducted at the homes of 31 African American, Hispanic, and non‐Hispanic White seniors who regularly receive home‐delivered meals. This interpretive methodology was developed to systematically assess health and dietary self‐management in older adults who receive home‐delivered meals. The interview guide focused on 5 areas: general health; history and perception; self‐management; program planning; and social support. Thematic analysis shows that participants felt liable for their health status, but attributed their non‐compliance to lack of social and economic assistance. The seniors in this study felt competent, but rarely had the opportunity to take protective measures to manage their DM due to a number of barriers. Key barriers to self‐management include financial hardship, food access, coping mechanisms, and psychological well‐being. These results contribute to better understanding of how to approach, support, and motivate homebound older adults with DM while addressing barriers that offer insight to the development of self‐management interventions. Recommendations include training volunteers as community health workers to help seniors with problem‐solving and better management of DM.
Principles and a Decision‐Making Process for Accountable Partnership Engagement to Create Healthy Food and Active Living Environments in the United States
Authors: Kraak Vivica , Story Mary
Published: June 2021

Objective

Voluntary engagement strategies are used by national governments, industry and non‐governmental organizations to address obesity and non‐communicable diseases (NCDs) through research, policy, programs and advocacy in the United States (U.S.) and globally. Clear principles and procedures are needed to ensure that alliances and cross‐sectoral partnerships with the food, beverage and entertainment industries are trusted, effective and accountable.

Design

We conducted a desk review of electronic databases, United Nations System and U.S. federal agency websites, and grey literature to identify principles, procedures and a decision‐making process to assist institutional stakeholders optimize voluntary engagement to address obesity and NCDs.

Results

Examples of philanthropic, transactional and transformative partnerships are described

image

We propose five principles to guide public‐private partnerships (e.g., public interest, innovation, compatibility, stewardship and accountability) and a six‐step decision‐making process and toolkit to guide voluntary partnership engagement

image

.

Conclusions

A systematic and transparent approach that emphasizes principles, procedures and a decision‐making process can guide institutional partners to synergize efforts to create healthy food and active living environments to address obesity and NCDs.
Conducting Formative Research to Understand Patterns and Determinants of Small‐quantity LNS Utilization in Rural Malawi and Mozambique
Authors: Kodish Stephen , Aburto Nancy , Nseluke Hambayi Mutinta , Dibari Filippo , Buanausse Vasco , Gittelsohn Joel
Published: June 2021

Objective

To understand household utilization of a 20‐gram, lipid‐based nutrient supplement (LNS) for children 6 – 23 months

Methods

In Malawi and Mozambique, we conducted home‐feeding trials with small‐quantity, LNS for 8 and 6 weeks, respectively. In‐depth interviews (n = 38), direct meal observations (n = 80), full‐day observations (n = 38), and spot checks of LNS supply (n = 23), were conducted (n = 35 in Malawi; n = 24 in Mozambique) as triangulation. We analyzed data drawing from Grounded Theory with Atlas.ti v7.0 and using basic statistics.

Results

The LNS was utilized contrary to recommended use, with 50% of households in Malawi running out of stock early and 87% of households in Mozambique either over‐ or under‐using it. Salient patterns of LNS sharing occurred in three ways: 1) caregiver consumption of LNS, 2) caregiver sharing of LNS with children >2 years, and 3) theft by older children due to lack of storage. In Mozambique, it was common for caregivers to not only provide >1 LNS sachet to children 6 – 23 months, but also forget or not be permitted by husbands to provide it. In Malawi, caregivers often gave LNS leftovers to children >2 years. LNS utilization was largely governed by rational decision making in line with core cultural values and as coping mechanisms in light of food insecurity, rather than a mere disregard for program guidelines.

Conclusion

Interventions need to address reasons behind household choices to over‐ or under‐use a small‐quantity LNS and utilize strategies to intervene at key behavioral decision points to maximize adherence.

Funded by Children's Investment Fund Foundation
Association Between Anemia Subtypes and Insomnia Symptoms in Community‐Dwelling Older Adults
Authors: Chen‐Edinboro Lenis , Murray‐Kolb Laura , Simonsick Eleanor , Ferrucci Luigi , Allen Richard , Payne Martha , Spira Adam
Published: June 2021

Insomnia and anemia can lead to poor health. We determined the cross‐sectional association between anemia and insomnia symptoms in 1,066 adults (71.6±10.7 yr) from the Baltimore Longitudinal Study of Aging. Anemia status categories were non‐anemic, iron‐deficient anemic, and anemic without iron deficiency. Iron measures included ferritin, transferrin saturation, mean cell volume, and hemoglobin. Subjects reported sleep duration and insomnia variables from the Women's Health Initiative Insomnia Rating Scale: waking up several times at night, trouble falling asleep, waking earlier than planned, trouble getting back to sleep, and sleep quality. In models adjusted for demographics, BMI, smoking, alcohol, medical conditions, Center for Epidemiologic Studies Depression Scale, and Restless Legs Syndrome, iron‐deficient anemics had longer sleep duration than non‐anemics (B=‐0.62, 95% CI ‐1.16‐(‐0.08)). Anemic adults without iron deficiency had more nighttime awakenings than non‐anemics (B=0.39, 95% CI 0.04‐0.74)). Results suggest that anemia subtypes are differentially associated with insomnia‐related variables. We need studies with objective sleep measures to further examine the association between anemia and disturbed sleep.
Postprandial Endotoxemia Increases with Fat Amount in Obese Men: Inflammatory Impact of LPS Handling
Authors: Michalski Marie‐Caroline , Vors Cécile , Pineau Gaëlle , Drai Jocelyne , Malpuech‐Brugère Corinne , Vidal Hubert
Published: June 2021

Objectives: LPS, so‐called endotoxins, are now recognized as a triggering factor of the low‐grade inflammation observed in obesity. Recent findings revealed that digestion of a lipid‐rich meal induces a postprandial endotoxemia contributing to increased metabolic risk. However, the possible nutritional modulation of postprandial endotoxemia by various fat amounts remains largely unknown in humans, especially regarding the impact of BMI.

Methods: Normal‐weight (NW) and obese men ingested meals containing 10g or 40g fat. Endotoxemia was measured in plasma and chylomicrons during 8h, together with inflammatory mediators and LPS transporters.

Results: Chylomicrons increased in all subjects according to ingested fat amount (P<0.01), but only obese men had higher postprandial endotoxemia after 40g fat (P<0.05). Their chylomicrons also got more enriched with LPS than in NW. We observed neither NFkB translocation, nor IL‐6 gene expression in leukocytes, regardless of BMI or meal. In both groups, fat amount did not modify postprandial response of plasma IL‐6. However, postprandial AUC of IL‐6 in obese was higher than in NW subjects (P<0.05) parallel to their higher fasting LPS‐Binding Protein (LBP, P<0.05). In fact, postprandial AUC of IL‐6 was correlated with LBP (P<0.01).

Conclusions

Fat amount contributes to modulate postprandial endotoxemia in obese subjects. The further endotoxin handling in plasma through chylomicrons and LPS transporters appears to be critical in driving the acute inflammatory response. This can contribute to the long term low‐grade inflammation, especially for high cardiometabolic risk individuals.
Accounting for the Influence of Inflammation on Retinol Binding Protein in a Population Survey of Liberian Preschool‐Aged Children
Authors: Larson Leila , Addo O.Yaw , Sandalinas Fanny , Baawo Kou , Faigao Katherine , Kupka Roland , Flores‐Ayala Rafael , Suchdev Parminder
Published: June 2021

Vitamin A deficiency (VAD) is an important contributor to child morbidity and mortality. The prevalence of VAD, measured by retinol binding protein (RBP) and retinol, is overestimated in populations with a high prevalence of inflammation. We aimed to quantify and adjust for the effect of inflammation on VAD prevalence in a nationally representative survey of Liberian children 6 to 35 months of age.

We compared four methods to adjust RBP for inflammation and estimate VAD prevalence: 1) ignoring inflammation, 2) excluding individuals with inflammation (elevated C‐reactive protein (CRP) or alpha1‐acid glycoprotein (AGP), 3) multiplying each individual's RBP by a correction factor, and 4) using regression (corrected RBP = RBP ‐ β1(CRPobs‐CRPref) ‐ β2(AGPobs‐AGPref). Corrected RBP was based on a regression model where CRP and AGP were set to the maximum of the lowest quintile.

The unadjusted prevalence of VAD was 28%. Children with elevated CRP and/or AGP had significantly lower RBP concentrations (by 14%) than apparently healthy children. Using methods 2‐4 resulted in a prevalence of VAD of 20%, 18%, and 7%, respectively. Depending on the approach, ignoring inflammation would result in an overestimation of VAD prevalence of 28‐75%.

Further quantification of the influence of inflammation on biomarkers of vitamin A status from national surveys is needed to compare and recommend the preferred adjustment method across populations.

Support: BMGF, CDC, GAIN, NICHD
Reliability and Validity of an Online Questionnaire to Measure Food Literacy in Primary School Children
Authors: Skeaff Sheila , O'Sullivan Teresa
Published: June 2021

Food literacy is a term used to describe the knowledge, skills and behaviors needed to achieve a healthy and environmentally friendly diet. Improving food literacy in children is gaining momentum as a strategy to address the issue of obesity in this age group. To our knowledge, there are no measures of food literacy in children. An online questionnaire for children aged 9‐10 years living in New Zealand (NZ) was developed based on the following components of food literacy; food origins, nutrition knowledge, and food skills. The 65‐item questionnaire underwent three phases of testing with revisions made after each phase. In Phase 1, the questionnaire was reviewed by an expert panel (n=11) to assess content validity; the content validity index for the questionnaire was 0.83, indicating good content validity. In Phase 2, the questionnaire was pre‐tested with children using cognitive interviews (n=4) and a focus group (n=4); the questionnaire was revised to ensure items were correctly interpreted by children to achieve face validity. In Phase 3, the questionnaire was pilot tested in children (n=85) at two primary schools on two occasions to assess reliability and validity; items that failed to meet item difficulty and discrimination criteria were removed. The internal consistency of each of the content sections was acceptable to good (Cronbach's alpha 0.69‐0.79) and the Intraclass Correlation Coefficients demonstrated good test‐retest reliability for each section (0.69‐0.83) and for the overall questionnaire (0.89). The final 42‐item questionnaire is a reliable and valid measure of food literacy in NZ school children, which is easily adapted for use in other countries, and shows promise as a tool for evaluating the efficacy of food literacy interventions or programs implemented in schools.
Change of Plasma Metabolites in Response to Omega‐3 Fatty Acids in Chinese Patients with Type 2 Diabetes: A Double‐Blinded Randomized Controlled Trial
Authors: Li Duo , Zheng Ju‐Sheng , Lin Mei , Wang Ling
Published: June 2021

The objective was to examine the change of metabolites in response to omega‐3 fatty acid supplementation in Chinese diabetic patients. Fifty‐nine patients with type 2 diabetes were randomized into three groups: fish oil (FO, n=20, 50% of C20:5n‐3+C22:6n‐3), flaxseed oil (FLO, n=20, 63% of C18:3n‐3) and corn oil (CO, n=19). The patients consumed corresponding capsules (4 capsules/d) for 6 months. Seventeen healthy subjects without diabetes were recruited as healthy controls (HC) for metabolomic analysis. At baseline, plasma C20:5n‐3 and C22:6n‐3 were significantly lower in diabetic patients compared with HC (P<0.05). FO supplementation significantly increased plasma C20:5n‐3 and C22:6n‐3 (P<0.05), while FLO supplementation significantly increased plasma C18:3n‐3 (P<0.05), compared with CO. In addition, FO intake significantly increased sterol metabolites campesterol and beta‐sitosterol compared with CO (P<0.05). Baseline furan fatty acid metabolite 3‐carboxy‐4‐methyl‐5‐propyl‐2‐furanpropanoate (CMPF) was significantly lower in diabetic patients compared with HC, while FO supplementation significantly increased plasma CMPF. Baseline plasma C20:5n‐3 was positively correlated with CMPF (r=0.44, P=0.001). In conclusion, fish oil supplementation may have beneficial effects on diabetic patients by increasing tissue n‐3 fatty acid compositions and regulating sterol and furan fatty acid metabolites.
Early Introduction of Complementary Foods is Associated with Higher BMI‐for‐Age but Not % Body Fat at 3 Years in Breast Fed Infants
Authors: Gallo Sina , Abell Jennifer , Allice Farra , Vanstone Catherine , Weiler Hope
Published: June 2021

Nutrition during the first months of life can affect the long term development of obesity. Previous studies were limited by retrospective analysis of infant feeding. We aimed to establish whether timing of complementary foods was associated with BMI and body composition at 3 years of age using a longitudinal design. Healthy breastfeeding infants were recruited from the vitamin D dose response study (NCT00381914) in Montreal, Quebec. Age of first solid food introduction and infant's diet were recorded during the first year. Children were evaluated at 3 years of age for weight and height to calculate BMI‐for‐age Z‐scores using CDC growth charts. Body composition was assessed using dual‐energy x‐ray absorptiometry. Timing of introduction of solids was significantly associated with BMI‐for‐age Z‐score but not % body fat or lean mass at 3 years of age (Table 1). In a multivariate regression model, introduction of solids 蠄4 months, predicted a +0.96 (95% CI: 0.28, 1.64) increase in BMI‐for‐age Z‐score compared to starting solids between 4 ‐ 6 months. This sample represents some selection bias; however, suggests timing of complementary foods may impact growth by 3 y of age.

Table 1 Mean ± SD (n) BMI‐for‐age Z‐score and body composition at 3 years by timing of solid food introduction (n=65)

At 3 years
Timing of Introduction of Solids
P‐value

≤ 4 months (n=8)
4 ‐ 6 months (n=46)
≥ 6 months (n=11)

BMI for age Z‐score, CDC growth charts
1.37 ± 0.85
0.48 ± 0.71
0.14 ± 0.89
0.003

n (%) Overweight, ≥ 85th and <95th percentile
4 (50%)
10 (22%)
3 (27%)
0.048

n (%) Obese, ≥ 95th percentile
1 (12.5%)
0
0

% Body Fat
30.5 ± 4.1
29.8 ± 4.2
27.0 ± 5.7
0.138

% Lean Mass
65.6 ± 4.0
66.2 ± 4.2
68.8 ± 5.5
0.176

Grant Funding Source: Canadian Institutes of Health Research
Tocotrienol Attenuates Insulin Resistance through Inhibition of Nlrp3 Inflammasome Activation in Diabetic Leptin Receptor Knockout Mice
Authors: Chung Soonkyu , Wang Wei
Published: June 2021

We have demonstrated that tocotrienol (T3) supplementation reduces adipose inflammation, M1 macrophage infiltration, and insulin resistance. However, mechanisms remain unrevealed. Emerging evidence suggests that obesity activates Nod‐like receptor 3 (Nlrp3) inflammasome instigating the pathogenesis of type 2 diabetes. In this study, we hypothesized that T3 supplementation inhibits activation of Nlrp3‐dependent inflammasome. To test this, leptin receptor‐deficient (db/db) mice were fed with or without 0.1% T3 for 8 weeks. T3 supplementation substantially delayed the onset of diabetes by reducing hyperglycemia, hyperphagia, diabetic thirst, and polyuria. Consistently, infiltration of M1 macrophage (F4/80+/CD11b+) into adipose tissue was markedly decreased in T3‐fed mice. To determine whether attenuated insulin resistance is attributed to an inhibition of Nlrp3 inflammasome activation, peritoneal macrophages (PM) were isolated. T3 supplementation significantly decreased 1) Nlrp3 gene expression, 2) caspase1 cleavage, and 3) Nlrp3 inflammasome‐dependent IL‐1b and IL‐18 expression and 4) autophagy activation in PM. Intriguingly, co‐treatment with autophagy inhibitor and T3 abolished inhibitory effects of Nlrp3 inflammasome activation. Taken together, our results suggest that T3‐mediated autophagy activation attenuates Nlrp3‐inflammasome in macrophage, which in turn disconnects proinflammatory signaling axis between macrophage and adipocyte leading to an improvement of insulin sensitivity.

Funding Source: American Heart Association Scientist Development Grant
Diverse Classes of Bitter Phytochemicals Modulate Carbohydrate Metabolism and Immune Responses through Gastrointestinal Bitter Taste Receptors
Authors: Palatini Kimberly , Wilson Mickey , Alley Jessica , Esposito Debora , Komarnytsky Slavko
Published: June 2021

Plant foods are the primary source of both carbohydrates and bioactive phytochemicals in unprocessed diets, yet most of the latter compounds are bitter. Since bitter principles are often aversive to the consumer, the food industry routinely removes them from diet through selective breeding and debittering. Bitter taste type 2 receptors (T2Rs) were first identified in the oral cavity, however recent findings suggest that they are also expressed throughout the gut. We therefore hypothesized that T2Rs are capable of perceiving bitter tasting plant‐based phenols, flavonoids, isoflavones, terpenes, and glucosinolates, to subsequently regulate glucose metabolism in anticipation of the incoming carbohydrate load. Indeed, gavage with bitter tastants followed by a gavage of glucose to lean and diet‐induced obese mice improved oral glucose tolerance, glucose utilization, GLP‐1 and insulin secretion. Additionally, they modulated levels of glucose transporters, insulin signaling, bioenergetic profiles, and immune responses throughout the mouse gastrointestinal tract. Taken together, this data suggests the gastrointestinal system perceives most, if not all, bitter phytochemicals as external signals to prime uptake and utilization of plant based carbohydrates. If confirmed in humans, these findings may explain how structurally diverse phytonutrients modulate carbohydrate metabolism, and highlight a critical role of bitter tasting phytochemicals in our diet.
Serum Carotenoid Concentrations and Prostate Cancer Risk: Results from the Prostate Cancer Prevention Trial
Authors: Nash Sarah , Till Cathee , Song Xiaoling , Platz Elizabeth , Schenk Jeannette
Published: June 2021

Epidemiologic studies examining associations of circulating concentrations of retinol and carotenoids with prostate cancer risk have been mixed. This study examined associations with serum retinol and carotenoids in a case‐control study nested within the Prostate Cancer Prevention Trial (n = 1752 controls, 1687 cases). Presence or absence of cancer was determined by prostate biopsy, recommended during the trial due to elevated prostate specific antigen (PSA) or abnormal digital rectal examination (DRE), and offered to all men at trial end. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) adjusting for age, race, BMI, family history of prostate cancer, and serum cholesterol. In the placebo arm, men in the highest quartile of serum retinol had a 30% (OR (95% CI): 1.30 (1.00, 1.68), P‐trend = 0.04) and 74% (OR (95% CI): 1.74 (1.14, 2.68), P‐trend = 0.02) increased odds of total and high‐grade prostate cancer, respectively, relative to those in the lowest. The highest quartile of serum α‐carotene was associated with a 32% (OR (95% CI): 1.32 (1.01, 1.73), P‐trend = 0.03) increased odds of total prostate cancer, relative to the lowest. Associations with retinol were strongest in men who used vitamin A supplements, or who were diagnosed due to abnormal PSA or DRE. There were no associations with serum retinol and α‐carotene in the finasteride arm, or with β‐carotene and β‐cryptoxanthan in either treatment arm. This study was supported by the National Cancer Institute: P01 CA108964, U01 CA37429.
Effects of Aging and Respiratory Syncytial Virus Infection on the uPA/Plasmin System in Pulmonary Fibrosis
Authors: Gharaee‐Kermani Mehrnaz , Gyetko Margaret , Macoska Jill
Published: June 2021

Rationale

Idiopathic pulmonary fibrosis (IPF) is a serious disease often resulting in death. Aging, infection, pulmonary type 2 (Th2) immune responses and impaired fibrolytic activity play central roles in IPF. We hypothesize that aging and viral infection reduces lung urokinase (uPA) levels and increases uPA inhibitor PAI‐1 and that this leads to altered immune responses and TGF‐beta signaling, resulting in worsened fibrosis.

Methods

We compared the severity of bleomycin‐induced pulmonary fibrosis (BLM‐IPF) in mice deficient for uPA (uPA‐/‐) and its receptor (uPAR‐/‐) to wild type (WT) young and aged mice in the presence or absence of RSV infection.

Results

WT mice have diminished uPA expression following infection and BLM challenge, uPA activity levels and uPA total antigen levels diminished in the serum and lung tissues of infected BLM challenged WT aged mice compared to young mice. Whereas the PAI‐1 expression was significantly higher in uPA‐/‐ or uPAR‐/‐ aged BLM challenged mice compared to the WT mice. uPA or uPAR deficient viral infected and BLM treated mice showed increased fibrosis compared to WT as shown by hydroxyproline, total lung collagen, lung histology, and increased TGF‐beta expression. Lung T cells from infected uPA‐/‐ or uPAR‐/‐ aged mice produced lower levels of Th1, Th17 and higher levels of Th2 cytokines compared to WT mice.

Conclusions

This novel study provided both in vivo and in vitro data that showed how age‐infection‐related changes in the uPA/plasmin system impact the development of IPF. Supported by a VA Merit Review Grant (MRG.)
Endomucin Plays a Role in Retinal Vascular Development and in VEGF‐Induced Endothelial Cell Migration, Growth, and Morphogenesis
Authors: Park‐Windhol Cindy , Yang Jinling , Primo Vincent , Ng Yin‐Shan , Saint‐Geniez Magali , D'Amore Patricia
Published: June 2021

Angiogenesis is central to both normal and pathologic processes. Endothelial cells (ECs) express high levels of O‐glycoproteins that are believed to play important roles in vascular development and stability. Endomucin‐1 (EMCN) is a type I O‐glycosylated, sialic‐rich glycoprotein, specifically expressed by venous and capillary endothelium. Although ECs express high levels of EMCN, its possible role in vascular development has not been examined. A role for EMCN in angiogenesis was studied by modulating gene expression in vitro and in vivo. Postnatal day (P) four C57BL/6 mice were injected intravitreally with siEMCN or scramble siRNA (siCtrl). Knockdown of EMCN mRNA was significant at 48 hrs after injection compared to siCtrl mice. We observed a delay in radial expansion of the developing mouse vasculature in siEMCN‐injected P6 mice (51±2.2 vs. 69±1.8%, P<0.0001), accompanied by reduced vessel density (49±1.9 vs. 66±4.8%, P<0.01), branch point number (43±1.1 vs. 64±4.0 mm2, P<0.0001), and tip cell number (18±0.6 vs. 28± 2.1 mm, P<0.05) when compared to siCtrl mice. Knockdown of EMCN in human retinal ECs led to a reduction in VEGF‐induced migration (22±1.3 vs. 59±2.7%, P<0.0001), proliferation (1.51 x 104±125.0 vs. 2.25 x 104±1500 cell/cm2, P<0.05), and morphogenesis (7201±86 vs. 9157±273.0 mm, P<0.005) compared to siCtrl cells, without compromising cell survival. VEGF stimulation of siEMCN transfected ECs showed reduction in phospho‐VEGFR2, phospho‐ERK1/2 and phospho‐Akt levels. Taken together, our study indicates a novel role for EMCN as an important regulator of angiogenesis.
C‐Met And β‐catenin Co‐delivery By Hydrodynamic Tail Vein Injection Promotes HCC Development In Mice
Authors: Tao Junyan , Singh Sucha , Monga Satdarshan
Published: June 2021

Hepatocellular carcinoma (HCC) isthe fifth mostfrequently diagnosed type of cancer worldwide and second most frequent cause of cancer related deaths. Thus generation of a mouse model that mimics human HCC will improve understanding of biology and provide opportunity to test novel therapies. Hepatocyte growth factor receptor c‐Met is overexpressed in HCC. Also β‐catenin mutations affecting serine 33 (S33) and S45 but not N‐terminal deletions affecting exon‐3 are frequently observed in HCC patients. Intriguingly, expression of mutant forms of β‐catenin or c‐Met alone fail to induce HCC development in mice. Previous study has shown that co‐delivery of β‐catenin N‐terminal deletion mutant with c‐Met induced HCC, but there is no study on crosstalk of β‐catenin point mutants and c‐Met. We co‐delivered c‐Met and β‐catenin point mutants (S33Y and S45Y) by hydrodynamic tail vein injection to initiate liver tumorigenesis. Microscopic nodules were apparent at 4 weeks and large tumors were evident at 9 weeks post injection of c‐Met/S45Y‐β‐catenin. Microscopic nodules were apparent at 6 weeks while large tumors were evident at 12 weeks after c‐Met/S33Y‐β‐catenin injection. Tumors in both conditions were HCCs that displayed overexpression of several downstream targets of Wnt and HGF pathways. In summary, our results demonstrate that c‐Met cooperates with point‐mutant‐β‐catenin to promote growth and development of HCC.
Evaluation of YAP as a therapeutic target in HCC and CCA
Authors: Bai Haibo , Nguyen Quy , Zhu Qingfeng , Alpini Gianfranco , Anders Robert
Published: June 2021

Background

For Hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), the outcome is dismal; incidence is rapidly increasing, and mechanistic understanding is limited. YAP, the effector of Hippo signaling pathway, is an oncoprotein that promotes cell proliferation and inhibits apoptosis. Genetic manipulation of YAP results in biliary hamartoma and HCC. Therefore, we hypothesize that YAP is driver of liver cancer and a potential therapeutic target.

Methods

Expression of YAP and its transcriptional targets GPC3 and Survivin was surveyed in normal human liver and primary liver cancer tissues. Efficacy of YAP inhibitor Vertepofin and Survivin inhibitor YM155 was tested in HCC and CCA cell lines with MTT assay.

Results

Compared to the non‐tumor tissue, nuclear YAP expression significantly increased in both HCC and ICC specimens. Nuclear YAP levels significantly correlate with nuclear Survivin levels in HCC and ICC tissues, but not with GPC3 in HCC tissues. We also found that verteporfin and YM155 suppressed HCC and CCA cell proliferation in vitro and had an additive effect to sorafenib treatment. Moreover, HCC cell lines with higher YAP expression were more sensitive to verteporfin treatment.

Conclusions

Our findings suggested that YAP contributes to primary liver tumorigenesis and likely mediates its oncogenic effects through modulating Survivin expression. Small molecules that target YAP and Survivin activity could be a promising therapeutic strategy for treatment of HCC and CCA with high YAP expression.
Effects of Alcohol metabolism on Hepatocellular carcinoma progression
Authors: Puszyk William , Hlady Ryan , Tiedemann Rochelle , Robertson Keith , Liu Chen
Published: June 2021

Hepatocellular carcinoma (HCC) is the second most common cause of cancer deaths worldwide. HCC is known to be a CpG Island methylator Phenotype (CIMP) cancer. Tumor development in CIMP cancers is characterized by epigenomic changes including changes in DNA methylation. We have previously shown that overlapping methylation abnormalities are conserved between primary tissue and cell culture models of HCC. Alcohol consumption is known to increase the risk of development of HCC and has also been shown to alter DNA methylation in a manner that contributes to liver disease. Here we study the effect of alcohol as a driver to tumor progression in HCC. We have developed in vitro models of HCC to identify the gene targets altered by ethanol metabolism during tumor progression over an extended period of time.
Structural Basis of Broad Neutralization of Viral Pathogens
Authors: Wilson Ian
Published: June 2021

Ian A. Wilson, Department of Integrative Structural and Computational Biology
The Scripps Research Institute, La Jolla, CA 92037 USA.

HIV‐1, Influenza, and Hepatitis C viruses constitute significant threats to global health. These viruses are all highly variable and provide challenges to our immune system to find solutions to prevent infection against the diverse strains and subtypes of these viruses. Increasing our knowledge of how the human immune system can respond to infection by these viruses can aid in design of novel vaccines. Recently, many human antibodies have been identified that can broadly neutralize HIV‐1 and influenza viruses through binding to functionally conserved sites, such as the receptor binding site or the fusion domain. My laboratory has determined atomic structures of a wide range of broadly neutralizing antibodies in complex with the envelope proteins of HIV‐1, influenza and hepatitis C viruses. This structural information is now being used in structure‐assisted vaccine design for HIV‐1 and HCV, and for design of a more universal flu vaccine. IAW is supported by NIH grants AI100663, AI082362, AI84817, AI099275 and GM094586 and the Crucell Vaccine Institute.
Periodontal Disease and the Oral Microbiome in Minority Populations
Authors: Kumar Purnima , Mason Matthew
Published: June 2021

It is known that several oral infections have a strong ethnic predilection. Evidence is emerging that periodontitis, the sixth most prevalent disease in the world, has a definite ethnic distribution, after controlling for socio‐economic and environmental factors. Evidence is also emerging that oral biofilms as well as host immunity differs between ethnicities. This presentation will review the evidence to support the association between ethnic preference and oral diseases, especially periodontal disease.
The Split Personality of Human O‐GlcNAc Transferase
Authors: Walker Suzanne
Published: June 2021

O‐GlcNAc Transferase (OGT) is an essential glycosyltransferase that catalyzes the attachment of N‐acetylglucosamine (GlcNAc) to serines and threonines of numerous nuclear and cytoplasmic proteins. Global O‐GlcNAcylation is sensitive to changes in the concentration of OGT's substrate, UDP‐GlcNAc, which is affected by cellular glucose levels. Increased O‐GlcNAcylation is associated with widespread changes in gene expression, but the molecular mechanisms underlying these changes remain poorly understood. Recently, OGT was shown to catalyze another post‐translational modification: the cleavage of the cell cycle regulator Host Cell Factor 1 (HCF‐1). We will describe our work on the unusual mechanism of HCF‐1 cleavage by OGT. We will show that cleavage requires UDP‐GlcNAc as a cosubstrate, implying that HCF‐1 cleavage, like O‐GlcNAcylation, is coupled to UDP‐GlcNAc concentration. Hence, key cell cycle regulatory functions of HCF‐1 are linked to nutrient levels through a remarkable proteolytic action of OGT.
Human Precision‐Cut Tissue Slices as a Tool to Study Fibrosis and the Efficacy of Antifibrotic Compounds
Authors: Mutsaers Henricus , Westra Inge , Stribos Isabel , Oosterhuis Dorenda , Olinga Peter
Published: June 2021

Fibrosis is a common endpoint of a multiplicity of chronic diseases resulting in scarring and loss of organ function. To improve and accelerate antifibrotic drug discovery, there is an urgent need for reliable and reproducible human in vitro methods that also include the cellular diversity that epitomize specific organs. The objective of our study was to investigate fibrogenesis in precision‐cut tissue slices (PCTS) from human liver and kidney. Moreover, we strove to elucidate the effect of imatinib ‐ a promising antifibrotic compound in rat ‐ in the early stages of liver fibrosis.

PCTS were successfully prepared from human livers and kidneys, and cultured up to 72 hours. Viability of PCTS was assessed by the ATP content of the slices. Furthermore, gene expression of several fibrosis markers was determined. The antifibrotic effect of imatinib was studied at the maximal non‐toxic concentrations.

Both liver and renal PCTS were viable up to 72 hours. Furthermore, after 48 hours of incubation, the early onset of fibrosis was observed in liver PCTS, as demonstrated by an increased expression of Pro‐Collagen 1A1 and Heat Shock Protein 47. Moreover, treatment with imatinib for 48 hours did neither impact the gene expression of fibrosis markers nor the protein expression of collagen I in human liver PCTS. Which is in stark disparity to the antifibrotic effects observed in animal models. The gene expression profile of renal PCTS during incubation is currently being evaluated.

Thus, human PCTS can be used to study the onset of fibrosis, are promising models to test the efficacy of antifibrotic compounds and can reveal species differences in fibrosis.
GIT1 Regulates Lung Cancer Metastasis through Modulating Rac1/Cdc42 Activity and Acts as an Independent Prognostic Factor in Human Non‐Small Cell Lung Cancer.
Authors: Chang Jeng‐Shou , Hua Kuo‐Tai , Kuo Min‐Liang , Hsiao Michael
Published: June 2021

Lung cancer is the leading cause of cancer‐related deaths worldwide and the prognosis of NSCLC remains poor. Identification of novel prognostic markers and therapeutic targets are urgently needed. Here we identified G‐protein‐coupled receptor‐kinase interacting protein 1 (GIT1) gene from 5,000 High‐throughput antibodies library screening using tissue microarray (TMA) after comparing protein expression differences of five major human cancer primary tumors and normal adjacent tissues. The results were further confirmed by online microarray database analysis to show GIT1 as a top‐ranked prognosis predictor in NSCLC. Further multivariate analysis showed high GIT1 expression is significantly associated with poor prognoses in DFS and OS. Mechanistically, we identified GIT1 as a master regulator of Rac1/Cdc42 axis in regulating lung cancer cell motility in vitro and in vivo. GIT1 can promote lung cancer cell metastasis by altering Rac1/Cdc42 activity. Taken together, our results showed GIT1 overexpression is associated with poor prognosis and can be considered an early prognosis marker in patients with NSCLC.
Use of Freshwater Prawn Larval Locomotor Activity and Electrophysiological Recording at the Adult Neuromuscular Junction to Assess the Effects of Urban River Contaminants on Behavior and Nervous System Function
Authors: Crooke Rosado Jonathan , Rivera Chéverez Nilsa , Sosa Llorens Maria
Published: June 2021

Puerto Rico's population density is one of the world's highest, with a third of the population concentrated in the northeastern metropolitan area. Urbanization and the resulting anthropogenic activities have an impact on the quality of water resources. We seek to understand how this dramatic level of urban development has impacted the rivers in the area and how these changes affect the behavior and nervous system of aquatic fauna in this habitat. Our lab uses freshwater prawns as model systems to study behavior and its underlying neural mechanisms and modes of regulation. Here we show how prawn larvae can be used to assess the effects of water contaminants on locomotion and the animal´s levels of activity during alternating cycles of light and darkness. Two species of prawns, Macrobrachium rosenbergii and M carcinus, showed opposite responses to the light/dark cycles, the latter also showing a decrease in locomotor activity after exposure to low levels (0.006 mg/L) of dibutyl phthalate, but not of chromium (0.100 mg/L), both contaminants found in Puerto Rico´s rivers. We also present preliminary data on how the prawn's neuromuscular junction may be used to assess potential effects of urban river contaminants on synaptic function.
Pathology Encountered during Cadaver Dissection Provides an Opportunity for Integrated Learning and Critical Thinking
Authors: Zhang Guiyun , Fenderson Bruce
Published: June 2021

Cadaver dissection engages medical students in active learning, critical thinking, and problem solving. During dissection, students at Jefferson Medical College are encouraged to document pathologic findings in their cadavers and discuss the findings with their peers. Here, we describe two cases that provided opportunities for integrating anatomy with pathology and clinical medicine. The first case was a benign ovarian neoplasm. This large pelvic mass displaced the urinary bladder and uterus, and compressed the ureters and rectum. Students discussed clinical complications of this pelvic mass and reviewed pathologic findings that differentiate benign from malignant neoplasms. The second case was breast cancer with widespread metastases and pulmonary atelectasis. Students examined the histopathology of breast cancer and discussed mechanisms of tumor metastasis. Pathologic findings and evidence of past surgical procedures are frequently encountered during cadaver dissection. These findings provide a valuable opportunity for integrating the preclinical basic sciences and stimulating the development of critical thinking skills.