bluuebunny/crossref_metadata_2025_split huggingface dataset:
Weight Loss Via Alternate Day Fasting Increases Circulating Endogenous Secretory RAGE and is Associated with Markers of Adipocyte Health
Authors: Miranda Edwin R , Varady Kristina , Haus Jacob M 
Published: November 2023

The receptor for advanced glycation end products (RAGE) is a transmembrane receptor that upon binding of its ligand induces inflammation and promotes the development of complications associated with obesity, diabetes, and aging. Soluble isoforms of RAGE (sRAGE) produced by proteolytic cleavage (sRAGEc) or alternative splicing (endogenous secretory RAGE, esRAGE), inhibit RAGE signaling by scavenging RAGE ligands. RAGE plays a role in adipocyte hypertrophy and individuals with obesity present with lower circulating levels of sRAGE. This phenotype may permit RAGE signaling to persist, contributing to further adipose expansion and an increase in pro‐inflammatory adipokine production.PURPOSEThe purpose of this study was to determine if a 24‐week dietary weight loss intervention via alternate day fasting (ADF) could increase circulating sRAGE isoforms and if these changes in sRAGE were related to changes in fat mass and circulating adiopokines.METHODS42 participants (7 Males, 35 Females) were randomized to either control (CON) or ADF. The ADF group (BMI 33.8 ± 3.9 kg/m2) consumed 25% of their caloric requirements followed by ad libitum eating on alternating days whereas the CON group (BMI 33.3 ± 4.8 kg/m2) ate ad libitum every day. Total sRAGE, esRAGE, adiponectin, and IL‐6 were measured via ELISAs. sRAGEc was calculated by subtracting esRAGE from total sRAGE.RESULTSFollowing the intervention, the ADF group lost more body weight than the CON group (−7.1 ± 1.1 kg vs −0.72 ± 0.51 kg, p < 0.05) and the ADF group displayed a greater increase in esRAGE compared to CON (28.1 ± 79.9 pg/mL vs −30.9 ± 61.1 pg/mL p < 0.05). When changes in body weight or fat mass were stratified into tertiles, individuals with the greatest body weight and fat mass change displayed the greatest increases in esRAGE. In addition, changes in each of the sRAGE isoforms negatively correlated with changes in body weight and fat mass. Interestingly, changes in the sRAGEc:esRAGE ratio positively correlated with changes in fat mass (Rho = 0.327, p < 0.05) and negatively correlated with changes in adiponectin (Rho = −0.356, p <0.05). The baseline sRAGEc:esRAGE ratio was also negatively correlated to baseline levels of IL‐6 (Rho = −0.462, p <0.01).CONCLUSIONThese data are the first to demonstrate that weight loss, via caloric restriction, increases circulating esRAGE in obese individuals. Further, this is also the first evidence to relate reductions in fat mass loss to increases in sRAGE isoforms, suggesting a mechanistic link between adipose tissue and sRAGE. Additionally, the relationship between sRAGEc:esRAGE and adipopkines suggests that sRAGEc and esRAGE may be independently modulated with weight loss. Future research is warranted to investigate the mechanisms of caloric restriction on RAGE and sRAGE biology.
How Can We Reach World Health Assembly 2025 Nutrition Targets? Using the Lives Saved Tool to Support Strategic Planning by the Nutrition Sector in Low‐ and Middle‐Income Countries
Authors: Heidkamp Rebecca Anne , Clermont Adrienne , Walker Neff 
Published: November 2023

In 2012, World Health Assembly (WHA) Member States committed to ambitious global targets for improved nutrition outcomes among women and children by the year 2025. Many countries lack systematic approaches to selecting interventions and setting feasible coverage targets in order to move toward these goals. The Lives Saved Tool (LiST) is a software tool used by governments and partners in more than 90 low‐ and middle‐income countries to model how changes in coverage of maternal, newborn, and child health and nutrition interventions impact mortality and nutrition outcomes including stunting and wasting. In 2015–2016 we carried out a comprehensive review and update of the nutrition‐related pathways in LiST to include new interventions (e.g., early initiation of breastfeeding), linkages (e.g., impact of malaria prevention on anemia) and outcomes (e.g., anemia in women of childbearing age, low birth weight) consistent with WHA targets. We used the updated tool with government partners in Malawi and Tanzania to refine national and subnational 5‐year strategic plans. In each country, we examined historical trends in nutrition outcomes and intervention coverage over the last 10–15 years (based on data from nationally representative household surveys such as Demographic and Health Surveys and Multiple Indicator Cluster Surveys) and then used LiST to prospectively model multiple 5–10 year intervention scale‐up scenarios. For example, in Malawi, we found that if the country were to reach its current National Nutrition Monitoring and Evaluation Framework targets, stunting among children would only decrease from 45.8% in 2014 to 43.7% in 2020, far short of the 38% target. If Malawi were to add three additional effective interventions to its current plan – including providing macronutrient supplements for food insecure children 6–23 months and pregnant women with low body‐mass‐index – stunting would be further reduced to 41.2% in 2020. In both Tanzania and Malawi, our findings suggest that intervention mix and coverage targets should vary at sub‐national level. LiST is a useful tool for target setting in the nutrition sector but limitations related to the availability of coverage data and the lack of ability to model nutrition‐sensitive interventions need to be addressed for it to fully support nutrition planning processes.Support or Funding InformationChildrens Investment Fund Foundation (CIFF)
Additional Zinc Delivered as a Tablet and SQ‐LNS May Increase Fat Free Mass Accrual in Young Burkinabe Children
Authors: Jimenez Elizabeth Yakes , Abbeddou Souheila , Coulibaly Nadine , Some Jerome W , Ouedraogo Jean‐Bosco , Brown Kenneth H , Hess Sonja Y 
Published: November 2023

Small‐quantity lipid‐based nutrient supplements (SQ‐LNS) provide additional energy (~120 kcal/d) and micronutrients and may affect body composition in young children. Previous analyses found that Burkinabe children who received SQ‐LNS from 9 to 18 months, along with treatment for diarrhea, malaria, and fever, gained more weight and length than those who did not, regardless of the amount of supplemental zinc; but the composition of weight gain was not reported. In the present analyses, we compare the composition of tissue gained for a subgroup of children participating in the iLiNS‐Zinc trial.Using a two‐stage cluster randomized trial design, communities were randomly assigned to the intervention cohort (IC) or non‐intervention cohort (NIC), and family compounds within the IC were randomly assigned to different zinc dose groups (SQ‐LNS without zinc+placebo tablet; SQ‐LNS with 5mg zinc+placebo tablet; SQ‐LNS with 10mg zinc+placebo tablet; or SQ‐LNS without zinc+5mg zinc tablet). All IC children received the SQ‐LNS+tablets daily from 9–18 mo along with treatment for malaria, diarrhea and fever. Body composition was assessed for IC (n=202) and NIC children (n=74) at 9 and 18 months using the deuterium dilution method. This was about 70% of the desired sample size because collection of saliva was challenging. A mixed linear model was used to examine average change in fat free mass (FFM) and % fat mass (%FM) between 9–18 mo by zinc dose group and by cohort. Analysis included a random effect of the community to account for intra‐community correlation.There was a high variability in response, but on average, children had increased FFM and decreased %FM from 9 to 18 mo. Change in FFM differed significantly between the NIC group (1.40 [mean]±0.07 [SD] kg) and the IC group (1.61±0.05 kg; p=0.005), and specifically between the NIC group and the group that received SQ‐LNS without zinc+5mg zinc tablet (1.73±0.08 kg; p=0.02). These results remained significant after controlling for baseline FFM. Patterns for change in FFM closely reflected patterns for overall weight gain. There were no significant differences in the change in %FM between NIC and IC or among the zinc dose groups.Zinc delivered in tablet form and SQ‐LNS may positively affect fat free mass accrual from 9 to 18 months of age. Zinc tablets and SQ‐LNS did not seem to affect changes in %FM from 9 to 18 months of age. Not achieving the desired sample size is a limitation for interpreting findings indicating no differences, and more work is needed to identify fast and easy methods to accurately measure young children's body composition in field settings.Support or Funding InformationFunded by the Bill & Melinda Gates Foundation
Paradoxical Relationships Between Vitamin D and Body Composition in Collegiate Athletes Training in the Midwest
Authors: Hew‐Butler Tamara , Landis‐Piwowar Kristin , Aprik Carrie , Byrd Brigid 
Published: November 2023

ObjectiveTo assess both changes and relationships between serum 25‐hydroxyvitamin D (vitamin D) and body composition in NCAA D1 athletes (training latitude 42.6°N) over the Fall season.MethodsStudent‐athlete volunteers from seven sport teams (men and women's cross country, swimming, and basketball plus women's soccer) were tested both pre‐season (August–September) and post‐season (January–February) for vitamin D (Crittenton Hospital laboratory), and body composition (dual energy x‐ray absorptiometry scan). Data reported as mean±SD with significance set at p<0.05.Results24 males and 49 females (N=73) completed both pre and post‐season testing. Significant decreases noted in vitamin D (pre‐season vs. post‐season) when all athletes were combined (40±14 vs. 33±13ng/mL;p=0.005;N=73) and more specifically in male basketball (22±8 vs. 15±6ng/mL;p=0.03;n=9) and cross country (47±5 vs. 38±6ng/mL;p=0.001;n=9) athletes. Combined data (N=73) revealed significant inverse relationships between pre‐season vitamin D vs. pre‐season total bone mineral content (BMC; r=−0.32;p=0.005), pre‐season total lean mass (r=−0.36;p=0.002), and post‐season minus pre‐season change (Δ) in total fat mass (r=−0.23;p=0.04). When separated by sex, male athletes demonstrated more robust inverse correlations between pre‐season vitamin D vs. pre‐season: BMC (r=−0.71;p=0.000), bone mineral density (BMD;r=−0.60;p=0.002), and total fat mass (r=−0.61;p=0.001). Male basketball players (n=9) demonstrated the strongest inverse correlations between post‐season vitamin D vs. post‐season BMD (r=−.85;p=0.004) and BMC (r=−.78;p=0.01) despite having the lowest pre‐season and post‐season vitamin D levels and highest (pre‐season and Δ) BMC (3697±404g and 55±86g) and BMD (1.37±0.09g/cm3 and 0.02±0.02g/cm3). Female athletes demonstrated significant negative relationships between pre‐season vitamin D vs. Δ BMC (r=−.35;p=0.02), Δ %body fat (r=−.34;p=0.02), and Δ total fat mass (r=−0.31;p=0.03).ConclusionsVitamin D levels (on average) decreased in all tested teams, regardless of indoor (swimming and basketball) or outdoor (cross country, soccer) training. No significant relationships were noted between the Δ in Vitamin D vs. the Δ in any total body composition variable. However, significant (inverse) linear relationships were noted at single testing time points (pre‐season or post‐season) between vitamin D versus bone (BMD or BMC), lean and fat mass which were driven largely by the male athletes (particularly the basketball players). Collectively, higher pre‐season vitamin D levels were paradoxically associated with reduced pre‐season bone and muscle (lean) mass with greater fat mass losses (over the season) observed in this cohort of male and female Fall sport athletes.Support or Funding InformationSupport provided by the Oakland University Athletics Department
Increased Study Length of Retinol Isotope Dilution with Compartmental Modeling Alters Kinetic Parameters and Calculated Vitamin A Stores
Authors: Gannon Bryan M , Valentine Ashley R , Davis Christopher R , Howe Julie A , Tanumihardjo Sherry A 
Published: November 2023

BackgroundRetinol isotope dilution is considered an accurate, indirect measure of vitamin A (VA) status. Multi‐compartment mathematical modeling of isotope dilution data is used to refine study design and equations to calculate VA stores from isotope dilution. Previous studies suggest some VA may be in slowly turning over pools that is not traced if follow‐up is not long enough. Data and resulting models from long‐term studies are limited.ObjectivesDetermine the effect of study duration on mathematical models of VA metabolism including kinetic parameters and model outcomes.MethodsAdult females (22 ± 3 y; n = 7) were given 2 μmol 13C‐VA and had blood sampled in a staggered serial design from 4 h to 152 d; fraction of dose in serum against time were modeled with compartmental models of VA metabolism. Four model time categories were created; full models were developed using all data (133 ± 23 d), and truncated data simulating shorter studies of 52 ± 6, 28, and 14 d to determine effect of study length on number of needed model compartments to adequately model the data, kinetic parameters, total traced VA mass, and time to dose equilibration. To gain insight into even longer follow‐up, an additional subject was given 17.5 μmol 13C‐VA, and data were modeled as long as the dose was detectable above baseline enrichment (5 y).ResultsIncreased follow‐up affected numerous kinetic parameters and modeling outcomes. Compared to the shortest 14 d model, full models required an additional compartment to adequately fit the model (14.3 vs. 100%, P = 0.0047) and had greater half‐life (30.8 ± 30.5 vs. 162 ± 80.2 d, P = 0.0006), time to dose equilibration (4.44 ± 2.08 vs. 19.8 ± 8.72 d, P < 0.0001), and total traced mass (209 ± 110 vs. 629 ± 490 μmol VA, P = 0.0031).ConclusionsExtending the duration of isotope dilution and mathematical modeling studies alters numerous outcomes in a dose‐response fashion. It is important to consider these results when using mathematical models for calculating total body VA stores or kinetic parameters related to VA metabolism.Support or Funding InformationSupported by NIHNIDDK 61973
Fluid shear stress induces upregulation of COX‐2 and PGI2 release in endothelial cells via a pathway involving PECAM‐1, PI3K, FAK, and p38
Authors: Tarbell John , Russel‐Puleri Sparkle , Cancel Limary , Paz Nathaniel dela , Adams Diana , Chattopadhyay Mitali , Ebong Eno , Orr Wayne , Frangos John 
Published: November 2023

Vascular endothelial cells play an important role in the regulation of vascular function in response to mechanical stimuli in both healthy and diseased states. Prostaglandin I2 (PGI2) is an important anti‐atherogenic prostanoid and vasodilator produced in endothelial cells through the action of cyclooxygenase (COX) isoenzymes COX‐1 and COX‐2. However, the mechanisms involved in shear‐induced production of COX‐2 and PGI2 have not been elucidated. We used cultured endothelial cells exposed to steady fluid shear stress (FSS) of 10 dyn/cm2 for 5‐hrs to examine shear stress induced induction of COX‐2/PGI2. Our results demonstrate the relationship between mechanosensor platelet endothelial cell adhesion molecule‐1 (PECAM‐1) and intracellular mechano‐responsive molecules phosphatidylinositol 3‐kinase (PI3K), focal adhesion kinase (FAK), and mitogen‐activated protein kinase p38, in the FSS induction of COX‐2 expression and PGI2 release. Knockdown of PECAM‐1 (small interference RNA) expression inhibited FSS‐induced activation of α5β1 integrin, upregulation of COX‐2 and release of PGI2 in both bovine aortic endothelial cells (BAECs) and human umbilical cord endothelial cells (HUVECs). Furthermore, inhibition of the PI3K pathway (LY294002)substantially inhibited FSS activation of α5β1 integrin, upregulation of COX‐2 gene and protein expression and release of PGI2 in BAECs, while we showed that inhibition of integrin associated FAK (PF573228), and MAPK p38 (SB203580) also inhibited the shear induced up‐regulation of COX‐2. Finally, a PECAM‐1 −/− mouse model was characterized by reduced COX‐2 immunostaining in the aorta and reduced plasma PGI2 levels compared to wild type mice, as well as complete inhibition of acute flow‐induced PGI2 release compared to wild type animals.We conclude that FSS up‐regulation of COX‐2 and PGI2 in endothelial cells is mediated by PECAM‐1/PI3K integrin activation propagated through downstream signaling cascades FAK and p38.Support or Funding InformationThis work was supported by the National Institutes of Health (NIH), Research supplement to promote diversity in health related research grant: PA‐08‐190 (S.R‐P.)and the National Heart, Lung, and Blood Institute Grants RO1 HL094889 (J.M.T.), MERIT Award R37 HL040696 (J.A.F.), R01 HL098435 and R01 HL133497 (A.W.O).
lncRNAH19/ZEB1/EpCAM Regulatory Axis In Cholestatic Liver Fibrosis
Authors: Song Yongfeng , Liu Chune , Wang Li 
Published: November 2023

AimThis study aims at elucidating the function of the imprinted lncRNA H19 in biliary hyperplasia, bile acid (BA) homeostasis, and cholestatic liver fibrosis.MethodsC57BL/6 mice were injected with AAV8‐Null and AAV8‐H19 virus via tail vein for gene overexpression or Adeno‐GFP and Adeno‐shH19 for gene knockdown. Mice underwent sham or bile‐duct ligation (BDL) for 1 week. Assays: liver histology H&E and trichrome staining, serum ALT, AST, total and direct bilirubin levels, serum and fecal bile acid levels, qPCR, Western blot, ChIP, and dual luciferase reporter analysis.ResultsH19RNA was expressed at low levels in normal adult liver but its levels were markedly induced by BDL. Hepatic overexpression of H19RNA augmented BDL‐induced liver fibrosis and biliary hyperplasia. This was accompanied by the elevation of serum ALT, AST, total and direct bilirubin levels, increased serum BA and BA pool size but decreased fecal BA. In addition, the genes related to liver fibrosis (αSMA, Col1a1) and biliary hyperplasia (CK7, CK9, EpCAM) were increased whereas in genes in BA metabolism (Fxr, Fgfr4, Cyp7a1, Cyp8b1, Cyp7b1) were decreased in H19‐BDL vs Null‐BDL mice. Knockdown of H19RNA attenuated the effect of BDL. Moreover, hepatic ZEB1 expression was decreased in H19 mice. At the molecular level, ZEB1 repressed EpCAM mRNA and protein by inhibiting EpCAM promoter activity via binding to the ZEB1 site. H19RNA prevented ZEB1 binding to the EpCAM promoter and reversed the effect of ZEB1, which in turn induced the expression of EpCAM. The effect of H19 on BDL‐induced liver injury was rescued by either overexpression of ZEB1 or knockdown of EpCAM in mouse liver.ConclusionDysregulated hepatic H19 expression contributed to cholestatic liver fibrosis through the ZEB1/EPCAM pathway.Support or Funding InformationNIH R01DK104656, R01DK080440, R01ES025909, R21AA022482, R21AA024935, VA Merit Award 1I01BX002634
Smoothened Deficiency Accelerates Fas‐Induced Liver Injury
Authors: Chen Weina , Wang Ying , Han Chang , Zhang Jinqiang , Song Kyoungsub , Kwon Hyunjoo , Yao Lu , Wu Tong 
Published: November 2023

Hedgehog (Hh) signaling pathway is considered to be inactive in adult healthy liver, but it is activated after acute and chronic liver injury. Here, we reported that hepatocyte specific Smo deficiency accelerated Fas‐induced liver injury. Hepatocyte Smo deficiency (Smo KO) mice showed higher mortality, more serum transaminases, more apoptotic hepatocytes, more cleavage of caspases and PARP than wild type (WT) mice after Jo2 treatment. The liver tissues from Jo2‐treated Smo KO mice expressed lower levels of NK‐κB, EGFR and p‐Akt. Hh pathway was activated in the WT mice but not in the Smo KO mice after Jo2 injection. NK‐κB activation was Smo and Gli1 dependent. NK‐κB can bind to the EGFR promoter. Overexpression NK‐κB in Smo KO mice blocked Jo2‐induced liver injury. The primary hepatocytes isolated from Smo KO mice also accelerated Fas‐induced apoptosis in vitro in comparison to hepatocyte from WT mice. Smo KO hepatocytes showed lower levels of NK‐κB, EGFR and p‐Akt after Jo2 treatment compared with WT hepatocytes. These findings demonstrate that Hh pathway plays an important role in hepatocyte. Hh pathway was activated after Jo2 treatment. Smo deficiency in hepatocytes accelerated Fas‐induced apoptosis both in vivo and in vitro due to the inhibition of NK‐κB/EGFR/Akt pathway.Support or Funding InformationSupported by National Institutes of Health grants CA102325 and DK077776 (to T.W.)
Local innervation modulates lymph node cellularity
Authors: Chen Chien Sin , Ince Louise , de Juan Alba , Hergenhan Sophia , He Wenyan , Druzd David , Kraus Kerstin , Scheiermann Christoph 
Published: November 2023

The sympathetic nervous system has been shown to modulate systemic and local immune responses but the function and the mechanism of nerve‐driven immune regulation remain largely unclear. Using surgical approaches, we ablated neural projections innervating peripheral lymph nodes and observed strong alterations in leukocyte populations and the local microenvironment. One week after unilateral transection of nerves, popliteal lymph nodes (popLNs) were found to be dramatically enlarged on the deneverated side compared to the sham‐operated lateral control side and remained high for the entire four week observation period. Nodal expansion was largely due to increased overall numbers in B and T lymphocytes. However, also strong increases in key microenvironmental cell types were observed including higher numbers of vascular and lymphatic endothelial cells and fibroblastic reticular cells. Two weeks after surgery, increased TNF‐α and interleukin‐4 levels were observed in denervated popLNs, along with a reduction in levels of the chemotactic molecule CCL19, without changes in other investigated cytokines and chemokines. Multiple germinal centers with pronounced proliferation of B cells were detected in denervated popLNs as assessed by immunofluorescence staining for Ki67. To selectively abolish sympathetic input to lymph nodes, we performed a unilateral superior cervical ganglionectomy (SCGx), and also found more germinal centers in sympathectomized superficial parotid LNs. These results indicate that direct sympathetic innervation can regulate lymph node cellularity.Support or Funding InformationFunded by the German Research Foundation (Emmy Noether SCHE 1645/2‐1 and SFB914 projects B09 and Z03) and the European Research Council (CIRCODE, 635872)
Network Models: Connecting Anatomy to Systems Biology
Authors: Esteve‐Altava Borja 
Published: November 2023

Systems biology studies systems composed of biological components, ranging from molecules to species, focusing on the complexity that emerges in living systems from the non‐linear interaction among parts. Quantitative tools to study the structure and dynamics of biological systems of interacting components include new experimental techniques, as well as theoretical approaches, such as the development and analysis of mathematical and computational models. Among these tools, network models stand out for their conceptual elegance, and mathematical power to highlight the organization of complex living systems as different as a brain and an ecosystem. Network models are currently used to study complex anatomical systems, offering a novel, transversal approach to the analysis of the evolution and development (and pathology) of form. An anatomical network model formalizes body parts, such as bones and muscles, and their interactions as the nodes and links of a network, a structural organization that is readily accessible through mathematical analysis using methods from the field of Network Theory. Here we will learn how to create and use anatomical network models to study the morphological organization of anatomical systems, with examples from the study of the morphological complexity and modularity of the skull, the key morphological re‐organizations that took place during the evolutionary transition from fins to limbs, and the development of human pathologies such as craniosynostosis.Support or Funding InformationThis project received funding from the European Union's Horizon 2020 research and innovation programme under Marie Sklodowska‐Curie grant agreement No 654155, and the American Association of Anatomists Innovations Program.