bluuebunny/crossref_metadata_2025_split huggingface dataset:
The homeodomain protein Cux1 regulates cell cycle progression in polycystic kidney disease through specific chromatin interactions
Authors: Livingston Safia , Carlton Carol , Sharma Madhulika , Baybutt Richard , Heuvel Greg Vanden 
Published: November 2023

Cux1 is a homeodomain protein involved in cell cycle regulation and kidney development. Cux1 represses the cyclin kinase inhibitor p27 during early kidney development, promoting cell proliferation in the nephrogenic zone. Promoter reporter analysis of p27 revealed that Cux1 represses p27 in a concentration dependent manner, and immunoprecipitation showed that Cux1 interacts with the co‐repressor Grg4 and the histone deacetylases HDAC1 and HDAC3. Chromatin immunoprecipitation (ChIP) identified the interaction of Cux1, Grg4, HDAC1, and HDAC3 at two different sites in the p27 promoter. To determine whether there was an interaction between these two loci in the developing kidney, we performed chromatin conformation capture (3C) assay. Analysis of newborn kidney tissue with 3C and ChIP‐3C showed that the p27 promoter forms a loop intersecting at these two loci and that Cux1 bridges these two sites. To determine whether HDACs are required for Cux1 repression of p27 we analyzed p27 promoter activity in the presence of the HDAC inhibitor trichostatin A (TSA). TSA treatment completely relieved the repression of p27 by Cux1 and Grg4, demonstrating that Cux1 represses p27 in an HDAC dependent manner. To begin to test whether HDAC inhibitors could be used to target Cux1 repression of p27 for the treatment of PKD, we treated Pkd1 targeted pregnant mice with TSA or Valproic acid or vehicle beginning at embryonic day 10.5 until embryonic day 18.5. Newborn Pkd1 mutant mice that received vehicle exhibited extensive collecting duct cysts, while newborn Pkd1 mutant mice that received TSA showed a significant reduction in cysts. Moreover, p27 expression was upregulated in TSA treated Pkd1 mice. Taken together, these results suggest that HDACs are required for cyst growth, and raise the possibility that HDAC inhibitors may be an effective treatment for PKD.Support or Funding InformationNational Institutes of Health (NIDDK)
Ontogeny of Monocarboxylate Transporter 1 and CD147 Expression in Rat Liver
Authors: Ng Michael , Cao Jieyun , Felmlee Melanie A 
Published: November 2023

PurposeMonocarboxylate transporter 1 (MCT1) is integral in cellular energy metabolism and drug disposition. The ancillary protein CD147 (basigin) has been shown to complex with MCT1 for translocation of the transporter to the cell membrane. The maturation of MCT1 and CD147 expression is not fully understood. Differential hepatic expression levels and functional activities during development can lead to altered drug disposition of MCT1 substrates. The objective of the present work is to quantify the hepatic maturation of MCT1 and CD147.MethodsLivers were collected from male and female Sprague Dawley rats from birth through sexual maturity (postnatal day (PND) 42) (N = 4 per sex at each age). Sex was assigned in animals less than PND 21 based on ano‐genital distance and confirmed by PCR analysis of the SRY gene on the Y chromosome. Whole cell protein extract and total membrane preparations were evaluated for MCT1 and CD147 expression using western blot, with expression levels normalized to the house‐keeping protein Na+/K+ ATPase.ResultsSignificant age‐related differences were observed in liver total and membrane MCT1 and CD147 expression, with the highest levels observed just prior to weaning. In whole cell proteins of male and female rats, MCT1 levels increased to peak at PND 14, before decreasing through PND42. Whole protein CD147 followed the MCT1 trend, with highest expression at PND 14 and 18. MCT1 membrane expression was significantly increased at PND 10 to 18 in males, and PND 14 and 18 in females. CD147 membrane expression for both sexes followed the same pattern as membrane‐bound MCT1. There was a significant difference in CD147 membrane expression between sexes, with males having increased CD147 levels at every age group. There is strong positive correlation between membrane‐bound MCT1 and CD147 expressions for both sexes.ConclusionsMaturation of hepatic MCT1 expression occurs with a distinct pattern from typical drug transporters. Expression levels are highest just prior to weaning which may lead to increased hepatic drug uptake during this period. Liver membrane CD147 correlates significantly with membrane MCT1 indicating cellular trafficking is an important mediator of cell surface expression of the functionally active transporter during mammalian development. Further studies will evaluate the underlying regulatory mechanisms contributing to the age‐related changes in MCT1 expression, as well as drug disposition to observe developmental changes in transporter activity. As MCT1 is widely expressed, maturation will be assessed in additional tissues involved in drug disposition.
Docosahexaenoic Acid is More Effective than Eicosapentaenoic Acid in Increasing the Omega‐3 Index Measured in Red Blood Cell Membranes
Authors: Allaire Janie , Harris William , Vors Cécile , Tchernof André , Couture Patrick , Lamarche Benoît 
Published: November 2023

BackgroundWhether eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids have distinct effects on cardiometabolic risk remains unclear as most studies to date have used a mixture of the two fatty acids in various forms and proportions. The Omega‐3 Index (O3I) reflects the sum of EPA and DHA as percent of fatty acids in red blood cell (RBC) membranes and has been inversely associated with the risk of coronary heart diseases and coronary mortality in epidemiological studies. The objective of this study was to assess if supplementation with high dose EPA differentially modify the O3I compared with high dose DHA in men and women at risk of cardiovascular diseases.MethodsUsing a randomized double‐blind controlled crossover design, 48 men and 106 women with abdominal obesity and subclinical inflammation were randomized to a sequence of three treatment phases: 1–2.7g/d of EPA, 2–2.7 g/d of DHA, 3‐ and 0g/d of EPA+DHA (corn oil). All supplements were provided as 3×1g capsules for a total of 3g/d. Treatment phases had a duration of ten weeks each and were separated by nine‐week washouts. RBC membrane fatty acid composition was measured at baseline and the end of each phase. Differences in RBC membrane fatty acid composition and in the O3I between treatments were assessed using mixed models for repeated measures. Potential confounders of the response to treatments such as weight, sex, age and O3I baseline values were considered.ResultsThe increase in the O3I after DHA (+87% vs. control, p<0.0001) was significantly greater than after EPA (+52% vs. control, p<0.0001; p<0.0001 between DHA and EPA). There was a significant sex*treatment interaction (p=0.046) in the O3I response to EPA and DHA, with similar O3I changes among men and women in response to EPA (0% difference between sexes), but slightly greater O3I increase after DHA among men (+9% compared with women). EPA supplementation increased docosapentaenoic acid (DPA) proportions in RBCs (+84% vs. control, P<0.0001) while DHA decreased DPA in RBCs (−28% vs. control, p<0.0001; p<0.001 between DHA and EPA).ConclusionsHigh‐dose DHA may be more effective than high dose EPA in increasing the O3I, perhaps even more so among men than among women. Because DPA levels are not accounted for in the O3I, in vivo elongation of EPA to DPA may partly explain the difference between EPA and DHA in modulating the O3I. Long‐term intervention studies are needed to determine how this difference relates to cardiovascular risk in men and women.Support or Funding InformationThis study was supported by a grant from the Canadian Institutes for Health Research (CIHR, MOP‐123494). Douglas Laboratories provided the EPA, DHA and control capsules used in this study. Janie Allaire is a recipient of a PhD Scholarships from the CIHR and Fonds de recherche du Québec ‐ Santé.
Greater Stimulation of Postexercise Muscle Protein Synthesis after Consumption of Whole Eggs versus Egg Whites in Healthy Young Men
Authors: van Vliet Stephan , Shy Evan L. , Beals Joseph W. , Ulanov Alexander V. , Li Zhong , Paluska Scott A. , Moore Daniel R. 
Published: November 2023

The majority of protein consumed in the diet is obtained from whole food sources that contain a mixture of macro‐ and micronutrients. Whereas the majority of research investigated the effect of isolated protein sources on protein metabolism, our aim was to assess the muscle anabolic potential of consuming a complete protein within its naturally occurring, nutrient dense food matrix during recovery from resistance exercise in young men. In crossover trials, 10 healthy resistance‐trained men (21±1 y; 88±3 kg; bodyfat: 16±1%) received primed continuous L‐[ring‐2H5]phenylalanine and L‐[1‐13C]leucine infusions. Repeated blood and muscle biopsies were collected before and after a single bout of resistance exercise (4 sets of 10 repetitions at 80% of 10‐RM for both leg press and leg extensions). Immediately after resistance exercise, participants ingested intrinsically L‐[5,5,5‐2H3]leucine labeled whole eggs (18 g protein, 17 g fat) or egg whites (18 g protein, 0 g fat) cooked in scrambled form. Exogenous leucine appearance rates increased (P<0.001) after protein ingestion with peak values of 513±57 nmol leucine·kg−1·min−1 occurring at 75 min after egg white ingestion compared with 496±38 nmol leucine·kg−1·min−1 at 120 min after whole egg ingestion. The total amount of protein derived leucine that became available in circulation over the 300 min postprandial period was similar (P=0.53) between whole egg (75±2.3%) and egg white ingestion (77±1.7%). Whole egg ingestion supported greater post‐exercise myofibrillar protein synthesis rates when compared to egg white ingestion (0.034%/h and 0.024%/h respectively; P=0.02). We conclude that whole egg ingestion stimulates the muscle protein synthetic response more effectively than the consumption of isonitrogenous amounts of egg whites during recovery from resistance exercise in healthy young men. This effect is not attributed to divergent postprandial protein‐derived amino acid availability, suggesting that some intrinsic factor within whole eggs and/or the divergent macronutrient profile may have modified the anabolic potential of this complete protein.Support or Funding InformationVision 20/20 Grant, Division of Nutritional Sciences, University of Illinois, Urbana‐Champaign
Impact of Home Fortification of Complementary Foods Program on Child Anemia and Stunting in Bihar, India
Authors: Young Melissa Fox , Mehta Rukshan , Gosdin Lucas , Kekre Priya , Verma Pankaj , Larson Leila , Girard Amy Webb , Ramakrishnan Usha , Chaudhuri Indrajit , Srikantiah Sridhar , Martorell Reynaldo 
Published: November 2023

Home fortification of complementary foods with multiple micronutrient powders (MMP) is recommended to reduce child anemia in resource‐poor settings. However, there is a lack of program effectiveness data in Bihar, India to guide policies. We conducted a cluster randomized effectiveness trial in West Champaran, Bihar in over 4000 children aged 6–18 months for a duration of one year, within the context of an ongoing program (CARE, India: Integrated Family Health Initiative) delivered by community front line workers. 70 health sub‐centers were randomized to intervention (MMPs and Infant and Young Child Feeding (IYCF) counseling) or control (only IYCF counseling). The MMPs included a daily RDA of iron, zinc, iodine, folic acid, and vitamins A, C and B12, for children. The study aimed to determine impact on measures of nutritional status (anemia, stunting, underweight and wasting) and child feeding practices and inform potential statewide scale‐up. A secondary objective was to examine potentially adverse outcomes (diarrhea, hospitalization and fever). We used a difference in difference approach using cross‐sectional baseline and endline surveys to evaluate impact and adjusted for caste, socioeconomic status, age, gender, maternal education, young mother status, and religion. The duration of the intervention was one year and at baseline, 72% of children were anemic and 33% were stunted. Although 86% of caretakers indicated that they would like to continue using the powders, only 38% of children had consumed MMPs in the last month and 24% were currently consuming MMP at endline. Anemia declined significantly by 7.8% (6.7% in adjusted models; p<0.05) with a greater decline among children 12–18 months (9.3%, p<0.05). There were no overall effects on the prevalence of stunting, underweight or wasting but there was a significant decline of 8.4% in stunting for children aged 12–18 months (7.2% in adjusted models; p<0.05). There were no significant differences in IYCF (age of initiation of complementary feeding, feeding frequency, dietary diversity or minimum acceptable diet). There were no differences in severe morbidity (bloody diarrhea, severe diarrhea, persistent diarrhea, hospitalizations or fever) and there was a significant 4% decrease in the prevalence of any diarrhea self‐reported in past 2 weeks in the intervention communities. In conclusion, home fortification of complementary foods is a promising intervention associated with modest improvements in anemia and possibly stunting within the existing government run program context in Bihar, India.Support or Funding InformationFunding support provided by a BMGF grant through a subcontract with CARE‐India
The Role of Metastasis‐Associated Protein 1 (MTA1) in Breast Cancer Exosome‐Mediated Intercellular Communication
Authors: Hannafon Bethany N. , Gaskill Katy , Calloway Cameron , Ding Wei‐Qun 
Published: November 2023

BackgroundExosomes are small vesicles that mediate cell‐to‐cell communication and are thought to contribute to tumor progression and metastasis by modifying the tumor microenvironment at both local and distant sites. We recently identified Metastasis‐Associated Protein 1 (MTA1) in exosomes secreted from breast cancer cells, ductal fluids, and breast cancer patient plasma samples. MTA1 is a nuclear co‐regulatory molecule that is highly expressed in many cancers and correlates with tumor metastasis and progression. However, the precise role of MTA1 in breast cancer progression and metastasis is unclear.ObjectiveOur objective was to determine the role of MTA1 in exosome‐mediated signaling in the tumor microenvironment of breast cancer.MethodsAn antibody array was used to identify MTA1 in breast cancer exosomes. Exosome‐MTA1 expression was confirmed by western blot. tdTomato‐tagged MTA1 expression and transfer were monitored by fluorescent microscopy and flow cytometry. Luciferase reporter constructs were used to monitor gene expression regulation by exosome‐MTA1 transfer. The CRISPR/Cas9 technique was used to knockout MTA1 in breast cancer cells. Endothelial cell tube‐formation assays were performed to ascertain the role of exosome‐MTA1 in angiogenesis.ResultsMTA1 protein expression was detected in exosomes derived from breast cancer cells, ductal fluids, and breast cancer patient plasma samples. MTA1‐tdTomato expression and exosome‐mediated transfer of MTA1 was observed by fluorescent microscopy and flow cytometry. Importantly, we found that exosome‐MTA1 regulates hypoxia signaling via exosome‐transfer between breast cancer and endothelial cells. Furthermore, exosome‐MTA1 modified the tube formation by endothelial cells.ConclusionsThis is the first report showing that breast cancer exosomes contain MTA1 and that exosome‐MTA1 alters signaling events in the tumor microenvironment. These observations suggest that exosome‐mediated transfer of MTA1 contributes to breast cancer progression and exosome‐MTA1 may serve as a biomarker and therapeutic target for breast cancer.Support or Funding InformationGrant Support: Oklahoma Center for the Advancement of Science and Technology (HR14‐147) and the Oklahoma Shared Clinical and Translational Resources (NIGMS #U54GM104938).
Revisiting the Evolution of Low Trabecular Bone Density in Modern Humans
Authors: Chirchir Habiba , Dean Hannah , Carlson Kristian , Ruff Christopher 
Published: November 2023

Evidence suggests that recent modern humans have low trabecular bone density (i.e., bone volume fraction) compared with other primates and fossil hominins. This has been linked to the increased sedentism observed at the beginning of the Holocene with the advent of agriculture. Additionally, among recent humans, sedentary agricultural populations have been shown to have lower density skeletons compared with foragers. However, these findings relied primarily on either comparisons between sedentary populations and fossil hominins, or between limited samples of agricultural and foraging populations. Thus, the extent to which trabecular bone density in recent human populations with varying subsistence strategies (i.e., farmers, foragers, and populations transitioning from foraging to farming) differs from that of different fossil hominins, and, in turn, how hominins differ from extant anthropoids is unclear. Therefore, we test the hypothesis that populations with subsistence strategies demanding high physical activity will exhibit greater trabecular density than sedentary populations, and will be more similar to fossil Homo, and australopiths will be more similar to anthropoids due to the greater mechanical loading on their skeletons. We measure trabecular density using pQCT and microCT in lower and upper limb joints in recent modern humans (five populations), anthropoids (Chlorocebus aethiops, Papio anubis, Pongo pygmaeus, Pan troglodytes), and fossil hominins (Australopithecus africanus, Australopithecus sediba, Paranthropus robustus, Homo neanderthalensis, and early Homo sapiens).The results show that in the lower limb joints, there is a significant and uniform decline in trabecular density among all recent humans in the Holocene, while fossil hominins and extant anthropoids show similar, higher trabecular density values. In contrast, in the upper limb, there is no significant shift in trabecular density among humans; active recent human populations display trabecular density that is similar to the fossil Homo. In addition, some anthropoids are not significantly greater in density than the active recent human populations. These results suggest that trabecular density of the lower limb only reflects a reduction in mobility as humans became more sedentary throughout the Holocene. The lack of a significant decline in trabecular density in the upper limb in recent humans may reflect the active use of the arms and hands that is needed for food production and processing even among sedentary populations. While the results support the recent evolution of low trabecular density in modern humans resulting from reductions in activity levels in the Holocene, it is important to compare multiple skeletal elements across a diverse set of recent modern humans with varying subsistence strategies when drawing conclusions about changes in bone density in the human skeleton.
Association of Snacking Frequency with Patterning of Daily Energy Intake and Weight Among US Toddlers and Preschoolers
Authors: Fisher Jennifer Orlet , Davey Adam , Kachurak Alexandria , Bailey Regan K 
Published: November 2023

Snacking is nearly universal among young children but associations with weight status are not well studied especially among young children for whom snacks are believed to be important for growth. The objective of this research was to evaluate the cross‐sectional association of snacking frequency with weight status and daily energy intake among 4,271 US toddlers and preschoolers aged 12–71 months participating in the 2007–2014 National Health and Nutrition Examination Survey. Snacking and nutrient intakes were estimated using the mean of 2, 24‐hr dietary recalls. Overweight among toddlers was defined as weight‐for‐length ≥ 97.7th percentile and overweight/obesity among preschoolers was defined as BMI z‐score ≥ 85th percentile. Models used American Academy of Pediatrics recommendations of 2–3 snacks/d as the reference group; data were adjusted for survey design and sample weights, demographics and energy reporting accuracy. In the total sample, 8.7% of children 12–23 mo and 23.8% of children were overweight or obese. Children consumed, on average, 28% (419.3 ± 6.1 kcal) of daily energy from snacks eaten at 2.91 ± 0.03 occasions/d. Children consuming 4+snacks/d (n=610, 13.5%) had greater odds of being OW/OB (OR=1.50, 95CI=2.09–0.02, p<0.05), consumed slightly greater daily energy (Mean (SE)= 1495 (14.0) vs.1462 (4.9), p<0.05), and consumed a greater proportion of daily energy from snacks (42% (0.7) vs. 27% (0.5), p<0.0001) than children consuming 2–3 snacks/d (n=2189, 55.1%). Risk of OW/OB and energy intake among children consuming 0–1 snacks/d did not differ from children consuming 2–3 snacks/d in the full sample. Among preschoolers, however, those children consuming 0–1 snacks/d had a lower risk of OW/OB than children consuming 2–3 snacks/d (OR=0.75, 95CI=0.57–0.98, p<0.05). These findings provide first evidence of associations between snacking frequency and weight status among young US children < 5 years. These findings indicate that US toddlers and preschoolers who snack more frequently than recommended guidelines may consume greater daily energy and be at elevated risk of OW/OB than those who do not. That preschoolers who consumed fewer than 2–3 snacks/d had the lowest risk of OW/OB points to potential age‐related changes in the role of snacking in healthy weight. Longitudinal and experimental studies are needed to evaluate causal influences of snacking on appetite and growth in early childhood.Support or Funding InformationNIH R21 HD085137‐01A1