bluuebunny/crossref_metadata_2025 huggingface dataset:
The nuclear lamins are major determinants of nuclear architecture
Authors: Goldman Robert , Adam Stephen A. , Goldman Anne E. , Shimi Takeshi , Kittisopikul Mark , Jaqaman Khuloud , Turgay Yagmur , Medalia Ohad
Published: November 2023

The major structural components of the nuclear lamina are the Type V intermediate filament proteins, the nuclear lamins. There are four nuclear lamin isoforms (Lamins A, C, B1 and B2), which interact along with their binding partners to form a molecular interface between the inner nuclear envelope membrane and chromatin, the nuclear lamina in mammalian cell nuclei. Evidence has accumulated that the lamins play important roles in DNA replication, transcription, chromatin organization, DNA damage repair, the regulation of nuclear size and shape, and the disassembly and reassembly of the nucleus during mitosis. In addition, hundreds of mutations have been discovered in the gene encoding lamins A and C that cause a wide range of human diseases known as the “laminopathies”. Our studies of the nuclear phenotypes resulting from these mutations have provided important insights into the structure and function of both the A‐ and B‐type lamins in normal cells; especially those mutations which cause typical and atypical forms of premature aging (progeria). To date our observations of progeria nuclei demonstrate that the lamins play regulatory roles in the positioning and epigenetic modifications of chromatin and in premature replicative senescence. These studies have also revealed that the A‐ and B‐type lamins form different networks within the lamina. Expanding on this finding we have carried out 3D‐Structured Illumination Microscopy (3D‐SIM) analyses to show that the 4 lamin isoforms assemble into different filamentous meshworks within the lamina of normal human diploid and mouse embryonic fibroblasts. These findings are now being correlated with higher resolution images obtained by cryo‐EM tomographic analyses. 3D‐SIM is also revealing a close association between lamin filaments in the NL and peripheral domains of heterochromatin. These associations appear to be altered in the nuclei of cells in which one or more lamins are depleted.

Support or Funding Information

This work is supported by National Institutes of Health grants GM106023 and the Progeria Research Foundation.
Single molecule transcription factor dynamics in mammalian cells and the syncytial Drosophila embryo
Authors: Darzacq Xavier , Mir Mustafa
Published: November 2023

Formation of the large protein complexes regulating transcription such as the pre‐initiation complex (PIC) is the result of equilibrium in between the frequency at which its principal components assemble and disassemble. To date a lot of information has been collected on how the off rate of a specific interaction is regulated. Here I will concentrate on two mechanisms controlling the on rate of proteins assembly at the level of their ability to sample the nucleoplasm using efficient strategies to search for their targets.

During early development in the Drosophila embryo, cell fates are determined over the course of just 2 hours with exquisite spatio‐temporal precision. One of the key regulators of this process is the morphogen Bicoid that is enriched at the anterior of the embryo establishing polarity in a concentration dependent manner. Bicoid has also been suspected to play a role in the posterior where there are only a few molecules per nucleus but the lack of a mechanism for such an activation lead to much controversy. Here we use lattice light sheet microscopy to overcome the technical barriers of sample thickness and auto‐fluorescence to characterize the single molecule dynamics of Bicoid. We find that Bicoid binds to DNA transiently consistent with its concentration modulated activity. When analyzing the few molecules present in the posterior nuclei we observed a significant dynamic change affecting the on rates of binding as well as massive clustering of bicoid molecules. In the context of a concentration dependent model for bicoid activity, this data is consistent with a locus dependent and regulated transcriptional function in the drosophila embryo posterior. Different mechanisms of regulation as well as current experiments to sort them apart will be discussed.

Support or Funding Information

Funding was provided by the National Institute of Health grants (U54‐DK107980) and (U01‐EB021236) to XD. California Institute for Regenerative Medicine (CIRM, LA1‐08013 to XD)
Repurposing Drugs to Ameliorate Aging
Authors: Partridge Linda
Published: November 2023

The aging process has proved to be malleable, and interventions that extend lifespan in general also prevent age‐related pathology. The nutrient‐sensing insulin/Igf/mTOR signaling network has proved to have a role in aging that is conserved over large evolutionary distances. This signaling network contains targets of several drugs, all of which have been developed to combat specific diseases rather than the aging process itself. These drugs are now proving able to extend lfiespan in laboratory animals, through mechanisms that are currently being investigated. These findings are pointing towards the propsect of a broad‐spectrum, preventative medicine for the diseases of human aging.
Evolution and the proteome: Insights into protein function from deeply conserved gene modules
Authors: Marcotte Edward
Published: November 2023

I'll describe our attempts to test the extent to which deeply homologous genes and pathways are predictive across distant eukaryotic species, including our search for new models of human disease among phenotypes of distant organisms, our attempts to systematically humanize yeast cells, and our program to apply high‐throughput protein mass spectrometry in order to measure conserved physical interactions among the thousands of proteins shared across the eukaryotic tree of life. Studies such as these reveal the evolutionary basis for traits and diseases, help annotate the expressed proteomes of major eukaryotic lineages, and reveal the evolutionary conservation, divergence, and rewiring of protein complexes across eukaryotic proteomes.
Using kinase regression to elucidate host signaling pathways that control infection
Authors: Kaushansky Alexis , Arang Nadia , Kain Heather S. , Glennon Elizabeth K. , Dudgeon Denali R. , Walter Emily N.F. , Gujral Taranjit S.
Published: November 2023

Intracellular pathogens have extensive needs from their host cells. For example, Plasmodium parasites are dependent on hepatocyte infection for life cycle progression. During their residence within the hepatocyte, malaria parasites rely on their host for protection against cell death and for the acquisition of nutrients that supports their development. Unfortunately, technical hurdles have led to only a sparse knowledge of molecular factors that regulate liver stage malaria infection. Here, we assessed 37 host‐targeted kinase inhibitors for their capacity to eliminate malaria‐infected hepatocytes. We used these data, along with pre‐existing activity profiles of each inhibitor against 300 host kinases, to inform a predictive computational model that identified host kinases which facilitate Plasmodium liver stage infection. Our predictions yielded 49 kinases, including five kinases previously described to impact infection and 44 novel regulators of infection that include multiple Receptor Tyrosine Kinases and members of the Protein Kinase C cascade. Our approach also facilitated the prediction of several novel host‐targeted kinase inhibitors of infection, including multiple compounds which have already been used in humans and are active against Plasmodium parasites in vitro and in vivo. Moreover, this straight‐forward approach facilitates a kinome‐wide assessment of critical host factors involved in infection by a wide range of pathogens. By comparing host regulators of infections by parasites, bacteria and viruses, we hypothesize multiple kinases that regulate cellular processes that underlie infection by a wide variety of pathogens. This suggests that host‐targeted kinase inhibitors could curtail a wide variety of infections.

Support or Funding Information

R00AI111785
Directed evolution of nanobody chaperones that stabilize GPCR:G‐protein complexes
Authors: Manglik Aashish , Kruse Andrew C. , Koehl Antoine , Kobilka Brian K. , Ring Aaron M.
Published: November 2023

G protein‐coupled receptors (GPCRs) sense external signals through a stereotyped mechanism that couples ligand‐induced conformational changes to nucleotide exchange in associated heterotrimeric G proteins. The conformational states in both GPCRs and G proteins that mediate this process are transient and thus challenging to study. Single‐domain camelid antibody fragments (“nanobodies”) have proven invaluable tools to capture GPCRs in particular conformations for crystallography, spectroscopy, and in vivo studies. Nb35 is a conformationally‐selective nanobody that binds to Gs to stabilize the nucleotide‐free state and its complex with activated GPCRs, including the Beta‐2 adrenergic receptor. Similar chaperones for other heterotrimeric G proteins such as Gi and Gq have not yet been described. To obtain these valuable probes, we used structure‐based directed evolution of Nb35 with yeast surface display to alter its specificity for Gi and Gq. After selection, we obtained two variants, NbD7 and NbD12 that respectively bind Gi and Gq in a fashion analogous to Nb35 for Gs. Biochemically, NbD7 and NbD12 protect GPCR:G‐protein complexes from GTP‐induced disassociation. Furthermore, NbD7 enables crystallization of a complex of heterotrimeric Gi and a GPCR. Together with Nb35, NbD7 and NbD12 allow for conformational control of the vast majority of GPCR:G‐protein complexes and provide a facile template to prepare additional nanobody chaperones against other G protein families.
Tart Cherry Juice Improves Visual Sustained Attention and Subjective Memory Ability in Older Adults
Authors: Chai Sheau C , Davis Kristina , Wright Regina S , Zhang Zugui , Luo Jing , Lee Krystal
Published: November 2023

Tart cherries or their bioactive components have been shown to improve neuronal‐behavioral performance and decrease levels of oxidative and inflammatory markers. However, the ability of tart cherries to improve cognitive function in older adults has not been investigated. Hence, a randomized placebo‐controlled trial was conducted to evaluate whether older adults consuming 16 fluid ounces (fl. oz) of tart cherry juice daily for 12 weeks would improve cognitive function. Thirty‐seven (N=37) older adults between the ages of 65–80 years were recruited. Participants were randomly assigned to consume tart cherry juice or placebo daily for 12 weeks. Subjective memory and objective cognitive performance was assessed using a validated questionnaire and a standardized battery of tests. Fasting blood samples were also collected to measure oxidative stress and inflammatory biomarkers. Statistical analysis was performed using a nonparametric one‐way ANOVA with Wilcoxon in SAS Version 9.2. Our findings indicate that perception of everyday memory ability (P=0.0268) and visual sustained attention (P<0.0001) increased significantly in the tart cherry group, as compared to the placebo group, from baseline to posttest. 8‐oxoguanine glycosylase, a DNA glycosylate enzyme that are necessary for the excision 8‐oxoguanine and repair of a damaged DNA was significantly increased in the tart cherry group compared with the placebo group. Inflammatory markers were not altered by tart cherry juice or placebo. The findings of the present study suggest that tart cherry juice may improve cognitive function through its anti‐oxidative properties.

Support or Funding Information

Cherry Marketing Institute
Femoral and L5 Spine Trabecular Bone Are Differentially Influenced by Dietary Calcium Restriction and Genetics in Growing Mice
Authors: Chanpaisaeng Krittikan , Reyes‐Fernandez Perla C. , Mace Sarah , Replegle Rebecca A. , Lan Xu , Fleet James C.
Published: November 2023

Trabecular bone (Tb) has a high surface‐to‐mass ratio that makes it valuable for rapid exchange of calcium (Ca) ions in times of physiologic need (i.e. when dietary Ca intake is low). Previous studies showed there is heterogeneity in Tb structure at different skeletal sites and this might explain why certain sites are more vulnerable to osteoporosis. We hypothesized that peak Tb mass at the distal femur and lumbar spine is differentially regulated by dietary Ca intake, genetics, or their interaction. Sixty‐two (62) genetically distinct mouse lines were fed diets with basal (0.5%) or low (0.25%) Ca levels from 4 to 12 wks of age (n=8/diet/line). At termination, the right femur and L5 vertebrae were removed and Tb was analyzed by micro‐computed tomography (μCT). Means were adjusted for the confounding influence of body size by ANCOVA. The response of μCT parameters to dietary Ca restriction (RCR) was calculated and used as a separate parameter. On the basal diet, the L5 spine is more dense than femur, i.e. Tb mass (bone volume/total volume, BV/TV), number (Tb.N), and thickness (Tb.Th) were significantly higher, while separation (Tb.Sp) was lower. The Structural model index (SMI) indicates that Tb structure was more rod‐like in femur (i.e. a weaker structure) and more plate‐like in spine (i.e. a stronger structure). Low dietary Ca intake reduced BV/TV and made Tb structure more rod‐like at both sites. However, dietary Ca restriction had a differential effects on Tb bone at each site, e.g. there was more loss of Tb.N in the femur (RCR = −7.58% (femur) vs. −2.15% (spine)) suggesting there is a greater impact of low Ca intake on the structural integrity of femoral Tb compared to L5 spine Tb. There was a large phenotypic diversity across the 62 lines for all femur and spine parameters, suggesting that genetics is a major regulator of Tb. Consistent with this, the narrow sense heritability (h2) was high for all parameters at both sites (e.g. BV/TV in the basal diet group; h2 = 0.52 in femur and 0.56 in spine). Similarly, the RCR was significantly different among lines for all parameters, reflecting gene‐by‐diet (GxD) interactions, but the effect was more modest, e.g. BV/TV RCR, h2 = 0.37 for femur and 0.25 for spine. Lastly, there was a significant site‐by‐line interaction affecting the basal and RCR parameters that indicates site‐specific genetic effects on Tb. Our research is important because it demonstrates that a complex interaction exists between dietary Ca intake and genetics and this can influence development of peak Tb mass in the femur and L5 spine. Further genetic mapping studies will be conducted to identify the loci and candidate genes that account for these genetic and GxD effects.

Support or Funding Information

Supported by NIH award ES019103 to JCF and Royal Thai Government Scholarship to KC
Hemoglobinopathies and Child Feeding Practices as Predictors of Anemia in Rural Laotian Children: Evidence from the Lao Zinc Study
Authors: Barffour Maxwell Adusei , Hinnouho Guy‐Marino , Wessells Kimberly Ryan , Brown Keneth H , Chanhthavong Bigphone , Ratsavong Kethmany , Sanchaisuriya Kanokwan , Kounnavong Sengchanh , Fucharoen Supan , Hess Sonja Y
Published: November 2023

Understanding the genetic and nutritional determinants of anemia is critical in designing interventions. We compared differences in anemia by hemoglobinopathy status and child feeding practices, using baseline data of 6–23 month old children (n=900) from rural Khammouane district, Lao PDR, who are participating in the Lao Zinc Study. First, we explored the associations between anemia and two structural hemoglobin variants, namely a) Hemoglobin (Hb) E‐trait (defined as normal (HbAA), homozygote‐HbEE or heterozygote (HbEA)), and b) Hemoglobin F (defined as hereditary persistence of fetal hemoglobin (HPFH) if relative abundance ≥5%, or normal if otherwise). Next, on the basis of the results of the anemia‐hemoglobinopathy analyses, we evaluated the associations between anemia and child feeding practices, stratified by HbE‐trait. We defined breastfeeding (BF) as at least one‐time breastfeeding in the past month. Using World Health Organization (WHO) guidelines, adequate meal frequency (AMF) was defined as a minimum meal frequency of 2 (6–8 month) or 3 (9–23 month) if BF or 4 if non‐BF. Adequate dietary diversity (ADD) was defined as consumption of at least 4 of 7 food groups as specified by the WHO, in the past 24 hours. Consumption of animal source food (ASF) was defined as intake of at least 1 of 4 animal source foods in the past 24 hours. Anemia was defined as Hb <110 g/l. The distribution of children by HbE was 31% (HbAA), 57% (HbEA) and 12% (HbEE). Prevalence of HPFH was 15%. The prevalence of breastfeeding was 67%, AMF was 12%, consumption of ASF was 72% and ADD was 24%. Overall anemia prevalence was 51%, although prevalence differed by HbE status (40% for HbAA, 53% for HbEA and 70% for HbEE; p<0.001) and by HbF status (67% for HPFH and 48% if otherwise; p<0.001). In a multivariate logistic regression model including HbE, HbF and age, the odds of anemia was increased in children with HbEA (OR=1.7, P=0.001) and HbEE (OR=3.4; P<0.001) relative to the HbAA children. HbF was not associated with increased anemia risk after adjusting for HbE and age. In the HbE‐stratified analyses, we found no evidence of an association between anemia and either AMF or ASF, irrespective of HbE or BF status. However, in HbAA children, ADD was associated with a lower anemia prevalence in BF children (OR=0.44, P=0.037), but not non‐BF children (OR=1.64, P=0.303). Our data suggests that in this population, hemoglobinopathies, breastfeeding and complementary feeding practices are important predictors of anemia.

Support or Funding Information

Funding for this research was provided by the Mathile Institute for the Advancement of Human Nutrition, the Micronutrient Initiative and the Bill & Melinda Gates Foundation.
Chestnut Leaf Extract Increases Sensitivity of Breast Cancer Stem Cells to Paclitaxel by Inhibiting Nrf2 Activity
Authors: WOO YAEJIN , Oh Jisun , Kim Jong‐Sang
Published: November 2023

Tumor cells consist of various clonal subpopulations, thus displaying heterogeneous tumorigenicity. Only a subset of tumor cells, called cancer stem cells (CSCs), uniquely possesses high potency to initiate tumorigenesis and to locally or systematically disseminate tumor cells. Based on their properties, CSCs come to be a critical target for the development of chemotherapeutic strategies. Interestingly, it has been known that Nrf2‐mediated antioxidant enzymes are highly expressed in CSCs, which may be responsible for lowering the intracellular ROS level and the vulnerability to chemotherapeutic agents. As anticancer drugs usually utilize ROS as an arsenal for killing cancer cells, we hypothesized that suppression of Nrf2 activity may increase susceptibility of CSCs to anticancer drugs, improving their therapeutic efficacy. Our findings demonstrate that MCF‐7 CSCs having a CD44high/CD24low phenotype formed mammospheres and highly expressed Nrf2 compared to original MCF‐7 cells. In addition, total 89 kinds of Korean edible plant extracts were screened for the inhibitory activity against Nrf2 signaling pathway using an ARE‐luciferase assay system. Among these samples, Chestnut (Castanea crenata) leaf extract dramatically decreased nuclear translocation of Nrf2 and its downstream protein expression of antioxidant enzymes in MCF‐7 CSCs, and also attenuated the resistance to paclitaxel. These findings suggest that Chestnut leaf extract or its constituents could be utilized to increase therapeutic efficacy of anticancer agents through inhibition of Nrf2 signaling pathway.

Support or Funding Information

This study was supported by the National Research Foundation (Grant No. R2014R1A2A2A01005773, funded by the Ministry of Science, ICT and Future Planning; Grant No. 2013R1A1A2013362, funded by the Ministry of Education) Republic of Korea.
The impact of policies to reduce trans fat consumption: A systematic review of the evidence
Authors: Downs Shauna , Bloem Milan , Zheng Miaobing , Catterall Elise , Meertens Beth , Veerman Lennert , Wu Jason
Published: November 2023

The consumption of industrially produced trans fatty acids (TFA) has been associated with an increased risk of heart disease. In recognition of this, countries, states and cities worldwide have implemented TFA policies (e.g., mandatory or voluntary limits, labeling) aimed at reducing their availability in the food supply. This study builds on a previously published review that examined the impact of TFA policies worldwide from 2000–2013. A systematic literature search of the peer reviewed and grey literature was conducted to identify additional studies examining the impact of TFA policies published between 2013 and 2016. Studies that were: 1) empirical, 2) examined a TFA policy and 3) examined the effect of the policy on TFA levels/availability pre and post policy intervention were included. Modelling studies examining the impact of TFA policies were also included. A total of 13 studies published between 2013 and 2016 were included in the review, including seven modelling and six studies examining ‘real world’ TFA policies. Overall, the modelling studies indicated that TFA bans would reduce heart disease risk, would benefit socioeconomically disadvantaged populations the most and would be cost saving. The ‘real world’ TFA policy studies all reported reductions in TFA. When combined with the findings of the previous review which included a total of 15 studies, there is strong evidence to suggest that mandatory TFA bans lead to the largest reductions in TFA levels and that whilst labelling policies also lead to reductions in TFA levels/intakes additional progress could still be made given that high levels of TFA remain in some products. The combined studies also show that reformulation of products to reduce TFA has had variable effects on saturated fat levels in these foods – in some cases saturated fat levels increased, in others they decreased and for some products they remained the same. Policies aimed at reducing TFA in the food supply are effective and will likely reduce the burden of diet‐related disease, particularly among the most vulnerable socioeconomic groups. Moving forward, national, regional or global approaches to reducing TFA should be adopted in order to further reduce the levels of TFA in the food supply.

Support or Funding Information

National Heart Foundation of Australia
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.

PURPOSE

The 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.

METHODS

42 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.

RESULTS

Following 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).

CONCLUSION

These 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.
Characterization of Spontaneous Severe Hypertriglyceridemia in Diabetic Nonhuman Primates
Authors: Hansen Barbara Caleen , Newcomb Jennifer D , Chaudhari Uddhav Caleen
Published: November 2023

Severe hypertriglyceridemia is a condition where serum triglyceride levels increase above 500 mg/dl. Severe hypertriglyceridemia may result from primary (genetic defects in triglyceride metabolism) or may occur secondary to a high fat diet, excess alcohol consumption, obesity or type 2 diabetes. Severe hypertriglyceridemia has serious consequences for the development of coronary artery disease, pancreatitis and glomerulonephritis. In mice, diet‐induced hypertriglyceridemia and transgenic models of hyperlipidemia have been used to investigate the pathophysiology and associated co‐morbidities induced by hypertriglyceridemia. None of these models has, however, reproduced either severe hypertriglyceridemia (triglyceride levels above 1000mg/dl) or the co‐morbidities associated with the human condition. In the present study of 173 adult genetically unrelated nonhuman primates, ingesting only a low fat diet, we have characterized the progression of hypertriglyceridemia using the ATP National Cholesterol Education Program classifications: normal <150 mg/dl; borderline‐high 150–199; high 200–499; very high >500 mg/dl. This progression of hypertriglyceridemia was found to increase in parallel to the progression of metabolic syndrome to prediabetes and overt, then severe diabetes in the nonhuman primates. Ninety‐nine monkeys were normal, and the elevated triglyceride groups had respective means of 176.9 ± 23.6 mg/dl (N=15); 275.4±40.5 mg/dl (N=34); and 643.5 ± 43.4 (N=25). In addition, 8 monkeys had naturally occurring very severe hypertriglyceridemia (1000–4000 mg/dl). Hypertriglyceridemia was significantly correlated with HbA1c% (r2 =0.2564). Further analysis of serum lipase and amylase levels showed increased levels of lipase in overt diabetes (57.7 ± 3.5 U/L). This is the first report showing the development of spontaneous severe hypertriglyceridemia in prediabetic and diabetic rhesus macaques and associated increased serum lipase levels. Characterization of this nonhuman primate model of naturally‐occurring severe hypertriglyceridemia provides a spontaneously occurring and ideal animal model for understanding the pathophysiology of severe hypertriglyceridemia and for evaluating therapeutic interventions.
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 Information

Childrens 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 Information

Funded 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

Objective

To 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.

Methods

Student‐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.

Results

24 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).

Conclusions

Vitamin 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 Information

Support 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

Background

Retinol 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.

Objectives

Determine the effect of study duration on mathematical models of VA metabolism including kinetic parameters and model outcomes.

Methods

Adult 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).

Results

Increased 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).

Conclusions

Extending 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 Information

Supported 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 Information

This 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

Aim

This study aims at elucidating the function of the imprinted lncRNA H19 in biliary hyperplasia, bile acid (BA) homeostasis, and cholestatic liver fibrosis.

Methods

C57BL/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.

Results

H19RNA 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.

Conclusion

Dysregulated hepatic H19 expression contributed to cholestatic liver fibrosis through the ZEB1/EPCAM pathway.

Support or Funding Information

NIH 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 Information

Supported 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 Information

Funded by the German Research Foundation (Emmy Noether SCHE 1645/2‐1 and SFB914 projects B09 and Z03) and the European Research Council (CIRCODE, 635872)