bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of an encapsulated fruit and vegetable juice concentrate on obesity‐induced systemic inflammation
Authors: Wood Lisa G , Williams Evan J , Berthon Bronwyn S , Baines Katherine A
Published: November 2023

Study Objectives

Phytochemicals from fruits and vegetables have been shown to reduce systemic inflammation. This study examined the effects of an encapsulated fruit and vegetable juice concentrate on risk factors for chronic disease in overweight and obese adults.

Methods

A double‐blinded, parallel, randomised placebo‐controlled trial was conducted in 56 adults aged ≥40 years, with BMI ≥28 kg/m2. Before and after 8 weeks daily treatment with 6 capsules of fruit and vegetable juice concentrate or placebo, peripheral blood gene expression (microarray and qPCR), plasma TNFα (ELISA), plasma carotenoids (HPLC), body composition (DEXA), HbA1c, cholesterol and triglycerides were assessed.

Results

Total carotenoids (0.73mg/L (week 0) versus 0.85mg/L (week 8), p=0.017) and β‐carotene (0.11mg/L versus 0.16mg/L, p<0.0001) were significantly increased in plasma following consumption of the juice concentrate. Correspondingly, total cholesterol (5.70mmol/L versus 5.50mmol/L, p=0.015), LDL cholesterol (3.63mmol/L versus 3.50mmol/L, p=0.032), plasma TNF‐α (1.04pg/mL versus 1.02pg/mL, p=0.037) and systolic blood pressure (131.7mmHg versus 125.9mmHg, p=0.005) were decreased and total lean mass (49.3kg versus 50.0kg, p=0.018) was increased following supplementation with the juice concentrate. Between group differences were observed for plasma total carotenoids, lycopene and β‐carotene. Gene expression of various signalling pathways was altered, including 3 genes involved in lipogenesis, 10 NF‐kB associated genes and 2 AMPK associated genes.

Conclusions

Systemic inflammation, blood lipids and body composition were improved in obese individuals following an 8 week intervention with an encapsulated fruit and vegetable juice concentrate. Hence, this supplement may provide a useful strategy for reducing the risk of obesity‐induced chronic disease.

Support or Funding Information

Financially supported by research grant from NSA, LLC (Collierville, TN).
Dietary Blueberries Attenuate Vascular Inflammation and Dysfunction in Diabetic db/db Mice
Authors: Bharat Divya , Petersen Chrissa , Gholami Samira , Denetso Christopher , Cutler Brett , Kim Ji‐Seok , Symons J David , Velayutham Anandh Babu Pon
Published: November 2023

Background

Patients with diabetes are 2–4 fold more susceptible to cardiovascular complications. High glucose‐induced vascular inflammation and the subsequent vascular dysfunction play a major role in the development of atherosclerosis in the context of diabetes. In preliminary studies we showed that relative to vehicle (BSA) treated arteries, dysfunction was less severe in segments that incubated 18–24 h with palmitate + blueberry metabolites vs. palmitate alone. Based on these data from arterial segments treated ex vivo with blueberry metabolites, we tested the hypothesis that blueberry supplementation attenuates vascular complications in diabetic db/db mice.

Methods

Seven week old male diabetic db/db mice that consumed standard chow (db/db) or chow supplemented with 3.8% freeze‐dried blueberries (db/db+BB) for 10 weeks were compared to non‐diabetic control mice (db/+). Based on normalization to body surface area, this dose in mice is equivalent to ~1.5 servings of BB (~240 g) in humans. At ~17 weeks the following in vivo analyses were completed: (i) body weight and food intake; (ii) glucose (GTT) and insulin (ITT) tolerance; and (iii) systemic arterial blood pressure (tail cuff). Ex vivo analyses included the assessment of vascular inflammation (fluorescent labeled monocyte binding to aortic endothelium), and determination of mesenteric arterial reactivity (isometric tension procedures).

Results

Compared to db/+ animals, both diabetic groups displayed similar increases (p<0.05) in weight gain and impairments (p<0.05) in glucose and insulin tolerance. Arterial pressure (systolic, diastolic, and mean) was higher (p<0.05) in db/db vs. db/+ mice, but the severity of hypertension was attenuated (p<0.05) in db/db+BB mice. After precontraction with ~ 10−6 M phenylephrine, acetylcholine (ACh; 10−8–10−6 M) evoked vasorelaxation was impaired (p<0.05) in db/db vs. db/+ animals, but no differences existed between db/db+BB vs. db/+ mice. Vasorelaxation to sodium nitroprusside (10−9–10−4 M) was complete and similar among groups. Fluorescent‐labeled mouse monocyte WEHI 78/24 cells exhibited higher (p<0.05) binding to aortic endothelium from db/db vs. db/+ mice, but this response was reduced (p<0.05) in aortic endothelium from db/db+BB mice. Ongoing studies are focused on identifying the effect of blueberries on inflammatory molecules in the vasculature, and exploring the molecular signaling mechanisms responsible for the protective effects of blueberries.

Conclusion

Blueberry consumption may be a potential adjunct therapy to prevent, delay, and/or limit the severity of vascular complications in diabetes.

Support or Funding Information

Supported by University of Utah Seed Grant and College of Health Research Pilot Grant.
Anti‐inflammatory Activity of Aronia Berry Polyphenols in Jurkat T Cells
Authors: Martin Derek , Bolling Bradley
Published: November 2023

INTRODUCTION

Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the gastrointestinal tract resulting from an aberrant immune response to the microbiota. T cells and their cytokines influence contribute to the ongoing inflammation in IBD. Diets rich in fruits and vegetables have been shown to decrease the risk of developing IBD. Dietary polyphenols are considered to be responsible for many of the benefits of fruit and vegetable consumption. Aronia berries are a concentrated source of polyphenols including anthocyanins, proanthocyanidins, and phenolic acids. Polyphenols, in general, have limited intestinal absorption and are extensively metabolized by the gut microbiota. Microbial catabolism may contribute to the health benefits associated with polyphenol consumption.

OBJECTIVE

The objective of this study was to determine the anti‐inflammatory activities of an aronia berry extract, aronia polyphenol fractions, and microbial polyphenol metabolites in Jurkat T cells.

METHODS

Aronia anthocyanin and neutral phenols fractions were obtained from an ethanolic aronia extract by elution from a C18 solid phase extraction column. Aronia proanthocyanidin rich fraction was obtained from whole aronia berries extracted with acetone/water/acetic acid (70/29.5/0.5 v/v) followed by elution from a Sephadex LH‐20 column. Polyphenols in the extract and fractions were determined by HPLC. Jurkat T cells were stimulated with 50 ng/mL phorbol myristate acetate and 1 μg/mL ionomycin for 4 h in the presence of a commercial aronia berry extract, aronia berry polyphenol fractions, or known microbial polyphenol metabolites. Tumor necrosis factor (TNF)α in supernatant was determined by immunoassay. Statistical significance was determined by one‐way ANOVA.

RESULTS

At 250 μg/mL, the aronia extract significantly inhibited TNFα production by 33.6% (p<0.01) without reducing cell viability. At 50 to 100 μg extract/mL, there was no inhibition of TNFα. The anthocyanin and proanthocyanidin rich fractions did not affect TNFα production, but the neutral phenols fraction exhibited dose‐dependent inhibition. 3,4‐Dihydroxyphenylpropionic acid inhibited TNFα production at 100 and 0.1 μM, by 14.1 and 15.1% (p<0.05 and p<0.01, respectively) and 3,4‐dihydroxyphenylacetic acid inhibited TNFα production by 20.6% at 0.1 μM (p<0.0001). 3,4‐Dihydroxybenzoic acid (protocatechuic acid) and ferulic acid did not inhibit TNFα production at any tested concentration.

CONCLUSION

The aronia extract, neutral phenols fraction, and select microbial metabolites inhibited T cell TNFα without apparent loss of cell viability. The anti‐inflammatory capacity of aronia berry polyphenols may help to prevent and minimize intestinal inflammation associated with IBD by inhibiting T cell TNFα.

Support or Funding Information

USDA Hatch WIS01836
Effect of Bonded Arginine Silicate on Inflammatory Markers and Arthritis
Authors: Ojalvo Sara Perez , Sahin Kazim , Komorowski James
Published: November 2023

Background

The purpose of this preclinical study was to examine the effects of inositol‐stabilized arginine silicate supplementation (ASI; Nitrosigine®) on inflammatory markers and joint health in an arthritis‐joint health model. ASI is a sports nutrition ingredient that has been clinically shown to provide efficacious levels of arginine and silicon, reduce markers of muscle damage, and increase nitric oxide levels among other sports nutrition endpoints. This preclinical study was designed to evaluate the potential of ASI to reduce inflammatory markers and promote joint health, important endpoints to athletes, fitness enthusiasts and people with joint pain due to inflammation. The study recorded arthritis score, inflammation score, inflammatory markers, and serum and joint arginine and silicon levels upon administration of ASI in rats with collagen‐induced arthritis.

Methods

Female Wistar rats were reared at 22 ± 2°C in a 12/12 hour light/dark cycle and randomized into four groups (n=7 in each group; 8 weeks‐old):

Control group

Arthritic control group

Arthritic group supplemented with a simple mixture of arginine HCl + silicon + inositol (A+S+I) at doses equivalent to those in ASI

Arthritic group supplemented with ASI at a dose of 1.81 g/kg/day (corresponding to a human dose of 1500mg/day)

Rats were dosed for 30 days. On day 14 and day 29, rats were analyzed for arthritis score, inflammation score, and 10 inflammatory markers in the blood and tissue: TNF‐α, IL‐17, IL‐6, ghrelin, obestatin, sclerostin, DKK‐1, Cox‐2, NF‐κB, and B‐catenin.

Results

Day 29 arthritis scores and inflammation scores were both significantly lower in the ASI group (IV) compared to the arthritic control group (II) and the A+S+I group (III). Seven inflammatory markers tested in the blood — TNF‐α, IL‐17, IL‐6, ghrelin, obestatin, sclerostin, and DKK‐1 — were significantly lower in the ASI group (IV) compared to the arthritic control group (II). Four of five inflammatory markers tested in the tissue — Cox‐2, TNF‐α, IL‐6, NF‐κB, and B‐catenin — were significantly lower in the ASI group (IV) compared to the arthritic control group (II).

Conclusions

ASI supplementation significantly improved markers of inflammation and overall arthritis and inflammation score over the arthritic control group and the A+S+I group. These results demonstrate that ASI may be effective in reducing inflammation and that the ASI complex is more effective than a combination of the individual ingredients. ASI may also be of physiological benefit to athletes and fitness enthusiasts concerned with joint health and inflammation and to those experiencing joint pain due to inflammation.

Support or Funding Information

Funding for this study was provided by Nutrition 21, LLC (Purchase, NY, USA) through a restricted grant.
Comparison of the Predictive Ability of an Empirical and a Literature‐derived Index of Dietary Inflammation Potential
Authors: Tabung Fred K. , Smith‐Warner Stephanie A. , Chavarro Jorge E. , Fung Teresa T. , Hu Frank B. , Willett Walter C. , Giovannucci Edward L.
Published: November 2023

Background

Inflammation plays an important role in the development of many chronic diseases and dietary factors can modulate inflammation. An empirical dietary inflammatory pattern (EDIP) comprised of food groups as reported on a food frequency questionnaire (FFQ) and a literature‐derived dietary inflammatory index (DII) comprised mainly of nutrients, exist to describe dietary inflammation potential.

Objective

To compare the ability of the EDIP and DII in predicting levels of inflammation markers in two cohorts.

Design

Both EDIP and DII scores were calculated from FFQ data reported by 5826 women in the Nurses' Health Study‐II and 5227 men in the Health Professionals Follow‐up Study. We used multivariable‐adjusted linear regression analyses to calculate relative concentrations of four plasma inflammation markers: C‐reactive protein (CRP), interleukin‐6 (IL6), tumor necrosis factor alpha receptor 2 (TNFαR2) and adiponectin across quintiles of the dietary indices.

Results

Correlations between the EDIP and DII scores were modest (Spearman r=0.28, women; 0.23, men; all P<0.0001). In both women and men, higher index scores were associated with higher (lower for adiponectin) concentrations of inflammation markers, except for no association between DII and adiponectin in men. EDIP scores explained a higher proportion of variance in biomarker concentrations and with associations of higher magnitudes compared to DII scores except for IL6 in men; e.g., in EDIP quintile 5, the percent change in relative concentrations of biomarkers was: CRP, +23.2%; IL6, +2.4%; TNFαR2, +0.1%; and adiponectin, +13.9% higher compared to DII quintile 5 in women; and CRP, +5.8%; IL6, −9.7%; TNFαR2, +1.9%; and adiponectin, +9.1% higher in men.

Conclusion

Despite design differences, the EDIP and DII both assess dietary inflammation potential, with the EDIP showing a higher ability to predict concentrations of plasma inflammation markers in these cohorts. Both indices may be useful in predicting inflammation‐mediated diet‐disease associations.

Support or Funding Information

Drs. Fred K. Tabung, Jorge E. Chavarro and Frank B. Hu were supported by National Institutes of Health (NIH) grants K99 CA207736, P30 DK046200 and U54 CA155426 respectively. The HPFS and NHS‐II cohorts are supported by NIH grants: UM1 CA167552 and UM1 CA176726, respectively
Diet Quality Indexes and Colorectal Cancer Risk: the Multiethnic Cohort Study
Authors: Park Song‐Yi , Boushey Carol , Wilkens Lynne , Haiman Christopher , Le Marchand Loïc
Published: November 2023

Healthy eating patterns assessed by diet quality indexes have been related to lower risk of colorectal cancer. Previous studies have been performed mostly among whites. We investigated the associations between four diet quality indexes, the Healthy Eating Index 2010 (HEI‐2010), the Alternative Healthy Eating Index 2010 (AHEI‐2010), the alternate Mediterranean diet (aMED) score, and the Dietary Approaches to Stop Hypertension (DASH) score, and colorectal cancer risk in a multiethnic population. We performed a prospective analysis using data from 190,949 adults aged 45–75 years who enrolled the Multiethnic Cohort Study by completing a self‐administered questionnaire in 1993–1996. Participants were African Americans, Native Hawaiians, Japanese Americans, Latinos and whites living in Hawaii and California. During an average 16 years of follow‐up, 4,770 invasive colorectal cancer cases were identified. Cox proportional hazards models were used to compute hazard ratios (HRs) and 95% confidence intervals (95% CIs). Both in men and women, all four scores were inversely associated with risk of colorectal cancer adjusting for age and race/ethnicity in a dose‐dependent manner. In multivariate models, further adjustment for covariates slightly weakened the associations, especially in women, and the associations with the AHEI‐2010 and aMED score were no longer statistically significant. Tests for heterogeneity did not show statistically significant differences in the associations between men and women (P's for heterogeneity > 0.13). In men, the risk reductions were greater for the HEI‐2010 (HR=0.69, 95% CI: 0.59–0.80 for quintile 5 vs. 1), AHEI‐2010 (HR=0.75, 95% CI: 0.65–0.85), and DASH score (HR=0.75, 95% CI: 0.66–0.86) than for the aMED score (HR=0.84, 95% CI: 0.73–0.97). Associations were stronger for the left colon and rectum than for the right colon for all indexes. The inverse associations were less strong in African Americans than in the other four racial/ethnic groups for all four indexes. Our findings support that high diet quality is associated with a lower risk of colorectal cancer in most racial/ethnic subgroups.

Support or Funding Information

This work was supported by the National Institutes of Health (U01 CA164973, NCI HHSN261201200423P, P30 CA071789).
Potential Roles of Lutein in Mammary Gland Development and Breast Cancer Cell Growth
Authors: Yuan Yan , Harrison Earl
Published: November 2023

Breast cancer is the most common form of malignancy and the second leading cause of cancer mortality in women. The most recent epidemiological studies have shown an inverse relationship between the blood lutein concentration and breast cancer risk, particularly for estrogen receptor negative (ER−) tumors. However, it is currently unclear whether it is the lutein itself, or a metabolite of lutein that plays a role in breast tissue protection, or whether lutein is a biomarker of another exposure. To better understand the impact of dietary lutein on breast development, we performed an in vivo feeding study by using a modified AIN‐93G diet, to which lutein was added at a concentration of 0.01%. C57/BL6 virgin female mice were fed with diets with or without lutein supplementation. Plasma, mammary gland, and liver were collected after 5, 10, and 15 weeks of feeding. Plasma lutein levels were determined by HPLC. Whole mount staining and immunohistochemistry (IHC) analyses were conducted to evaluate the development of mammary glands. To investigate the function of lutein on breast cancer risk, we also performed an in vitro study by using both ER+ and ER− human breast cancer cell lines (T47D, SKBR3, ZR‐751, MCF7, MDA‐MB‐231) treated with 10 uM lutein, or 10 uM β‐carotene, and assessed cell growth with MTT assay. Whole mount staining and IHC showed no difference in proliferation and branching of the glands between two dietary groups. Our in vitro studies showed there was no significant effect of lutein on cell growth, in contrast to β‐carotene which led to a 30% decrease in cell growth. Thus, the association between plasma lutein and breast cancer risk may result from lutein being a biomarker of vegetable intake, or a marker of other phytochemicals, and not a direct effect of lutein itself.

Support or Funding Information

NIH Grant R01‐HL49879
The Unfolded Protein Response Regulates Pancratic Neuroendocrine Tumor Growth
Authors: Oakes Scott A. , Qi Jenny Y. , Moore Paul C , Warren Rachel A. , Thamsen Maike , Ghosh Rajarshi , Gliedt Micah J. , Maly Dustin J. , Backes Bradley J , Papa Feroz R.
Published: November 2023

The Unfolded Protein Response (UPR) is an intracellular signaling pathway that communicates the protein folding status of the endoplasmic reticulum (ER) to the nucleus to maintain ER homeostasis. Hypoxia, nutrient deprivation, proteasome dysfunction, sustained demands on the secretory pathway or somatic mutations in its client proteins‐‐conditions often encountered by cancer cells—can lead to the accumulation of misfolded proteins in the ER and cause “ER stress.” However, the precise role of UPR signaling in the development and maintenance of cancer remains controversial. We reasoned that pancreatic neuroendocrine tumors (PanNETs) might be one class of solid tumor that may be particularly sensitive to protein folding stress due to their high secretory activity.

The Master UPR regulator IRE1 (Inositol requiring enzyme 1 alpha) is an ER transmembrane kinase/endoribonuclease (RNase) that acts as a critical life‐death switch depending on the level of ER stress. We analyzed primary human PanNET samples for activation of UPR components and found strong evidence of ER stress and IRE1 hyperactivation in this tumor type. We used a variety of chemical‐genetic tools to selectively manipulate IRE1's homeostatic and apoptotic outputs in a PanNET xenograft model and found that the precise balance of IRE1 signaling is critical for tumor growth in vivo. Disrupting this balance by pushing the pathway in either direction is detrimental to PanNET growth and survival. Moreover, targeting IRE1 with highly selective small molecules in a preclinical mouse model phenocopied the results of genetic manipulation. Our results indicate that IRE1 is an important regulator of PanNET cell survival and growth and provide a strong rationale for therapeutically targeting this kinase/RNase in PanNETs and other cancers that experience high levels of ER stress.

Support or Funding Information

This work was supported by an American Cancer Society Research Scholar Award, American Association for Cancer Research‐Caring for Carcinoid Foundation Award, Harrington Discovery Institute Scholar‐Innovator Award, and the National Institutes of Health: R01CA136577, R01DK095306, U01DK108332.
Targeting debris‐stimulated angiogenesis and primary tumor growth by resolvin mediated clearance
Authors: Chang Jaimie , Gilligan Molly , Sulciner Megan , Huang Sui , Kieran Mark , Serhan Charles , Panigrahy Dipak
Published: November 2023

Background

Standard cancer therapy reduces tumor burden by killing tumor cells, yet simultaneously creates tumor cell debris and associated inflammation in the tumor microenvironment. Thus, cancer therapy is inherently a double‐edged sword. Since tumor growth is angiogenesis‐dependent, we hypothesize that the accumulation of chemotherapy‐generated debris, stimulates tumor growth via tumor angiogenesis. ω‐3 fatty acid‐derived lipid autacoids termed ‘Specialized pro‐resolving mediators’ (SPMs), including resolvins, stimulate the resolution of inflammation by activating macrophage clearance of cell debris and promote wound healing and regeneration. While SPMs inhibit VEGFA‐mediated corneal and retinal neovascularization, the role of SPMs in tumor angiogenesis had not been studied to date. Thus, resolvins may represent a novel therapeutic approach to cancer through inhibition of tumor angiogenesis.

Results

Here, we show that co‐injecting tumor debris generated by the chemotherapeutic agent 5‐Fluorouracil (5‐FU), with living murine colon carcinoma (CT26) cells stimulated tumor growth in a dose‐dependent manner up to 100‐fold. In contrast, tumor cell debris alone did not produce any visible tumors, even at 100 days post‐injection. Next, we titrated the number of living tumor cells to a fixed quantity of 5‐FU‐generated tumor cell debris. The presence of debris promoted CT26 tumor growth even at an inoculum of 1×102 or 1×103 living tumor cells, which do not result in a visible tumor when injected alone, even at 150 days post‐injection. Tumor cell debris stimulated angiogenesis in a matrigel plug assay as measured by increased infiltration of CD31+ endothelial cells via flow cytometry analysis. 5‐FU‐generated debris also stimulated macrophage production of the pro‐angiogenic factors, MIP‐1α, serpin E1, and osteopontin. We also detected increased osteopontin levels in the plasma of mice bearing debris‐stimulated tumors compared to mice injected with living tumor cells alone. Systemic administration of resolvins inhibited primary growth of human colon xenografts (CCL‐188) via reduced microvessel density (as measured by CD31+ endothelial cells). Resolvins also stimulated macrophage phagocytosis of tumor cell debris.

Conclusions

We show that chemotherapy‐generated tumor cell debris stimulates tumor angiogenesis and primary tumor growth. Stimulating the clearance of tumor cell debris via SPMs, such as resolvins, represents a novel approach to preventing tumor growth and progression by inhibiting tumor angiogenesis.

Support or Funding Information

R01‐170549
The effect on the content of Nogo‐A in the damage area of the rats brain with Fasudil after traumatic brain injury
Authors: Duan Hubin , Hao Chunyan , Liu Cuiming , Li Shuzhen , Gao Ling , Zheng Xiaojun
Published: November 2023

Objective

To explore the nerve regeneration mechanism after traumatic brain injury (TBI) by detecting the content of the Nogo‐A in the damage area of the rats brain and the intervention experiment with Fasudil after traumatic brain injury.

Methods

The rats model with TBI was prepare by Feeney's methods. 45 male SD rats were randomly divided into Sham operation group(Sham group), traumatic brain injury group (TBI group) and Fasudil treatment group(F group). Fasudil treatment group rats were immediately given Fasudil (9mg/kg, Qd) after TBI for 3 days. Immunohistochemistry measurement was used to detect the content of the Nogo‐A in the damage area of the rats brain. Using electron microscope to observe the ultrastructure changes of the damage area and the surrounding tissue in each group.

Results

Nuclei deformation, shrivel and irregular were observed in the cells of damage area of the TBI group and F group rats brain. Scattered nucleoli, increased chromatin, mitochondria scattered distribution, edema, mitochondrial crest disappear were also observed in above cells. Furthermore, these phenomena in TBI group rats brain were more serious than F group rats brain. There are significant difference among the Nogo‐A protein content in the damage area of rats brain tissue in Sham group, TBI group and F group (P<0.05). The Nogo‐A protein content in TBI group is the highest and the one in Sham group is lowest(P<0.05).

Conclusion

Craniocerebral trauma can cause brain damage, including the nucleus, mitochondria and other structural damage, cell edema, NOGO ‐ A content increased, which inhibite the nerve regeneration. Fasudil can block the Rho/ROCK signaling pathways, dilate cerebrovascular, increase the blood flow in the cerebrovascular, and promote nerve regeneration and functional recovery.

Support or Funding Information

This study was supported by the National Natural Science Foundation Youth (Fund No.30600637), China Postdoctral Foundation (Fund No.2014M561207), Research Project Supported by Shanxi Scholarship Council of China(Fund No. 2011‐096 and Key projects No.4)
Autoantigen‐specific T and B Cell Cross‐reactivity to a Gut Commensal in Antiphospholipid Syndrome
Authors: Dehner Carina Anja , Ruff William , Vieira Silvio Manfredo , Goodman Andrew , Kriegel Martin Alexander
Published: November 2023

The microbiota provides an enormous antigenic challenge to the adaptive immune system. We hypothesized that a homeostatic adaptive immune response to commensals can trigger and sustain autoreactive T and B cells via cross‐reactivity with autoantigens in an HLA‐susceptible host. We used antiphospholipid syndrome (APS), an autoimmune clotting disorder targeting the plasma protein b2‐glycoprotein I (b2GPI), as a human model.

Protein BLAST and Clustal Omega queries revealed that the human gut commensal Roseburia intestinalis contains peptide sequences with high homology to the immunodominant b2GPI T and B cell epitopes. Patient PBMCs proliferated significantly more to R. intestinalis protein extracts compared to phylogenetically closely related Eubacterium rectale, which lacks homologous sequences. We next established a MHCII tetramer for a major pathogenic T cell epitope in domain V of b2GPI, which shares a highly homologous region with an unrelated R. intestinalis protein. Sorting on tetramer‐positive CD4 memory T cells, we sought to determine if clones cross‐react with R. intestinalis proteins and peptides. Tetramer‐positive T cells proliferated significantly more to heat‐killed whole R. intestinalis bacteria in a dose‐responsive manner compared to controls. Cytokine measurements revealed a heterogeneous but pathogen‐associated phenotype. Tetramer positive clones showed an increase in GM‐CSF, TNF‐α IL‐9, IL‐13, and IL‐21.

To demonstrate cross‐reactivity functionally in vivo, BALB/c mice were immunized with whole heat‐killed R. intestinalis and proliferation studies using splenocytes and lymphocytes were performed. Lymphocytes from draining lymph nodes and splenocytes showed significant proliferation in response to b2GPI compared to littermate mice immunized with adjuvant alone. Furthermore, ELISA revealed significant anti‐b2GPI titers in 1 of 3 R. intestinalis‐immunized animals compared to controls. In vitro, immunoblotting using APS patient plasma and an RGGMR epitope‐specific monoclonal antibody showed strong reactivity with R. intestinalis proteins including one at 24 kDa at the size of the major mimic‐containing candidate protein.

In summary, we have identified human epitope‐specific b2GPI‐reactive CD4 memory T cell clones, which have a pathogen‐associated phenotype and cross‐react to whole heat‐killed R. intestinalis. Additionally, immunization of BALB/c mice with R. intestinalis produces human b2GPI‐reactive lymphocytes and autoantibodies, the latter are also supported in vitro by an epitope‐specific monoclonal anti‐human b2GPI antibody binding to R. intestinalis protein. To our knowledge this work represents the first study to demonstrate b2GPI‐specific T and B cell cross‐reactivity to a common human‐commensal bacterium. Further studies to determine the R. intestinalis proteins and epitopes recognized by the patients' adaptive immune system are ongoing.

Support or Funding Information

NIH/NIAID
Unlocking the Skull: New Views into the Anatomy of Olfaction and Respiration in Mammals
Authors: Van Valkenburgh Blaire
Published: November 2023

The combination of high resolution CT scanning and complex 3D visualization software has opened a new window into skull anatomy. Two formerly cryptic but now readily visible structures are the complex nasal turbinal bones and cribriform plate (CP). Anteriorly, the maxilloturbinals function in respiration as an expanded surface area for conditioning inspired air and reducing heat and water loss. Above and posterior to them are the naso‐ and ethmoturbinals, respectively, both of which function in olfaction. The bony CP separates the nasal cavity from the brain. Using a comparative approach, we have explored quantitative variation in the size and architecture of the turbinals and the associated cribriform plate in relation to function in mammals both within and among species. For example, marine mammals are expected to have enlarged maxilloturbinals and enhanced respiratory surface area (SA) relative to terrestrial mammals in response to greater demands for heat and water conservation. Comparisons of maxilloturbinal SA in aquatic and terrestrial species in four carnivoran families supported this hypothesis and showed that the enlarged maxilloturbinals of the aquatic species (both freshwater and marine) are associated with a marked reduction in ethmoturbinals. In a related study, we analyzed maxilloturbinal SA variation within a single species of deer mouse, Peromyscus maniculatus, that is known to exhibit physiological adaptations to living at high altitudes. Our prediction was that high altitude individuals should exhibit expanded maxilloturbinals relative to individuals from low altitudes, due to their known higher ventilation rates and the cooler, drier climate. The prediction was upheld and is perhaps the first example of intraspecific variation in turbinal morphology in response to differences in habitat. Our studies of osteological correlates of olfaction have also revealed the imprint of ecology. Marine carnivorans that forage under water exhibit greatly reduced ethmoturbinals relative to terrestrial species. Similarly, felids have relatively smaller ethmoturbinals than canids, and are thought to rely more on vision and hearing and less on olfaction when foraging. Recently, we have explored the association between olfactory receptor (OR) gene number and cribriform plate (CP) size across Mammalia. Positioned between the olfactory bulb and the olfactory turbinals, the CP is traversed by olfactory nerves and its SA is positively correlated with ethmoturbinal SA. Moreover, across 26 mammal species, CP size is highly correlated with the number of functional OR genes. Because the CP is likely to be better preserved in fossils than turbinals, CP size could be used to infer OR number in extinct species and provide insights into the evolution of olfactory function.
Adherens junctions, force‐sensing, and epithelial homeostasis
Authors: Yap Alpha
Published: November 2023

Cadherin‐based cell‐cell junctions play central roles in epithelial morphogenesis and homeostasis. Major advances in the cell biology of adherens junctions have come from understanding how they integrate adhesion with cytoskeletal activity and cell signaling. Recently, the realization that adherens junctions are mechanically‐active structures, which generate and sense force, has provided an encompassing model to investigate the role that they play in epithelial tissues. In this talk, I will discuss some of our ongoing work to characterize mechanochemical signaling at AJ and how junctional tension‐sensing participates in epithelial homeostasis, with a focus on apoptotic cell extrusion.
Guitarfishes in Rocks of All Ages
Authors: Claeson Kerin M. , Underwood Charlie
Published: November 2023

The Batoidea (rays, skates and guitarfishes) comprise over half of living chondrichthyans, and presently inhabit virtually all marine, and some freshwater, environments. An extremely morphologically and ecologically disparate clade, all of its major lineages are known, or predicted, to have appeared prior to the end of the Cretaceous and as early as the Jurassic. Little study has been carried out on the affinities of Jurassic batoids, despite their key role in understanding batoid evolution. Although fossil chondrichthyans are known largely from isolated teeth, several species of batoids are known from the Late Jurassic on the basis of well preserved skeletons within lägerstatten. These Jurassic forms are morphologically conservative and all fit within the “guitarfish” or “rhinobatid” body plan. Modern “guitarfish” are now recognized as a polyphyletic group sharing a primitive body shape, but it is unclear whether the Jurassic taxa belong within one or more of the extant clades, would form a basal sister clade to crown Batoidea, or represent a paraphyletic group of stem batoids. The discovery of two incomplete but exceptionally well preserved batoid specimens from the Kimmeridge Clay Formation (Kimmeridgian to Lower Tithonian) of Kimmeridge, southern England represent the first examples of batoid skeletons from Britain, and also the first from offshore mudstone facies. These specimens represent a previously unknown taxon and have allowed the phylogenetic position of Late Jurassic batoids to be investigated along side the extant members of Batoidea. Preliminary phylogenetic analyses indicate Jurassic batoids are not the same as modern ‘rhinobatoids’ while Cretaceous batoid skeletons do resemble modern ‘rhinobatoids.’ However, neither the Jurassic nor Cretaceous batoids lend support to a monophyletic Rhinobatidae.
Retrieval Practice is a Superior Method for Learning Anatomy and Physiology Information
Authors: Dobson John
Published: November 2023

Retrieval practice is a learning strategy that was developed by cognitive scientists and is based on the act of recalling information after exposure. Although dozens of studies have demonstrated meaningful learning advantages with retrieval practice, most educators and students are not familiar with the strategy. The purpose of this presentation is to share five studies in which our lab found that retrieval practice resulted in superior learning when compared to more commonly‐used strategies such as reading/rereading. These advantages included superior recall and a greater ability to synthesize complex information that is typically found in anatomy & physiology, structural kinesiology and exercise physiology courses.

Support or Funding Information

None
Modeling human lumbar spinal osteoarthritis and low back pain through preclinical studies
Authors: Little Joshua W
Published: November 2023

Low back pain (LBP) is a prevalent condition and the primary cause for global disability. This is likely a result, in part, of poor pain management that stems from a lack of understanding of the pathophysiological mechanisms that contribute to this complex condition. To better understand the underlying mechanisms of LBP, we use preclinical animal pain models to mimic the human condition and examine the neurobiological processes induced from spine‐related tissues that contribute to pain. We are currently investigating two common causes for LBP, lumbar facet joint degeneration and muscle pain. Facet joint degeneration that is consistent with spinal osteoarthritis (OA) has distinctive patterns of histopathological findings. We wanted to determine if a rat model of lumbar vertebral segmental hypomobility induces degeneration that replicates these characteristic findings to mimic spinal OA. We performed time‐dependent investigations to determine the location, severity, and progression of histopathological changes to the articular cartilage following the onset of hypomobility. Our findings suggest that lumbar spine hypomobility induces facet joint histopathological changes that mimic spinal OA histopathology, location (patterning), and progression. We have also identified the potential contribution of adjacent joint tissues including the synovium, capsule, and subchondral bone in the onset and progression of OA. The low back muscles are also a clinically relevant source of LBP. We are investigating a rat model to mimic chronic low back muscle pain (LBPm) using nerve growth factor (NGF), a critical regulator of pain signaling and essential to muscle pain including LBPm. Repeated lumbar paraspinal intramuscular NGF injections in rats induce prolonged pain behavioral responses (e.g., paraspinal mechanical hyperalgesia) and enhanced response profiles of dorsal horn nociceptive neurons. These findings are consistent with central (spinal) sensitization, a pathophysiological state implicated in chronic pain. Central sensitization is associated with a glial cell mediated inflammatory process called neuroimmune activation, which is defined experimentally as glial cell hyperactivation with the release of proinflammatory cytokines. We hypothesized that repeated NGF paraspinal muscle injections contribute to persistent mechanical hyperalgesia and central sensitization, in part, through spinal cord neuroimmune activation. Our time course studies revealed that the development of NGF induced LBPm is associated with lumbar spinal cord dorsal horn microglial hyperactivation; suggesting that neuroimmune activation contributes to LBPm. Collectively, these models are promising and may provide a better mechanistic understanding to develop therapeutic approaches that offer meaningful LBP relief.

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SLU Center for Neuroscience and NCMIC
Are Early Eocene Asiadapid Primates Primitive or Derived? Implications for Behavior and Morphology of the Ancestral Euprimate
Authors: Dunn Rachel
Published: November 2023

The oldest known primates of modern aspect (euprimates) appear at the beginning of the Eocene across the Holarctic. At the time of their appearance they are already clearly divided into two distinct clades: Adapoidea (basal members of Strepsirrhini, lemurs, lorises, and bushbabies) and Omomyidae (basal Haplorhini, tarsiers, monkeys, and apes). However, postcranial remains from these earliest euprimates are rare and fragmentary, and most of our knowledge of postcranial adaptations within euprimate groups is based on younger, more derived fossils, which show postcranial specializations for leaping. This evidence has led researchers to suggest that leaping played a key role in the evolution of euprimates as a clade. Fossil adapoids (family Asiadapidae) and omomyids (the genus Vastanomys) from the early Eocene of India are among the earliest fossil euprimates for which well‐preserved postcrania are known, making them ideal for addressing the question of the ancestral euprimate locomotor mode. These early euprimates are represented mostly by teeth and jaws that clearly place them within adapodiea or omomyidae, but the isolated postcranial elements are unique in showing little specialization for leaping. While it is generally accepted that the Indian primate postcrania lack derived traits seen in younger fossils, there is disagreement about whether the lack of specialization in asiadapids, specifically, reflects the ancestral euprimate condition or represents a reversal from a more specialized leaping ancestor. This talk reviews functional and comparative analyses of the Indian primate postcrania in a phylogenetic context to assess whether asiadapid morphology is likely due to plesiomorphy or homoplasy. The assertion that the non‐specialized morphology in asiadapids is due to homoplasy requires assumptions that are not well supported by the fossil record (that asiadapids evolved from a large‐bodied ancestor) and that reversals occur in body size and across the skeleton in both asiadapids and Vastanomys; however, it is consistent with previous conceptions of the ancestral euprimate as a specialized leaper. If asiadapids are considered to represent an ancestral morphology, this would suggest that the ancestral euprimate was small, and that the early divergence of strepsirhines and haplorhines was driven by differences in hind‐limb behaviors, both of which are supported by our current knowledge of the fossil record. However, this scenario suggests that the ancestral euprimate was a generalized arboreal quadruped, rather than a specialized leaper, which necessitates an alternative explanation for the evolution of traits uniting euprimates.

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National Geographic Society, Leakey Foundation, Belgian Science Policy Office, Wadia Institute of Himalayan Geology
Paleontological and Developmental Evidence for the Origin of Baleen and the Loss of Teeth in Baleen Whales
Authors: Thewissen J. G. M. , Hieronymus Tobin L. , George John C. , Suydam Robert , Stimmelmayr Raphaela , McBurney Denise
Published: November 2023

Postnatally, modern baleen whales do not have teeth. Instead, they have hundreds of baleen plates implanted in their upper jaw, and this system is used in procuring food. Fetal baleen whales do initiate the development of several dozens of teeth in upper and lower jaws. These tooth germs reach the bell stage and are sometimes mineralized, but toward the end of prenatal life, they are resorbed and no trace remains after birth. Around the time that the germs disappear, the baleen plates start to form in the upper jaw. Early cetaceans, so called archaeocetes, had two generations of teeth and were heterodont. The prenatal teeth of modern baleen whale fetuses are usually interpreted as an evolutionary left‐over. We investigated the development of teeth and baleen in bowhead whale fetuses using histological and immunohistochemical methods. We found that upper and lower dentition initially follow similar developmental pathways. As development proceeds, upper and lower tooth germs diverge developmentally. Lower tooth germs differ along the length of the jaw, reminiscent of a heterodont dentition of cetacean ancestors, and lingual processes of the dental lamina represent initiation of tooth bud formation of replacement teeth. Upper tooth germs remain homodont and there is no evidence of a secondary dentition. After these germs disappear, the oral epithelium thickens to form the baleen plates, and the protein FGF‐4 displays a signaling pattern that foreshadows the placement of baleen plates. In laboratory mammals, FGF‐4 is not involved in the formation of hair or palatal rugae, but it is involved in tooth development. This leads us to propose that the signaling cascade that forms teeth in most mammals has been exapted to be involved in baleen plate ontogeny in mysticetes.
X‐Ray Computed Tomography Reveals Hidden Morphology in an Extinct Mammalian Relative
Authors: Wallace Rachel Veronica Simon
Published: November 2023

High Resolution X‐ray computed tomography is commonly used to study internal structures of fossil skulls. CT allows inference about the structure of brain surface morphology, the inner ear, and internal bony elements such as turbinates. Computed tomography data is frequently published in figures as isosurface renderings of either the segmented endocranial volume or of the surface of the specimen. Here I demonstrate how CT improves upon superficial anatomical understanding of fossils in a Late Triassic early mammal relative from the Ischigualasto Formation in Argentina. When the specimen, PVSJ 882, was first discovered and initially described, it was assumed to be closely related to mammals on account of the perceived absence of two circumorbital bones, the prefrontal and postorbital. It was not until the specimen could be viewed non‐destructively in cross section that the prefrontal and postorbital were identified to be present. However, other derived early mammalian features grew apparent, including a fusion of the prootic and opisthotic to form the petrosal, as well as cochlea housed within a bony promontorium. The discovery of primitive orbital elements in a specimen with such a derived ear is new to mammal paleontology. The superficial morphology of other derived mammal relatives is encouraged to be studied with CT. Furthermore, I demonstrate how adjusted volume renderings can more accurately communicate the morphology of the specimen in question, while isosurfaces can be misleading for the same reasons that photos of the specimen in rock matrix can be misleading. While isosurface renderings have advantages in figures depicting CT data, they should not be used to the exclusion of volume renderings when volume renderings can depict subtle sutures, unprepared foramina, and deep, delicate bone buried under rock matrix.

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The Jackson School of Geosciences at the University of Texas at Austin
Fracture Property Experimentation On Hadrosaurid Dinosaur Wavy Enamel Reveals Energy‐Robbing Crack Deflection and Channeling To Localize Damage: A Rare Case of Mammalian‐Like Dental Sophistication In Reptiles
Authors: Erickson Gregory M , Kuhn‐Hendricks Stephen M , Krick Brandon A
Published: November 2023

Reptiles rarely approached the biomechanical sophistication of feeding or dietary diversity seen in mammals. Their teeth are typically non‐occluding, semi‐conical structures with simplistic parallel‐crystalite enamel surrounding an orthodentine core. Conversely, most mammals possess multi‐cusped teeth that are drawn across one another during mastication and self‐wear to their functional morphology. Mammalian enamel is complex ‐‐ a fiberglass‐like composite composed of bundles of hydroxyapatite crystals known as prims, surrounded by compliant proteinacous sheaths. Among the most sophisticated prism architectures is the modified radial enamel (MRE) of grazing ungulates whose coarse tooth surfaces enable grinding of tough, abrasive‐laden plant matter. MRE conveys exceptional fracture toughness and controlled fracture propagation minimizing damage to the brittle enamel crests. Hadrosaurid (duck‐billed dinosaurs) are notable in independently evolving self‐wearing grinding dentitions and complex wavy enamel (WE) composed of folded layers of hydroxyapatite crystals whose biomechanical import is unknown. We tested the hypothesis that WE served an analogous role to ungulate MRE by: 1) tribologically modeling the effects on hadrosaurid occlusal surfaces should a section of enamel become fractured; 2) introducing enamel fractures to the teeth of hadrosaurids, outgroups lacking WE, and horses and bison using Vickers‐tipped indenters; 3) testing for controlled‐crack propagation using Watson's Two‐Sample Test of Homogeneity; and 4) contrasting the results in comparative ecological contexts. Removal of enamel sections leads to aberrant self‐wear to hadrosaurid chewing pavements (= “wave mouth” in equine veterinary science) inhibiting functionality. Non‐WE enamels show isotropic fracturing and catastrophic damage to the enamel shells. WE and MRE three‐dimensionally limit damage in enamel crests through energy‐robbing crack deflection at kinks in the enamel fabrics or prism boundaries and channeling perpendicular to the enamel‐dentine junction. Hadrosaurid WE represents an alternative reptilian solution for damage resistance in grazing taxa, one that evolved millions of years earlier than in mammalian ungulates. Our findings add to a growing body of evidence that material properties are preserved in fossil teeth and can be used to explore dental form and function throughout the fossil record and to develop biologically‐inspired industrial materials.

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NSF EAR 0959029 awarded to GME