bluuebunny/crossref_metadata_2025 huggingface dataset:
Sensory innervation of the rat hind paw: morphometric comparison between sural and saphenous nerves.
Authors: Silva Letícia Oliveira Nery , Campos Stella Andrade Rodrigues , Sanada Luciana Sayuri , Fazan Valéria Paula Sassoli
Published: June 2021

Previous studies on dermatome mappings of the rat hind paws investigated the C‐fibers distribution and then assumed that the A‐fibers distributions resemble that of the C‐fibers. We investigated the morphometry of fascicles and myelinated fibers (A‐fibers) in the sural and saphenous nerves in young rats. Six 30‐day‐old female Wistar rats had their right and left sural and saphenous nerves prepared for light microscopy and morphometry. Comparisons were made between segments (proximal vs distal) and sides (left vs right) for the same nerves and between nerves (sural vs saphenous) from the same side and differences were considered if p<0.05. Both the sural and saphenous nerves are longitudinally symmetrical on both sides. Both nerves also exhibited lateral symmetry. Also, no significant differences were found between nerves. Myelinated fibers and respective axons diameter, as the G ratio histograms are unimodal in both nerves, regardless of segments or sides. This indicates that the nerves investigated did not reach fully development in animals aged 30 days. The similar number of myelinated fibers, associated with their similar size in both sural and saphenous nerves suggests that the innervation territory for both nerves is equally distributed at the foot. This information is useful for studies of sensory neuropathies, in particular, studies of nerve regeneration.
The influence of locomotion and modularity on craniocaudal patterns of vertebral growth
Authors: Jones Katrina E , German Rebecca
Published: June 2021

Heterochrony (i.e., changes in the rate or timing of growth) is important in evolution of the adult phenotype. However, very little is known about the growth of the vertebral column. The objective of this project is to quantify craniocaudal growth patterns in the thoracolumbar spine using longitudinal data. We examine the influence of locomotion by comparing growth between generalist, quadrupedal mammals and those with a convergently‐acquired, half‐bound gait that emphasizes sagittal extensions of the spine. Lateral x‐rays of 38 specimens from two specialized (Oryctolagus cuniculus and Chinchilla lanigera) and two non‐specialized (Cavia porcellus and Monodelphys domestica) species of similar size were the source of centrum length measurements on individual vertebrae. The same individuals were radiographed soon after birth and again at adult size using a repeated measurements design. Data show a craniocaudal increase in both absolute growth and interspecific variability that coincides with developmental and functional modules of the spine. Half bounders have increased lumbar growth relative to non‐specialists, resulting in a larger craniocaudal growth gradient in these taxa. These results indicate that growth patterns are correlated with locomotor behavior resulting in both intra‐ (serial) and interspecific heterochronies in the vertebral column.

Grant Funding Source: NA
Deubiquitinases as a signaling target of oxidative stress
Authors: Huang Tony T
Published: June 2021

Deubiquitinating enzymes (DUBs) constitute a large family of cysteine proteases that have broad impact on numerous biological and pathological processes, including the regulation of genomic stability. DUBs are often assembled onto multiprotein complexes to assist in their localization and substrate selection, yet it remains unclear how the enzymatic activity of DUBs is modulated by intracellular signals. Herein, we show that bursts of reactive oxygen species (ROS) reversibly inactivate DUBs through the oxidation of the catalytic cysteine residue. Importantly, USP1, a key regulator of genomic stability, is reversibly inactivated upon oxidative stress. This, in part, explains the rapid nature of PCNA monoubiquitination‐dependent DNA damage tolerance in response to oxidative DNA damage in replicating cells. We propose that DUBs of the cysteine protease family act as ROS sensors in human cells and that ROS‐mediated DUB inactivation is a critical mechanism for fine‐tuning stress‐activated signaling pathways.
Form, function, and evolution of archosaur mandibular symphyses
Authors: Holliday Casey M
Published: June 2021

Archosaurs radiated into numerous trophic niches during their evolution, resulting in a diversity of cranial adaptations and feeding behaviors. The mandibular symphysis is a poorly understood cranial joint which may offer significant insight into cranial development and function, feeding ecology, and evolution in these vertebrates. We investigated the anatomy and evolution of archosaur symphyses with a focus on Alligator mississippiensis and crocodyliforms. Character complexes of extant and fossil species were identified and their evolution was traced using a current phylogeny of archosauriforms. During ontogeny, alligators rapidly develop a complex, interdigitated, Class III symphysis coupled with fused Meckel's cartilages. Major iterative transitions from plesiomorphic Class I to derived, rigid Class II–IV symphyses and beaks occurred along the lines to phytosaurs, aetosaurs, poposauroids, crocodyliforms, pterosaurs, ornithischians, and birds. These transitions in symphyseal morphology appear to correlate with changes in function, the origin of beaks, and potentially inferred diet.

Grant Funding Source: n/a
The Role of CSF1 in Hepatocellular Carcinoma‐Recruited Macrophages
Authors: Dougherty Grace , Duncan Michael B. , Rohlman Christopher E. , Rehman Abdul , Thakur Priyanki
Published: June 2021

Hepatocellular carcinoma (HCC) is the most common form of liver cancer and it is clear that local tissue microenvironment plays a key role in its progression. Macrophages are suspected to effect tumor expansion and malignancy by promoting inflammatory responses and tissue remodeling. Colony stimulating factor (CSF1) has been shown to promote macrophage differentiation, survival and proliferation. Although CSF1 is highly expressed in liver, little is known about how CSF signaling impacts macrophages in HCC. We found that CSFR positive macrophages are located in hyperplastic non‐tumor and peri‐tumoral regions of a chemically induced murine HCC model. This expression mimics that seen in HCC specimens from human patients with a poor prognosis. We hypothesized that CSF1 derived from HCC cells promotes macrophage differentiation and viability. Murine bone marrow derived precursor cells were differentiated into macrophages using HCC conditioned culture media. Macrophages treated with a colony stimulating receptor small molecule inhibitor (CSFRi) exhibited altered morphology and decreased proliferation in vitro. Small molecule mediated inhibition of CSFR promoted a shift in macrophage polarization from M2 (pro‐tumor) to M1 (anti‐tumor). These findings suggest a critical role for HCC‐cell mediated CSF signaling in macrophage proliferation, viability, and polarization.
Sphingolipid metabolism modulates motor neuron degeneration in Drosophila
Authors: Sahoo Ishtapran , Hebbar Sarita , Osborne Kathleen Amy , Schwudke Dominik , Kraut Rachel Susan
Published: June 2021

We are interested in the involvement of sphingolipids in neurodegeneration in Drosophila. To look at this, we study animals deficient in Blue cheese, a BEACH domain protein involved in autophagy and lysosomal transport, and highly expressed in the nervous system. Blue cheese mutants exhibit shortened life span, extensive neuronal loss and accumulation of ubiquitinated proteins in the brain (Finley et al, 2003). The role of BEACH domain in the FAN protein, which triggers neutral sphingomyelinase activity (Segui et al, 1999), and the involvement of sphingolipids in various human neurodegenerative conditions (Cutler et al, 2002, 2004; Han et al, 2004), led us to hypothesize that blue cheese mutation could lead to degeneration by altering sphingolipid balance. We introduced mutations in the sphingolipid‐biosynthetic pathway into the blue cheese background to look for modification of the phenotype (motorneuron count). Lace (SPT) and slab (CDase) mutants and overexpressors in the background of the blue cheese mutation indeed modulated neuronal survival, in a way that suggests that ceramide availability in the brain is critical. Mass spectrometric quantification of sphingolipid levels in mutant larval brains show dysregulation of ceramides and changes in activation of putative ceramide‐regulated MAPK signaling pathway targets P‐Akt, P‐JNK and P‐MKK4, which may affect neuronal survival. Based on these sphingolipid changes and genetic interactions, we propose a possible mechanism whereby blue cheese may regulate sphingomyelinase and SPT, and act synergistically with ceramidase.

Research Grant: Biomedical Research Council (BMRC), A‐star, Singapore
Stromal galektin‐1 and myofibroblasts are reponsible for invasive behavior of the head and neck squamous cell carcinoma
Authors: Fik Zdenek , Valach Jarolsav , Smetana Karel , Strnad Hynek , Chovanec Martin , Gabius Hans Joachim
Published: June 2021

Cancer‐associated fibroblasts (CAFs) play a significant role in the cross‐talk between tumor storma and the tumor cells. CAFs frequently express smooth muscle actin and are capable to support the developement of invasive cancer cells, which are responsible for establishing of metastases.

We set the immunohistochemical presence of smooth muscle actin‐positive (SMA) CAFs in relation to galectin‐1. To pinpoint further correlations on the molecular level, microarray analyses was applied to the transcription profiles of the corresponding tumors, focusing on genes, representing poor prognosis for patient.

In the squamous cell carcinomas of head and neck, upregulation of galectin‐1 was significantly correlated to presence of SMA‐positive CAFs in the tumor. Significant correlations of several transcripts were detected in the tumor epithelium with the protein level of galectin‐1 in the CAFs (MAP3K2, SPIN1, etc.).

These results provide new insights into the significance of presence of myofibroblasts in squamous cell carcinoma and shows relationship between stromal reactivity and gene expression, associated with cancer progression directly in the samples of head and neck squamous carcinomas.

This work was supported by the project PRVOUK No. 27–1 and GAUK No. 291811 of the Charles university.
Maternal high fat diet programs gene expression of adipogenic transcription factors through regulating histone modifiers in a gender‐dependent manner
Authors: Zhou Dan , Wang Huan , Pan Yuan‐Xiang
Published: June 2021

Maternal high‐fat (MHF) diet projects long‐term physiological outcomes and leads to metabolic disorder in offspring. In our study, we determined epigenetic regulation of adipogenic transcription factors in fat tissue. Offspring were exposed to control or HF diet throughout gestation and suckling and fed with control diet afterweaning. The growth curve and food consumption of offspring were not affected by MHF. Transcription of adipogenic markers PPARγ and C/EBPα in fat tissue were measured by qPCR and showed decrease only in the female offspring. Chromatin immunoprecipitation showed that in female adipose tissue, trimethyl histone H3 K 27 increased significantly at the promoter and coding region, whereas trimethyl histone H3 K 36 were decreased at promoter of both PPARγ and C/EBPα in the MHF. Moreover, mRNA expression of SETD2, a histone H3 K 36 methyltransferase, and KDM6B, a histone H3 K 27 demethylase in the adipose of female offspring were repressed by MHF diet. The downstream genes, such as Glut4, IRS‐1 and PEPCK, were also reduced in the female by MHF. Therefore, we concluded that MHF environment increased susceptibility to metabolic disorder in female offspring potentially through programming the histone code of adipogenic factors and thus impairing adipocyte differentiation, insulin signaling transduction and fatty acid recycling in the fat tissue.
Coffee intake and cognitive functioning in men
Authors: Noel Sabrina , Manjourides Justin , Scott Tammy M. , Spiro Avron , Tucker Katherine L.
Published: June 2021

More than 50% of US adults consume coffee daily. Coffee contains antioxidants and other compounds that may be protective against age‐related cognitive decline. However, few longitudinal studies have investigated these associations. This study examined the up to 17‐y prospective association between coffee intake and cognitive function among 554 men aged 21–81 y, from the Veteran's Administration Normative Aging Study. Dietary intakes from food frequency questionnaires were assessed beginning in 1987 and cognitive data were assessed from 1993. Follow‐up questionnaires were given every 3–5 y. Coffee intake was calculated as an average of all reported intakes prior to the final cognitive measure. Multivariable linear regression models were adjusted for age, education, smoking, BMI, homocysteine concentration, baseline cognitive test, and time between cognitive measures. Each serving of total coffee (regular/decaffeinated) intake was associated with a 0.17 point higher Mini‐Mental State Examination (score range 0–30, P=0.028), but not with other cognitive tests. Total caffeine intake tended to be associated with cognitive functioning, but this did not reach significance (P=0.11). Greater coffee intake may be associated with less cognitive decline in men, as measured by global cognitive function, but this may be due to protective factors other than caffeine. Kraft Foods Global, Inc. supported this study.
Local concepts of infant illness among Mam‐Mayan women and impact on feeding practices: a qualitative study in the Western Highlands of Guatemala
Authors: Kincaid Mariah , Bermudez Odilia I. , Chomat Anne Marie , Escobar Marta , Garcia Maria , Garcia Rosario , Scott Marilyn E. , Koski Kristine G. , Solomons Noel W.
Published: June 2021

Objectives

To examine maternal beliefs regarding etiology, presentation and treatment of prevalent child illnesses in rural Mam‐Mayan Guatemalan communities.

Methods

9 pregnant and 9 early‐lactating women already enrolled in a concurrent maternal‐infant health study participated in semi‐structured, in‐depth interviews. Two focus groups were conducted with community women. All interviews were audio recorded, transcribed and analyzed with HyperResearch.

Findings

Most women ascribe infant parasitic, diarrheal and respiratory illnesses to a mix of local/culture‐bound and biomedical concepts of illness. Traditional herbs are routinely used to treat or prevent these conditions. Compliance with food requests made by the infant was mentioned as being protective against parasites, including during the first 6mo of life. Whereas “cold air” was associated with respiratory illness, specific foods considered “cold” in local narratives (fruits, chicken, avocado, potatoes) were associated with gastrointestinal illness.

Conclusions

Maternal beliefs about childhood illness influence infant feeding practices and may determine both exclusivity of breastfeeding during lactation and infant diet variety. Better comprehension is needed of how socio‐cultural realities impact health‐related behaviors and feeding practice outcomes.

Funding: TUSM, IDSA, ASTMH
California WIC: New Classification Criteria and WHO Growth References Alter Anthropometric Risk Estimates
Authors: Merchant Kathleen Marie , Tayag‐Cruz Norliza , Taylor Kelly
Published: June 2021

WIC California has recently switched (October 2012) from use of CDC Child Growth Curves to use of WHO Child Growth Curves in evaluating the growth of children under 2 years of age. Additionally, WIC California has changed the criteria for classification of anthropometric risks. The objective of this study is to examine changes in the prevalence of risk based on the new classifications and the use of WHO standards relative to the previous classifications and CDC references. Five categories of risk are defined, Underweight (UW), At‐risk‐of‐underweight (ARUW), High Weight‐for‐Length (HWL), Short Stature (SS), and At‐risk‐of‐short‐stature (ARSS). Using one month of child growth data collected at 11 WIC offices within San Diego County (n=8027), of children between 3 months and 21 months of age, the new and old classifications of risk were each calculated relative to WHO and relative to CDC. Comparisons were then made between incidence of the five risk types using Pre‐October criteria with CDC (OLD) and Post‐October criteria with WHO (NEW). For those classified as UW: OLD resulted in 1.27% (n=102) versus NEW 0.04% (n=3); ARUW: OLD 1.91% (n=153) vs. NEW 0.20% (n=16); HWL: CDC 7.75% (n=622)vs. WHO 6.98% (n=579); SS:OLD 9.63% (n=773) vs. NEW 2.84%(228); ARSS: CDC 2.69% (n=216) vs WHO 2.78 % (n=223). Changes in criteria as well as growth curves resulted in significant and meaningful shifts in risk classifications. Additionally, interesting patterns emerge by gender, ethnicity, and feeding choice. Funded by SDSURF/WIC.
Sodium and Potassium Intake among US Infants and Preschool Children, 2003–2010
Authors: Tian Niu , Zhang Zefeng , Loustalot Fleetwood , Yang Quanhe , Cogswell Mary E.
Published: June 2021

To estimate sodium and potassium intakes among U.S. infants and preschoolers, and to compare these estimates by race/ethnicity and breastfeeding status, we analyzed cross‐sectional survey data on 699 infants (7–11 months) and 4271 preschoolers (1–3 and 4–5 years) from the National Health and Nutrition Examination Survey 2003–2010. We assessed mean intakes and the prevalence of excess sodium and inadequate potassium intakes relative to the Institute of Medicine Dietary Reference Intakes, Tolerable Upper Intake Levels (UL) or Adequate Intake (AI), respectively, adjusting for sociodemographic and other characteristics. Overall, 79% (95% CI: 76.5%–81.5%) of preschoolers aged 1–3 years and 87% (95% CI: 84.3%–89.7%) aged 4–5 years exceeded the UL for sodium. Among non‐Hispanic blacks, 84% (95% CI: 79.7%–88.3%) and 97% (95% CI: 94.1%–99.9%) exceeded the UL, respectively. Non‐Hispanic black infants and preschoolers had the highest mean sodium intakes than all other groups. Only 1% to 5% of preschoolers met the AI for potassium and mean potassium intake was highest among Mexican‐American preschoolers. Non‐breastfed infants and preschoolers had significantly higher mean sodium intake than those breastfed (p<0.05).

Conclusion

Most U.S. preschoolers consume excessive sodium, and consumption is highest among non‐Hispanic blacks. Very few preschoolers consume enough potassium. Support: No external funding.
Factors Associated with Fast Food Consumption at Global Fast Food Restaurant in the Tokyo Region
Authors: Yoshizawa Kazuko K
Published: June 2021

Background

Fast food consumption has increased in Japan. Even though t is speculated that younger people eat fast food more often than older people do, it is not well known which factors associated with the increased level. Objective of this study is to find what factors are associated with the fast food intake.

Method

A questionnaire was disseminated to 1464 residents aged 10s – 60s in Tokyo and its suburbs by use of internet in Sept. 2011. The questionnaire includes questions about preference of fast food restaurants, its reasons, etc. Logistic regression was used for statistical analyses. Results were statistically significant if p‐value was less than 0.05.

Results

The most frequently visited fast food restaurant by all age groups was McDonald. The proportion of the category of housewife who visits McDonald was 84% and that of businessman was 25%. Logistic regression analysis showed that location (OR 2.52, 95% CI 1.84–3.42) and tastiness (OR 2.40, 95% CI 1.78–3.26) were associated with fast food consumption adjusting for convenience, serving size, and price.

Conclusion

The important factors associated with increased levels of fast food consumption are location and tastiness while portion size, convenience and price were not important factors.
Effect of lactation on antioxidant indices and bone mineral density in adult women
Authors: Kamp Fernanda , Gomes Vivianne Magalhães , Silva Danúbia Incutto , Bezerra Flávia Fioruci , Torres Alexandre Guedes
Published: June 2021

The aims of this study were to compare indices of antioxidant status and bone mineral density (BMD) during lactation and to investigate the relationship of those indices with BMD. Lactating women (30.8 ± 4.8 y) with low calcium intake (≈600 mg/d), participated in the study at 2–4 (early lactation, EL; n= 14) and at 12–14 (middle lactation, ML; n= 11) wk postpartum. Indices of antioxidant status [ferric‐reducing ability of plasma (FRAP); erythrocyte aminolevulinic acid dehydratase activity (d‐ALAD); in vitro zinc‐d‐ALAD activation (Zn‐d‐ALAD%)] and measures of BMD [at total body (TBMD) and at lumbar spine (L2–L4)] were evaluated. When compared to EL, FRAP did not change, but Zn‐d‐ALAD% increased (P < 0.01), and d‐ALAD (P ≤ 0.05), TBMD (P ≤ 0.02) and L2–L4 (P ≤ 0.01) decreased, at ML. d‐ALAD was negatively associated with Zn‐d‐ALAD% (r= −0.63; p < 0.02), and tented to be positively associated with L2–L4 (r = 0.49; P = 0.07). No associations between FRAP and bone measurements were observed. Our results suggest that the decrease in d‐ALAD during lactation appears to be related to an impairment on zinc status, that could further contribute to accentuate bone loss during lactation, mainly in low calcium intake.

Financial support: CNPq (Brazil)
Korean pine nut oil decreases the amount of white adipose tissue by affecting lipid metabolism in C57BL/6 mice
Authors: Shin Sunhye , Park Soyoung , Lim Yeseo , Han Sung Nim
Published: June 2021

Korean pine nut oil (PNO) has been reported to reduce weight gain and the amount of white adipose tissue. Effects of PNO on lipid metabolism were investigated to understand the mechanisms of decrease in amount of white adipose tissue. Five‐wk‐old C57BL/6 mice were fed control diets containing 10% kcal fat from PNO or soybean oil (SBO) (PC or SC) or high‐fat diets containing 35% kcal fat from lard and 10% kcal fat from PNO or SBO (PHF or SHF) for 12 weeks. Expression levels of jejunal Cd36, Ifabp, Dgat2, and Apoa4, and epididymal Lpl, Plin1, Ucp2, Adrb3, Pparg, Ppargc1a, and Ppard were determined by Real‐time PCR. There was no difference in daily food intake between SBO‐ and PNO‐fed mice. Overall, PNO‐fed mice gained less weight (P = 0.014) and had less white adipose tissue (P = 0.004). PC and PHF groups had significantly less amount of white adipose tissue compared with SC group (30% less, P = 0.046) and SHF group (18% less, P = 0.033), respectively. Overall, PNO downregulated the mRNA expression of Cd36 (P = 0.025) and Lpl (P = 0.020). PC group had significantly lower Lpl mRNA expression (0.62‐fold, P = 0.035) than SC group. Overall, PNO tended to downregulate the Apoa4 mRNA expression (P = 0.068) and upregulate Adrb3 mRNA expression (P = 0.081). These results indicate that PNO is less efficiently absorbed, utilized, and stored in the body than SBO, which leads to less accumulation of fat mass in C57BL/6 mice.

Supported by the Korea Research Foundation grant funded by the Korea government (KRF‐2010–0024878)
Acute lipids response to fructose beverage in adolescents with NAFLD
Authors: Jin Ran , Le Ngoc‐Anh , Vos Miriam
Published: June 2021

Objective

Dyslipidemia and insulin resistance are commonly reported in nonalcoholic fatty liver disease (NAFLD). In this study, we investigated the acute lipid response to fructose in adolescents with NAFLD (hepatic fat >; 5% by MRS), and examined the difference as compared to similar overweight adolescents with normal hepatic fat (< 5%, non‐NAFLD).

Methods

We recruited overweight Hispanic adolescents that self‐reported high consumption of sugar beverages (≥24 oz per day) as this is known to be a high risk population for NAFLD. 50 recruited subjects underwent a fructose tolerance test, and their blood samples were collected at fasting and 30, 60, 90 min after oral fructose load (50 grams).

Results

Over 70% of study population had NAFLD, and they had higher ALT (p=0.003), AST (p<0.001), fasting TG (p=0.003), insulin (p=0.005), HOMA‐IR (p=0.01), and adipose IR (p<0.001), as compared to non‐NAFLD. With fructose load, plasma glucose response was not different between the two groups; however, NAFLD subjects had high AUC of insulin (40.6 ± 6.1 vs. 17.2 ± 3.1, p=0.001) and less FFA suppress (AUC: 0.19 ± 0.07 vs. 0.46 ± 0.09, p=0.05).

Conclusion

Overweight Hispanic adolescents with increased hepatic steatosis are more insulin resistant compared to similar non‐NAFLD overweight adolescents. This insulin resistance results in decreased tolerance of an oral fructose bolus as demonstrated by failure of NEFA suppression.
Short‐term high‐fat diet impairs regulation of hepatic lipogenesis in rats
Authors: Axen Kathleen , Harper Marianna A. , Kuo Yu‐Fu , Axen Kenneth
Published: June 2021

Chronic high‐fat intake can produce obesity, fatty liver, and insulin resistance in rodents. We have found that a long‐term (>; 10 wk) high‐fat diet impairs the induction of SREBP‐1c and lipogenic enzymes by carbohydrate feeding. The present study investigated the early effects of the same diet on male Sprague Dawley rats consuming either a low‐fat (LF, 15%kcal, N=6) or a high‐fat (HF, 55% N=6) diet ad libitum for 1 wk. Although body weights were similar, HF rats had higher body fat (p< 0.02), liver lipid concentration (p< 0.02), and HOMA (p< 0.05 ) than LF rats. Analysis of liver samples collected from either 24 h food deprived rats or rats refed a high‐carbohydrate (55% kcal) diet for 16 hr, showed that refeeding increased mRNA for SREBP‐1c (10X), Acetyl CoA Carboxylase (7X), Fatty Acid Synthase (40X) and Pyruvate Kinase (6X) in LF, but only by 1.5 ‐ 3X in HF livers. Despite similar plasma insulin responses, LF showed greater feeding‐induced increases than HF in hepatic mTORC1 activity (increased p‐S6/total S6), and SREBP‐1c maturation, both mediators of insulin‐stimulated lipogenesis. Refeeding increased Fatty Acid Synthase protein content similarly in HF and LF at wk1, but did not do so at wk 10. These findings show that even short‐term HF diets impair early events in carbohydrate‐induced hepatic lipogenesis. NIH 1SC3GM086298
Isorhamnetin modulates the γ‐aminobutyric acid transporter GAT‐3 in mesencephalic and cortical astrocytes exposed to neurotoxic manganese
Authors: Fordahl Steven Craig , Erikson Keith
Published: June 2021

Excessive manganese (Mn) exposure leads to a Parkinson's‐like disorder characterized by neurochemical imbalances. A disruption in γ‐aminobutyric acid (GABA) is an early event of Mn‐toxicity, and evidence suggests that Mn impairs the function of GABA transporters leading to elevated synaptic GABA. We suspect that Mn inhibits GABA uptake by altering the density of GABA transporters on the plasma membrane (PM). The purpose of this study was to characterize the effect of Mn on the cellular localization of the GABA transporter GAT‐3 in astrocytes, and to identify whether the blood‐brain permeable quercetin metabolite, isorhamnetin (ISO), preserves membrane GAT‐3 protein levels and function. Primary astrocytes were isolated from the cortex and mesencephalon of Sprague‐Dawley rats at postnatal day two. Astrocytes were exposed to 500μM Mn for 1, 6, or 24hrs with or without 72hr ISO (10μM) pre‐treatment. Western blot analysis of GAT‐3 and phospho protein kinase C‐δ (PKC‐δ) were conducted on PM and cytosolic fractions. Mn decreased total GAT‐3 protein in astrocytes from both regions after 24hr exposure. ISO pre‐treatment did not improve total GAT‐3 levels, but shifted GAT‐3 from the cytosol to the PM in astrocytes from both regions, which corresponded with elevated phospho‐PKCδ at the PM. ISO also enhanced 3H‐GABA uptake in astrocytes. These data suggest that ISO may protect against early events in Mn‐toxicity.
Effects of safflomide‐type phenolic amides on expression of adipokines in hypertrophic 3T3‐L1 cells and rats fed a high‐fat diet.
Authors: Park Jae , Wang Thomas
Published: June 2021

Adipokines (e.g., adiponectin, leptin, TNF‐á, IL‐6, and MCP‐1/CCL2) are produced in adipose and related cells, and their expressions are often modulated depending on adipocyte hypertrophy and antioxidant status. Safflomide is a antioxidant and serotonergic phenolic amide found in plants (e.g., Carthamus sp, Centaurea sp. Coffea sp. and Ipomoea sp.). Therefore, the potential effects of safflomide on the expression of adipokines were investigated in vitro and in vivo. Safflomide did not affect the expressions of TNF‐á, IL‐6, and MCP‐1/CCL2, but significantly up‐regulated adiponectin mRNA at concentrations less than 20 microM (P < 0.05) in hypertrophic 3T3‐L1 cells. Using safflomide analogues and serotonin blockers, we found that the up‐regulation of adiponectin was likely associated with serotonergic and antioxidant activities. Rats fed a high‐fat diet supplemented with safflomide (3mg per day) showed no plasma TNF‐á, IL‐6, and MCP‐1/CCL2 increases, but a significant adiponectin increase (more than 30%) with a considerable reduction in body weight compared to non‐supplemented rats. These data suggest that safflomide may be a potent bio‐active component able to increase adiponectin in an obesity‐related condition.
Antioxidant and antimicrobial activities of three different solvent extracts of guava leaf (Psidium guajava L.)
Authors: Seo JongKwon , Lee Soo Jung , Elam Marcus , Carter Ashley , Johnson Sarah A. , Feresin Rafaela G. , Arjmandi Bahram H.
Published: June 2021

Guava is a tropical plant found in hot climate areas in South America, Europe, Africa and Asia. Previous research has shown that the phenolic compounds found in guava leaves possess antioxidant and antimicrobial properties. The aim of this study was two‐fold: 1) to determine the antioxidant capacity of guava leaf water, ethanol, and methanol extracts by measuring their total phenol and flavonoid content, and 2) to evaluate the antimicrobial capacity of guava leaf extracts against four different microbes (S. aureus, E. coli, T. mentagrophytes, and T. rubrum). Phenolic content was the highest in the guava leaf water extract, and the flavonoid content in the guava leaf water and ethanol extracts were higher than in the methanol extract. Radical scavenging property, as denoted by 2,2‐diphenyl‐1‐picrylhydrazyl radical (DPPH•) and 2,2′‐azinobis‐(3‐ethylbenzothiazoline‐6‐sulfonic acid) (ABTS) levels, was higher in the guava leaf water extracts. Nitric oxide scavenging capacity was not significantly different among the guava leaf extracts. Ethanol, methanol, and water guava leaf extracts significantly inhibited microbial growth, with the ethanol guava leaf extract showing the highest activity against the S. aureus and E. coli. This suggests a relationship between the phenolic content and the antioxidant activity, as well as between the flavonoid content and antimicrobial activity of guava leaf extracts.
Interlukin‐18, An Indicator of Insulin Resistance?
Authors: Mabrouk Randa Reda , Ghareeb Hala , Elkabarity RANIA Hamdy
Published: June 2021

Adipose tissue expression of IL‐18 is increased in obesity but is not affected by weight loss, indicating that its plasma changes is related to insulin resistance rather than obesity. The study was designed to detect the level of IL‐18 and to determine its correlation with insulin resistance and inflammation in both morbidly obese and normal subjects.

Quantitative analysis of hs‐CRP, IL‐18, Homeostasis Model Assessment ‐ Insulin Resistance Index (HOMA‐IR), and fasting insulin was performed in 35 morbidly obese individuals with fasting blood glucose>;100mg/dl and in matched healthy control group.

IL‐18 was significantly higher in patients than in the control group. There was also a statistically significant correlation between IL‐18 and hs‐CRP (P<0.05) and a statistically significant correlation between IL‐18 and insulin and HOMA (P<0.05). Receiver‐operating characteristic (ROC) curve analysis was applied to assess the performance of IL‐18 as predictor of insulin resistance. The area under curve (AUC) was 0.890, and the optimum cut‐off level was 171pg/ml. This had a diagnostic sensitivity 100%, specificity 71.9%, negative predictive value (NPV) 100%, positive predictive value (PPV) 80.9%, and diagnostic efficacy of 87.1%.

In conclusion, we have shown that high levels of IL‐18 are associated with an increased risk of insulin resistance, and that this is independent of obesity, hs‐CRP, triglycerides and cholesterol.
A Role for Palmitoleate in Regulating Macrophage Activation
Authors: Xu Hang , Guo Xin , Li Honggui , Woo Shih‐lung , Wu Chaodong
Published: June 2021

Increased macrophage proinflammatory activation contributes to atherosclerotic problems. We investigated the effects of palmitoleate treatment on the inflammatory status of bone marrow‐derived macrophages (BMDM). After differentiation, wild‐type BMDM were treated with palmitoleate (50 μM) for 48 h in the presence of lipopolysaccharides (LPS, 100 ng/ml) for the last 30 min to stimulate macrophage proinflammatory signaling or interleukin‐4 (IL‐4, 10 ng/ml) for 48 h to inhibit macrophage proinflammatory activation. LPS stimulation caused an increase in the phosphorylation of JNK1/2 and NF‐κB p65 in BMDM. This stimulatory effect of LPS was partially blunted by treatment with palmitoleate. On the other hand, IL‐4 displayed a weak effect on decreasing the phosphorylation of JNK1/2 and NF‐κB p65 in BMDM. However, in palmitoleate‐treated BMDM, the inhibitory effect of IL‐4 was much more potent, evidenced by the fact that the combined treatment with IL‐4 and palmitoleate nearly abolished the phosphorylation of JNK1/2 and significantly decreased the phosphorylation of NF‐κB p65. Together, these data suggest that palmitoleate is anti‐inflammatory bioactive lipid which may be useful for prevention of cardiovascular disease.

Grant Funding Source: American Diabetes Association, American Heart Association
A combinational therapy on atherosclerosis
Authors: Han Jihong , Chen Yuanli , Duan Yajun
Published: June 2021

LXR, a ligand‐activated transcription factor, plays a central role in cholesterol and fatty acid biosynthesis/metabolism. LXR activation induces macrophage ABCA1 expression, a molecule facilitating cholesterol efflux and inhibiting formation of macrophage/foam cells and development of atherosclerosis. LXR ligands inhibit atherosclerosis but induce severe hypertriglyceridemia. Our previous report demonstrates that ERK1/2 inhibitors synergize LXR ligand‐induced macrophage ABCA1 expression and cholesterol efflux (JBC 2010;285:6316–6326) indicating the application of LXR ligands plus ERK1/2 inhibitors on atherosclerosis. We herein report that the combination of an LXR ligand (T09013170) and an ERK1/2 inhibitor (U0126) both at low doses inhibited atherosclerosis in apoE−/− mice. More importantly, the T0901317‐induced hypertriglyceridemia was blocked by U0126. The mechanism study indicated that the combinational therapy had a little effect on fatty acid biosynthesis but greatly promoted expression of genes responsive for triglycerides metabolism. Furthermore, we investigated the effect of the combinational therapy on regression of atherosclerosis. Our results indicated the combinational therapy had little effect on lesion development in mice with advanced lesions and continued on a high‐fat diet. However, a regression of lesion development was observed in the mice receiving the combinational therapy while returning to normal chow from the high‐fat diet. Taken together, our study suggests that the combinational of LXR ligands and ERK1/2 inhibitors can be a novel therapy to inhibit and regress atherosclerosis without adverse effects.
IT Telehealth Center for Telecytopathology
Authors: Markovic Olivera , Markovic Nenad
Published: June 2021

Since 2004, when for the first time, we presented our MarkPap® biomarker‐based platform technology, we followed‐up on subsequent EB meetings with the results of our translational research from manual to semi‐automated procedures, from diagnosis at the Point‐of‐Care (POC) to diagnosis at distance (digital and wireless), from its primary application in detecting abnormal cells on cervical specimens to other applications, including self‐collection of specimens at home.

This presentation is the most recent development: The IT Telehealth Center as a prototype design for an architecture (application software and hardware) of a local center implemented with a proprietary communication network to a global networking system, connected with a unique medical diagnostic protocol to enable automatic exchange of secure digital image (high resolution, still, metadata) files between humans on both sides of the networking system (POC and medical centers). The automation makes this center a low‐cost device for mass cancer screening.

We acknowledge the support of Dr. Oleg Panashchenko, Mr. Stephen McJonathan, and Ricca Chemical Company, USA.
Transcriptional regulation of endothelial Arginase 2 by Histone Deacetylases and its role in atheresclerosis
Authors: Pandey Deepesh , Romer Lewis , Berkowitz Dan
Published: June 2021

A critical event in the development of endothelial dysfunction (ED) in atherosclerosis is elevated arginase (ARG) expression and activity that results in local L‐arginine depletion and nitric oxide synthase (NOS) uncoupling, which ultimately leads to nitros‐redox imbalance in the endothelial cells (EC) and ED. There is significant deficit in knowledge regarding mechanism underlying increased ARG expression in cardio vascular diseases (CVD). Inhibition of Histone Deacetylases (HDACs) increase histone acetylation that results in increased transcriptional accessibility and therefore increased gene expression. Recent findings have implicated HDAC3, 5 and 7 in VEGF signaling, EC proliferation, survival and growth suggesting its role in CVD. In our current study, human aortic endothelial cells (HAEC) and isolated mice aortic rings exposed to broad HDAC inhibitor, Trichostatin A (TSA) elicited a robust increase in ARG2 (ARG2) protein and mRNA expression. Aortic rings exposed to 200nM of TSA for 8 hours resulted in almost 50% reduction in acetylcholine‐mediated relaxation, which was significantly restored with ARG2 inhibitor. We have also found robust increase in ARG2 promoter activity in EC treated with TSA suggesting that TSA is important in transcriptional regulation of ARG2. Taken together, these studies will allow us to determine whether HDAC represents a novel target for the effective treatment of CVD.
What are the advantages/disadvantages of postdoctoral training in industry?
Authors: Saleh Lana
Published: June 2021

Biotech and pharmaceutical companies recruit postdoctoral researchers to perform cutting‐edge research beyond the scope of the designated program. A postdoctoral position in industry provides a young scientist an insight into the world of applied scientific research, as well as into the management lifestyle of industry, which differs tremendously from that of academia. It also offers the opportunity of conducting scientific research using state‐of‐the‐art research facilities and interacting with an extremely diversified team of talented scientists, engineers, and business professionals. Financially, industrial postdoctoral salaries are considerably higher than their counters in academic programs. But most important of all, an industrial postdoctoral position offers the candidate exposure inside the company that might lead to a permanent position. However, it is important to know that many companies do not view their postdoctoral programs as recruitment tools. Research is usually focused on an aspect related to commercial technology, and publications delayed to ensure proprietary information remains private. As a result, the scope for future job hunts might be narrow. In summary, an industrial postdoctoral position offers a candidate the industrial experience and leadership potential they will need for landing a position in industry but is not without its own disadvantages.
Methylene‐dioxy‐pyrovalerone (MDPV) is a potent inhibitor of hDAT and hNET
Authors: Solis Ernesto , Cameron Krasnodara N , Kolanos Renata , Glennon Richard A , De Felice Louis J
Published: June 2021

Bath salts is a relatively new abused drug with varying composition of either a single or a combination of β‐ketophenylethylamines. A common ingredient of bath salts is methylenedioxypyrovalerone (MDPV). Recent studies have shown MDPV is a potent uptake inhibitor for the human dopamine transporter (hDAT) and the human norepinephrine transporter (hNET). Here we explore the effect of MDPV on the electrical currents mediated by hDAT expressed in Xenopus laevis oocytes, as well as its effect on the uptake of fluorescent substrates mediated by hDAT or hNET expressed in HEK‐293 cells. These data will characterize MDPV action on catecholamine transporters and further our understanding of this abused drug. Our data shows MDPV is 30 fold more potent than cocaine (COC) in inhibiting dopamine (DA) uptake and its inhibition is longer lasting in both expression systems. We will further investigate the structural determinants responsible for the unique properties of MDPV.
Effects of neonatal visceral pain on morphine tolerance, dependence, and withdrawal in rats
Authors: Norwood Andrew P , Fantegrossi William E
Published: June 2021

Changes in brain opioid systems have been demonstrated in response to neonatal visceral pain (NVP), but few studies have examined the impact of these changes on opioid pharmacology. In these studies, we examined the effects of NVP on the development of tolerance, dependence, and expression of withdrawal effects of morphine in the rat. Experimental rats were subjected to a colorectal distension procedure on postnatal days 4, 6, and 8 to induce NVP, while control rats were not exposed to the NVP procedure. All rats were gradually shaped to a terminal FR20 schedule reinforced by food presentation. Once responding was stable and reliable, saline was injected subcutaneously (SC) before behavioral sessions, and morphine was administered (SC) immediately after behavioral sessions. Morphine doses were increased one quarter‐log every 7 days, from 1.0 mg/kg, to a final dose of 30 mg/kg, upon which rats were maintained for the duration of the experiment. Various doses of the opioid antagonist naltrexone (NTX) were sometimes administered 10 min before behavioral sessions to precipitate withdrawal. For both groups of rats, NTX dose‐dependently suppressed response rates, indicative of a precipitated withdrawal effect on food‐maintained responding. However, NTX induced more pronounced rate suppression in NVP rats at all tested doses. These findings demonstrate that the changes in brain opioid systems elicited by NVP have persistent pharmacological consequences into adulthood, are consistent with our previous studies suggesting that NVP increases sensitivity to abuse‐related effects of opioids across development, and extend our characterization of this vulnerable phenotype to include an increased susceptibility to antagonist‐precipitated withdrawal. These studies supported by the UAMS Center for Translational Neuroscience (RR020146) and the UAMS Translational Research Institute (RR029884).
A toxicological evaluation of the C‐terminal fragment of Clostridium perfringens enterotoxin as a claudin‐3/‐4 binder
Authors: Iida Manami , Suzuki Hidehiko , Li Xiangru , Kakutani Hideki , Nagase Shotaro , Doyama Ryo , Watari Akihiro , Kondoh Masuo , Yagi Kiyohito
Published: June 2021

Claudins (CLs) are tetratransmembrane proteins that function as intercellular sealing components of tight junctions. Recent progress in epithelial pharmaceutical sciences provides us new insight into the use of CLs as potent targets for drug development. The C‐terminal fragment of Clostridium perfringens enterotoxin (C‐CPE) was the first identified CL‐3/‐4 binder. We previously showed that CL‐3/‐4 could play a role in the mucosal absorption of drugs, in cancer therapy, and in mucosal vaccination using C‐CPE as a CL binder. Since CL‐3/‐4, are highly expressed in the liver and kidney, evaluations of the safety and antigenicity of C‐CPE are needed for future clinical applications. Here, we evaluated whether C‐CPE in mice leads to tissue injury or production of antibodies. Intravenous administration of 5 mg/kg C‐CPE, which is a dose over 25‐fold higher than that used in a murine mucosal absorption model, did not increase biochemical markers of liver and kidney injury, even after 11 weekly injections. Similarly, nasal administration of 2 mg/kg C‐CPE weekly for 11 weeks did not increase these biochemical markers, but 6 administrations of C‐CPE resulted in elevation of C‐CPE‐specific serum IgG. These results indicate that development of a CL modulator with lower antigenicity will be essential for future clinical application of a C‐CPE‐based mucosal absorption enhancer.
Multiscale computational models of microvascular reactivity from ion channels to intercellular signaling
Authors: Kapela Adam , Parikh Jaimit , Tsoukias Nikolaos M.
Published: June 2021

Detailed compartmental, continuous, and multicellular computational models of smooth muscle (SM) and endothelial cell (EC) electrophysiology were developed and validated from patch clamp and calcium (Ca2+) imaging data. These models examine localized Ca2+ events from individual ion channels, role of signaling microdomains, effect of ion channel distribution, and homo‐ and hetero‐cellular signaling in regulation of vascular tone. Activation of TRPV4 channels in EC generates sparklets that activate colocalized IKCa channels and EDHF. EDHF is transmitted robustly by hyperpolarizing current through gap junctions, but less so by extracellular potassium. During SM stimulation, diffusion of IP3, and to smaller degree Ca2+, from SM to EC projections induces localized Ca2+ events and EDHF, which closes the myoendothelial feedback loop. Spatial heterogeneities in Ca2+ handling components generate oscillatory Ca2+ waves. In vasomotion, Ca2+ oscillations in SM can be synchronized by electrical or IP3 coupling through SM gap junctions. Conducted relaxation is mediated mainly by electrotonic spread of local hyperpolarization along the endothelium, but EC Ca2+ spread from the stimulus site and facilitation mechanism along the conduction can amplify the response. In conclusion, vasoreactivity involves complex signaling, which can be analyzed with the aid of computational models. Supported by NIH SC1HL95101.
Long‐term physiologic T3 supplementation as an adjunct therapy in hypertensive heart disease
Authors: Pol Christine Jantina , Weltman Nathan Y , Zhang Youhua , Koder Adrienne , Raza Sarah , Plummer Maria , Gerdes A Martin
Published: June 2021

Re‐expression of the fetal gene phenotype in hypothyroidism and hypertension suggest low cardiac thyroid hormone (TH) levels during hypertension. Short‐term TH treatment in Spontaneously Hypertensive Heart Failure (SHHF) rats near heart failure is known to promote beneficial remodeling. The current study examined the effects of long‐term T3 treatment in SHHF rats. SHHF rats were treated with a physiological oral T3 dosage (4ìg/kg/day) from 12–24 months of age. SHHF rats had a decline in serum free TH levels and cardiac tissue T3 levels, cardiac dysfunction, and elevated LV collagen content compared to normotensive controls. Normalization of serum and cardiac tissue TH levels in T3 treated rats normalized heart rate, LV end‐systolic diameter, fractional shortening, systolic wall stress, and LV collagen levels. Improvements in LV end‐systolic pressure, maximal rate of pressure development and decline, and time constant of isovolumic relaxation trended toward improvement but did not reach statistical significance.

In conclusion, hypertension in rat leads to chronic low serum and cardiac tissue TH levels. Long long‐term treatment with T3 is safe. In the absence of anti‐hypertensive treatment, cardiac dysfunction could not be completely prevented. But, results suggest that T3 treatment of patients with hypertension might serve as a helpful adjunct to existing therapy. Supported by the NIH RO1 HL103671‐01A1.