bluuebunny/crossref_metadata_2025 huggingface dataset:
A high‐fat meat, dairy and sweets pattern is negatively associated with BMI in Mexican preschool children
Authors: Peterson Karen E. , Jiang Yunyun , Zhang Zhenzhen , Sanchez Brisa N. , Ettinger Adrienne S. , Cantoral Alejandra , Park Sung Kyun , Tellez-Rojo Martha Maria
Published: June 2021

Dietary patterns have been related to adult obesity in countries undergoing the nutrition transition, but few studies have examined these relationships during sensitive periods for development of child obesity. We describe dietary patterns and their cross‐sectional associations with BMI among 1041 Mexico City children aged 4 yr. Principal components analysis of 100 FFQ items defined 3 patterns: Vegetable/fish; Fruits/grains; Meats/dairy/sweets. We used quantile regression to model the association of each factor with BMI at 10th, 25th, 50th, 75th, and 90th percentiles of the analytic sample, adjusting for child's age, sex, energy intake, birth weight; breastfeeding duration; maternal BMI, schooling. Mean child BMI was 15.9, BW 3.1 kg, breastfeeding 8.5 mo; maternal BMI 26.0, schooling 10.4 yr. The Meat/dairy/sweets pattern was higher in fat, protein and calcium and associated with lower BMI across all quantiles (10th ‐0.19, p=.0004; 25th ‐0.11, p=.005; 50th ‐ 0.12, p=.014; ‐0.17, p=.002), except the highest (‐0.16, p=.16). This pattern could be related to lower BMI at 4 yr of age if children are experiencing higher linear growth but have not have undergone adiposity rebound. Further research should address the association of dietary patterns with longitudinal BMI and stature trajectories. Research support: NIEHS/EPA P20 ES01817101/RD834800 and NIEHS R01 ES007821; P30 ES017885.
Development of the Healthy Eating Index‐2010
Authors: Guenther Patricia M. , O'Connell Kellie M. , Reedy Jill , Kirkpatrick Sharon I. , Hiza Hazel A.B. , Kuczynski Kevin J.
Published: June 2021

The Healthy Eating Index (HEI) is a measure of diet quality based on federal dietary guidance. Publication of the Dietary Guidelines for Americans, 2010 prompted an interagency working group to update the HEI‐2005 using the revised USDA Food Patterns. The HEI‐2010 retains several features of the previous version: (1) it has 12 components (many unchanged); (2) it uses a density approach to set standards (i.e., per 1000 calories or as a percent of calories); and (3) it employs least‐restrictive standards (i.e., those that are easiest to achieve among recommendations that vary by energy level or among subpopulations). Changes to the index include: (1) a moderation component, Refined Grains, replaces the adequacy component, Total Grains, to assess over‐consumption; (2) Seafood and Plant Proteins has been added to capture specific choices from the protein group; (3) Fatty Acids (a ratio of poly‐ and mono‐unsaturated to saturated fatty acids) replaces Oils and Saturated Fat to better assess the quality of dietary fat; and (4) Beans and Greens replaces Dark Green and Orange Vegetables and Legumes. Evaluations of the updated index are underway to assess validity and reliability. The HEI‐2010 captures the key recommendations of the 2010 Guidelines and will be used to assess the diet quality of the U.S. population and subpopulations, in evaluating interventions, and in dietary patterns research. Support: USDA/CNPP and NCI.
The carbon isotope ratio of RBC alanine is a biomarker of sugar‐sweetened beverage (SSB) intake
Authors: OˈBrien Diane Marie , Choy Kyungcheol , Nash Sarah
Published: June 2021

We are developing biomarkers of sugar‐sweetened beverage (SSB) intake for application in a Yup'ik Eskimo population, to detect associations with chronic disease risk. The naturally‐occurring carbon isotope ratio of human serum and RBC has been proposed as a biomarker of SSB intake, based on the elevated carbon isotope ratio of corn syrup and cane sugar. However, the marker's utility is diminished by a concurrent relationship with meat from corn‐fed animals. Here we evaluated the association of SSB intake and the carbon isotope ratio of individual amino acids in RBC, to investigate whether one might provide a biomarker that was more specific to SSB intake. The carbon isotope ratio of alanine was strongly (r = 0.70) associated with SSB intake but not associated with intake of corn‐fed market meat. Alanine can be readily synthesized in cells from pyruvate, which derives from glucose. We suggest that this synthetic pathway allows the capture of carbon from dietary sugars in tissue proteins, such as RBC, providing a stable biomarker of intake. This study was funded by a Center of Biomedical Research Excellence grant from the NIH NCRR (P20 RR16430‐10) and NIH NIDDK R01DK07442
Wnt/β‐catenin pathway is activated by thyroid hormone and is required for its hepatomitogenic activity
Authors: Fanti Maura , Perra Andrea , Pibiri Monica , Schwartz Michael , Monga Satdarshan P. , Ledda-Columbano GM , Columbano Amedeo
Published: June 2021

Thyroid hormones regulate cell growth, cell differentiation, and metabolic functions via their interaction with the thyroid hormone nuclear receptors (TRs). Recently, it was shown that intestinal epithelial cell proliferation is controlled by triiodothyronine (T3), and that TR‐β directly controls transcription of the β‐catenin gene. However, whether T3 has any effect on the activation of the Wnt pathway and β‐catenin in the liver, is unknown. Here we show by immunohistochemistry that livers from T3‐treated rats exhibited a strong increase in β‐catenin protein with its accumulation in the cytoplasm and an overall increase in the number of β‐catenin‐positive hepatocytes. The increased expression of β‐catenin was associated with increased glutamine synthetase, and an enhancement in nuclear accumulation of cyclin D1, both known targets of β‐catenin. Moreover, while T3 induced hepatocyte proliferation in wt mice, no proliferative response was observed in Ctnnb1−/− mice. T3 treatment also caused enhanced levels of Cyp2E1 mRNA, another gene known to be up‐regulated by β‐catenin. The increased expression of Cyp2E1 was associated with liver injury and mortality induced by a single administration of acetaminophen.

Conclusion

Our results indicate that T3 induces Ctnnb1 transcription and that high levels of this hormone may be responsible, through activation of β‐catenin, of increased hepatocyte proliferation and an enhanced susceptibility to drug‐induced liver injury. AIRC and PRIN, Italy.
α(1,3)‐Fucosylation alters STAT3‐dependent IL‐17 production in vivo
Authors: Mackey Lantz C. , Rose Jason M , Homeister Jonathon W.
Published: June 2021

Mice deficient in α(1,3)‐fucosyltransferase (FucT)‐IV and ‐VII (DKO) lack selectin ligand activity, have severe deficiencies in leukocyte trafficking, and have a marked increase in circulating IL‐ 17a compared to wild‐type (WT) mice. We sought to determine how the loss of FucT‐IV/‐VII activity alters the intracellular signaling cascade responsible for IL‐17a induction. Mononuclear leukocytes were isolated from the spleen of WT and DKO mice. Messenger RNA was isolated and converted to cDNA. qPCR was performed using Sybr green‐based detection and standardized to B‐actin. DKO mice have elevated transcript levels of RORγT and IL‐17a (18‐fold and 30‐fold, respectively) compared to WT, and reduced levels of STAT3 and SOCS3 transcript (5‐fold and 6‐fold, respectively). Protein for western blots was isolated from the whole spleen of 12 week old male mice, separated on a 10% polyacrylamide gel, transferred to a 0.22 μm nitrocellulose membrane and probed with antibodies to SOCS3, RORγT, STAT3, or γ‐Tubulin. DKO mice have drastically reduced levels of STAT3 and SOCS3 protein and increased levels of RORγT protein compared to WT mice. These data show that loss of FucT‐IV and ‐ VII activity alters the STAT3 signaling cascade thought to be solely responsible for IL‐17a induction. They suggest that loss of FucT‐IV and ‐VII activity may allow an alternate signaling pathway to drive IL‐17a production independent of STAT3.
Proinflammatory macrophage ablation in CD11b‐diphtheria toxin receptor (DTR) transgenic mice impairs skeletal muscle regeneration
Authors: WANG HANZHOU , Porter Laurel , Sarwar Zaheer , McManus Linda M. , Shireman Paula K.
Published: June 2021

Macrophages can be beneficial or detrimental to regeneration following muscle injury and macrophage polarization states are not well‐defined during this process. We previously demonstrated that macrophage ablation with diphtheria toxin (DT) given at day 1 after cardiotoxin injury increased residual necrotic myofibers and resulted in smaller regenerated myofibers in DTR mice compared to control mice that received mutant DT while mice receiving DT at day 4 were similar to controls. We used flow cytometry to evaluate the kinetics of macrophage surface markers to investigate the role of macrophage subtypes in muscle regeneration. In control mice, the majority of macrophages (CD11b+/F480+) were Ly6C+7/4+proinflammatory macrophages at day 1–2 after injury and switched to Ly6C−7/4−macrophages at day 4 after injury. M2 markers CD206+ or CD301+ were present on a small percentage of cells. Interestingly, the predominate macrophage population present from day 3–6 was negative for all 4 markers (Ly6C, 7/4, CD206 and CD301). Administration of DT at day 1 in DTR mice resulted in macrophage ablation at day 2–3 after injury with an increase in macrophages at day 4. Thus, the early recruitment of proinflammatory macrophages was critical for muscle regeneration; further studies are needed to define markers present on macrophages in the later stages of the regenerative process.

Funding: Veterans Administration and NIH HL07423
A role for Galectin‐9 in neutrophil trafficking
Authors: Cooper Dianne , Iqbal Asif J , Niki Toshiro , Hirashima Mitsuomi , Perretti Mauro
Published: June 2021

Galectin‐9 (Gal‐9) was initially characterized as a potent eosinophil chemoattractant but has subsequently been found to have immunosuppressive effects in models of collagen‐ induced arthritis and carageenan paw oedema. Its effects on neutrophil recruitment and behavior during inflammation have not been thoroughly investigated. Here we show that Gal‐9 binds readily to the surface of freshly isolated PMN and binding is not augmented upon activation with PAF but is sensitive to lactose addition. Gal‐9 binding to endothelial cells is low in comparison to PMN and is not modulated by endothelial activation by TNFα. Neutrophils were found to transmigrate to Gal‐9 under static conditions with peak recruitment observed at 10nM. This concentration was not however found to be directly chemotactic for neutrophils in a Boyden chamber assay. Pre‐incubation of PMN with Gal‐9 significantly increased neutrophil transmigration whilst pre‐incubation of HUVEC with Gal‐9 was without effect. At concentrations active in the flow chamber, Gal‐9 did not significantly alter PMN or endothelial adhesion molecule expression (active CD11b, L‐selectin shedding, E‐selectin, VCAM‐1, ICAM‐1). In conclusion, these data indicate that neutrophils rather than endothelial cells are target cells for Gal‐9 and that Gal‐9 promotes neutrophil transmigration during acute inflammation indicating a novel role for this protein.

This work was supported by a Non‐Clinical Career Development Fellowship from Arthritis Research‐UK (18103).
EFFECTS OF GROWTH HORMONE ADMINISTRATION ON CARDIAC REMODELING PROCESS IN RATS WITH AORTIC STENOSIS‐INDUCED HEART FAILURE
Authors: Lima Aline Regina Ruiz , Damatto Ricardo , Campos Dijon , Martinez Paula , Guizoni Daniele , Bonomo Camila , Cézar Marcelo , Silva Frederico , Zanati Silméia , Campana Alvaro , Okoshi Katashi , Okoshi Marina
Published: June 2021

Objective

To evaluate the growth hormone (GH) administration influence on cardiac structures and function in aortic stenosis‐induced chronic heart failure rats.

Methods

Male wistar rats were submitted to surgery to induce aortic stenosis. After heart failure findings detection, rats cardiac structures and ventricular function were assessed by transthoracic echocardiogram. Aortic stenosis group (EAo) animals were randomly subdivided in two groups, EAo GH treated group (EAo‐GH, n=10) and EAo without treatment group (EAo, n=15). Sham group was also constituted(n=18). After the treatment period, all animals were yet submitted to echocardiogram.

Results

GH administration preserved body weight (BW) (Sham 484±42; EAo 415±31; EAo‐GH 476±58 g; p<0.05 EAo vs Sham and EAo‐GH). Left ventricular diastolic diameter/BW was higher in EAo group than Sham; EAo‐GH and Sham groups were similar (Sham 15.5±1.5; EAo18.5±3.2; EAo‐GH 16.5±3.6 mm/kg; p<0.05 EAo vs. Sham). Left ventricular posterior wall thickness was higher in both EAo groups than Sham (Sham 1.43±0.09; EAo2.25±0.25; EAo‐GH 2.41±0.37 mm; p<0.05 EAo and EAo‐GH vs. Sham). Fractional shortening was smaller in EAo group than other groups (Sham 59.1±5.6; EAo 49.8±14.7; EAo‐GH 59.8±12.1 %; p<0.05 EAo vs. Sham and EAo‐GH).

Conclusion

Growth hormone administration attenuates cardiac remodeling process in aortic stenosis‐induced heart failured rats.
Adiponectin Deficiency Accentuates High Fat Diet‐Induced Cardiac Hypertrophy and Contractile Dysfunction through Regulation of Autophagy
Authors: Guo Rui , Ren Jun
Published: June 2021

Objectives

Adiponectin (APN), an adipose‐derived adipokine, offers cardioprotective effects although the precise mechanism behind APN‐exerted beneficial action is unclear. The aim of this study was to examine if autophagy plays a role in APN‐exerted cardiac effects in high fat diet‐induced obesity.

Methods

Adult C57BL/6 wild‐type and APN deficient mice were fed a low (10% calorie from fat) or high fat (45% calorie from fat) diet for 22 weeks. Cardiomyocyte contractile and Ca2+ transient properties were evaluated, including peak shortening (PS), duration and maximal velocity of shortening/relengthening (TPS/TR90, ± dL/dt), electrically stimulated change in fura‐fluorescence intensity (ΔFFI), and intracellular Ca2+ decay rate. Myocardial function was evaluated using echocardiography. DEXA was used to evaluate adiposity. Lipid deposition was examined using myocardial histology. Energy expenditure, oxygen consumption and physical activity were monitored by metabolic cages system. Glucose tolerance test and protein markers of autophagy pathway including LC3, p62 and Beclin‐1 were also performed.

Results

High fat diet induced obesity, glucose intolerance, cardiac hypertrophy, dampened metabolic ability, and cardiac dysfunction, the effects of which were accentuated by APN deficiency. Furthermore, ANP deficiency augmented fat diet‐induced increased in LC3II, ratio of LC3II to LC3I and the autophagy adaptor p62, as well as decrease in Beclin‐1.

Conclusions

Our results revealed that APN deficiency aggravates high fat diet‐induced obesity, glucose intolerance, metabolic ability and cardiac dysfunction through decreased autophagosome formation and fusion.

The research is supported by Wyoming INBRE (P20RR016474)
Fibroblast growth factor‐2 exerts protective effects on cardiac mitochondria
Authors: Srisakuldee Wattamon , Nickel Barbara E , Kardami Elissavet
Published: June 2021

Fibroblast growth factor‐2 (FGF‐2) is a potent cardioprotective agent, by a mechanism linked to connexin43 (Cx43) phosphorylation at protein kinase C (PKC) target serines such as S262. Here we have examined the effects of FGF‐2 on mitochondrial resistance to calcium‐ induced opening of the permeability transition pore (swelling), in relation to cardiac mitochondrial Cx43 levels and phosphorylation.

Subsarcolemmal mitochondria isolated from FGF‐2‐treated hearts: (a) showed 1.5–2 fold increase in total Cx43, PKCε, TOM20 translocase, and a over 30‐fold increase in phospho‐S262‐Cx43, compared to control mitochondria obtained from untreated hearts; (b) were more resistant to calcium‐induced swelling and cytochrome C release; (c) were resistant to calcium‐induced mitochondrial Cx43 degradation. Calpeptin, a potent inhibitor of the calcium activated protease calpain, prevented Cx43 degradation in control mitochondria. Stimulation of control mitochondria with the phorbol‐ester PMA, or FGF‐2, increased both mitochondrial Cx43 phosphorylation at S262 and resistance to calcium‐induced swelling / cytochrome c release.

Our data imply that FGF‐2 cardioprotection is mediated by increasing mitochondrial resistance to calcium damage, via Cx43 translocation to mitochondria and mitochondrial Cx43 phosphorylation.

This work is supported by Heart and Stroke Foundation of Canada and St. Boniface Hospital Research Foundation.
Central sympathoinhibition improves left ventricular function and survival during the transition from hypertrophy to heart failure in Dahl salt‐sensitive rats
Authors: Honda Nobuhiro , Hirooka Yoshitaka , Matsukawa Ryuichi , Itou Koji , Sunagawa Kenji
Published: June 2021

Background

Sympathetic hyperactivity is cardinal manifestation in heart failure (HF). Enhanced central sympathetic drive leads to poor prognosis in HF. Moxonidine is a sympathoinhibitory antihypertensive drug acting on the imidazoline receptors in the central nervous system. Therefore, we hypothesized that moxonidine improves hypertension induced cardiac remodeling, function, and survival in Dahl‐salt sensitive hypertensive rats.

Methods and Results

Dahl salt‐sensitive rats fed 8% NaCl diet from age 7 weeks served as hypertension‐induced HF and followed until 20 week‐old. Salt loading increases blood pressure, left ventricle hypertrophy, and progressive urinary norepinephrine excretion (uNE). Fractional shortening (%FS) was gradually reduced overtime. Intracerebroventricular infusion of moxonidine or vehicle was performed from 14 to 20 week‐old. Moxonidine tended to lower heart rate and blood pressure. Moxonidine attenuated the reduction of %FS (37±1.3 vs. 43±0.9%, n=7, n=4, p<0.05) and lowered uNE (3.0±0.2 vs. 0.6±0.2μg/day, n=7, n=4, p<0.001). Furthermore, moxonidine improved the survival rate (50 vs. 80%, 20 week‐old, n=10, n=5 p<0.05).

Conclusion

Moxonidine acting on the central nervous system improves the cardiac function and prognosis in this rats model of hypertension associated with sympathoinhibition.
A cell permeable hairpin peptide inhibits hepatitis C viral NS5A‐mediated translation and virus production
Authors: Khachatoorian Ronik , Arumugaswami Vaithilingaraja , Ruchala Piotr , Maloney Eden Marie , Raychaudhuri Santanu , Miao Edna , Dasgupta Asim , French Samuel Wheeler
Published: June 2021

Non‐structural protein 5A (NS5A) is a key regulator of the hepatitis C virus (HCV) life cycle including RNA replication, assembly and HCV internal ribosome entry site (IRES)‐mediated translation. We have previously identified an NS5A/heat shock protein 70 (HSP70) complex that is important for HCV IRES mediated translation. We have mapped the HSP70 interaction site on NS5A to a beta‐sheet hairpin in domain 1. Mutation of this site reduced NS5A‐augmented IRES‐mediated translation. We designed a cell permeable hairpin peptide derivative of this site which blocked NS5A/HSP70 complex formation in vitro compared to scrambled control. This peptide also inhibited IRES‐mediated translation, viral RNA replication and infectious virion production in a dose‐dependent manner. These results support the hypothesis that the NS5A/HSP70 complex is involved in IRES‐mediated translation and identify a sequence specific element in NS5A responsible for complex formation. Identification of this element will allow for further interrogation of NS5A‐mediated IRES activity, sequence specific HSP recognition and rational drug design.
Three‐dimensional reconstruction and measurement of cervical vertebral CT images: Anatomical bases for cervical anterior transpedicular screw fixation
Authors: Ouyang Jun , Chen Chun , Wu Changfu , Wu Peidong
Published: June 2021

Objective

To study the morphometric characteristics of Chinese lower cervical vertebrae in order to investigate the feasibility of cervical anterior transpedicular screw (ATPS) fixation and provide anatomical data.

Methods

Cervical CT images from 50 healthy volunteers (35 male and 15 female) were collected. All the images from C3–C7 were reconstructed by Mimics 13.0 software. We measured the dimensions of the vertebral bodies and pedicles from images of multiplanar reconstruction, as well as the parameters related to ATPS technology.

Results

Some of the vertebrae parameters has a statistic differences between the male and female groups (P<0.05). And the sagittal Pedicle Angles increased with the number of cervical vertebrae in all specimens (P<0.05).

Conclusions

This study provides the cervical spine morphological parameters from Chinese population, which provides the basis for ATPS research for osteoporosis patients.
Migration of Breast Cancer Cell Lines in Response to Pulmonary Laminin 332; Implications for Metastasis
Authors: Carpenter Philip M. , Hua Spencer S. , Xiao Cally , Ngo Tuan , Gershon Paul D.
Published: June 2021

In order to determine whether lung tissue secretes a motility factor for breast cancer, minced fresh human pulmonary tissue was co‐cultured with MCF‐7 breast carcinoma cells. Dose‐dependent MCF‐7 migration was observed, consistent with a motility response to a factor secreted by the lung tissue. Pulmonary epithelial cells were isolated and cultured in defined medium. Concentrated conditioned lung culture medium induced motility in the breast carcinoma cell lines MDA‐MB‐231, SKBR3, and BT‐20 using a Boyden chamber assay. For MCF‐7, the motility was dose dependent by a scattering assay, when the concentrate was either in a soluble form or after deposition on tissue culture plastic. The deposited material was analyzed by mass spectrometry, revealing the α3 and β3 chains of the motility factor laminin 332 (LN332). Blocking antibodies to LN332 and to the LN332 receptor for motility, α3β1 integrin, inhibited motility to the same extent as the inhibition of motility that occurred when these antibodies were applied to MCF‐7 cells incubated with purified LN332. Finally, LN332 in normal lung was confirmed by immunohistochemistry. These experiments together showed that pulmonary LN332 induced motility in MCF‐7. These findings provide a mechanism for the migration of metastatic tumor cells from their arrest in the pulmonary vasculature into the surrounding tissue, allowing their establishment as a metastatic colony.
Kaiso: A Key Regulator in EMT and Cancer Progression
Authors: Jones Jacqueline Denise , Wang Honghe , He Peter , Grizzle William , Turner Timothy , Yates Clayton
Published: June 2021

Advanced stages of cancer are characterized by increased aggressiveness, invasiveness, and the downregulation of tumor suppressor genes via methylation. Kaiso, a bi‐modal transcription factor, interacts with DNA through either a DNA consensus sequence or methylated CpG di nucleotides thus regulating gene expression. A clinical role for Kaiso expression in advanced stages of breast cancer remains unclear. Here we investigate the ability of kaiso to decrease the metastatic functional characteristics of breast cancer progression. Immunohistochemistry was performed to examine protein expression and localization in human breast tissue. siRNA kaiso treated cells were used to assess cell motility and invasion. An overall increase in Kaiso expression was found in primary tumor samples and this increased as cancer progressed to distant sites. Additionally, nuclear localization of Kaiso was observed in primary tumor and lymph node metastasis in breast tumors. Construct treated cell lines showed a delay in cell motility, invasion. 5‐aza‐2′‐deoxycytidine treated cells showed a re‐expression of tumor suppressor E‐cadherin, which correlated with E‐cadherin re‐expression in siRNA Kaiso treated cells. Downregulation of E‐cadherin, migration and invasion are key to cancer progression and metastasis. Our results reveal kaiso as a potential indicator and/or therapeutic agent of breast cancer metastasis.
Adenosine A2A receptor activation attenuates Th1 and Th17 polarization in the airway
Authors: Pei Hong , Ken Ruey , Huynh Nhut , Linden Joel
Published: June 2021

Objective

To determine the role of A2A receptor activation on the appearance of Th1 and Th17 cells in mouse lung following exposure to LPS and allergens, and on the production of cytokines by established Th1 or Th17 cells upon allergen challenge.

Methods and Results

Th1 and Th17 asthma mouse models were established by airway sensitization with LPS and allergens followed by rechallenge with allergens alone. A2A receptor activation with CGS28160 during sensitization strongly inhibited the development of Th1 and Th17 cells; increased CD4 Foxp3 positive cells; and reduced pulmonary inflammation, vascular permeability and airway hyperresponsiveness (AHR). In contrast, the application of CGS28160 only before allergen rechallenge only moderately reduced IFN‐γ production and neutrophil infiltration into lung; had no effects on IL‐17A production, vascular permeability and AHR.

Conclusions

the results indicate that A2A receptor activation plays an important role in controlling the polarization of naïve T cells to Th1 and Th17, but fails to inhibit the release of IL‐17A from Th17 cells. The results suggest that A2AR activation may be more effective at inhibiting allergen sensitization that the response to allergens in sensitized lungs.
Hyperoxia‐induced Retinal Microvasculopathy Correlates with Lung Injury and Inflammation in Neonatal Mice
Authors: Mezu-Ndubuisi Olachi Joy , Reddy Narsa M , Wanek Justin , Teng Pang-yu , Shahidi Mahnaz , Reddy Sekhar P
Published: June 2021

Objective

Premature infants with respiratory failure require oxygen supplementation, which can destroy developing lungs and lead to acute lung injury (ALI). Continued oxygen use also damages retinal tissue by disrupting normal angiogenesis, leading to retinopathy of prematurity (ROP). Using a mouse model of oxygen‐induced retinopathy (OIR) and ALI, we assessed the correlation between retinal microvascular abnormalities in vivo and lung tissue injury ex vivo.

Methods

Neonatal C57BL6/J mice were exposed to 75% oxygen from postnatal day 7 (P7) to P12 and then exposed to room air until P17. Fluorescein angiography (FA) images of the retinal vasculature were acquired in vivo. Bronchoalveolar lavage (BAL) was performed on the mice lung tissue ex vivo, followed by cytometry and protein estimation of the BAL fluid. The total cell count was used as a measure of lung inflammation; while total protein estimation was used to assess lung injury.

Results

In vivo FA imaging of retinal vasculature revealed aberrant neovascularization and regions of capillary network loss in mice exposed to hyperoxia compared to room air exposed controls (Figure 1A). There was a 4‐fold increase in total inflammatory cells (Figure 1B) and a 3‐fold increase in protein levels in BAL fluids of hyperoxia‐exposed mice compared to room air controls.

Conclusions

Our findings demonstrate a correlation between retinal microvasculopathy and lung tissue injury and inflammation in neonates, suggesting in vivo imaging of retinal microvasculature could be a potential biomarker for lung injury.

Source of Research Support: R01 HL66109, R01 ES011863 and R01 EY017918
Protective Effect of Perilla Leaf Extract and its Constituents on t‐BHP‐induced Oxidative Stress in Liver
Authors: Yang Sung-Yong , Hong Chung-Oui , Koo Yun-Chang , Nam Mi-Hyun , Lee Kwang-Won
Published: June 2021

Perilla frutescens are popular plant in East Asia, and the leaves of perilla were known for antioxidant, anti‐allergic, anti‐inflammatory and anti‐tumor effect. According to our previous study, P. frutescens included two major polyphenolic compounds, caffeic acid and rosmarinic acid. Previous our study showed protective effect of P. frutescens extract (PLE) on oxidative hepatotoxicity. Our group isolated of caffeic acid from P. frutescens and it enhanced γ‐glutamylcysteine synthetase activity and glutathione level. Based on high performance liquid chromatography analysis data, PLE have 1.32 μg caffeic acid/mg dry material (DM) and 26.84 μg rosmarinic acid/mg DM. And in vitro study showed that PLE and its constituents have protective effect on t‐BHP‐induced oxidative stress in HepG2 cells. Also, in vivo study showed pretreatment with PLE (1000 mg/kg b.w.), caffeic acid (1.32 mg/kg b.w.) and rosmarinic acid (26.84 mg/kg b.w.) for 5 days before a single dose of t‐BHP (i.p. 0.5 mmol/kg b.w.) lowered lipid peroxidation level and increased the reduced form of glutathione. And mixed caffeic acid and rosmarinic acid has more protective effect than single dose of compound on oxidative stress. Therefore, we conclude that caffeic acid and rosmarinic acid from Perilla frutescens has synergistic protective effect on oxidative stress in vitro and in vivo.

Grant Funding Source : Ministry of Education, Science and Technology. Korea
Analysis of Lymphocyte Specific Protein‐1 (LSP‐1) expression in normal primary rat hepatocytes and liver following partial hepatectomy
Authors: Koral Kelly , Paranjpe Shirish , Mars Wendy , Jongstra Jan , Michalopoulos George
Published: June 2021

Hepatocellular carcinoma (HCC), the most frequently diagnosed form of liver cancer, is associated with high mortality rates. A recent finding of our laboratory shows that a portion of the gene for lymphocyte‐specific protein 1 (LSP1), an intracellular F‐actin binding protein expressed in neutrophils, macrophages and endothelial cells, is deleted or amplified in a majority of HCCs evaluated. The deletions of LSP‐1 correlated with large tumor size indicating that LSP‐1 may play an inhibitory role in hepatocyte growth. Based on these findings, we hypothesize that LSP‐1 expression is a critical regulator of cellular growth underlying HCC development. However, the expression of LSP‐1 in hepatocytes and normal liver remains to be elucidated. Utilizing immunoblotting and Reverse Transcriptase PCR (RT‐PCR), we examined the total protein and mRNA expression of LSP‐1 in primary rat hepatocytes in vitro and in rat liver tissue after partial hepatectomy. In the rat, LSP‐1 has three known splicing variants; therefore we will examine the expression of the isoforms of LSP‐1 using RT‐PCR with isoform specific LSP‐1 primers. Results from both immunoblotting and RT‐PCR experiments indicate that primary rat hepatocytes and tissue from partial hepatectomized livers express LSP‐1 and that the expression correlates inversely with the rate of growth. Future studies aim to address the function of LSP‐1 in normal and diseased liver states and whether LSP‐1 plays a critical role in hepatocyte growth. Research supported by grant 5T32HL094295‐02.
Injectable extracellular matrix derived hydrogel for cardiac repair
Authors: Christman Karen
Published: June 2021

Injectable materials present the exciting opportunity of minimally invasive therapy to prevent heart failure by providing a temporary scaffold to replace the damaged extracellular matrix (ECM) that occurs post‐myocardial infarction (MI). To date, no material appropriately mimics the ECM composition and structure and most have failed to translate to catheter‐based delivery. We have developed an injectable form of myocardial ECM that retains native proteins, peptides, and polysaccharides, and self‐assembles into a nanofibrous gel upon injection into the myocardium. We have recently demonstrated that this injectable myocardial matrix preserves left ventricular (LV) volume and cardiac function post‐ MI in a rat model, as well as increases post‐MI endogenous cardiomyocyte survival. We have also shown that the myocardial matrix can be delivered via a percutaneous transendocardial approach using the NOGA guided Myostar catheter and improves LV volume and cardiac function in a porcine MI model. This acellular scaffold has the potential to be an effective minimally invasive treatment for MI and heart failure, providing the appropriate extracellular environment to replace the damaged ECM. The material has also been shown to increase maturation of human embryonic stem cell derived cardiomyocytes, and thus also has potential as a scaffold for cell‐based cardiac tissue engineering.
Nano‐fibrous microspheres with sustained growth factor delivery for bone regeneration
Authors: Liu Xiaohua
Published: June 2021

In this study, we developed a unique scaffolding system in which the biodegradable nano‐fibrous microspheres (NF‐MS) serve both as an injectable scaffold and as a growth factor carrier for bone regeneration. The NF‐MS were fabricated by a novel approach, which integrated an emulsification and a thermally induced phase separation technique. The NF‐MS mimicked the architecture of natural collagen fibers at a nanometer scale and had many unique properties including extraordinarily high surface area and extremely low density. Growth factors were effectively encapsulated (>90%) into the NF‐PLLA microspheres through a simple process without using any organic solvent. In vitro release kinetics indicated that the encapsulated recombinant human bone morphogenetic protein 7 (rhBMP‐7) in the NF‐MS were released in a temporal controlled manner. When used as an injectable scaffold for repairing the rat critical‐size calvarial defects, the rhBMP‐7‐loaded NF‐MS induced a much more significant amount of new bone formation than the rhBMP‐7‐free NF‐MS control. We conclude that the nano‐fibrous architecture combined with the sustained release of bioactive rhBMP‐7 from the NF‐MS are excellent cell carrier for bone regeneration. Support: NIH5P30DE20742

Grant Funding Source: NIH 5P30DE20742
The Lamins are Major Determinants of Nuclear Architecture
Authors: Goldman Robert , Adam Stephen , Goldman Anne E. , Butin-Israeli Veronika , Shimi Takeshi
Published: June 2021

The A‐and B‐type nuclear lamins (LA/C, LB1 and LB2) form separate but interconnecting networks within the nuclear lamina and nucleoplasm. Hundreds of mutations in the LMNA gene cause a wide range of diseases including the premature aging disease, Hutchinson‐Gilford Progeria Syndrome (HGPS). The nuclei of HGPS patients’ cells exhibit a wide range of changes in the architecture of their nuclei, including the formation of LA/C rich nuclear envelope blebs, a loss of peripheral heterochromatin, alterations in epigenetic modifications of chromatin, and changes in the RNA pol II transcriptional machinery. Recently we have focused our attention on the mechanisms responsible for the premature senescenece of cells derived from HGPS patients. The results demonstrate that the nuclear lamins are critical factors in the proliferation and senescence of both normal diploid and HGPS cells. Supported by the NCI and the Progeria Research Foundation.
The evolution of the nucleus
Authors: Lake James A.
Published: June 2021

Recent genomic analyses, Cox et al., (PNAS, 2008, and Phil. Trans. Roy. Soc. B, 2009) have reinvestigated the archaeal origins of the eukaryotes and found strong evidence that the nucleus may have evolved according to the Eocyte tree, rather than the Woeseian three domain tree (see, Zimmer, C. On the Origin of Eukaryotes, Science, 2009). This has major implications for the evolution of the eukaryotic nucleus. For example it explains how many eukaryotic information processing proteins, including ribosomal proteins L35Ae, S7e, S26e, L13e, etc., and rRNA processing molecules such as RNA polymerase Rpc34 and pre‐mRNA cleavage complex II protein, are found in the eocyte prokaryotes. Here I explore the alternative that the nucleus, in addition to the mitochondrion and chloroplast, may itself be an endosymbiont.
An innovative approach teaching 650 medical students in the Anatomy course at St. George's University in Grenada
Authors: Loukas Marios , Hage Robert , Burns Danny , Jordan Robert , Curry Brian , Brahim Feisal , Marshall Ewarld , Bubb Kathleen , Wade Alena , George Rachel
Published: June 2021

Since the Flexner reports of 1910, great debate has surrounded medical school curricula. Recently, both problem‐based and traditional teaching modalities within medical school gross anatomy curriculum have been the subject of considerable controversy. This paper describes the modified, multimodal, anatomy curriculum at St. George's University School of Medicine. The reformed program emphasizes the importance of a balance of both traditional and problems based curriculum to ensure a horizontal and vertical integration of core concepts of the basic sciences and clinical competencies. More specifically, the paper describes the teaching modalities employed to teach 650 students per semester including lectures, PBL sessions, gross lab sessions (with the use of cadaver, plastinated cadavers and endoscopes), imaging sessions ultrasound hand on experience sessions, physical examination sessions and research sessions. The usmle type of anatomy exams and faculty team based approach to teaching will also be presented. The innovative curriculum reform, fueled by technological advancements, improves upon previous course standards thereby equipping students with the tools to become lifelong learning physicians.
The Basic Science Survey Series for Dentistry – Trends in gross anatomy within the North American dental schools
Authors: Lambert H Wayne , Gould Douglas J , Lee Lisa MJ , Burk Dorothy T , Atsas Stavros , Hutchins Bob
Published: June 2021

The Basic Science Survey Series for Dentistry was initiated to assess how undergraduate dental students are taught the basic sciences via nine Web‐based surveys completed by course directors. The purpose of this educational project was to help dental faculties in their curricular planning efforts by establishing what topics are taught, faculty involvement, and pedagogy in the dental basic sciences. The response to the dental gross anatomy survey was impressive with 71 respondents reporting data representing all of the 67 US and Canadian dental schools (or a 100% response rate). The results of the surveys indicate, amongst other things, that: 1) reliance upon medical school faculty and facilities is high; 2) emphasis on clinical topics has increased; 3) a general trend for a decrease in student contact hours is ongoing; 4) the use of computer‐assisted instruction tools has increased; 5) a pattern of increased use of integrated dental curricula has emerged; and 6) the experience levels of faculty indicate a future need for young faculty competent at teaching in the anatomical sciences. These results are impacting the construction of a Biomedical Sciences Foundations document within dental education.
Anatomy in dental education: past, present, future
Authors: Davenport William D
Published: June 2021

Today we see the labor intensive hours in the classroom and laboratory diminishing. Methods of delivery are also evolving with the development of technology and the modality in which today's student reportedly best learns. With the advent of the competency based model, dentistry has embarked on curriculum changes that have been designed to incorporate life‐long learning, critical thinking, and translational integration across disciplines. Even now there is a focus on interdisciplinary training across the various health care professions. In looking at the various anatomical science curricula across North American Dental Schools, the objectives are still to teach the basic anatomical science foundation as well as include new contemporary information and emphasizing the relevance of the discipline to the practice of contemporary clinical dentistry. The delivery modalities currently include: traditional lecture/lab, PBL, hybrid lecture‐PBL, web‐based, modular, and integrated. Fortunately, there are many ways to “skin a cat” and even schools that are in the continual flux of curriculum renovation report success in delivering adequate foundation knowledge in the anatomical sciences. What is used to assess this? In all instances, it is “passing” the course and “passing” Part I of the National Dental Boards. We have no tool for measuring true learning and application much less any critical thinking skills that should have been developed along the way. Once over the academic hurdle of the basic sciences, the concentration is in the clinical arena where we see considerable disparity in the way the basic foundation knowledge is reinforced in the various clinical disciplines. With the current proliferation of new dental schools, whose curricula range from traditional to unique, we can only look forward to a continued decrease in the available hours for anatomical science education, the lack of facilities for wet lab study of anatomical specimens, an increased integration of the with other disciplines, and an expansion of teaching technologies.
Early Events in DNA Replication
Authors: Diffley John F.X.
Published: June 2021

The eukaryotic cell cycle coordinates the accurate duplication and segregation of the genome during proliferation. The large genomes of eukaryotic cells are replicated from multiple replication origins during S phase. These origins are not activated synchronously at the beginning of S phase, but instead fire throughout S phase according to a pre‐determined, cell type specific program. Only after the entire genome is completely replicated do cells proceed into mitosis.

Ensuring that each origin is efficiently activated once and only once during each S phase is crucial for maintaining the integrity of the genome. This is achieved by a two‐step mechanism. The first step, known as licensing, involves the loading of the Mcm2–7 proteins into pre‐replicative complexes (pre‐RCs) at origins. We have recently reconstituted this reaction with purified proteins (Remus et al. Cell 2009 139: 719–30). In this reaction, Mcm2–7 are loaded as a head‐to‐head double hexamer around double stranded DNA. Mcm2–7 loading requires the Origin Recognition Complex (ORC) as well as Cdc6 and Cdt1. I will describe recent experiments showing that individual Mcm subunits play distinct roles during pre‐RC assembly by interacting with different assembly factors. I will also show that the role of cyclin dependent kinases in promoting initiation has been conserved, at least in part, between yeast and humans.
Insights into membrane dynamics in autophagy
Authors: Yoshimori Tamotsu
Published: June 2021

In autophagy, the unique double membrane‐bound autophagosomes transiently emerge in the cytoplasm, sequester portion of cytosol and organelles, and eventually fuse with lysosomes to degrade the contents. The longstanding question in the filed is where autophagosome membrane comes from. We found that one of autophagy‐related (Atg) proteins, Atg14L localizes to the endoplasmic reticulum (ER) as well as autophagosome and the cytosol and its localization to the ER is essential to autophagosome formation. Meanwhile, electron tomography revealed that a subdomain of the ER forms a cradle encircling an immature autophagosome and the membranes were interconnected. Taken together, we suggest that the ER is a platform of autophagosome biogenesis. Furthermore, we revealed that autophagosome formation involves the linkage between the ER and mitochondria, which is also suggested as the autophagosome generator by another group.

In addition, through investigation of autophagy against invading Salmonella, we showed that the LC3 (Atg8) system is recruited through a mechanism that is independent of the autophagosome membrane generation machinery, providing new insights into the mechanisms and the widely accepted model for selective autophagy.
Alteration of Metabolic Program by whiB6 Enhances Tuberculosis Persistence
Authors: Jacobs William , Weinrick Brian
Published: June 2021

Persisters, drug sensitive survivors of drug treatment, may be the basis of the need for lengthy treatment regimens to cure tuberculosis and could also contribute to the ability of the bacteria to establish a latent infection.

We established a basic model of persistence by treating M. tuberculosis cells with isoniazid, an antibiotic that induces lytic cell death. After four days exposure 99.9% of the initial inoculum is killed and the remaining population is significantly enriched in persisters. The transcriptional profile of these persister cells was compared to untreated cells. The most differentially expressed gene not also affected by short‐term isoniazid treatment was a putative transcription factor, whiB6.

We created whiB6 knock out and complemented strains and identified the whiB6 regulon by transcriptional profiling. The whiB6 regulon is composed of genes involved in lipid anabolism, energy metabolism, and adaptation to hypoxia, heat shock, and oxidative stresses. The whiB6 mutant displayed drug tolerance alterations only under conditions simulating in vivo growth. We investigated the behavior of the whiB6 mutant in a mouse model of drug treatment, latency, and reactivation. The mutant was more effectively killed by drug treatment and may be less likely to enter a latent state.
Developing Administrative/Organizational Skills
Authors: Bond Judith S
Published: June 2021

Careers in science call for orchestration of many skills, talents and resources to achieve success. Scientists at all stages of their careers feel that there is too much to do and too little time. Individuals have to develop skills and strategies to deal with multiple career demands, frustration and their personal lives. Failure to acquire needed approaches and strategies makes one vulnerable to being pulled in many directions at once. As a result, you will be reacting to the most immediate deadlines and not reaching your long‐range goals. There are several tools that enable one to develop strategies that work. The first step is to identify career and personal goals with short‐term and long‐term landmarks. This step needs to be re‐visited periodically, especially when unanticipated circumstances arise. Next, make an inventory of strengths and weaknesses, organization/department priorities, written and unwritten rules. Also, learn how to take advantage of opportunities, how to choose mentors, and how to find a unique role in an organization and profession. Each career plan is unique, evolves, must be flexible, and may lead to unexpected and rewarding, endpoints.
Opportunities in the Private Sector
Authors: Rosenberg Martin
Published: June 2021

The number of life science graduates (BS, MS, PhD and post doc) entering the job market continues to significantly outpace the career opportunities available for academic research faculty positions. This trend has been ongoing for decades but has certainly become more pronounced in recent years. During the 1980s and ‘90s the growth in private sector jobs for life scientists (e.g., the Biotech industry, R&D expansion in Pharma, etc.), in addition to increased hiring in the public sector (e.g., government) provided alternative careers for the ever‐increasing numbers of graduates. Many of the jobs in the non‐academic sectors did not require bench skills but did require strong scientific acumen.

In the past decade however, a variety of factors (e.g., economic) have resulted in major shifts in the availability of non‐academic bench and non‐bench opportunities for life scientists. Jobs in academia remain stagnant and the training period for PhDs and post docs has expanded, in part, due to the slow down in employment opportunities.

We will discuss the impact of these various changes on the current and future trends in the life sciences job markets. Are there bright spots? What skill sets are needed to be competitive? Are the current training systems adequate and appropriate for meeting the needs? My hope is to stimulate your thinking about how to maximize your marketability and competitiveness in these challenging times.
Effective Use of Social Networking for Career Development
Authors: Balbes Lisa Marie
Published: June 2021

Globalization, the Internet and information technology have changed the way we do business. But they have also changed the way we find business, jobs, and even careers. New technological tools such as blogs, social networking sites, wikis, location‐based services, and video conferencing provide a wealth of information ‐ both for you and about you. This presentation will focus on tools and techniques of particular use to scientists, and how they can be used for active and passive professional career development.