bluuebunny/crossref_metadata_2025_split huggingface dataset:
Plasma Kallistatin is Associated with Leukocyte Telomere Length in Young African Americans
Authors: Zhu Haidong , Chao Julie , Raed Anas , Huang Ying , Bhagatwala Jigar , Parikh Samip , Dong Yanbin 
Published: November 2023

ObjectiveLarge population studies demonstrate that African Americans versus their Caucasian counterparts have a steeper decline in leukocyte telomere lengths (LTL) with age. Telomere shortening plays an important role in cellular aging. Kallistatin, a novel tissue kallikrein inhibitor, has anti‐inflammatory and anti‐oxidant properties. Recently we have shown that kallistatin inhibited vascular injury and cell apoptosis in animal models and cultured cells. Thus we aimed to test our hypothesis that plasma kallistatin levels are positively associated with LTL in African Americans.MethodsLeukocyte telomere lengths (the relative ratio of telomere repeat copy number (T) to single‐copy gene copy number (S)) were determined by a quantitative polymerase chain reaction method in 188 (60 males and 128 females) apparently healthy young African American subjects aged 13 to 49 years. Plasma kallistatin levels were measured by enzyme‐linked immunosorbent assay.ResultsCompared to males, females were older (24.0 ± 9.19 vs 17.9 ± 4.5 years, p<0.001), and had slightly shorter LTL (T/S ratio 1.00 ± 0.23 vs 1.09 ± 0.27, p= 0.03). In the whole sample, plasma kallistatin levels are positively and significantly associated with LTL (r=0.31, p<0.001). The significance persisted after adjusting for age, sex, and body mass index (r= 0.16, p=0.04).ConclusionThis is the first study to examine the relationship between kallistatin and telomeres in humans. Kallistatin may have anti‐cellular aging effect, which may be attributed to its anti‐inflammatory and anti‐oxidant properties. These finding indicate that plasma kallistatin might serve as a biomarker for cellular aging in humans.Support or Funding InformationHZ and YD are supported by NHLBI PO1 HL69999 and AHA 14GRANT20480211.
Adipose Depot‐Specific Differences in Transcriptome and MicroRNA Expression in High Fat Diet Induced Obese Mice
Authors: Wijayatunga Nadeeja N , Pahlavani Mandana , Kottapalli Rao , Dawson John A , Ramalingam Latha , Gunaratne Preethi H , Coarfa Cristian , Rajapakshe Kimal , Kalupahana Nishan S , Moustaid‐Moussa Naima 
Published: November 2023

Obesity is characterized by white adipose tissue (WAT) expansion which contributes to chronic diseases such as diabetes and cardiovascular disease. Two main types of adipose tissue are WAT (subcutaneous, SAT and visceral adipose tissue, VAT) and brown adipose tissue (BAT). These exhibit anatomical, physiological and metabolic differences that contributes to energy balance, metabolic regulation and immunity. Our aim was to compare transcriptomic and microRNA (miRNA) signatures of SAT, VAT and BAT to gain mechanistic insight into the role of these depots in metabolic disorders. We performed RNA‐sequencing and miRNA profiling of SAT, VAT and BAT depots from diet‐induced obese C57BL/6J male mice fed high fat diets (45% kcal fat). We used a transcriptomic approach to dissect adipose depot‐specific genetic and functional signatures in obesity. RNA sequencing was performed using Illumina Hi‐Seq and differential gene expression was studied by pair wise comparisons of fat depots. Functional and pathway analyses performed using Ingenuity® Pathway Analysis software revealed inflammatory pathways such as cytokine and integrin signaling increased along with immune‐related processes in VAT compared to BAT. In contrast, pathways involved in fatty acid oxidation, apoptosis and energy expenditure (peroxisome proliferator activated receptor (Ppar)/retinoid X receptor (Rxr‐α)) were higher in BAT than in VAT. X‐box binding protein‐1 (Xbp1), an unfolded protein response (UPR) mediator in endoplasmic reticulum (ER) stress, was a common upstream regulator that was consistently activated in both VAT and SAT in comparison to BAT. Xbp‐1 targets include ER related genes such as glucose‐regulated protein 78 and 94 (Grp78, Grp94), calreticulin, protein disulfide isomerase family A 3 and 6 (Pdia3 and Pdia6) all of which showed higher expression in VAT than BAT. Interestingly, miR‐30c‐2‐3p which causes downregulation of Xbp1 was lower in VAT than in BAT, in agreement with higher Xbp1 levels in VAT compared to BAT. Furthermore, other miRNA‐mRNA pairs involved in UPR such as miR‐455‐calreticulin were also identified. Additionally, miRNAs miR‐221‐3p and miR‐222‐3p, related to higher inflammation and ER stress were activated in VAT compared to BAT, suggesting more inflammation and ER stress in VAT compared to BAT as expected. In summary, high fat diets differentially regulate specific miRNAs and gene expression in different adipose tissue depots with significant induction of ER stress and inflammation in VAT. Currently, studies are ongoing to validate these findings which would provide insight into the contribution of different fat depots to various metabolic pathways and will potentially impact various diseases associated with obesity.Support or Funding InformationStartup funds from TTU
Location of Iron and Ferritin in the Midgut of the yellow fever mosquito, Aedes aegypti
Authors: Love Maria B , Geiser Dawn L , Winzerling Joy J 
Published: November 2023

Dengue and Yellow Fever are caused by viruses transmitted by mosquitoes that each year infect 390 million and 200,000 people, respectively, and cause more than 2 million deaths. For mosquito eggs to develop and produce viable offspring, iron is required as an essential nutrient from the blood meal. Our previous research has shown iron from the blood meal is absorbed and transported by ferritin from the midgut to the ovaries in Aedes aegypti (yellow fever mosquito). Thus, understanding iron accumulation and utilization in the mosquito midgut is important to finding potential strategies to interfere with mosquito fecundity, decrease mosquito populations, and reduce transmission rates of vector‐borne diseases. However, it is unknown where in the midgut iron accumulates after a blood meal. To demonstrate this, Ae. aegypti midguts were dissected from sugar fed, 24 h post‐blood meal (PBM), and 72 h PBM animals to measure tissue iron accumulation after a blood meal by iron inductively coupled plasma mass spectrometry (ICP‐MS). Dissected midguts were also stained with Prussian Blue to visualize ferric iron deposition. Our results indicate that iron is present in the midgut prior to a blood meal, accumulates at 24 h PBM, and decreases by 72 h PBM, and the deposition of ferric iron is observed throughout the tissue before and after a blood meal. Further, immunohistochemistry studies of the midguts show three different subunits of the iron storage and transport protein, ferritin. Coalescence of ferritin and iron in mosquito midguts confirms the role of ferritin in this tissue for export of iron to other tissues, including the ovaries for oogenesis and ovarian homeostasis.Support or Funding InformationThis research was supported by funds from the Arizona Agricultural Experiment Station, the College of Agriculture and Life Sciences, the Undergraduate Biology Research Program, and the Honors College at the University of Arizona.
Blueberry supplementation attenuates oxidative stress within the monocytes and modulates immune cell levels in adults with Metabolic Syndrome
Authors: Nair Anand R , Mariappan Nithya , Stull April J , Francis Joseph 
Published: November 2023

Background and rationaleBlueberries (BB) have been shown to have extensive health benefits in animals, including improvement of mitochondrial integrity, inflammation and redox status. In addition, we have found that BB improves insulin sensitivity in obese, pre‐diabetic humans and rodents, and decreases oxidative stress and inflammation, and protects against cardiovascular and renal damage in rodents. These findings indicate that BB have a whole body effect and are not limited to a particular organ system. In order for BB to exert beneficial effects on the whole body, the mechanism would logically have to operate through modulation of cellular humoral factors. The blood leukocytes are important cells protecting against injury or infection. The present study investigated the role of BB in modulating cellular humoral factors in subjects with metabolic syndrome (MetS).MethodA placebo‐controlled study was conducted on adults with MetS, where they received a BB or placebo smoothie twice daily for six weeks. Free radical production in the whole blood and monocytes, dendritic cells (DC) measurement, gene expression levels of cytokines in monocytes and serum inflammatory marker levels were assessed pre‐ and post‐intervention. MetS patientsResultsBaseline free radical levels in the whole blood and monocyte of MetS patient samples were not different in both groups.. In contrast, treatment with BB markedly decreased superoxide and total ROS in the whole blood and monocytes compared to placebo treated MetS patients samples (p<0.05). Next we examined the dendritic cell number and inflammatory markers in the blood of MetS patients. There was no significant difference in the baseline DC number for both myeloid and plasmatoid DCs in MetS patients samples. Treatment with blueberries markedly increased myeloid DC and had no effect on plasmatoid cells. In addition, BB treatment also decreased monocyte and plasma inflammatory molecules in MetS patients when compared with placebo treated controls. These findings indicate that BB exerts immuno‐modulatory effects, in addition to its antioxidant and anti‐inflammatory effects, thereby protecting against MetS.ConclusionsBlueberries modulates immune cells and attenuate oxidative stress and inflammation in the blood of MetS patients.Support or Funding InformationThis work was supported by U.S. Highbush blueberry council (USHBC) grant to Dr. Francis.
A Novel Element in the Cytoplasmic domain of the Type I TGFβ Receptor Mediates Basolateral Targeting in Polarized Epithelial Cells
Authors: Yin Xueqian 
Published: November 2023

Delivery of biomolecules to the correct subcellular locales is critical for proper physiological function. To that end, we have previously determined that the type I and II TGFβ receptors (TβRI and TβRII, respectively) localize to the basolateral domain in polarized epithelia. While TβRII targeting was shown to be regulated by sequences between amino acids 529–538, the analogous region(s) within TβRI is unknown. To address that question, sequential cytoplasmic TβRI truncations and point mutations identified a targeting motif between residues 158 to 163 (VxxEED) required for basolateral TβRI expression. Further studies documented that receptor internalization, downregulation, direct recycling, or Smad signaling were unaffected by motif mutations which caused TβRI mislocalization. However, a 70 amino acid stretch containing the targeting motif was able to direct basolateral expression of the apically sorted Neurotrophin receptor (p75; extracellular and transmembrane regions) in a dominant manner. Lastly, co‐expression of apically targeted type I and type II TGFβ receptors mediated Smad3 signaling from the apical membrane of polarized epithelial cells. These later findings demonstrate that the absence of apical TGFβ signaling in normal epithelia reflects domain‐specific receptor expression and not an inability to couple with the signaling machinery.Support or Funding InformationThis work was supported by Public Health Service grants GM‐055816 and GM‐054200 from National Institutes of General Medical Sciences.
CREB regulates the expression of PERK and IRE1a, and controls unfolded protein response under hypoxic conditions
Authors: Nakayama Koh 
Published: November 2023

Cells are frequently exposed to different stresses. Hypoxic condition induces ER stress, and activates unfolded protein response (UPR) to maintain homeostasis. Whereas Hypoxia‐inducible factor plays a major role in an adaptation to hypoxia, we previously identified that transcription factor CREB also has an important role in this process. To further understand the role of CREB in hypoxic response, CREB stable knock‐down cells (CREB‐KD) were established from breast cancer MDA‐MB231 cells and analyzed.CREB was found to be activated by ER stress, and the activation of CREB and UPR pathway occurred in a coordinated manner by various stimuli, including ER stress‐inducing chemicals, hypoxia and oxygen‐glucose deprivation (OGD). Depletion of CREB decreased the expression of PERK and IRE1a, two of the critical UPR signaling molecules. ChIP assay and promoter analysis indicated that CREB interacts with the promoter region of these molecules and regulate the expression of them. ER stress induced by hypoxia was found to be reduced in CREB‐KD cells, which led to less pulmonary metastasis in mice. Finally, OGD strongly activated UPR and induced cell death in control cells, whereas this activity was moderate in CREB‐KD cells, thus more resistant to cell death.Taken together, the study demonstrates a previously unknown role of CREB as a regulator of ER stress in cells, which is required for a proper response to the stressful conditions, such as hypoxia.Support or Funding InformationGrant‐in‐Aid for Scientific Research C, and Grant‐in‐Aid for Scientific Research on Innovative Areas(KAKENHI).
Reactive Oxygen Species‐Dependent PKB Activation Contributes to Insulin‐Like Growth Factor 1‐Induced Phosphorylation of Histone Deacetylase 5 in Vascular Smooth Muscle Cells
Authors: Pietruczuk Paulina , Srivastava Ashok K 
Published: November 2023

Insulin‐like growth factor 1 (IGF‐1), a potent mitogenic and vasoactive factor, has been shown to play an important role in the development of cardiovascular diseases. This occurs through the generation of reactive oxygen species (ROS) as well as through the hyperactivation of mitogenic and growth promoting signaling pathways and the subsequent alteration in gene expression. Histone deacetylases (HDACs), by their ability to modify the acetylation status of lysine residues in histone and non‐histone proteins, regulate gene transcription. Recent studies have demonstrated that a heightened activation of HDACs, notably HDAC5, is associated with vascular disorders such as atherosclerosis. However, a role of IGF‐1 in HDAC activation by phosphorylation remains poorly characterized. Therefore, in the present studies, we examined the effect of IGF‐1 on the phosphorylation of HDAC5 in vascular smooth muscle cells (VSMCs) and identified the signalling pathways involved in this process. Treatment of A10 VSMCs with IGF‐1 enhanced the phosphorylation of HDAC5 at serine 498 in a time and dose‐dependent fashion. Pretreatment of cells with AG1024, a selective pharmacological inhibitor of IGF‐1 receptor, significantly inhibited IGF‐1‐induced HDAC5 phosphorylation in A10 VSMCs whereas AG1478, a selective inhibitor of epidermal growth factor receptor, did not have an inhibitory effect on the levels of phospho‐HDAC5. Pharmacological blockade of the MAPK pathway with PD98059 and UO126 had no effect on HDAC5 phosphorylation, however wortmannin and SC‐66, inhibitors of the PI3K/PKB pathways, almost completely attenuated IGF‐1‐induced HDAC5 phosphorylation. In addition, pretreatment of A10 VSMCs with Diphenyleneiodonium (DPI) and apocynin, two NAD(P)H oxidase inhibitors, as well as the antioxidant N‐Acetyl‐Cysteine (NAC), resulted in an attenuation of IGF‐1‐induced phosphorylation of HDAC5 as well as PKB. In summary, these data demonstrate that IGF‐1 induces the phosphorylation of HDAC5 in a ROS‐ and PKB‐dependent fashion in VSMCs.Support or Funding InformationSupported by a grant from the Canadian Institutes of Health Research.
O‐GlcNAc Regulates p53 in Ovarian Cancer
Authors: Queiroz Rafaela Muniz , Chien Jeremy , Madan Rashna , Slawson Chad , Dias Wagner 
Published: November 2023

O‐GlcNAcylation is a dynamic post‐translational modification (PTM) that consists of an addition of a single N‐acetylglucosamine sugar to serine and threonine residues in nuclear, cytoplasmic and mitochondrial proteins. The enzyme O‐linked β‐N‐acetylglucosamine transferase (OGT) adds the modification, while enzyme O‐GlcNAcase (OGA) removes the modification. O‐GlcNAc regulates enzymatic activity, localization, stability and protein‐protein interactions on a wide range of proteins such as transcription factors, structural proteins and kinases. In cancer, when comparing O‐GlcNAc levels in normal and tumor cells, tumor samples present higher O‐GlcNAcylation in vitro and in vivo. This aberrant O‐GlcNAc pattern contributes to changes in important signaling pathways and could contribute to the progression of the disease. Interestingly, the tumor suppressor p53 is modified by O‐GlcNAc. The transcription factor p53 regulates diverse cellular processes like cell survival and the cell cycle. Most solid tumors contain mutations in p53 leading to increased degradation or loss of p53 function, which promotes malignant tumor growth. Ovarian cancer has one of the highest frequencies of p53 mutation rates. The goal of this work is to understand the relationship between O‐GlcNAcylation and p53 function in ovarian cancer. First, O‐GlcNAcylation, OGT and OGA protein and mRNA levels were measured in a series of human ovarian cancer cell lines and no correlation was found between p53 genetic status and O‐GlcNAcylation. Overexpression or silencing of p53 in a p53 wild‐type cell line (A2780) had little effect on O‐GlcNAcylation. On the other hand, pharmacological inhibition of OGA with the inhibitor Thiamet‐G (TMG) leads to an increase in nuclear localization of p53 and increased mRNA levels of p53‐target genes (p21 and Bax). Overexpression of OGA or OGT leads to increased p53 protein but not mRNA levels and a concurrent increase in p53‐targets (Mdm‐2, p21 and Bax) expression. Also, p53 acetylation on lysine 382, a transcriptional activating modification, is higher in OGA/OGT overexpressing cells. In conclusion, O‐GlcNAcylation regulates p53 function through stabilization and activation.Support or Funding InformationSupport and funding: Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Science Without Borders Program, NIH NIDDK R01 DK 100595.
BLT2 receptor protects against lethal acute lung injury induced by a pneumococcal toxin pneumolysin
Authors: Shigematsu Misako , Koga Tomoaki , Saeki Kazuko , Okuno Toshiaki , Yokomizo Takehiko 
Published: November 2023

Pneumonia is one of the major causes of death over the world, and the capital cause of infectious pneumonia is S. pneumoniae (pneumococcus). The key virulence factor of pneumococcus is a pore‐forming toxin pneumolysin (PLY). By its direct cytotoxic effect, PLY is known to cause acute lung injury, leading to pneumococcal invasion and subsequent severe bacteremia. Leukotriene B4 (LTB4) receptor type 2 (BLT2) is a G‐protein coupled receptor that was originally identified as a low‐affinity receptor for LTB4, and recently we elucidated that the high affinity endogenous ligand for BLT2 is 12‐hydroxyheptadecatrienoic acid (12‐HHT), an arachidonic acid metabolite by cyclooxygenase. Previously we reported that BLT2 is expressed in intestinal epithelial cells and skin keratinocytes, and that 12‐HHT/BLT2 signaling exhibits important roles in maintaining mucosal integrity and in accelerating skin wound healing. However, the biological roles of BLT2 in other organs are still uncertified. In this study, we investigated the protective role of BLT2 in mouse lung using PLY‐induced acute lung injury model. Interestingly, BLT2‐deficient mice were more susceptible to PLY administration, and also exhibited increased vascular permeability and potent bronchoconstriction by PLY administration when compared to wild‐type mice. We found BLT2 in mouse lung is expressed in alveolar type II cells and vascular endothelial cells. The molecular mechanisms of how BLT2 exhibits the protective role for PLY‐induced acute lung injury are now under investigation.Support or Funding InformationThis work was supported by Grants‐in‐Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (MEXT) Nos. 22116001, 22116002, 15H05901, 15H05904, and 15H04708.
Integrating Rare Disease Research Into An Undergraduate Liberal Arts Curriculum To Enhance The Pace Of Rare Disease Gene Discovery For Underserved Populations And Promote STEM Retention
Authors: Jinks Robert N , Davis Beckley K , Roberts David M , Rice Elizabeth , Brigatti Karlla W , Puffenberger Erik G , Strauss Kevin A 
Published: November 2023

Next‐generation sequencing accelerates disease gene discovery, especially for orphan diseases, though at present it outpaces functional studies needed to provide ‘proof of causation.’Working from a small, community‐based, clinical laboratory, the Clinic for Special Children has identified more than 170 allelic variants associated with disability, disease, or untimely death among the Amish and Mennonite (Plain) populations of North America. In collaboration with the Clinic, we developed an HHMI‐funded program that integrates functional studies of novel disease gene alleles into our undergraduate curriculum. Roughly 150 students per year in our introductory cell biology and neuroscience courses clone human disease genes and study the functional impacts of gene variants through expression in mammalian cell culture. We use these authentic research experiences to teach key concepts in cell biology, genetics, and neuroscience. Students later build upon this experience in upper‐level courses in cell biology, neuroscience, genetics, cancer biology, and immunology in which they engage in semester‐long research projects in small teams. Teams conduct functional studies of disease gene variants or study novel cellular or animal models of disease. These experiences engender talented undergraduates to assume greater research responsibility through independent study and summer research projects that transition them into the role of co‐PI for their project. Data published through this project (e.g., PLoS ONE 7:e28936) have been used by other institutions to establish novel diagnoses, including a high‐profile diagnosis of a critically‐ill, non‐Plain newborn with lethal neonatal seizure‐rigidity syndrome (Sci Transl Med 4:154ra135). This provides important proof‐of‐concept for integrating novel disease gene functional studies into a carefully structured undergraduate research curriculum.Students in our Public Health program are collaborating with the Clinic to develop handbooks to help parents care for children with special medical needs with the goal of producing one to two high‐quality disease handbooks annually.Our program represents a model for engaging undergraduates in meaningful research at the front lines of biomedical science and public health in ways that directly impact the diagnosis and care of children with rare inherited disorders and promote STEM retention.Support or Funding InformationHHMI Undergraduate Science Education Awards 52006294 and 52007538.