bluuebunny/crossref_metadata_2025_split huggingface dataset:
CD4 regulation of activation‐induced cell death
Authors: Tinsley Kevin William , Tatari‐Calderone Zoreh , Leitenberg David 
Published: June 2021

Defects in FAS‐mediated activation induced cell death (AICD) are associated with the development of autoimmunity in both mouse models and human disease. We have previously found that mature T cells with a mutant CD4 co‐receptor unable to associate with Lck are resistant to AICD. Since activated CD4 mutant T cells express similar levels of FasL, Fas, and FADD compared to wild‐type cells, we hypothesize that the CD4‐dependent signaling pathways provide a “competency” signal required by T cells to become susceptible to AICD. In support of this hypothesis, mixing experiments indicate that FasL expression by wild type CD4 T cell blasts could not rescue the defect in AICD seen in CD4 mutant T cells. Additionally, we find that the AICD resistant phenotype in CD4 mutant T cells is primarily observed following peptide restimulation, while wild‐type and mutant CD4 T cells are similarly sensitive to AICD upon re‐stimulation with plate bound anti‐CD3. These experiments suggest that death receptor signaling pathways are compromised in mutant CD4 T cells following physiologic stimulation with peptide that involves CD4 signaling. Since CD4 association with Lck alters the compartmentalization of cellular Lck pools, these data suggest that that distinct pools of Lck may be differentially involved in modulating sensitivity to Fas signaling.Supported in part by a grant from the American Cancer Society.
SLE progression in human and murine SLE is accompanied by cell and pathway specific negative regulation of cytokine signal transduction
Authors: Hale Matthew , Nolan Garry P 
Published: June 2021

Systemic lupus erythematosus (SLE) is a cyclic, persistent disease of unknown etiology, with multiple lines of evidence supporting a model in which aberrant regulation of cytokine signaling pathways promote and sustain SLE. Postulating that such mechanisms may be disturbed in SLE patients, we used phospho‐specific flow cytometry to perform an extensive profile of cytokine signaling in a murine model of SLE and 47 human patients, revealing disease course‐dependent, cell type, and pathway specific negative regulation of the JAK‐STAT signal transduction pathways induced by the interferons. Specific down‐regulation of Stat1, Stat3, Stat5 responses in different immune cell subtypes was correlated with upregulated SOCS1 protein expression. SLE pathology involving the prominent IFNα model is here expanded to include additional signaling nodes, coupling these systems to negative feedback regulation. Pathogenic coupling of positive and negative feedback regulation may explain the cyclic nature of human SLE.This work was supported by NHLBI Proteomics Center contract N01‐HV‐28183 and NIH grant 8‐PA1036535C
Toll‐like receptor signaling increases production of 1,25‐dihydroxyvitamin D3 in bovine macrophages
Authors: Nelson Corwin D. , Beitz Donald C. , Reinhardt Tim A. , Lippolis John D. 
Published: June 2021

Activation of macrophages can occur through Toll‐like receptor (TLR) recognition of pathogen associated molecular patterns (PAMP). Recently, it has been discovered that TLR signaling can increase 1α‐hydroxylase (Cyp27B1) expression in human and mouse macrophages. The enzymatic activity of 1α‐hydroxylase produces the steroid hormone 1,25‐dihydroxyvitamin D3 (1,25(OH)2D3) from its precursor 25‐hydroxyvitamin D3 (25(OH)D3. Thus, we hypothesized that TLR recognition of PAMP can increase Cyp27B1 expression and conversion of 25(OH)D3 to 1,25(OH)2D3 in bovine macrophages. We supplemented bovine monocyte derived macrophages (BMDM) with 25(OH)D3 and stimulated them with ligands for TLR2 and TLR4. Quantitative real‐time PCR was used to measure changes in Cyp27B1 and 24‐hydroxylase (Cyp24A1) mRNA expression. Stimulation of BMDM with TLR2 and TLR4 ligands in the presence of 25(OH)D3 resulted in increased Cyp27B1 and Cyp24A1 mRNA expression. Conversion of 25(OH)D3 to 1,25(OH)2D3 in BMDM was demonstrated by increased expression of Cyp24A1, which is dependent on binding of the vitamin D receptor/1,25(OH)2D3 complex to the Cyp24A1 promoter. In conclusion, our results show that an autocrine vitamin D signaling pathway is present in bovine macrophages. Future studies will focus on the impact of vitamin D on the bovine immune system at the cellular and molecular level.Funded by USDA‐ARS CRIS 3625‐32000‐094‐00D
Novel function of complement C3d as an autologous helper T cell target
Authors: Knopf Paul , Hai Si‐Han , Rivera Daniel S. , Martin William , McMurray Julie , De Groot Anne S. 
Published: June 2021

The C3d fragment of complement component C3 has been shown to enhance immune responses to antigens that lack T‐cell epitopes such as bacterial polysaccharides by binding to the B cell complement receptor (CD21). Paradoxically, C3d has also been shown to enhance B cell and T cell responses in the CD21 KO mouse model, suggesting that that an auxiliary CR2‐independent pathway of immune activation may exist. We hypothesized that in addition to its molecular adjuvant property that enhances signal 1 during B cell activation (co‐signal 1), C3d also contains T cell epitopes that are able to stimulate autoreactive C3d peptide‐specific helper T cells which we term “co‐signal 2”.Using the EpiMatrix T‐cell epitope‐mapping algorithm, we identified 11 putative T‐cell epitopes in C3d. Stimulation of human PBMC with C3d‐derived peptides leads to dramatic increases IFN‐γ secretion. These IFN‐γ secreting cells were exclusively found to reside in the CD4+ T helper subset by FACS analysis.We believe that the discovery of these autologous T cells autoreactive for C3d provides evidence supporting the “co‐signal 2” hypothesis and may offer a novel explanation of the CD21 KO paradox. This data suggests a novel mechanism for the adjuvant effect of C3d and raises questions regarding self‐tolerance and suggests the possibility of AIRE‐independent differentiation into non‐pathogenic, self‐reactive T cells.All work funded by EpiVax, Inc.
Feeding acutely increases MyoD1 and decreases myostatin mRNA in human skeletal muscle
Authors: Atherton Philip , Smith Gordon , Villareal Dennis , Rankin Debbie , Mittendorfer Bettina , Rennie Michael 
Published: June 2021

Feeding a mixed meal doubles muscle protein synthesis (MPS) within 90 min, an effect sufficiently rapid to be mostly due to changes in anabolic signalling. We examined the possibility that feeding may also acutely modulate transcriptional activity of genes controlling muscle mass, viz, MyoD1 and myostatin.We studied the effect of intermittent small meals (Ensure®, to provide 70 mg protein·kg Fat free mass −1·h−1) in older men and women who were matched for age (65–80 y) and BMI. MPS was measured by incorporation of D3‐leucine into mixed muscle protein (13 men, 16 women). RT‐PCR was used to analyse changes in the expression in quadriceps muscle (7 men, 7 women) of the hypertrophy‐associated transcription factor, MyoD1 and myostatin, a negative regulator of muscle mass, with 28s mRNA used as a reference gene.The rate of postabsorptive MPS was ∼25% less in men than in women (P=0.02). At 2.5 h after beginning feeding, MPS increased by 30% (P<0.01) but only in men. Expression of mRNA for myostatin and MyoD1 were identical in men and women in the postabsorptive state, but feeding decreased expression of myostatin mRNA by 63±9% (P<0.05) and increased that of myoD by 83±5% (P<0.01).Thus, feeding acutely modulates the expression of genes likely to promote a milieu conducive to potential increases in muscle mass but these changes seem not to match the lack of an acute response of MPS to feeding in older women.
A Randomized Double‐Blind Active‐Controlled Study of the Safety of UP165 and its Effects on Assessments of Depression, Anxiety and Well Being
Authors: Kalman Douglas S , Arencibia Karina , Feldman Samantha 
Published: June 2021

This clinical trial compared the safety and effects of UP165, a dietary supplement that may be linked to mood function, with SAM‐e (s‐adenosylmethionine), a popular mood enhancing supplement. Assessments were made using the Beck Depression Inventory (BDI‐II), the Beck Anxiety Inventory (BAI), Schwartz Outcome Scale (SOS‐10) and Arizona Sexual Experiences Scale (ASEX). Forty‐two subjects (21–65 yo) were randomized to eight‐weeks of supplementation with UP165 or SAM‐e with questionnaires being administered at screening/randomization and weeks 4 and 8 of supplementation. Thirty‐four subjects were included in the efficacy analysis. There were no safety concerns raised by this study. UP165 and SAM‐e produced improvements in scores on the four questionnaires although no statistically significant differences were observed. UP165 was shown to be non‐inferior to SAM‐e with respect to depression (not within the ±8.35 equivalence tolerance interval) and equivalent to SAM‐e with respect to anxiety (fell within the ±6.4 equivalence tolerance interval). No superiority was noted between products. Future studies should examine increases in dose and or duration. A randomized double blind placebo‐controlled trial could strengthen the findings.Funded by a grant from: Unigen Pharmaceuticals
Variability in caffeic acid protection from dextran sulfate sodium‐induced colitis in mice
Authors: Ye Zhong , Hong Chung‐Oui , Lee Kwangwon , Hostetter Jesse , Wannemuehler Michael , Hendrich Suzanne 
Published: June 2021

To examine interindividual variability in the efficacy of caffeic acid protection against colitis, 36 10‐wk‐old CD‐1/IGS female mice were fed 120 mg caffeic acid/kg diet for 7 d, with 12 controls fed AIN93G diet. Half of the mice in each treatment were then given 1.25% dextran sulfate sodium (DSS) in drinking water for 5 days. Caffeic acid prevented mouse body weight loss by DSS (p < 0.05). Colon lengths in mice fed caffeic acid/DSS were longer than in DSS‐treated control. Myeloperoxidase (MPO) was inhibited in mice given caffeic acid/DSS compared with DSS‐treated controls. Cecal score (necrosis, edema, erosion and neutrophil infiltration) of DSS‐fed mice was significantly more severe compared with mice fed caffeic acid before and during DSS treatment. Two subgroups were identified after cluster analysis of cecal score in mice fed caffeic acid/DSS. Mice with severe cecal damage showed mean cecal score of 9.1 (n=8), greater than did mice showing mild cecal damage (mean score=5.6, n=7, p <0.05). Caffeic acid‐fed mice with severe cecal damage had significantly greater colonic MPO activity than did mice with mild cecal damage (p <0.05). These effects in mice fed caffeic acid/DSS are hypothesized to be due to differences in caffeic acid bioavailability, which is under analysis.Funded by Iowa State University Center for Designing Foods to Improve Nutrition.
Blood pressure lowering effect of Monascus starter fermented soy product in Spontaneously Hypertensive Rats
Authors: Chang Moon‐Jeong , Choi Pok‐Su , Kwon Ji‐Youn , Kim Sun‐Hee 
Published: June 2021

The present study was carried out to evaluate the effect of dietary soy product(SP) and Monascus starter fermented soy product(MS) on blood pressure(BP), angiotensin converting enzyme(ACE) activity and sodium(Na) balance in spontaneously hypertensive rat(SHR). Twenty‐week‐old SHRs(n=18) were randomly blocked into three groups according to the blood pressure(BP) and fed for 4 weeks either a diet containing casein(CO), SP or MS, respectively. The changes of systolic blood pressure were measured by tail‐cuff method and ACE activities of serum, lung and kidney were analyzed. The subsequent fecal and urinary excretions of Na were measured by ICP‐atomic emission spectrometry. The systolic BP of MS was lower than that of the control group(p<0.05). ACE activity of lung was lower in SP group than that of CO group(p<0.05), although those of serum and kidney were not affected by experimental diets. After feeding MS, significant increase in fecal Na excretion and decrease in Na retention were observed(p<0.05). Urinary Na excretion was not affected by SP or MS in SHRs. These results suggest that Monascus starter fermented soy product produce an antihypertensive effect that may be mediated by inhibiting Na absorption in gastrointestinal tract and decreasing Na retention.This study was supported by 2006 Seoul B&RD program.
Metastatic Papillary Thyroid Carcinoma in Brain: Report of Three Cases
Authors: Li Jianyi , Aldape Kenneth D , Fuller Gregory N , Powell Suzanne Z 
Published: June 2021

Background:Papillary thyroid carcinoma (PTC) is the most common thyroid neoplasm. PTC generally carries a good prognosis since it is usually confined to the thyroid and tends to metastasize to regional lymph nodes (ex. cervical and upper mediastinal nodes). Distant metastases occur in only 5 to 14% cases. Brain metastases are extremely rare, occuring in 0.1 to 5% of reported cases. We report 3 cases of total thryoidectomy (TT) for PTC followed by subsequent brain metastases.Case reports:69‐year‐old man treated with TT, radiation therapy and radioactive iodine six and half years ago who presented with acute onset of headache. MRI showed lesions in right temporal and occipital lobes.64‐year‐old woman underwent TT more than 15 years ago and presented with a mass in the left temporal lobe involving the lateral ventricle.50 year‐old man underwent TT 2 years ago and presented with a mass in right frontotemporal lobe.Tissue sections in all cases showed metastatic papillary carcinoma immunoreactive for thyroglobulin and TTF‐1.Conclusion:In general, central nervous system metastases from PTC are associated with high mortality rates. Resection of single metastasis to brain or irradiation of multiple lesions improves long‐term outcome. In patients with brain metastases with unknown primary which exhibit papillary architecture, thyroid origin should be considered in the differential diagnosis.
Evaluation of hormone receptor status and proliferation with a novel isoform of proliferating cell nuclear antigen (ca‐PCNA) in predicting recurrence of pediatric meningioma
Authors: Rushing Elisabeth J. , Agarwal Beamon , Man Yao‐Go , Santi Mariarita , Comeaux Jarmon C. , Hickey Robert J. , Malkas Linda H. 
Published: June 2021

BACKGROUNDMeningiomas are uncommon in children and experience is limited compared to their adult counterparts. Predicting recurrence does not reliably correlate with tumor grade.PURPOSE: To review hormone receptor status and proliferation in 13 cases of intracranial meningioma in children.METHODS AND MATERIALS: Clinicopathologic data were reviewed on thirteen patients (6 females, 7 males) treated for meningioma during a 19‐year period. The patients ranged in age from 8–20 (mean, 15.2 years; SD, 4) years at the time of diagnosis. In all cases, estrogen and progesterone receptor, proliferating cell nuclear antigen (PCNA), ca‐PCNA and Ki‐67 status were analyzed using immunohistochemistry on formalin fixed paraffin sections. On initial biopsy, all meningiomas were grade I, WHO 2007.RESULTS: Four patients developed recurrent disease after a latency period of 1–3 years (mean, 1.6 years, SD, 0.9). The mean Ki‐67 proliferative index was 1; overall, PCNA ranged 10–90% (mean, 66.7) and ca‐PCNA ranged from 10–90 (mean, 32.5). Mean ca‐PCNA value in recurrent meningiomas was 47.2% while in non recurrent it was 17.8%. Staining for hormone receptors revealed that 1–90% of cells expressed progesterone (mean, 34.6%) and none labeled with estrogen.CONCLUSION: There is a positive correlation between ca‐PCNA expression with meningioma recurrence in children.
De Novo Anaplastic Ganglioglioma in a 5 Year Old Female: A Case Report
Authors: Wagner Aaron Scott , Pearl Gary S. 
Published: June 2021

We report an unusual case of anaplastic ganglioglioma diagnosed do novo in a 5 year old female. The patient presented initially with new onset seizures in May of 2007. Her initial seizure workup showed a lesion of the left temporal lobe, which was subsequently 80% resected in August of 2007.The present case is unusual for several reasons. The patient had not previously had a diagnosis of ganglioglioma and as such had not received radiation therapy. Further, some anaplastic elements demonstrated neuronal differentiation with cells staining negative for EMA, GFAP and neurofilament protein and positive for S100 and focally for synaptophysin. No reticulin positivity was seen. MIB‐1 labeling showed 60% reactivity and the tumor was felt to be most consistent with a WHO grade 4 lesion.Anaplastic gangliogliomas (WHO grade III or IV) are rare lesions most often representing transformation or progression from previously diagnosed ganglioglioma (WHO grade I or II). Generally these lesions present following radiation therapy to affected patients. Typically the anaplastic elements demonstrate glial differentiation when immunohistochemically investigated.
CD24 inhibits demyelination in a mouse cuprizone‐demyelination model
Authors: Ray‐Chaudhury Abhik , Carl Joseph W 
Published: June 2021

CD24 is a glycosyl‐phosphatidylinositol (GPI) anchored protein expressed in the developing central nervous system (CNS). In adult CNS, CD24 is mainly expressed on ependymal cells and on neurons in zones of neurongenesis. However, its function in the CNS remains unclear. We have previously shown CD24 is required for the induction of experimental autoimmune encephalomyelitis (EAE). Mice deficient for CD24 are resistant to the induction of EAE, on the other hand, mice over‐expressing CD24 on astrocytes had a more severe course of disease with more de‐myelination after EAE induction. To test whether CD24 is involved in demyelination/remyelination process, we used a cuprizone model of demyelination to study the role of CD24 in demyelination/remyelination. At week 4 after cuprizone diet, the CD24‐KO mice had significantly less de‐myelination compared to WT mice, but by week 6 demyelination levels were the same. CD24‐KO mice remyelinated the corpus collosum at the same rate as WT mice after returning them to a normal diet following 6 weeks of exposure to 0.2% cuprizone diet. This study indicates that CD24 does not play a major role in the re‐myelination process, but inhibits the de‐myelination process.Supported by a Davis/Bremer Medical Research Grant, The Ohio State University, Office of Research, College of Medicine, Columbus Oh, 43210
An allosteric potentiator suggests a role for M4 muscarinic acetylcholine receptor (mAChR) in modulating excitatory hippocampal synaptic transmission
Authors: Shirey Jana K , Xiang Zixiu , Orton Darren , Brady Ashley E , Johnson Kari A , Williams Richard , Ayala Jennifer E , Rodriguez Alice L , Wess Jurgen , Weaver David , Niswender Colleen M , Conn P Jeffrey 
Published: June 2021

Numerous animal and human studies suggest that muscarinic acetylcholine receptors (mAChRs), specifically M1 and M4, may be viable targets for the treatment of neurodegenerative disorders such as Alzheimer's disease (AD). We have used cheminformatic and medicinal chemistry to develop novel, highly selective M4 allosteric potentiators. VU10010, the lead compound, potentiates the M4 response to acetylcholine (ACh) 47‐fold while having no activity at other mAChR subtypes. This compound binds to an allosteric site on the receptor and increases affinity for ACh and coupling to G proteins. Whole cell patch clamp recordings revealed that selective potentiation of M4 with VU10010 increased carbachol‐induced depression of transmission at excitatory but not inhibitory synapses in the hippocampus. The effect was not mimicked by an inactive analog of VU10010 and was absent in M4 knockout (KO) mice. This provides compelling evidence for selective regulation of excitatory transmission in this important forebrain structure by M4. We are now examining the effects of selective M1 and M4 activation on field excitatory postsynaptic potentials in the CA1 region to understand the involvement of these receptors in muscarinic long‐term potentiation and depression.This work supported by NIMH grants MH073676‐01A1 and 1 F31 MH80559‐01.
Characterization of ClC‐2 Chloride Channel/PKA Interaction in Mouse Heart
Authors: Huang Zheng Maggie , Britton Fiona , Yuan Can , An Changlong , Hatton William , Duan Dayue 
Published: June 2021

Background: A ClC‐2 encoded chloride inward rectifier channel (Cl.ir) has been identified in the heart of several species. Cl.ir may play a role in regulation of pacemaker activity of the heart. In this study, we studied the regulation of mouse cardiac ClC‐2 channels by protein kinase A (PKA) phosphorylation.Methods: RT‐PCR and Western Blot were used to examine the distribution of mClC‐2 in mouse heart. Whole‐cell voltage‐clamp was used to study the regulation mClC‐2 in NIH/3T3 cells. Coimmunoprecipitation (CoIP) and yeast two hybrid (Y2H) were used to identify the binding partners of mClC‐2 in the heart.Results: 1). ClC‐2 exists in mouse heart. Analysis showed 765Ser as a PKA phosphorylation site. 2). Expression of ClC‐2 in NIH/3T3 cells generated functional channels. Treatment by 8‐Br‐cAMP to activate PKA increased current density from −16.2±2.8 to −20.6±3.5 pA/pF at −140mV by 27.4±5% (mean±SD, n=3). The increase was reversed to −15.5±3.3pA/pF by 26.6±4.1% upon PKA inhibition. Phosphotases PP1 and PP2 inhibitor Calyculin A further increased current by 22±3.1%. 3). CoIP using mouse heart and mouse atrial cell line HL1 lysates both showed association of ClC‐2 to 1 adrenergic receptors, PKA catalytic subunit, and PP1. 4). Y2H identified PP1 as a binding partner of ClC‐2.Conclusion: Mouse cardiac ClC‐2 channels may be regulated by phosphorylation/dephosphorylation through a direct interaction with PKA and PP1.Source of support: National Institutes of Health, National Center for Research Resources, National Heart, Lung, and Blood Institute and American Heart Association Western Affiliate.
No relationship found between RNA editing of the serotonin 2c receptor and expression of Gαq protein
Authors: Canal Clinton Ernest , Mahautmr Kontip Connie , Jacobs Michelle M. , Sanders‐Bush Elaine , Airey David C. 
Published: June 2021

RNA editing of transcripts of the serotonin 2c receptor (5HT2CR) occurs at up to five places within the putative second intracellular loop of the receptor, a region involved in modulating receptor coupling to Gαq proteins. 5HT2CR edited isoforms differ in signal transduction efficiency depending on the degree of editing. In vitro, the fully edited (VGV) 5HT2CR shows the lowest level of constitutive and agonist‐stimulated activity, whereas the nonedited (INI) 5HT2CR exhibits the converse pattern. The mechanisms underlying the changes in signal transduction related to RNA editing of 5HT2CRs may involve changes in Gαq protein levels. To test the causality of a 5HT2CR‐Gαq relation, we measured RNA editing of 5HT2CR in Gαq knock‐out (KO) mice and Gq protein levels in transgenic mice solely expressing the INI isoform of 5HT2CR. Pyrosequences of RNA isolated from amygdaloid cortex of Gαq KO and wild‐type (WT) mice revealed no significant differences in 5HT2CR mRNA editing profiles. Cortical tissue from INI and WT mice was assayed separately for expression of Gαq and Gα11 subunits by Western blotting. No differences in signal density between INI and WT groups were found, suggesting equivalent levels of Gαq and Gα11 protein. Together, the data do not support a causal or compensatory relation between 5HT2CR RNA editing and Gq protein levels.Supported by: NIH T32 MH065215 (CEC), R01‐MH34007 (ESB) and R21‐MH077942 (DCA)