bluuebunny/crossref_metadata_2025_split huggingface dataset:
Impact of the genetic background on immune system
Authors: Buffa Silvio , Romano Giuseppina Colonna , Bulati Matteo , Pellicanò Mariavaleria , Candore Giuseppina , Caruso Calogero 
Published: June 2021

The aim of this study was to compare some immune parameters between healthy centenarian offspring (CO), healthy age‐matched old (O) and young (Y) controls to evaluate whether any difference exists in the naïve/memory compartments that might explain the familiar increased lifespan expectancy of centenarian offspring (CO). In fact it is now supposed that longevity is based on genetic background and it has been demonstrated that centenarian siblings have an increased probability to reach long life as well.MethodsPeripheral blood mononuclear cells (PBMC) were collected from CO, O and Y donors. Lymphocyte subsets were evaluated by cytofluorimetric analysis. We have studied the naïve/memory compartment in T and B cells evaluating the expression of CD45R0, CD27, CD28 (on CD4 and CD8 T cells) and IgD and CD27 (on CD19 B cells).ResultsOur results show that O show the most differentiated phenotype, Y display the less differentiated phenotype and CO show an intermediate profile between the other two control groups.ConclusionThese data support the hypothesis of a “familiar youth” of the immune system that can be a big advantage both to fight the main age‐related diseases, and to properly respond to vaccinations. So, T and B cell subset changes could represent an hallmark of successful or unsuccessful ageing and could be used as a biomarker of human life span.This work was supported by the Italian Ministry of Education, University and Research grant (Does parental longevity impact on the health ageing of their offspring? An immunological and genetic study) to C. Caruso.
Thymic stromal lymphopoetin is critical for recovery from DSS induced colitis
Authors: Reardon Colin , Lechman Matthias , Mak Tak W 
Published: June 2021

Thymic stromal lymphopoetin (TSLP) influences a plethora of immune functions; including in the colonic mucosa.AimsHere we assessed the role of TSLP in mediating recovery from colonic inflammation.MethodsControls (WT), mice deficient for TSLP (TSLP−/−), or bone marrow (BM) chimeric mice using TSLP receptor deficient (TSLPR−/−) BM were subjected to dextran sodium sulfate colitis (DSS; 5% w/v). Mice were assessed daily for weight loss, and inflammation assessed 8 days post‐DSS during overt disease.ResultsTSLP−/− mice do not display enhanced colonic inflammation during DSS‐induced colitis as determined by similar weight loss, TH1/TH17 cytokine production and histological damage compared to WT controls. Despite this, TSLP−/− mice failed to recover from colitis, with progressive weight loss resulting in death. Reduced collagen deposition and increased neutrophil elastase (NE) activity but not metallomatrix protease activity occurred in TSLP−/− as compared to WT mice. Increased NE activity was paralleled by a reduction in the endogenous inhibitor of this enzyme, secretory leukocyte peptidase inhibitor (SLPI). Critically, BM chimeras identified that TSLPR on non‐hematopoeitc cells were sufficient for recovery from DSS‐induced colitis. Additionally, we identified TSLPR on intestinal epithelial cells (IEC), and stimulation of this receptor induced the expression of SLPI.ConclusionTSLP‐elicited signaling through TSLPR on IEC is a critical mediator in wound healing that does not involve restraining of TH1/TH 17 cytokines. The disparity between TSLP−/− and TSLPR−/− mice suggests that signaling downstream of TSLPR could occur in response to cytokines other than TSLP.
Angiotensin converting enzyme (ACE) over‐expression in myelomonocytic cells markedly augments resistance to methicillin resistant S. aureus (MRSA) by increasing iNOS levels
Authors: Datta Vivekananda , Duodu Derrick O , Shen Xiao Gregory , Billet Sandrine , Bernstein Kenneth 
Published: June 2021

Despite changing the antibiotic forms, Staphylococcus aureus has become increasingly drug resistant, including Methicillin. A recent surge of MRSA has reached endemic proportions among hospital‐acquired nosocomial infections with serious consequences among immunocompromised patients. Fatal MRSA infections of epidemic proportions needs to be tackled by newer treatment modalities.ACE a crucial component of the Renin‐Angiotensin System, is thought to be involved in the immune modulation. The role of ACE peptidase in immunity is not well understood. We created a transgenic mouse strain, refered as ACE10, in which ACE is over‐expressed only in monocytes and macrophages, but lacks ACE expression else where. Transgenic mice when challenged with MRSA subcutaneously, produced a smaller ulcerated skin lesions compared to WT mice. Compared to WT mice, ACE10 mice has 50 times less bacterial burden in their lesions. Resistance to MRSA in ACE10 was reversed by treating these mice with ACE inhibitor. Inhibition of ACE in macrophages rendered ACE10 mice sensitive to MRSA. Although the baseline iNOS expression remains unchanged in the ACE10, ACE10 mouse strains when treated with iNOS inhibitor significantly increased the bacterial burden in the lesion.The presence of enhanced ACE activity in ACE10 mice macrophages, increases innate inflammatory response, through induction of iNOS and augmented nitrite production.
Scedosporium apiospermum presenting as a pulmonary mycetoma in immunocompetent male
Authors: Gupta Ekta , Shibli Muhammad , Gibbons Junette 
Published: June 2021

BackgroundScedosporium apiospermum the anamorph of the ascomycete Pdeudoallescheria boydii, is a significant opportunist with very high levels of antifungal resistance. Colonization of Scedosporium apiospermum is a rare event, which eventually occurs on previous damaged lung tissue such as cavity or a lung cyst. We report this rare case of pulmonary scedosporiosis in an immunocompetent male treated many years ago for pulmonary tuberculosis.Case presentationA 42 year old Ethiopian male with past medical history of successfully treated Pulmonary Tuberculosis, presented with cough and Hemoptysis off and on for the last few months, which got worse for 3 days. Imaging showed cavitary lesion in the right upper lobe of lung. Bronchoalveolar lavage after bronchoscopy was negative for AFB smear and culture. Patient had an episode of massive hemoptysis and was electively intubated for right upper and middle lobectomy. Patient felt better after surgery, and no further episode of Hemoptysis was reported. Later, bronchoalveolar lavage cultures grew – Scedosporium apiospermum.ConclusionScedosporium apiospermum infection is an emerging, potentially life‐threatening disease category which is difficult to diagnose and treat. In lungs, it is easily misidentified as Aspergillus, especially in post tubercular cavitary lesion. Even in culture, the species is frequently not recognized due to its morphological plasticity. This case is reported to highlight a rising incidence of this potentially lethal infection and the prognostic significance of early detection and therapy.
The Role of the Protein C System in Prostate Cancer
Authors: Glasscock Laura , Pardhanani Pooja , Brunson Lacey , Wilson Kim , VanNostern Chantelle , Teigland Chris , Wakeman Carolyn 
Published: June 2021

Thrombin bound to endothelial thrombomodulin (TM) activates protein C (PC) into activated protein C (APC) with the aid of endothelial protein C receptor (EPCR). We determined if TM and EPCR are also expressed in PC‐3 and DU‐145 prostate cancer (CaP) cell lines, their ability to activate PC into APC, and how each of the proteins involved in this system regulates CaP cell proliferation and invasion. Real‐Time PCR, Western Blotting, and confocal microscopy demonstrated that TM and EPCR are expressed by both cell lines and both cell lines activated PC into APC in the presence of thrombin. PC, APC, and thrombin alone did not affect CaP cell proliferation or invasion. Since APC affects ovarian tumor cell invasion by competing with urokinase type plasminogen activator (uPA) for binding to plasminogen activator inhibitor‐I (PAI‐1), we determined if APC also regulates CaP invasion. APC competed with uPA for binding to PAI‐1 in CaP cells, enabling uPA to increase DU‐145 invasion. We conclude that the CaP cells make TM and EPCR and generate APC. Although PC, APC, and thrombin alone do not affect CaP cell proliferation or invasion, in the presence of CaP cell TM and EPCR and exogenously added thrombin, PC, PAI‐1 and uPA, APC is generated and binds to PAI‐1, freeing uPA to facilitate CaP tumor cell invasion.This research was made possible by NIH Grant Number P20 RR‐016461, the McKay Urology Endowment Fund, and the Hemby Foundation.
Methyl gallate protects against oxidative stress‐induced apoptosis in PC12 cells
Authors: Crispo James , Piché Matthew , Ansell Dominique , Eibl Joseph , Tai Isabella , Ross Gregory , Tai T.C. 
Published: June 2021

Recent studies demonstrate that polyphenols reduce oxidative damage by increasing cell viability, decreasing intracellular ROS and altering GSH metabolism. In addition, polyphenols such as epigallocatechin gallate (EGCG) have been reported to inhibit apoptotic signaling and increase neural cell survival. In an effort to better understand the benefits associated with polyphenol consumption, the aim of this study was to investigate potential anti‐apoptotic effects of EGCG, methyl gallate (MG), gallic acid (GA) and N‐acetylcysteine (NAC) on H2O2‐induced apoptosis in PC12 cells and elucidate protective mechanisms. Pre‐treatment with MG and NAC significantly increase viability of H2O2‐stressed cells, while pre‐treatments with EGCG and GA exacerbates stress. Analyses of apoptosis and mitochondrial membrane potential reveals that MG pre‐treatment prevents mitochondria depolarization, however does not inhibit apoptosis. Further, analysis of DNA degradation and caspase cleavage shows that MG inhibits activation of caspase 9 and has a partial inhibitory effect on DNA degradation. These findings suggest that MG may have potential therapeutic properties against mitochondria‐mediated apoptosis.Research funded by the Northern Ontario School of Medicine and Natural Sciences and Engineering Research Council of Canada.
Novel Pyrimidin‐2‐yl‐benzylidene imines and 2‐[(pyrimidin‐ylimino)‐methyl]‐phenoles and their Antibacterial Activity
Authors: Hoti Ramiz , Kalaj Vuksan , Vehapi Idriz , Ismaili Hamit , Thaçi Veprim , Bicaj Muhamet 
Published: June 2021

Some new Pyrimidin‐2‐yl‐benzylidene‐imines are synthesized by catalytic reactions of aromatic aldehydes and corresponding 2‐Aminopyrimidines. Condensation of Benzaldehyde 1a and 2‐Aminopyrimidines 2(a,b) gave pyrimidin‐2‐yl‐benzylidene imines 3(a,b). By condensation of salycilaldehyde 1b and 2‐Aminopyridines 2(a,b), corresponding 2‐[(pyrimidin‐ylimino)‐methyl]‐phenoles 3(c,d) were synthesized. The antibacterial activity of products 3(a–d) were investigated and results were submitted for their activities against Escherichia coli, Clebsiella and Staphylococcus aureus.Compound 3a showed emphatic bactericide activity against Staphylococcus aureus. Compounds were more active against. Light activity against Escherichia coli exhibited compounds 3a and 3c, whereas 3d exhibited the strongest activity against Clebsiella. In general there was a direct positive correlation between increasing concentration of the compound and antibacterial activity
The Herpes simplex virus‐1 DNA polymerase exhibits 3′ phosphatase activity
Authors: Ravi Rupesh Kanchi , Boehmer Paul E. 
Published: June 2021

Herpes simplex virus‐1 (HSV‐1) is a large dsDNA virus that encodes its own DNA replication machinery, including enzymes involved in nucleotide metabolism. We recently demonstrated that the HSV‐1 DNA polymerase (UL30) exhibits AP and 5′ dRP lyase activities. Moreover, UL30 in conjunction with the viral uracil DNA glycosylase as well as cellular AP endonuclease and DNA ligase IIIα/XRCC1, perform uracil‐initiated Base Excision Repair (BER). As an alternative route to repairing base adducts and abasic sites, and as a mechanism to process ssDNA breaks we have investigated the ability of UL30 to process various 3′ ends. Interestingly, we find that UL30 can degrade 3′ sugar phosphate as well as 3′ phosphate terminated DNA. Moreover, UL30 exhibits a 3′ phosphatase activity that removes 3′ phosphate prior to 3′–5′ exonuclease action. These novel activities would allow UL30 to process AP sites following β‐elimination though incision by its inherent AP lyase activity or DNA breaks that result in 3′ phosphate terminated DNA following βδ‐elimination or X‐ray irradiation. Further studies will investigate how UL30 can repair this damage in conjunction with other factors. These findings further highlight the role of DNA repair in the maintenance of a viral genome with implications on both lytic replication and reactivation from latency.This work was supported by grant GM 062643 from the NIH.
A study of the role of GATA4 gene polymorphism in myocardial infarction
Authors: Bakhit Dana Mohammed , Muiya Paul , Gueco Daisy , Meyer Brian F , Al‐Mohanna Futwan , Alshahid Maie , Dzimiri Nduna 
Published: June 2021

The role of GATA4 in cardiovascular disease remain to be elucidated. We initially sequenced the GATA4 coding regions to identify variants of interest in 250 individuals, and investigated the role of 5 SNPs, rs3729855 (C>T), rs3729856 (A>G), rs1062219 (C>T), rs11785481 (C>T) and rs3203358 (C>G) in predisposing individuals to myocardial infarction (MI) by the real‐time PCR in 3803 individuals, all of Saudi origin. We then tested the impact of congenital heart disease (CHD) by comparing the CHD patients with the rest. The results pointed to a significant association for the rs3729856 (p.S377G) with CHD [Odds ratio(95% Confidence Interval) = [1.48(1.06–2.08); p=0.023], and protective effect for rs3729855 [0.96 (0.42–2.19); p=0.005. In order to rule out the influence of CHD on other relationships, we excluded CHDs from further analyses involving 2713 MI patients and 986 controls. Interestingly, the rs3729856 [1.16(1.01–1.34); p=0.034] also conferred risk for MI, while the rs3729855 [0.68 (0.52–0.89); p=0.005] showed protective properties. Furthermore, both the rs3729856 [1.14(0.99–1.31); p=0.076] and rs3729855 [1.37(1.00–1.88); p=0.052] were also associated with hypertension, but not with type 2 diabetes mellitus. These observations implicate the GATA4 as a susceptibility gene for both MI and CHD.This work was supported through the Royal Cardiovascular Research Grant of the King Faisal Specialist Hospital and Research Centre
Generation of Transgenic Mice Overexpressing a Hybrid Enzyme Up‐regulating Biosynthesis of Vascular Protector Prostacyclin
Authors: Mohite Anita J , Chillar Annirudha J , So Shui‐Ping , Ruan Ke‐He 
Published: June 2021

Prostacyclin (PGI2) is a potent vascular protector through its anti‐platelet aggregation and vasodilation properties. Non‐steroid anti‐inflammatory drugs (NSAIDs) by inhibiting PGI2 production promote heart diseases. Recently, we have successfully engineered a hybrid enzyme (COX‐1‐10aa‐PGIS, by linking cyclooxygenase isoform 1(COX‐1) with PGI2 synthase (PGIS) through a 10 amino acids (10aa) linker) with triple catalytic functions directly converting arachidonic acid into PGI2. PGI2 biosynthesis was upregulated in the mammalian cells, transfected with the hybrid enzyme cDNA. Thus, with the objective of translating these in vitro results into in vivo, we generated transgenic mice overexpressing COX‐1‐10aa‐PGIS. PCR using mouse tail tissue confirmed the incorporation of COX‐1‐10aa‐PGIS gene in the transgenic mouse chromosome. Permanent expression of the hybrid enzyme was identified by Western blot. The catalytic activity of the hybrid enzyme to form PGI2 was determined by enzyme activity assay and LC/MS analysis of transgenic mouse tail and urine, respectively. In conclusion, a transgenic mouse overexpressing the hybrid enzyme with upregulated PGI2 biosynthesis was successfully obtained. The mice can be used to further uncover the mechanisms of the vascular protection of PGI2 and test the side effects of NSAIDs.Funding: R01 HL56712 (for KHR); RO1HL079389 (for KHR) and RC1 HL100807 (for RD and KHR)
Transdermal dl‐methylphenidate potentiates the pharmacokinetic interaction with ethanol relative to oral dosing in a mouse model
Authors: Bell Guinevere Hannah , Novak Andrew , Griffin William , Patrick Kennerly 
Published: June 2021

ObjectiveTest the hypothesis that transdermal dl‐methylphenidate (MPH) potentiates the pharmacokinetic interaction with ethanol relative to oral MPH dosing; thus resulting in a greater elevation of d‐MPH and the metabolite l‐ethylphenidate (EPH) in blood, brain and urine.MethodsA novel murine model of transdermal MPH was developed using ¼ of a 12.5cm2 MPH patch (Daytrana®) with/without ethanol (3 g/kg po). Used MPH patches were analyzed to determine the average dose delivered (7.5 mg/kg) and this dose was used for oral MPH‐ethanol comparisons. MPH and EPH were enantioselectively quantified by GC‐MS of prolyl derivatized piperidyl fragments.ResultsThe concentration of d‐MPH was significantly elevated by ethanol, especially following transdermal dosing. Approximately 10X more l‐MPH reached the blood with transdermal delivery vs. oral. In the ethanol‐transdermal MPH group, the concentration of l‐EPH was significantly higher than d‐EPH.ConclusionsThe greater ethanol‐induced elevation of the “active” d‐MPH isomer when using transdermal vs. oral dosing appears to be mediated by the higher circulating levels of l‐MPH which competitively inhibit carboxylesterase 1. These findings have implications for abuse liability and cardiovascular toxicity of concomitant transdermal MPH and ethanol should this animal model hold for ADHD patients who consume ethanol. Supported by RO1AA16707.
INVOLVEMENT OF PRELIMBIC BUT NOT INFRALIMBIC CORTEX ON THE PRESSOR RESPONSE TO CHEMOREFLEX ACTIVATION IN UNANESTHETIZED RATS
Authors: Granjeiro Érica Maria , Scopinho América , de Aguiar Corrêa Fernando Morgan , Resstel Leonardo Barbosa 
Published: June 2021

INTRODUCTION AND OBJECTIVESThe ventral portion medial prefrontal cortex (vMPFC) comprises the prelimbic cortex (PL) and the infralimbic cortex (IL). It has been reported an important role of vMPFC on cardiovascular reflexes modulation. However, there is no study showing the role of this area on cardiovascular responses to chemoreflex activation. We report here a comparison between the effects of pharmacological inhibition of PL or IL neurotransmission on the pressor and bradycardic responses to chemoreflex activation evoked by KCN, i.v. administration.RESULTS AND CONCLUSIONBilateral microinjections of 200 nl of the unspecific synaptic blocker CoCl(2) (1 mM) into the PL significantly reduced the pressor (60 ± 3 vs 44 ± 3 mmHg, n=9, p<0.01) but had not effect on the magnitude of bradycardic response to chemoreflex activation (−219 ± 24 vs −201 ± 16 bpm, n=9, p>0.05). However, when local synapses in the IL were inhibited by bilateral injections of CoCl(2) into that area, no significant changes were observed on cardiovascular responses evoked by chemoreflex (n=6, p>0.05). These data indicate the involvement of the vMPFC PL area in modulation of the pressor response induced by chemoreflex activation but not in the decrease in heart rate evoked by this reflex. They also suggest that the neurons located on PL area do not play a major role in the neurotransmission of the autonomic responses to chemoreflex activation.
Vasoconstriction‐induced inward remodeling of isolated arterioles involves reactive oxygen species‐dependent activation of matrix metalloproteinases
Authors: Martinez‐Lemus Luis A. , Zhao Guiling 
Published: June 2021

We previously demonstrated that inward remodeling induced by prolonged agonist‐induced vasoconstriction in isolated arterioles requires reactive oxygen species (ROS) generation and activation of matrix metalloproteinases (MMPs). We hypothesize that ROS participate in the vasoconstriction‐induce inward remodeling process in part by promoting MMP activation. This hypothesis was tested in isolated and pressurized (60 mmHg) rat cremaster arterioles exposed to norepinephrine (NE, 10−5.5 M) plus angiotensin‐II (Ang‐II, 10−7 M) for 4 hours. Prolonged vasoconstriction induced inward remodeling and increased the gelatinolytic activity of arterioles (P<0.05). ROS‐inhibition with apocynin, tempol, or the Rac‐inhibitor, NSC, significantly affected the development of inward remodeling and reduced the arteriolar gelatinolytic activity induced by NE and Ang‐II. These results indicate that during prolonged vasoconstriction MMPs are in part activated through a pathway dependent on the generation of ROS, and that ROS are required for the acute remodeling of the vascular wall. As MMP‐inhibition prevents the development of inward remodeling, these results suggest that vasoconstriction‐induced inward remodeling in resistance vessels is associated with ROS‐dependent activation of MMPs.Funded by AHA and NIH.
The Effect of Chronic Kidney Disease on Endothelial‐Dependent Dilation and Progenitor Cells
Authors: Kuczmarski James Matthew , Darocki Mark , Sikes Robert A. , Cooper Carlton R. , Farquhar William B. , Edwards David G. 
Published: June 2021

The purpose of this study was to determine if circulating hematopoietic and myeloid progenitor cell subpopulations are reduced, colony forming ability (CFA) of peripheral blood mononuclear cells (PBMNC) is impaired, and endothelial‐dependent dilation (EDD) is attenuated in chronic kidney disease (CKD) patients as compared to healthy controls. Ten patients with stage 3–5 CKD and ten healthy controls were studied. Brachial artery flow‐mediated dilation was used to assess EDD. Circulating progenitor cells (CPC) were quantified in venous blood samples via flow cytometry and PBMNC were cultured to assess CFA. EDD was reduced in CKD (5.39 ± 1 vs. 10.12 ± 1.4; p = 0.007) as were hematopoietic CPC subpopulations CD34+/KDR+ (276.9 ± 65.9 vs. 475.2 ± 93.2, p = 0.046), CD34+/CD45‐ (131.8 ± 30.4 vs. 428.4 ± 100.7, p = 0.004), and CD34+/KDR+/CD45‐ (107 ± 2.8 vs. 298.5 ± 41.2, p < 0.001). Furthermore, myeloid CPCs CD45+ (9.9 × 104 ± 1.3 × 104vs. 1.32 × 105 ± 1.6 × 104, p = 0.07) and CD45+/KDR+ (1.1 × 104 ± 5.9 × 103vs. 4.1 × 104 ± 1.8 × 104, p = 0.07) were lower and CFA (2.64± .502 vs. 4.3 ± .953, p = 0.065) was impaired, approaching significance. Reductions in CPC populations may be a potential mechanism by which vascular integrity is compromised, leading to endothelial dysfunction, ultimately increasing the risk of cardiovascular disease and contributing to renal disease progression in CKD patients.Supported by Grants DK077306 and P20 RR016472‐09.