bluuebunny/crossref_metadata_2025_split huggingface dataset:
iTRAQ Proteomics Approaches Reveal Novel Mitochondrial Targets of Estrogen Deficiency in Aged Female Rat Heart
Authors: Korzick Donna Hope , Lancaster Timothy S , Jefferson Sarah J , Tomicek Nanette J 
Published: June 2021

BackgroundThe incidence of MI rises sharply at the time of menopause, implicating loss of estrogen (E2) in age‐related increases in ischemic injury.PurposeTo identify new mitochondrial protein targets for the treatment of acute MI in aged women using a state‐of‐the‐art proteomics approach. We hypothesized that E2 deficiency exacerbates age‐dependent disruptions in mitochondrial proteins in female rat heart.MethodsTargeted proteomic analyses were conducted in mitochondria isolated from left ventricles of adult (6 mo) and aged (24 mo) F344 ovary‐intact or ovariectomized (OVX) rats using the newly released isobaric tags for relative and absolute quantification (iTRAQ) 8plex labeling and mass spectrometry (n=4‐5/group).ResultsInitial multi‐dimensional protein identification technology (MudPIT) analyses revealed n=638 distinct mitochondrial proteins. With iTRAQ, significant group differences (false discovery rate < 5%) were observed in proteins related to cellular metabolism, ion transport, oxidative stress and cell death regulation. Effects of age‐associated E2 deficiency were primarily limited to proteins which regulate oxidative stress, and were not observed in adult OVX.ConclusionsProteomic analysis through iTRAQ is effective in identifying new candidate proteins for further in‐depth study of age‐ and E2‐dependent alterations in mitochondrial cardioprotective signaling.
Tracking the Anatomical Contents of the Quadrilateral Space: Clinical Implications
Authors: Frumberg David Benjamin , Beckman Michael Joseph , Marquez Samuel 
Published: June 2021

The quadrilateral space (QS), demarcated by osseo‐muscular borders, is the gateway for the axillary nerve (AN) and posterior circumflex humeral artery (PCHA) between anterior and posterior scapular regions. QS Syndrome is the condition whereby hypertrophy of associated musculature causes AN entrapment and compression of PCHA, potentially resulting in deltoid weakness, tenderness over the shoulder region, and pain radiating to the arm. This anatomical study assessed, identified, and categorized AN and PCHA transmission through the QS using a mixed‐sex sample size of 43 cadavers to determine the strength of association between AN and PCHA. Results showed AN present in all 86 QSs, while 89.5% contained PCHA. Variable arterial patterns observed were PCHA passing inferior to the teres major insertion on the humerus, originating from a common stem with the profunda brachii artery (9.3%) or from its own branch off the brachial artery (1.1%). One cadaver unilaterally possessed a PCHA in the QS and a branch from the profunda brachii artery. All unilateral arterial deviations occurred on the right side while two cadavers possessed bilateral deviations with PCHA arising from the profunda brachii artery. A full understanding of arterial variation in the QS region may help clinical characterization of QS Syndrome, and may obviate the need for arteriography to minimize postoperative bleeding and yield successful rehabilitation outcomes.Grant Funding SourceDO NOT HAVE FUNDING
Tracking Nasal Diversity in Multi‐Regional Populations: Insights into the Adaptive Significance of the Upper Respiratory System
Authors: Qureshi Naema , Gannon Patrick J , Obourn Chelsea , Márquez Samuel 
Published: June 2021

The nasal complex (nose and paranasal sinuses) contributes a critical role in respiration by treatment of inspiratory air at the gates of the upper respiratory tract before the proper exchange of gases can take place in the alveolar region. Key components of this complex, the maxillary sinuses (MS), are implicated in a role for air conditioning of inspired air (Gannon et al, 1997). Differences in skeletal and soft tissue anatomy of the nasal region have been shown to be distinct but none have factored in a morphometric approach. This study included four human population groups from Africa, Asia, Europe and North America. We measured internal and external nasal parameters (ENP) including piriform dimensions, MS and endocranial volumes. Results showed: 1) piriform aperture area (PAA) variable did not have the power to discern populations; 2) MS volumes determined significant differences between groups living in cold and hot climatic conditions (p < 0.05) but did not strongly discern populations; 3) external linear nasal measures displayed a strong parametric value for discriminating between groups; and 4) integration of MS volume and PAA with ENP was the strongest variable suite to distinguish population groups. Our results suggest that the variables we employed may be an integrated functional suite of characters that reflects adaptations of the nasal complex during migrations across a wide range of climatic conditions.Grant Funding SourceNA
Nuclear pore complex structure and assembly involve the ER membrane protein Rtn1
Authors: Lazarus Michelle Denise , Dawson Renee , Wente Susan 
Published: June 2021

Nucleocytoplasmic transport occurs exclusively through nuclear pore complexes (NPCs) which have been implicated in proper embryonic development. Although structural studies have resolved the complex NPC architecture, the mechanism that directs pore membrane fusion and NPC biogenesis remains unclear. Reticulons (RTNs) and Yop1/DP1 are conserved membrane protein families required to form and maintain the tubular endoplasmic reticulum (ER). Remarkably, whereas NPC membrane proteins such as Pom34 and Pom152 are not required for viability, an rtn1δ yop1δ pom34δ pom152δ quadruple null (δ) mutant is lethal. This suggests that Rtn1 and/or Yop1 play a role in NPC structure, assembly and/or maintenance. This lethality is rescued by expression of wild type RTN1, as well as by the more nuclear localized point mutant rtn1‐K48I. The exogenous expression of RTN1 and rtn1‐K48I also rescues a lethal pom34δ nup59δ double mutant. Nup59 is a structural NPC protein linked to NPC assembly. These results indicate that Rtn1 has at least a partial redundancy in function with NPC structural and transmembrane proteins. In addition, this suggests a function for the reticulons at the NE that is independent of RTNs role at the tubular ER. We hypothesize that RTNs and/or Yop1/DP1 stabilize the membrane curvature of the nuclear pore during NPC assembly.Grant Funding SourceIRACDA and NIH
SLC/CCR7 enhances the maturation of semi‐mature BMDCs by the pNF‐¿B p65 pathway
Authors: Liang Chun‐min , Zhou Shuang , Wu Wen‐qing , Zhong Cui‐ping 
Published: June 2021

The chemokine receptor CCR7 is highly expressed in dendritic cells (DCs), T cells, and other immune effector cells. The high‐affinity ligand that can bind to CCR7 is the secondary lymphoid tissue chemokine (SLC). The SLC/CCR7 axis plays an important role in the immune system by inducing the chemotaxis and migration of immune effector cells. In this study, we found that SLC also directly enhances the maturation of semi‐mature bone‐marrow‐derived dendritic cells (BMDCs), with increased expression of MHC II and CD86 (B7‐2) and enhanced antigen‐presenting cell (APC) function. pNF‐Bp65 was involved in this mechanism. The results indicated that there are cross‐talk signals underlying the SLC/CCR7 axis between the chemotaxis and maturation of BMDCs. Interestingly, we also found that while Ca2+ mobilization and subsequent migration of semi‐mature BMDCs could be totally inhibited by PTX, PTX only partially inhibited the maturation of semi‐mature BMDCs. The findings further suggested that the SLC/CCR7 axis uses different signaling modules to regulate its multiple functions in BMDCs.Grant Funding SourceNational Science Foundation of China No.30500280
Functional Diversification and Evolution of Animal Zinc‐Dependent Alcohol Dehydrogenases
Authors: Julián‐Sánchez Adriana , Magis‐Weinberg Lucía , Riveros‐Rosas Héctor 
Published: June 2021

Zinc‐dependent alcohol dehydrogenases (ADHs) comprise one of the best studied group of enzymes. Vertebrates possess eight distinct classes (I‐VIII) of ADHs, based upon sequence homology, catalytic activity and gene expression features. However, because many independent duplications occurred along the evolution of vertebrates, the identification of orthologous groups of proteins is not convincingly resolved. Since the number of ADH sequences in animals has been duplicated after the last analysis of these enzymes, a new phylogenetic analysis was performed.Results provide a comprehensive scenario, where is clear that ancestral class III ADH give rise in first place to the class I ADH, which is present in all classes of vertebrates. Later, class II and VII emerged by duplication of class III ADH before the amphibian‐amniota split, but interestingly, class VII ADH was lost in mammals. Finally, classes IV to VI have a more recent origin, because the duplication that gave rise to these three classes occurred just after the appearance of mammals. Class VIII ADH is restricted only to amphibians.The complex ADHs enzymogenesis in vertebrates is a consequence of the diverse physiological roles developed by these enzymes, as responsible to synthesize or catabolize several endogenous metabolites that regulate growth, metabolism, differentiation and neuroendocrine functions. Supported by DGAPA‐UNAM grant IN208308
Structural basis for midbody targeting of spastin by the ESCRT‐III protein CHMP1B
Authors: Yang Dong , Rismanchi Neggy , Renvoise Benoit , Lippincott‐Schwartz jennifer , Blackstone Craig , Hurley James 
Published: June 2021

The endosomal sorting complex required for transport (ESCRT) machinery, including ESCRT‐III, localizes to the midbody and participates in the membrane‐abscission step of cytokinesis. The ESCRT‐III protein chromatin‐modifying protein 1B (CHMP1B) is required for recruitment of the MIT domain‐containing protein spastin, a microtubule‐severing enzyme, to the midbody. The2.5‐A structure of the C‐terminal tail of CHMP1B with the MIT domain of spastin reveals a specific, high‐affinity complex involving a noncanonical binding site between the first and third helices of the MIT domain. The structural interface is twiceas large as that of the MIT domain of the VPS4‐CHMP complex, consistent with the high affinity of the interaction. A series of unique hydrogen‐bonding interactions and close packing of small side chains discriminate against the other ten human ESCRT‐III subunits. Point mutants in the CHMP1B binding site of spastin block recruitment of spastin to the midbody.
HIV protease inhibitors activate the ER stress response and disrupt the lipid metabolism in 3T3‐L1 adipocytes
Authors: Pecora Beth S , Sun Lixin , Wu Xudong , Zha Weibin , Gurley Emily , Studer Elaine , Hylemon Phillip B , Pandak William M. , Zhang Luyong , Wang Guangji , Zhou Huiping 
Published: June 2021

HIV protease inhibitor‐induced lipodystrophic syndrome is a major side effect of current anti‐HIV therapy. However, the underlying molecular mechanism remains unclear. We have recently shown that HIV PI‐induced ER stress and activation of the unfolded protein response (UPR) represents an important cellular mechanism by which HIV PIs disrupt lipid metabolism and induce inflammation in hepatocytes and macrophages. The aim of this study was to determine if HIV PIs also induce ER stress, activate the UPR, and affect the lipid metabolism and differentiation in adipocytes.MethodsMouse 3T3‐L1 adipocytes were used in this study. The effect of individual HIV PI on differentiation and lipid accumulation was examined by Oil red O staining. Activation of the UPR was determined by real time RT‐PCR and Western Blot analysis. The expression of adipokines/cytokines was determined by real‐time PCR and ELISA.ResultsDifferent HIV PIs had different effects on the UPR activation, cell differentiation, and lipid metabolism in adipocytes. Both lopinavir and ritonavir dose‐dependently activated the UPR, increased IL‐6 expression, reduced adiponectin expression, and induced cell apoptosis. But amprenavir had less effect.ConclusionsHIV PI‐induced ER stress response and activation of the UPR may represent a critical molecular mechanism underlying HIV PI‐associated lipodystrophy and metabolic syndrome.
Towards a Crystal Structure of Complete Histidine Kinase E in Bacillus
Authors: Sergeeva Oksana , Bick Matthew J , Darst Seth A 
Published: June 2021

Sporulation in Bacillus is controlled by five histidine kinases (HKs), KinA‐KinE, which are composed of an N‐terminal sensor domain and a C‐terminal kinase domain. Signals sensed in the sensor domain are transduced to the kinase domain, resulting in an autophosphorylation event on a conserved histidine. The crystal structure of the kinase domain from KinB in complex with the autophosphorylation inhibitor Sda, from the moderate thermophile Geobacillus stearothermophilis, has previously been solved in the Darst laboratory. The structure reveals a KinB dimer with Sda bound to a single monomer. Binding of Sda stabilizes the KinB dimer and prevents autophosphorylation.In order to gain insights into how signals are communicated in HKs, we focused on the crystallization of a complete HK. Currently, a structure of an HK containing both sensor and kinase domains is unavailable. Availing ourselves of the fact that two of the five sporulation HKs in Bacillus are soluble, we choose one of these, KinE, for structural studies. A double expression construct containing KinE and Sda was made from three different thermophilic Geobacillus species. Of the three constructs tested for expression, one from G. thermodenitrificans gave considerable amounts of soluble protein following expression in E. coli Rosetta2 cells. We have purified the KinE/Sda complex via nickel affinity, ion exchange, and size‐exclusion chromatography. Biochemical assays have shown that autophosphorylation of KinE, like KinB, is inhibited by Sda. Initial crystallization trials in the presence of ADP have given several promising leads.This work was supported by NIH GM081697 to S.A.Darst.
Iron status and LDL ‐ oxidation in a group of healthy adults from Argentina. Preliminary results
Authors: Langini Silvia , Lardo Mabel , Ghersevich Sergio , Aragone María , Carbia Claudio , Pandolfo Marcela , Fleischman Silvana , Lazarowski Alberto , Río María E 
Published: June 2021

Excess body iron (Fe) has been proposed to oxidize low ‐density lipoproteins (LDL). Blood samples from 109 non‐institutionalized healthy adults attending Hospital Italiano, Buenos Aires during 2006 were obtained. Samples negative for C‐reactive protein (PCR‐latex, Wiener lab) and risk population were studied: men (M) 23‐95y (n=30) and postmenopausal women (PostW) 51‐83y (n=31). Serum ferritin (SF) (quimiolumminescence analyzer‐ DPC‐Siemmens); unsaturated iron binding capacity (UIBC) (FerroZine‐) (Hitachi 917; automated systems‐ Roche diagnostics) and plasma oxidized LDL (ox‐LDL) (competitive ELISA developed at UNR, School of Biochemical and Pharmaceutical Sciences, Argentina, normal range 2.2‐3.8 U) were measured. Mean values ± SD, (range) and % of individuals with normal values were:No correlation was found between ox‐LDL and SF (r= 0.02) nor UIBC (r=0.006) levels in M and PostW. However, increased risk of chronic diseases may be possible, as wheat flour fortification with Fe is mandatory in Argentina since 2002 in spite of high meat intake (54.7 Kg /capita /y, FAO 2003). Partially supported by UBACyT B414, CONICET PIP 5068 & ROCHE, Argentina
Zinc supplementation does not alter plasma trace elements in Kenyan adults
Authors: Scrimgeour Angus , Lukaski Henry C , Polhemus Mark E , Otieno Lucas , Young Andrew J , Bovill Maria E 
Published: June 2021

Multiple micronutrient deficiencies constitute a significant public health problem in Kenya. Low iron (Fe) and zinc (Zn) status are frequent. As micronutrient homeostasis may be compromised when single‐micronutrients are used in intervention studies, we examined the effects of dietary Zn supplementation on other plasma trace elements (Ca, Cu, Fe, K, Mg, Mn and Se) in free‐living adults participating in an anti‐diarrheal study.MethodsA double‐blind, RCT involving 500 adults, aged 18‐55 years, were supplemented with either 20 mg elemental Zn (as Zn‐sulphate) or placebo, per day for 90 days. Plasma trace elements were analyzed by ICP‐OES. Indices of inflammation (serum ferritin, C‐Reactive Protein) and vitamin A (VA) were also analyzed, using standard kits.ResultsAt baseline, 99% of subjects had elevated plasma Mn (>0.15 µg/dL), 33% were Zn‐deficient (<65 µg/dL), 32% were VA‐deficient (<30 µg/dl), and 14% were Fe‐deficient (<60 µg/dL). After 90 days of supplementation, concentrations of plasma Zn increased 18.5% (p<0.0001) in subjects receiving Zn‐supplements, while it was not different in the placebo group (p=0.30). Zn‐supplementation did not modify Ca, Cu, Fe, K, Mg, Mn, Se, ferritin or CRP values.ConclusionZn supplementation at moderate doses does not lead to deleterious effects on plasma trace elements, or indices of inflammation, in adults in western Kenya.The study was funded by the U.S. Army MRMC
Nuclear and mitochondrial functions of p53 in zinc deficient human neuronal precursor cells
Authors: Corniola Rikki S , Levenson Cathy W 
Published: June 2021

Our previous work has shown a role for zinc and the tumor suppressor protein p53 in the regulation of neuronal precursor cell proliferation and survival in vivo and in vitro. In human neuronal precursor cells (NT‐2) zinc deficiency results in increased p53 nuclear abundance, where it acts as a DNA‐binding transcription factor to regulate 14 downstream target genes, including cell cycle arrest genes (eg 1.8‐fold up‐regulation of reprimo mRNA) and a number of pro‐apoptotic genes including transforming growth factor‐β (+1.4‐fold) and retinoblastoma‐1 (+4.5‐fold) leading to decreases in BrdU labeling and increases in cell death. A dominant‐negative p53 gene construct confirmed the p53‐dependent nature of this regulation during zinc deficiency. In addition to the nuclear translocation of p53, we have also shown that p53 translocates to the mitochondria where it plays a role in the generation of mitochondrial reactive oxygen species (ROS) as measured by dihydrorhodamine fluorescence. Pre‐treatment with pifithrin‐α, a p53 inhibitor, prevents the generation of ROS. Additionally, there is 50% decrease in total superoxide dismutase activity (p<0.05), and a 2‐fold increase in glutathione peroxidase mRNA. These data identify a role for zinc in the nuclear and mitochondrial mechanisms that control neuronal stem cell proliferation and survival. Supported by Susan E. Lucas Fellowship in the Neurosciences.Grant Funding SourcePhoenix Foundation
Different FGF‐2 isoform patterns influence drug sensitivity in human melanoma and murine fibroblast cell lines
Authors: Dini Germana , Schiavone Nicola , Magnelli Lucia 
Published: June 2021

The effect on drug sensitivity of FGF‐2 expression was evaluated in a murine fibroblast (Balb/A31) and in a human melanoma (MC) cell line. Human metastatic melanoma cells, negative for FGF‐2 expression, were transfected in order to express low (18 kDa), high molecular weight (HMW) and all (ALL) isoforms. Clonogenic assay showed that 18 kDa expression was related to chemoresistance to Dacarbazine (DITC), both in 18 kDa and ALL MC cells with respect to the mock transfected cell line. In contrast, the expression of High Molecular Weigth FGF‐2 isoforms alone produced a chemosensitive phenotype, even if compared to that of FGF‐2‐negative clones. Dacarbazine‐resistant clones were obtained following drug selection confirming that resistance was induced by 18 kDa low molecular weight isoform while high molecular weight isoforms produced a sensitive phenotype. Accordingly high molecular weight isoforms were lost and low molecular isoform was gained from DITC resistant ALL and 18 kDa cell line, respectively. Also we failed to obtain resistant clones from HMW cells.Balb/A31 exogenously expressing different human FGF‐2 isoforms were treated with increasing concentration of doxorubicin, cisplatin and 5‐fluorouracyl. Clonogenic survival was evaluated to determine drug resistance. Results showed a highly variable response dependent on both FGF‐2 isoform expression pattern and treatment.Grant: CRF 2003.0808
The Levels of Calcitonin Gene‐Related Peptide and Substance P in the Plasma of Rats with Traumatic Brain Injury and the Role of Neurogenic Inflammation in the Pathogenesis of TBI
Authors: Duan hubin , Hao chunyan , Li shuzhen 
Published: June 2021

Background and PurposeSubstance P (SP) is thought to play a crucial role in the traumatic brain injury (TBI). Calcitonin gene‐related peptide (CGRP) is an inflammatory neuropeptide found in neurons. The purpose of research is to explore the correlation between SP and CGRP in the rats plasma after TBI and to study their significance in the neuropathic mechanism of TBI.Methodsl68 male Wistar rats were randomized into the injury group and control group.Mild,moderate and severe injury models (0.5‐1.0 atm,1.5‐2.0 atm and 2.5‐3.0atm ) was produced with the fluid percussion brain injury (FPI) technique in anesthetized adult rats equipped with a closed cranial window.All groups were again stratified into 7 sub‐groups according to the time after TBI(0.5,2,6,12,24,48 and 72 h).The plasma levels of SP and CGRP were measured with ELISA at specific time after the injury.ResultsThere was a positive correlation between the plasma levels of SP and CGRP (r=0.879.P<0.01)after TBI.The plasma levels of SP and CGRP varied significantly across all groups with different severity of TBI(P<0.01) and time after injury (P<0.01).The peak and trough of plasma levels of SP were recorded in 0.5 h‐moderate (1.46±0.23ng)and 24h‐severe (0.43±0.17ng) sub‐groups,and those of CGRP were recorded in 2 h‐moderate (5.9±0.9ng)and 24 h‐severe sub‐groups(0.7±0.4ng) respectively.ConclusionThese data show that both plasma levels of SP and CGRP changed regularly with the severity of injury and the time after TBI. A positive correlation also be observed between the plasma levels of SP and CGRP.Therefore, detection of plasma SP and CGRP should be helpful to estimate the severity of injury and pathological changes of the TBI.
Cardiac anti‐fibrotic effect of Ang (1‐7) in L‐NAME‐treated mice does not involve AT2 receptor stimulation
Authors: Phua Damie Sher‐Maine , Jones Emma Susan , Widdop Robert Edward 
Published: June 2021

The aim of this study was to determine the chronic effects of Ang (1‐7) on L‐NAME‐induced cardiac remodelling in both wildtype (WT), and AT2 knockout mice (AT2KO). Cardiac remodelling was induced by treatment with L‐NAME (100mg/kg/day) for 4 weeks. Animals (n=10 in both WT and AT2KO, 16 wks old) were treated with L‐NAME in combination with Ang (1‐7) (24µg/kg/hr), the Mas receptor antagonist, A779 (48µg/kg/hr) and/or the COX inhibitor, indomethacin (2mg/kg/day). At the conclusion of treatment, hearts and aorta were removed to examine cardiovascular structure. Indices of cardiac (left ventricular to body weight ratio) hypertrophy were not influenced by any drug treatments. As expected, L‐NAME significantly increased blood pressure (BP) and cardiac interstitial fibrosis in both WT and AT2KO mice. However, Ang (1‐7) attenuated the increase in BP and interstitial fibrosis due to L‐NAME by a similar magnitude in both WT and AT2KO. Indomethacin, but not A779 inhibited the ability of Ang (1‐7) to prevent the L‐NAME‐induced hypertension implicating vasodilator prostaglandins in this effect. Thus, Ang (1‐7) exhibits an anti‐fibrotic effect that does not involve AT2R stimulation in this model.NHMRC (Australia)