bluuebunny/crossref_metadata_2025_split huggingface dataset:
Blood pressure and heart rate changes in simulated human apnea diving
Authors: Valic Zoran , Valic Maja , Giaconi JoAnn A , Peros Kristina 
Published: June 2021

Physiology exercise employing simulated human breath‐hold diving is used at University of Split School of Medicine to integrate knowledge in cardiovascular and respiratory physiology gained during lectures and seminars. We improved on otherwise widely used model, with emphasis on importance of continuous recordings of physiological signals. Pulsatile arterial pressure, heart rate and arterial oxygen saturation were continuously measured and digitalized signals stored for later analysis. All apneas lasted for 30 seconds, which produced no change in arterial oxygen saturation. Responses in arterial pressure and heart rate to breath‐hold in air, breath‐hold in water, breathing in air and cold water with snorkel, and applying warm and cold stimulus to forehead were analyzed. We describe our experience with organizing the exercise, and explain how application of modern technology can improve scientific investigation. Several points for discussion are accentuated in relation to possible medical problems (middle ear and sinus problems, regulation of breathing, death of most experienced divers/shallow water blackout) occurring during apnea diving.This study was supported by Croatian Ministry of Science, Education and Sports.
What does modern human variation in MT1 abduction angle and arch height reveal about hominid pedal morphology?
Authors: Kramer Patricia Ann 
Published: June 2021

Although modern humans exhibit many different morphologies, anthropological wisdom dictates that an effective bipedal foot is one with an adducted first metatarsal (MT) and medial longitudinal arch (MLA). The recently announced pedal morphology of Ardipithecus calls into question this assumption, prompting the question of what variation among modern human feet might reveal about the function of extinct hominid feet.Using anterior‐posterior and lateral radiographs of 50 osteological adults (aged 15–78 years, 25 women), arch height and the angle between MTs (MT12, MT23, MT34, MT45, MT15) were measured. MT12 of STW 575 and MT angles of OH 8 were measured on photographs/drawings of reconstructions.In the modern sample, MT12 ranged from 3–15° (mean = 9°, σ = 3°) and feet with more abducted 1st MT tended to have more abducted 5th MT (p = 0.051) and higher arches (p=0.018). MT12 measured 20° on STW 575 and 10° on OH 8.For MT12, STW 575 is > 3σ from the human mean, while OH 8 exhibits the human mean value. If the fossil reconstructions are accurate representations of weight‐bearing position, then the 1st MT of STW 575 was more abducted than is typically seen in modern humans, but what, if any, functional consequences accrue from this difference are less clear. As with other morphological features, effective bipedal feet can come in many forms.
Anatomy of the facial musculature in two diurnal anthropoid primates: exploring the relationship between facial mobility and the muscles of facial expression
Authors: Kandath Rachael E , Muldoon Kathleen M , Dobson Seth D 
Published: June 2021

Recent anatomical research suggests a pattern of uniformity in the muscles of facial expression across several primate species. This pattern appears to conflict with the observed diversity in facial mobility (the number of facial movements an individual can produce) among primate species. Exploring the potential disparity between uniformity of facial expression musculature and diversity of facial movements requires further expansion of the existing anatomical data on primate facial muscles. In this study, we examined the facial musculature of 2 species of diurnal anthropoid primates: Macaca mulatta (high facial mobility) and the previously unexamined Callithrix jacchus (low facial mobility). Using the ‘facial mask’ dissection technique, we determined the number (presence or absence) and degree of differentiation of the facial muscles in each species. We identified at least 18 highly differentiated muscles in Macaca as compared to 6 muscles with less differentiation in Callithrix. Our results indicate some degree of correspondence between facial expression musculature and facial mobility, and as such have implications for the role of these two variables in the evolution of primate social communication. This study was funded by the Claire Garber Goodman Fund to REK.Grant Funding Source: Claire Garber Goodman Fund (Anthropology Department)
Auditory Functional Analysis: Lessons From the Primate Auditory Ossicles
Authors: Carter Yasmin , Silcox Mary T. 
Published: June 2021

Soon after the auditory structures were first described, mechanical engineering theory was applied in order to understand the movements of the various components and the forces generated during this process, with the aim to accurately postulate the actual hearing of an individual or species. Many acoustic hypotheses are limited by their assumption of perfect conditions or ideal movements and rely on the ossicular chain functioning as a mechanical lever unit, however, changes in the angles between these bones have not been considered and until such studies are conducted, the movements of the ossicular chain under sound pressure cannot be accurately modelled. To address this issue, a landmark analysis was conducted on ultra‐high resolution computer tomography (UhrCT) scans of twenty‐six primate auditory ossicle chains. The study allowed not only visualisation but quantification of unexpected angles between bones and articulations which may answer questions regarding ossicle flexibility and relative motions. The morphometry of stand‐out specimens including the articulation angle of V.v. variegata, the relatively large chain of Daubentonia, the bulbous and shortened chain of A. calabarensis and the mediolaterally constricted bodies of T. bancanus suggest that many of the foundational mechanical theories of the auditory system will need to be revised to include more variables than they currently accept.Grant Funding Source: NSERC discovery grant to MTS and the Canadian Research Chairs program for YC
Positional variation in the molecular regulation of mammary gland development
Authors: Veltmaat Jacqueline M. 
Published: June 2021

Our lab aims to unravel the molecular mechanisms of early mammogenesis, using the five pairs of mammary glands in mouse embryos as a model. We found that loss of Gli3 results in induction of only mammary rudiment pairs #1, #2 and #4, but not #3 and #5. Moreover, the #2 and #4 pairs each have distinct morphogenetic defects, while pair #1 is morphologically normal. Our in vivo approach to rescue all defects by activating a pathway downstream of Gli3 resulted in induction of pair #3 only, but not of pair #5, nor did it restore morphogenesis of pairs #2 and #4. Analysis of the latter two pairs is ongoing. We conclude that all five pairs of mammary rudiments in mice differ in their molecular regulation of induction and early morphogenesis, despite their identical functional outcome. This contrasts with other multiples of the same structures, e.g. somites, limbs or hair follicles, which are generally thought to share the same inductive signals, while unique specification signals establish their anatomical and functional differences such as those between fore‐ and hind limbs. The variation in molecular inductive mechanisms of mammary glands may explain the differences in numbers and positions of mammary glands among mammalian species. It also increases the chances of survival of the species when a gene function is altered.Funding provided by CBCRP:10FB‐0116 and A*STAR.Grant Funding Source: A*STAR
VEGF up‐regulates pro‐inflammatory factors in the cervix of mice
Authors: Schwabe John , Boggess Bethany , Nguyen Bao‐Tran , Gosai Puja G. , Tashakkori Parisa , Mowa Nonde K , Mowa Chishimba N 
Published: June 2021

Cervical remodeling (CR) entails a physiological inflammatory response that can be induced by inflammatory agents, such as lipopolysaccharide (LPS), and inflammation is closely associated with vascular remodeling. Recently, we showed that LPS‐induced inflammation up‐regulates mRNA levels of vascular endothelial growth factor (VEGF) and its receptors, KDR and Flt‐1. Here, we sought to investigate whether VEGF can modulate inflammation by characterizing the expression pattern of pro‐inflammatory factors in VEGF‐treated mice using real time PCR. Our data revealed that VEGF up‐regulates a group of pro‐inflammatory factors in the cervix, including IL‐6. Collectively, our studies show a possible existence of a positive feed forward loop between inflammatory and vascular factors in the remodeling cervix.Grant Funding Source: Appalachian State University
Interactions between the U2 snRNP and SAGA reveal new links between co‐transcriptional RNA splicing and chromatin modification
Authors: Johnson Tracy L 
Published: June 2021

Recent studies have shown that mRNA splicing can occur co‐transcriptionally. The next key challenge is to identify the mechanisms by which specific factors couple the two reactions. We have discovered that Gcn5, which encodes the HAT activity of the SAGA, and other components of SAGA that support its catalytic activity, have functional interactions with the genes encoding the heterodimeric U2 snRNP proteins Msl1 and Lea1. ChIP analysis has revealed that Gcn5, and particularly its HAT activity, is required for co‐transcriptional recruitment of Msl1 and Lea1 to pre‐mRNA. Consistent with a role for Gcn5 in co‐transcriptional splicing, Gcn5 protein and Gcn5‐dependent histone acetylation are enriched in intron‐containing genes. These results have led us to examine how the activity of the SAGA complex affects ATP‐dependent rearrangements of the U2 snRNP that are critical for branchpoint recognition. A genetic analysis has revealed surprising interactions between the DExH/D box protein Prp5, which hydrolyzes ATP to remodel the U2 snRNP and facilitate branchpoint recognition, and components of SAGA. A lethal mutation in PRP5 that eliminates ATP‐binding is suppressed when components of the SAGA complex are deleted, thereby for the first time linking SAGA with a catalytic activity that drives spliceosomal rearrangements.(Supported by NSF CAREER grant MCB 0448010 and NRSA predoctoral fellowship 5F31 GM078745)
Estimating the activation barrier to each step of protein splicing for the non‐canonical P. abyssi PolII intein
Authors: York Daniel J. , Duffee Lauren R. , Dorval Deirdre M. , Reitter Julie N. , Mills Kenneth V. 
Published: June 2021

Protein splicing is a post‐translational event by which an intervening polypeptide, called an intein, facilitates its own excision from the flanking polypeptides, called the exteins, and the ligation of the exteins. We are able to study the protein splicing of the Pyrococcus abyssi PolII intein in vitro, and can determine the rate of the overall splicing reaction as well as that of each step. The robust temperature‐dependence of this reaction allows us to estimate the activation barrier for individual steps of the reaction. This is especially interesting for the third step of the reaction, cyclization of Asn or Gln coupled to peptide bond cleavage. We will use these data to assess mechanistic models for the catalysis of side‐chain cyclization.This material is based upon work supported by the National Science Foundation under Grant No. 0320824 and CAREER grant No. 0447647.
Mutational disruption of the nitric oxide synthase/calmodulin interaction causes increased formation of reactive oxygen species
Authors: Kellogg Dean L. , Masters Bettie Sue S. , Roman Linda J. 
Published: June 2021

The nitric oxide synthases (NOSs) catalyze the formation of nitric oxide (NO) from L‐arginine. The NOSs are bidomain enzymes, consisting of a heme‐containing oxygenase domain and a flavin‐containing reductase domain, bisected by a calmodulin (CaM) binding site. Occupancy of this site is required for NO formation. Recently, Xia et al. (2009, J. Biol. Chem., 284, 30708) published the structure of human iNOS CaM‐bound FMN domain, showing that the only interactions between the FMN domain and CaM involve R536 of iNOS, which makes a salt bridge with E47 of CaM and forms H‐bonds with N42 of CaM and S562, F565 and A564 in the FMN domain. Mutations of R530, the homologous residue in the murine iNOS reductase domain, and R753 in the nNOS reductase domain, yield enzymes active in electron transfer to cytochrome c and potassium ferricyanide. The rate of ferricyanide reduction is equivalent to that of wild‐type, but cytochrome c reduction is diminished by approximately 60%. NADPH oxidation in the absence of acceptor, however, is elevated by about 40% over that of wild‐type, indicating an increase in reduced oxygen species production by these mutants.Supported by NIH GM052419 to BSSM and LJR.
Molecular chaperone HSP90α isoform 1 forms telomerase complex
Authors: Zhdanov Dmitry , Kovalenko Natalia , Orlova Elena 
Published: June 2021

Telomerase is a specialized reverse transcriptase multiprotein complex responsible for synthesizing telomeric DNA repeats (TTAGGG) at the ends of eukaryotic chromosomes. One of six telomerase subunits is HSP90α that is thought to stabilize the complex. Two isoforms (IS1 and IS2) of HSP90α that are the result of HSP90AA1 gene alternative splicing are known. IS1 has 122 additional amino acid residues at the N‐terminus of the molecule. We examined HSP90α IS1 and IS2 expression and its correlation with the expression of telomerase catalytic subunit hTERT and telomerase activity to investigate which of HSP90α isoforms forms telomerase complex. Purified RNA from human colon and gastric adenocarcinoma was used for RT‐PCR analysis to examine the mRNA expression rate of HSP90α IS1 and IS2, hTERT and B2‐microglobulin (as positive control).Telomerase activity was detected using TRAP analysis. HSP90α IS2 constitutively expressed at the same level both in tumor and normal tissues. HSP90α IS1 was detected in colon and gastric tumor samples (p = 0.046) and was not found in normal tissues. Expression of this isoform correlated with telomerase activity (r = 0.86) and hTERT expression (r = 0.78), but did not depend on adenocarcinoma differentiation and a stage of disease.According to these data, we can suggest that HSP90α IS1 forms telomerase complex. It can be used as a target for production more specific telomerase inhibitors.
Metazoan mitochondrial alanyl‐tRNA synthetases – varying roles for a C‐terminal domain
Authors: Chihade Joseph , Anderson David , Borchert Karen , Brown Julia , Mork A. Jolene , Natala Nakita , Zhu Yirong 
Published: June 2021

Metazoan mitochondrial tRNAs are unusual.Some differences may affect tRNA identity, and are likely to result in compensatory changes in the corresponding aminoacyl‐tRNA synthetase (aaRS). We have focused our attention on two mitochondrial AlaRSs, from humans and C. elegans.Human mitochondrial (hm) tRNAAla lacks a G3:U70 wobble pair, a conserved identity element in non‐mitochondrial alanine tRNAs. Aminoacylation by hmAlaRS is insensitive to changes in the tRNA acceptor stem, but sensitive to changes in the variable loop‐anticodon stem. A C‐terminal domain, dispensable in non‐mitochondrial systems, is required for aminoacylation by hmAlaRS.In C. elegans mitochondrial (cem) tRNAAla a six‐nucleotide sequence replaces the usual T stem‐loop and variable loop. Unlike paralogs, cemAlaRS aminoacylates microhelix substrates as efficiently as full‐length tRNAs, suggesting that relevant contacts are only with the acceptor stem of the tRNA. Interestingly, cemAlaRS lacks a C‐terminal domain conserved in non‐mitochondrial systems.
The Role of Interleukin 1 Receptor Associated Kinase 1 (IRAK1) in lipid metabolic alterations associated with endotoxemia
Authors: Chang Samantha Mee , Maitra Urmila , Li Liwu 
Published: June 2021

Both inflammatory and metabolic alterations have been established in the pathology of endotoxemia and septic shock, making treatment very difficult. The metabolic alterations associated with endotoxemia contribute to multiple organ failure (MOF) and high mortality rate in septic patients. However, the mechanism behind the shift in metabolism during lipopolysaccharide (LPS) ‐mediated endotoxemia has not been defined. In this study, we examine the role of Interleukin 1 receptor associated kinase 1 (IRAK1), a kinase downstream of the innate LPS receptor Toll‐like receptor 4 (TLR4), in the lipid metabolic alterations associated with LPS. We report a decrease in fatty acid oxidation (FAO) and an increase in plasma levels of free fatty acid (FFA) and triglyceride (TG) in WT but not IRAK1−/− mice injected with a lethal dose of LPS (25mg/kg). Mechanistically, we demonstrate that LPS suppresses FAO by decreasing the expression of mitochondrial β‐oxidation enzymes including carnitine palmitoyl transferase 1□ (CPT1□) and medium chain acyl dehydrogenase (MCAD), as well as pyruvate dehydrogenase kinase 4 (PDK4). Additionally, LPS suppressed the levels of nuclear receptors PPAR□ and PGC‐1□ in tissues from WT but not IRAK1−/− mice after lethal LPS injection. In conclusion, this study establishes that IRAK1 plays a novel role in the lipid metabolic alterations associated with TLR4 stimulation by LPS.Research funded by the NIH T32 Program, mentorship provided by Dr. Liwu Li, member of the ASBMB.
Phosphatidylethanolamine modification contributes to levuglandin/isoketal induced cytotoxicity
Authors: Davies Sean Stephen , Sullivan C. Blake , Matafonova Elena , Roberts L. Jackson , Amarnath Venkataraman 
Published: June 2021

BackgroundLevuglandins and isoketals are γ‐ketoaldehyde isomers (IK) formed by non‐enzymatic rearrangement of prostaglandin H2 and H2‐isoprostanes, respectively. IK rapidly adduct to proteins and increases in IK protein adduct levels occur in several inflammatory conditions. IK induce cell death in cultured cells, potentially by adducting to cellular proteins. However, IK also adduct to other primary amines including phosphatidylethanolamine (PE) in vitro. Whether IK induces its biological activities by modifying PE has not been investigated.ObjectiveMeasure levels of IK‐PE in cells and determine whether IK‐ PE mediates the endothelial cell death induced by IsoK.Results40% radiolabeled IK added to HEK cells bound to phospholipids and only 8% with proteins. An LC/MS/MS assay using S. chromofuscus phospholipase D to convert IK‐PE to IK‐ethanolamine was used to measure IK‐PE adducts in IK treated endothelial cells (EC). IK‐PE added directly to EC dose‐dependently induced cytotoxicity (LC50 2.2 μM).ConclusionPE is a major cellular target of IK, and IK modified PE can mediate IK induced cytotoxicity.
Secretor phenotype and genotype are novel predictors of severe outcomes in premature infants
Authors: Morrow Ardythe L. , Meinzen‐Derr Jareen , Huang Pengwei , Schibler Kurt R. , Cahill Tanya , Kallapur Suhas G. , Newburg David S. , Tabangin Meredith , Warner Barbara B. , Jiang Xi 
Published: June 2021

BackgroundThe secretor gene (FUT2) and its products have important role in mucosal maturation, immunity, and host susceptibility to pathogens. We conducted the first investigation of secretor phenotype and genotype of premature infants in relation to their risk of death, necrotizing enterocolitis (NEC; Bell's stage II and III), and confirmed sepsis.MethodsSecretor phenotype was measured in infant saliva samples by enzyme immunoassay of H antigen, the primary antigen produced by transferases of secretor gene. The optimal cut‐point in salivary H values was identified and confirmed by computerized algorithms (CART and ROC analysis).ResultsOf the 410 study infants, 14% with low salivary H died, compared to 2% of infants with high salivary H (p<0.001). Modeled with clinical covariates, low H remained significant, and the overall model highly predicted death. Low H antigen was also associated with 10‐fold or greater odds of NEC and sepsis deaths, 3‐fold higher odds of surgical NEC and 2‐fold higher odds of NEC. Similarly, secretor genotype was a significant predictor: 13% of non‐secretors, 5% of heterozygotes, and 2% of secretor dominant infants died (p=0.01).ConclusionsLack of secretor antigen predicts adverse outcomes in prematurity. Sponsorship NICHD HD13021, HD059140
The Goldilocks Effect: Identifying the Mechanism by Which O‐GlcNAc Regulates the expression of OGT and O‐GlcNAcase in Response to Changes in Cellular State
Authors: Nimaga Bahawa , Doshi Shivang , Zachara Natasha E 
Published: June 2021

Over 500 nuclear, cytoplasmic and mitochondrial proteins are modified and regulated by O‐linked β‐N‐acetylglucosamine (O‐GlcNAc). The addition and removal of O‐GlcNAc to proteins is catalyzed by just two enzymes, the O‐GlcNAc transferase and the O‐GlcNAcase. Previously, it has been shown that when O‐GlcNAc levels are raised exogenously, the cell alters the expression of OGT (down) and O‐GlcNAcase (up) to return O‐GlcNAc levels to normal. We refer to this phenomena as the “goldilocks effect”. The mechanisms by which the cell fine‐tunes the expression of OGT and O‐GlcNAcase are unknown.In this study we have shown that: 1) When OGT is deleted, the expression and activity of O‐GlcNAcase are reduced. However, the level of O‐GlcNAcase transcript is not affected suggesting that the expression of O‐GlcNAcase in the cell is regulated by protein turnover. 2) In cells with O‐GlcNAc, but deficient in OGT, O‐GlcNAcase expression is maintained, suggesting that the expression of O‐GlcNAcase is dependent on the level of O‐GlcNAc. 3) In cells with exogenously elevated levels of O‐GlcNAc, O‐GlcNAcase expression was elevated. But, when these cells were stressed, a cellular state in which elevated O‐GlcNAc levels are desirable, O‐GlcNAcase over‐expression was ablated. Together these data suggest that the cell can sense both the level of stress and O‐GlcNAc in the cell, and adjust the expression of OGT and O‐GlcNAcase accordingly.
Cleavage of Arrestin3 by Caspases Prevents Apoptosis via Modulation of JNK‐dependent Cell Death Pathway
Authors: Kook Seunghyi , Gurevich Vsevolod , Gurevich Eugenia 
Published: June 2021

Ubiquitously expressed arrestin2 and arrestin3 (ARR3) regulate numerous GPCRs and many other signaling proteins, including key players in life‐or‐death decisions, such as Src, ERK, and JNK. Here we show that arrestin3 is specifically cleaved at Asp366, Asp405 and Asp406 by caspases during apoptosis induced by a variety of stimuli in different cell types. Caspase‐generated ARR3(1–366) dose‐dependently increases the survival of etoposide‐treated cells, whereas caspase‐resistant D366/405/406E mutant significantly facilitates apoptosis. We recently showed that all four vertebrate arrestins bind the three kinases in ASK1‐MKK4‐JNK3 cascade, but only arrestin3 facilitates the activation of pro‐apoptotic JNK3. We found that the deletion of ARR3 C‐terminus by caspases does not prevent JNK3 binding, but abolishes its ability to activate JNK3. In contrast, caspase‐resistant D366/405/406E mutant activates JNK3 as effectively as WT ARR3. Thus, caspase‐generated ARR3(1‐366) prevents signaling in ASK1‐MKK4‐JNK3 cascade and protects cells. These findings demonstrate the involvement of ARR3 in the regulation of apoptotic cell death via JNK3 activity.NIH grants NS065868 (EVG), GM077561, GM081756 (VVG)