bluuebunny/crossref_metadata_2025_split huggingface dataset:
Morphologic growth of the hominoid choanae: Implications for understanding functional integration of the basicranium and respiratory tract.
Authors: Pagano Anthony S , Yuan Derek Y , Laitman Jeffrey T 
Published: June 2021

The internal nares (choanae) lie at the nexus of key respiratory tract functions, yet their comparative and functional morphology in hominoids has been poorly studied. We examined the growth of the choanae and adjacent facial and basicranial regions in crania of extant hominoids (Homo sapiens, n= 130; Pan troglodytes, n= 32; Gorilla gorilla n= 22; Pongo pygmaeus, n= 17; Symphalangus syndactylus, n= 19; Hylobates hoolock, n= 39) from eruption of the first through third permanent maxillary molars. Shape variation was quantified using 3D landmarks and analyzed with generalized procrustes analysis (GPA). Results show that ontogenetically the relative size and proportions of the choanae remained stable in all observed species. Humans are characterized by shorter, broader choanae than pongids, but not hylobatids, whose choanae are nearly twice as wide as they are tall. Among all hominoids, choanal area is negatively (and significantly; p<.01) correlated with the area of the piriform aperture, flexion at the spheno‐occipital synchondrosis, and facial kyphosis. These results imply a functional relationship between the dimensions of the osseous nasopharynx and overall basicranial flexion.Grant Funding Sourcen/a
Evaluating the relationship between thoracic form and individual rib cross‐sectional shape
Authors: Eaves‐Johnson K. Lindsay 
Published: June 2021

Within the context of human evolution, differences in rib cross‐sectional shape have been explained as a means of preserving equivalent pulmonary function in differently shaped thoraces during respiratory excursions (Jellema et al., 1993.). Relatively flat ribs should then be associated with a narrower trunk (modern), whereas rounded ribs should accompany a thorax that is transversely broad ("archaic"). This study tests whether the more modest variation in thoracic shape within living humans related to climatic adaptation may also elicit these differences. To test the influence of thoracic form on individual rib cross‐sectional shape, external shape data was collected from the 4th and 8th ribs of males from within two ecogeographically distinct populations: Inuit (n=20) and Zulu (n=20). Overall thoracic shape at each level was characterized using measures modified from Franciscus and Churchill (2002), and external rib shaft molding was used to capture cross‐sectional shape. The 2‐D outline of each cross‐section was acquired using TPS software (Rohlf, 2007). As predicted, the Inuits, with their wider torso, are determined to have statistically significantly rounder ribs, accounted for by greater medio‐lateral dimensions, though not greater cross‐sectional area. Results are presented in the context of climatic adaptation, as well as previous considerations regarding rib shape and resistance to bending.Research funded with generous support from University of Iowa Student Government, UI Graduate Student Senate, Center for Global and Regional Environmental Research, the Stanley ‐UI Foundation Support Organization.Grant Funding SourceUniversity of Iowa Student Government, UI Graduate Student Senate, Center for Global and Regional Environmental Research, the Stanley â€“UI Foundation Support Organization
The association between patella alta and structural features of osteoarthritis on MRI: The Multicenter Osteoarthritis (MOST) Study
Authors: Stefanik Joshua Jon , Zhu Yanyan , Gross K Douglas , Clancy Margaret , Zumwalt Ann , Lynch John , Felson David 
Published: June 2021

Patella alta (PA) is present when the patella position is high relative to the femoral trochlea, and is a known risk factor for patellar dislocation and anterior knee pain in young persons. PA is defined as present when the Insall‐Salvati ratio (ISR), length of the patellar tendon (LT) divided by length of the patella (LP), is = 1.2. The purpose of this study was to determine, in middle aged and older persons at risk for knee osteoarthritis, the association between PA and patellofemoral joint (PFJ) cartilage morphology and bone marrow lesions (BMLs). We measured the ISR on the lateral radiograph in 443 subjects from a cohort study of persons aged 50‐79 years. Cartilage morphology and BMLs were graded on MRI using a semi‐quantitative scale (0‐6, 0‐3 respectively, with 0 representing absence of pathology) in the medial and lateral PFJ. Using logistic regression, we determined the association between the ISR and cartilage morphology and BMLs, adjusting for age, sex, and BMI. The mean ISR was 1.095 and 113 subjects' (26%) ISR was = 1.2. Compared with subjects who did not have PA, those with PA had 1.82 (95% CI 1.26, 2.63) and 2.38 (1.59, 3.58) times the odds of lateral PFJ cartilage damage and BMLs, respectively. We are currently investigating the biomechanical mechanism for the changes seen in bone and cartilage in subjects with PA. This research was supported by the NIH and Arthritis Foundation.Grant Funding SourceNIH and Arthritis Foundation
Biomechanical characteristics of cortical bone regenerate after mandibular distraction osteogenesis in dogs
Authors: Zapata Uriel , Kontogiorgos Elias , Elsalanty Mohammed E , Dechow Paul C , Opperman Lynne A 
Published: June 2021

ObjectivesBiomechanical quality of the newly formed cortical bone after mandibular distraction is critical for assessing distraction successfully. This study examined bone density, ultrasound speed, and directions of maximum stiffness in distracted canine mandibles. The hypothesis tested was that because of the orientation of the distraction loads, cortical bone will be stronger in the distraction direction.MethodsFive adult foxhound dogs had a distraction device placed to close a 35 mm mandibular defect. After 7 days of latency, the device was activated 1 mm/day for 5 weeks. After a healing period of 12 weeks animals were sacrificed. 35 cylindrical cortical bone specimens were tested to determine the relationship between the specimen diameter and the minimum time delay from the longitudinal ultrasonic pulse through the specimen in the direction of maximum stiffness. In an additional test, densities were obtained.ResultsDensity was significantly less in the regenerate bone (1721.7±177.8 mg/cm3) than in the control cortical bone (1974.9±87.2 mg/cm3). There is significantly reduced maximum ultrasonic speed in the regenerate bone specimens (4.0±0.4 mm/ μs), compared to the control bone (4.3±0.1 mm/µs).ConclusionsThe mechanical quality of the regenerate bone was lower on the side of the device placement within the time frame of the experiment.Grant Funding SourceNIH/NIDCR DE017259‐01 and a grant from COLCIENCIAS (Bogotá, Colombia)
Dental phenotype of a mouse model expressing a truncated form of ameloblastin
Authors: Wazen Rima Marie , Moffatt Pierre , Zalzal Sylvia Francis , Yamada Yoshihiko , Nanci Antonio 
Published: June 2021

Ameloblastin (AMBN) is the second most abundant protein produced by ameloblasts and is found mainly in forming enamel. Our aim was to characterize the tooth phenotype in a mouse model lacking expression of full‐length AMBN (AMBN−FL). Since after building enamel ameloblasts and associated cells participate in the formation of the gingival attachment to the tooth (junctional epithelium, JE), we have also examined its integrity. Materials andMethodsMandibles from normal and AMBN−FL mice were processed for morphological analyses and immunohistochemical detection of AMBN. Freeze‐dried enamel organs and enamel were prepared for molecular and biochemical analyses.ResultsOur data show that absence of full‐length AMBN causes structural changes at the level of the enamel organ, shows displatic enamel layer, and loss of integrity of the JE. Immunohistochemical staining indicated that the enamel organ in these mice continued to produce an AMBN‐related peptide that is translated from a truncated RNA missing exons 5 and 6. The protein was deduced to have 295 amino acids and an apparent molecular weight of 32‐35 kDa.ConclusionOur study shows that AMBN influences both cells and matrix events. Identification of the portion of AMBN protein still produced in this AMBN−FL mouse model provides new insights on the functional domains that may be implicated in these activities. Supported by the CIHR.
Revealing the DNA Structural Determinants for ATM Activation
Authors: Zou Lee 
Published: June 2021

Both the ATM and the ATR checkpoint kinases play important roles in the cellular response to double‐strand DNA breaks (DSBs). A number of protein factors implicated in the activation of ATM and ATR at DSBs have been identified and characterized. Nonetheless, how exactly DNA ends contribute to the activation of these kinases was unclear.To investigate the role of DNA in the activation of human ATM kinase, we have developed a new ATM activation assay using cellular extracts and defined DNA structures. Using this assay, we have systematically analyzed how the DNA structures associated with DSBs contribute to ATM activation. Our analysis has revealed that the activation of ATM is regulated by multiple structural components of DNA breaks. We found that distinct DNA structures are involved in the in initiation and enhancement of ATM activation. Surprisingly, the activation of ATM is inhibited by specific structures of DSBs, suggesting that ATM activation is not an irreversible event but a dynamic process regulated by the changes of DNA breaks. In addition, we have identified the key DNA structures that differentially regulate ATM and ATR at DSBs. These results have shed new light on how specific DNA structures contribute to the activation of ATM and ATR, and how the DNA‐damage specificities of ATM and ATR are determined at DSBs.
Diverse splicing patterns of exonized Alu elements in human tissues
Authors: Lin Lan , Shen Shihao , Tye Anne , Cai James J , Jiang Peng , Davidson Beverly L , Xing Yi 
Published: June 2021

Exonization of Alu elements is a major mechanism for birth of new exons in primate genomes. Prior analyses of expressed sequence tags show that almost all Alu‐derived exons are alternatively spliced, and the vast majority of these exons have low transcript inclusion levels. In this work, we provide genomic and experimental evidence for diverse splicing patterns of exonized Alu elements in human tissues. Using Exon array data of 330 Alu‐derived exons in 11 human tissues, and detailed RT‐PCR analyses of 38 exons, we show that some Alu‐derived exons are constitutively spliced in a broad range of human tissues, and some display strong tissue‐specific switch in their transcript inclusion levels. Most of such exons are derived from ancient Alu elements in the genome. In SEPN1, mutations of which are linked to a form of congenital muscular dystrophy, the muscle‐specific inclusion of an Alu‐derived exon may be important for regulating SEPN1 activity in muscle. Realtime qPCR analysis of this SEPN1 exon in macaque and chimpanzee tissues indicates human‐specific increase in its transcript inclusion level and muscle‐specificity after the divergence of humans and chimpanzees. Our results imply that some Alu exonization events may have acquired adaptive benefits during the evolution of primate transcriptomes.Supported by the Hereditary Disease Foundation (to YX and BLD) and Roy J. Carver Trust (to BLD).
A plant 5S rRNA mimic regulates alternative splicing of transcription factor IIIA pre‐mRNAs
Authors: Hammond Ming Chen , Wachter Andreas , Breaker Ronald R. 
Published: June 2021

Transcription factor IIIA (TFIIIA) is required for eukaryotic synthesis of 5S ribosomal RNA by RNA polymerase III. Here we report the discovery of a structured RNA element with striking resemblance to 5S rRNA that is conserved within TFIIIA precursor mRNAs (pre‐mRNAs) from diverse plant lineages. TFIIIA protein expression is controlled by alternative splicing of the exon containing the plant 5S rRNA mimic (P5SM). P5SM triggers exon skipping upon binding of ribosomal protein L5, a natural partner of 5S rRNA, which demonstrates the functional adaptation of its structural mimicry. Since the exon‐skipped splice product encodes full‐length TFIIIA protein, these results reveal a ribosomal protein‐mRNA interaction that is involved in 5S rRNA synthesis and has implications for cross‐coordination of ribosomal components. This study also provides insight into the origin and function of a newfound class of structured RNA that regulates alternative splicing.M. C. H. holds a Career Award at the Scientific Interface from the Burroughs Wellcome Fund, and A. W. held a postdoctoral fellowship from the German Research Foundation. The research also was supported by grants from the NIH (GM068819) and HHMI.
Changes in β‐secretase activity and regulation in aging and disease
Authors: Holler Christopher J , Webb Robin L. , Ahmed Rachel R. , Li Feng , Beckett Tina L. , Murphy M. Paul 
Published: June 2021

BackgroundAlzheimer's disease (AD) is thought to be causally related to the production of amyloid‐β peptide (Aβ); β‐secretase is the rate‐limiting enzymatic activity in this process and is considered to be a prime target for therapeutics. β‐secretase may increase in AD, although it is unknown whether this effect is specific for BACE1, the major isoform of the enzyme in brain. Our lab is interested in β‐secretase activity and its regulatory factors; one candidate is cellular nucleic acid binding protein (CNBP).ObjectiveTo determine how BACE1 and BACE2 change in aging and disease as it relates to CNBP levels.MethodsWe have developed a fluorometic assay that measures BACE1 or BACE2 activity. Using this assay, we analyzed a set of control and late‐stage human AD cases (N=11).ResultsBACE1 specific activity was significantly increased in AD brain, whereas BACE2 specific activity was significantly decreased. We also observed that CNBP levels decreased by 17% in AD cases.ConclusionsThese data indicate that BACE1 and BACE2 may have opposing enzymatic effects in AD, and that CNBP may play a regulatory role. In order to gain a better understanding of how BACE1/2, and CNBP change during disease, we will expand our analysis to include earlier clinical times (mild‐cognitive impairment and pre‐clinical AD). These studies will help guide the future development of therapeutic treatments for AD. Supported by NIH NS058382.
Chaperone Ability of Two Small Heat Shock Proteins from Maize
Authors: Klein Roger Davies , Bouchard Robert A. , Pett Virginia B. 
Published: June 2021

ZmHsp17.0‐CII and ZmHsp17.8‐CII are Class II small heat shock proteins (sHsps) found in maize (corn). These highly conserved Hsps protect client proteins from irreversible aggregation in times of stress. The sHsp was expressed as a fusion protein with a chitin‐binding domain on the C‐terminus that allows for chitin affinity column purification. Light scattering of the model substrate citrate synthase (CS) in solution was measured using a fluorescence spectrophotometer. Instrumental settings and improved processing of CS were devised to maximize reproducibility. After heat shock at 43 °C the light scattering increased over time as CS aggregated. By comparing the light scattering curves of CS alone with a solution containing CS plus varying amounts of ZmHsp17.0‐CII, a clear, consistent reduction in aggregation was seen for all molar ratios of sHsp monomer: CS monomer of 6:1 and greater. Preliminary results also indicate a significant difference between the aggregation suppression effects of ZmHsp17.0‐CII and 17.8. It has been determined that ZmHsp17.0‐CII and ZmHsp17.8‐CII are concentration‐dependant molecular chaperones that protect cellular proteins from aggregation during times of heat stress.This work was supported in part by a grant to The College of Wooster from the Howard Hughes Medical Institute through the Undergraduate Science Education Program.
The role of His349 in receptor‐stimulated iron release from the C‐lobe of transferrin
Authors: Steere Ashley N. , Byrne Shaina L. , Mason Anne B. 
Published: June 2021

The primary uptake and delivery pathway for iron in mammalian systems involves serum transferrin (Tf), a bilobal protein, which releases iron within the acidic environment of the endosome (pH ~5.6) in a receptor mediated manner. Following iron release, apo Tf remains bound to the Tf receptor (TfR) until the basic extracellular pH (~7.4) is reached, and Tf is released to continue the cycle. Previous structural and mutagenesis studies suggest that residue His349 in the C‐lobe of Tf makes essential contacts with the TfR to simulate iron release and stabilize the apo complex. Due to the physiologically relevant pKa of the histidine side chain (~6.5), His349 presumably undergoes a change in protonation state during endo‐and exocytosis. We sought to further investigate the role of His349 in iron release from the C‐lobe of Tf in the presence of the TfR using intrinsic tryptophan fluorescence and urea gel analysis of various His349 mutants in a monoferric C‐lobe construct. Mutation of His349 to a lysine causes a loss of receptor stimulated iron release, indicating that not only the charge, but the orientation of residue 349 is important for stabilizing the apo form of Tf in complex with the TfR. Likewise, mutation of His349 to an alanine, aspartic acid, leucine, tryptophan, or tyrosine residue also decreased iron release rates in the presence of the TfR as compared to the control. These results indicate an essential role of His349 in acceleration of iron release from Tf as stimulated by the TfR.This work was supported by USPHS Grant R01 DK 21739 (ABM) and NRSA Grant 5T32HL007594.
RGDSK/K rosette nanotubes induce inflammation and apoptosis through phosphorylation of p38 MAPK in human lung adenocarcinoma (Calu‐3) cells
Authors: Singh (Suri) Sarabjeet , Myles Andrew J , Fenniri Hicham , Singh Baljit 
Published: June 2021

Rosette nanotubes (RNTs), a novel class of biologically inspired nanotubes, hold tremendous potential as targeted drug delivery shuttle. We synthesized hybrid RNTs that composed of RGDSK‐ and K‐functionalized RNTs in a ratio of 1:10 M (RGDSK/K‐RNTs). We noticed the expression of avb3 integrin on Calu‐3 cells and believe that these RNTs may bind to integrin. We investigated cell signaling events caused by these RNTs for induction of inflammation and apoptosis in Calu‐3 cells. RGDSK/K‐RNTs rapidly induced phosphorylation of p38 MAPK. RGDSK/K‐RNTs (>10:100 μM) promoted p38 MAPK‐dependent secretion of TNF‐α. All the tested concentrations of RGDSK/K‐RNTs resulted in an increase in caspase‐3 activity and DNA fragmentation in Calu‐3 cells at 18 hours of the exposure. Blocking phosphorylation of p38 MAPK strongly inhibited caspase‐3 activity and DNA fragmentation. Pro‐apoptotic properties of RGDSK/K‐RNTs were also supported by over‐expression of pro‐apoptotic genes. We therefore conclude that RGDSK/K‐RNTs induce phosphorylation of p38 MAPK, which regulates secretion of TNF‐α, activation of caspase‐3 and apoptosis in Calu‐3 cells. These results suggest that the RGDSK/K‐RNTs could be used as a drug to induce apoptosis in cancer cells or as a versatile platform to deliver a variety of biologically active molecules for cancer therapy. Support: NSERC, AARI.Grant Funding SourceNSERC discovery, AARI
Histone‐folds: A novel membrane‐anchoring domain in Son of Sevenless
Authors: Yadav Kamlesh Kumar , Bar‐Sagi Dafna 
Published: June 2021

The RAS‐MAPK pathway controls a variety of cellular functions such as survival, proliferation and differentiation. The guanine nucleotide exchange factor SOS couples receptor tyrosine kinases to the RAS‐MAPK pathway by mediating a signal dependent activation of RAS. The activity of SOS is tightly regulated by multiple inter‐ and intramolecular interactions and the loss of this regulation due to germ line mutations leads to gingival fibramatosis type‐I and Noonan Syndrome (NS). SOS has a unique Histone Folds (HF) domain similar to H2A/H2B nuclear histones of as yet unknown function. Electrostatic modeling of the HF suggested a membrane binding function. Indeed, the isolated HF shows signal‐dependent membrane localization. A screen of 15 common membrane‐lipids, using recombinant HF, identified Phosphatidic acid (PA) as the specific lipid ligand. The motif for the PA binding on HF has been identified by mutagenesis studies and shown to be essential for the membrane localization of the HF and SOS‐mediated RAS activation. The gain of function NS mutation E108K, which lies in the PA binding motif, increases PA binding and membrane localization of the HF and enhances SOS‐mediated RAS activation. These findings identify a new membrane anchoring modality and provide insights into the spatial regulation of RAS activation.This work was supported by research grants from the National Institutes of Health to D.B.‐S. (CA55360 and GM078266).
The START domain Coq10 polypeptide binds Coenzyme Q and is required for mitochondrial respiratory electron transport
Authors: Morvaridi Susan , Saiki Ryoichi , Liau Wei‐Siang , Kawashima Tadashi , Clarke Cathy 
Published: June 2021

Coenzyme Q (Q) is a redox active lipid that is an essential component of the electron transport chain in the mitochondrial membrane. In Saccharomyces cerevisiae, ten COQ genes are required for Q biosynthesis and function in respiratory electron transport. Nine genes are required for synthesis of Q, COQ1 through COQ9. However, unlike the other coq mutants, each of which lack Q6, the coq10 mutant has near normal amounts of Q6 in mitochondria. The defect in oxidation of NADH and succinate in coq10 mutant mitochondria can be rescued by the addition of Q2, a water soluble analog.Coq10p is widely distributed in bacteria and eukaryotes and is homologous to proteins of the "aromatic‐rich protein family" Pfam03654. The structure of the Caulobacter crescentus Coq10 homolog, CC1736, identified it as a member of the START domain superfamily. The START domain containes a hydrophobic cavity that binds lipophilic molecules such as cholesterol or polyketides.Our data show that expression of C. crescentus CC1736 is able to rescue the respiratory deficiency of the yeast coq10 null mutant. The rescue depends on the presence of a mitochondrial leader sequence. An assay of Q binding shows that purified CC1736 is able to bind Q10, Q6 and Q2 in molar ratio near to one.Site directed mutagenesis shows that Valine 70 of CC1736 is crucial for both rescue of the coq10 mutant and the coenzyme Q10 binding. The results suggest that the Coq10 polypeptide:coenzyme Q, protein:ligand complex may serve an essential function in the delivery of Q from its site of synthesis in the inner mitochondrial membrane to the respiratory electron transport chain.
Auto‐inhibition of dynamin GTPase activity is regulated by PH domain interactions
Authors: Kenniston Jon A. , Lemmon Mark A. 
Published: June 2021

The dynamin GTPase drives receptor‐mediated endocytosis in addition to other membrane vesicle scission events. We aim to understand how vesicle interactions of the dynamin pleckstrin homology (PH) domain contribute to the conversion of basal, auto‐inhibited dynamin tetramers to an activated, multi‐oligomeric state with a >200‐fold increased rate of GTP hydrolysis. Although dynamin self‐assembly alone has been used to explain this activation, emerging evidence suggests that dynamin may have a more complex conformational interplay between its PH and GTPase domains. Through selective mutagenesis of the dynamin PH domain based on common PH‐GTPase interaction motifs in biology, we have identified an interface of the dynamin PH domain that regulates auto‐inhibition of dynamin GTP hydrolysis rates. Specifically, we find that mutations within this interface fall into two distinct groups: a "weak" class with modestly elevated basal and lipid‐stimulated GTPase activity, as well as an "uncoupled" class whose GTPase rates are elevated ~70‐fold even in the absence of lipid.Funding provided by The Jane Coffin Childs Memorial Fund for Medical Research (JAK) and NIH R01‐GM‐078345 (MAL)