cometadata/datacite-rtg-text-other-reclassification-records huggingface dataset:
Inhibition of the mitochondrial permeability transition by protein kinase A in rat liver mitochondria and hepatocytes
Creators: name: He, Lihua
name: Lemasters, John J.
name: Pediaditakis, Peter
name: Kim, Jae-Sung
name: Zhang, Xun
name: Graves, Lee M.
Publisher: name: The University of North Carolina at Chapel Hill University Libraries
Year: 2010

description: NO and cGMP administered at reperfusion after ischaemia prevent injury to hepatocytes mediated by the MPT (mitochondrial permeability transition). To characterize further the mechanism of protection, the ability of hepatic cytosol in combination with cyclic nucleotides to delay onset of the calcium-induced MPT was evaluated in isolated rat liver mitochondria. Liver cytosol plus cGMP or cAMP dose-dependently inhibited the MPT, required ATP hydrolysis for inhibition and did not inhibit mitochondrial calcium uptake. Specific peptide inhibitors for PKA (protein kinase A), but not PKG (protein kinase G), abolished cytosol-induced inhibition of MPT onset. Activity assays showed a cGMP- and cAMP-stimulated protein kinase activity in liver cytosol that was completely inhibited by PKI, a PKA peptide inhibitor. Size-exclusion chromatography of liver cytosol produced a single peak of cGMP/cAMP-stimulated kinase activity with an estimated protein size of 180–220 kDa. This fraction was PKI-sensitive and delayed onset of the MPT. Incubation of active catalytic PKA subunit directly with mitochondria in the absence of cytosol and cyclic nucleotide also delayed MPT onset, and incubation with purified outer membranes led to phosphorylation of a major 31 kDa band. After ischaemia, administration at reperfusion of membrane-permeant cAMPs and cAMP-mobilizing glucagon prevented reperfusion injury to hepatocytes. In conclusion, PKA in liver cytosol activated by cGMP or cAMP acts directly on mitochondria to delay onset of the MPT and protect hepatocytes from cell death after ischaemia/reperfusion.
Coronin 1C harbours a second actin-binding site that confers co-operative binding to F-actin
Creators: name: Holoweckyj, Nicholas
name: Roadcap, David W.
name: Bear, James E.
name: Chan, Keefe T.
Publisher: name: The University of North Carolina at Chapel Hill University Libraries
Year: 2012

description: Dynamic rearrangement of actin filament networks is critical for cell motility, phagocytosis and endocytosis. Coronins facilitate these processes, in part, by their ability to bind F-actin (filamentous actin). We previously identified a conserved surface-exposed arginine (Arg30) in the β-propeller of Coronin 1B required for F-actin binding in vitro and in vivo. However, whether this finding translates to other coronins has not been well defined. Using quantitative actin-binding assays, we show that mutating the equivalent residue abolishes F-actin binding in Coronin 1A, but not Coronin 1C. By mutagenesis and biochemical competition, we have identified a second actin-binding site in the unique region of Coronin 1C. Interestingly, leading-edge localization of Coronin 1C in fibroblasts requires the conserved site in the β-propeller, but not the site in the unique region. Furthermore, in contrast with Coronin 1A and Coronin 1B, Coronin 1C displays highly co-operative binding to actin filaments. In the present study, we highlight a novel mode of coronin regulation, which has implications for how coronins orchestrate cytoskeletal dynamics.
Targeted polyubiquitylation of RASSF1C by the Mule and SCF β-TrCP ligases in response to DNA damage
Creators: name: Lei, Qun-Ying
name: Guan, Kun-Liang
name: Li, Ting-Ting
name: Zhou, Xin
name: Feng, Xu
name: Hsiang, Esther
name: Xiong, Yue
Publisher: name: The University of North Carolina at Chapel Hill University Libraries
Year: 2012

description: RASSF1A [Ras association (RalGDS/AF-6) domain family member 1A] and RASSF1C are two ubiquitously expressed isoforms of the RASSF1 gene. The promoter of RASSF1A is frequently hypermethylated, resulting in inactivation in various human cancers. RASSF1A is implicated in the regulation of apoptosis, microtubule stability and cell cycle arrest. However, little is known about the regulation and function of RASSF1C. In the present study we show that exogenously expressed RASSF1C is a very unstable protein that is highly polyubiquitylated and degraded via the proteasome. Furthermore, RASSF1C degradation is enhanced when cells are exposed to stress signals, such as UV irradiation. Mule, a HECT (homologous with E6-associated protein C-terminus) family E3 ligase, but not SCFβ-TrCP [where SCF is Skp1 (S-phase kinase-associated protein 1)/cullin/F-box and β-TrCP is β-bransducin repeat-containing protein] or CUL4 (cullin 4)-DDB1 (damage-specific DNA-binding protein 1), is the E3 ligase for RASSF1C under normal conditions, whereas both Mule and SCFβ-TrCP target RASSF1C degradation in response to UV irradiation. GSK3 (glycogen synthase kinase 3) phosphorylates RASSF1C to promote RASSF1C degradation subsequently, which is negatively regulated by the PI3K (phosphoinositide 3-kinase)/Akt pathway. Thus the present study reveals a novel regulation of RASSF1C and the potentially important role of RASSF1C in DNA damage responses.
The Algebraic Duality Resolution at $p=2$
Creators: name: Beaudry, Agnes
Publisher: name: arXiv
Year: 2014
Subjects: subject: Algebraic Topology (math.AT)
subject: FOS: Mathematics

description: The goal of this paper is to develop some of the machinery necessary for doing $K(2)$-local computations in the stable homotopy category using duality resolutions at the prime $p=2$. The Morava stabilizer group $\mathbb{S}_2$ admits a norm whose kernel we denote by $\mathbb{S}_2^1$. The algebraic duality resolution is a finite resolution of the trivial $\mathbb{Z}_2[[\mathbb{S}_2^1]]$-module $\mathbb{Z}_2$ by modules induced from representations of finite subgroups of $\mathbb{S}_2^1$. Its construction is due to Goerss, Henn, Mahowald and Rezk. It is an analogue of their finite resolution of the trivial $\mathbb{Z}_3[[\mathbb{G}_2^1]]$-module $\mathbb{Z}_3$ at the prime $p=3$. The construction was never published and it is the main result in this paper. In the process, we give a detailed description of the structure of Morava stabilizer group $\mathbb{S}_2$ at the prime $2$. We also describe the maps in the algebraic duality resolution with the precision necessary for explicit computations.
description: Expository changes, with some clarifications and corrections. To appear in AGT
The dynamic nature of the kinome
Creators: name: Graves, Lee M.
name: Duncan, James S.
name: Whittle, Martin C.
name: Johnson, Gary L.
Publisher: name: The University of North Carolina at Chapel Hill University Libraries
Year: 2013

description: Recent advances in proteomics have facilitated the analysis of the kinome ‘en masse’. What these studies have revealed is a surprisingly dynamic network of kinase responses to highly selective kinase inhibitors, thereby illustrating the complex biological responses to these small molecules. Moreover these studies have identified key transcription factors, such as c-Myc and FOXO (forkhead box O), that play pivotal roles in kinome reprogramming in cancer cells. Since many kinase inhibitors fail despite a high efficacy of blocking their intended targets, elucidating kinome changes at a more global level will be essential to understanding the mechanisms of kinase inhibitor pharmacology. The development of technologies to study the kinome, as well as examples of kinome resilience and reprogramming, will be discussed in the present review.
Partnunia chenabi Panesar & Gerecke 1994
Creators: name: Pešić, Vladimir
name: Chatterjee, Tapas
name: Bordoloi, Sabitry
Publisher: name: Zenodo
Year: 2010
Subjects: Biodiversity
Taxonomy
Animalia
Arthropoda
Arachnida
Trombidiformes
Hydryphantidae
Partnunia
Partnunia chenabi

description: Partnunia chenabi Panesar & Gerecke, 1994
Records from the study area: Uttar Pradesh—Panesar & Gerecke (1994).
Habitat: Springs.
Distribution: India.
description: Published as part of Pešić, Vladimir, Chatterjee, Tapas & Bordoloi, Sabitry, 2010, A checklist of the water mites (Acari: Hydrachnidia) of India, with new records and description of one new species, pp. 1-54 in Zootaxa 2617 (1) on page 7, DOI: 10.11646/zootaxa.2617.1.1, http://zenodo.org/record/197964
Collar lemma for Hitchin representations
Creators: name: Lee, Gye-Seon
name: Zhang, Tengren
Publisher: name: arXiv
Year: 2014
Subjects: subject: Geometric Topology (math.GT)
subject: Differential Geometry (math.DG)
subject: FOS: Mathematics

description: In this article, we prove an analog of the classical collar lemma in the setting of Hitchin representations.
description: Section 3 updated to reflect recent progress
When is a growth-friendly strategy warranted? A matched comparison of growing rods versus primary posterior spinal fusion in juveniles with early-onset scoliosis
Creators: name: Stürmer, T.
name: Sanders, J.O.
name: Lin, F.-C.
name: Keil, L.G.
name: Golightly, Y.M.
name: Stone, J.D.
name: Louer, C.R.
name: Nash, A.B.
Publisher: name: Lippincott Williams and Wilkins
Year: 2021

description: Background: In 7 to 11-year-old juveniles with severe early-onset scoliosis (EOS) the optimal surgical option remains uncertain. This study compares growing rods (GRs) followed by definitive posterior spinal fusion (PSF) versus primary PSF in this population. We hypothesized that the thoracic height afforded by GRs would be offset by increased rigidity, more complications, and more operations. Methods: This retrospective comparative study included EOS patients aged 7.0 to 11.9 years at index surgery treated with GR→PSF or primary PSF during 2013 to 2020. Primary outcomes were thoracic height gain (ΔT1-12H), major curve, complications, and total operations. Primary PSFs were matched with replacement 1-to-n to GR→PSFs by age at index, etiology, and major curve. Results: Twenty-eight GR→PSFs met criteria: 19 magnetically controlled GRs and 9 traditional GRs. Three magnetically controlled GRs were definitively explanted without PSF due to complications. The remaining 25 GR→PSFs were matched to 17 primary PSFs with 100% etiology match, mean Δ major curve 1 degree, and mean Δ age at index 0.5 years (PSFs older). Median ΔT1-12H pre-GR to post-PSF was 4.7 cm with median deformity correction of 37%. Median ΔT1-12H among primary PSFs was 1.9 cm with median deformity correction of 62%. GR→PSFs had mean 1.8 complications and 3.4 operations. Primary PSFs had mean 0.5 complications and 1.3 operations. Matched analysis showed adjusted mean differences of 2.3 cm greater ΔT1-12H among GR→PSFs than their matched primary PSFs, with 25% less overall coronal deformity correction, 1.2 additional complications, and 2.2 additional operations per patient. Conclusions: In juveniles aged 7 to 11 with EOS, on average GRs afford 2 cm of thoracic height over primary PSF at the cost of poorer deformity correction and additional complications and operations. Primary PSF affords an average of 2 cm of thoracic height gain; if an additional 2 cm will be impactful then GRs should be considered. However, in most juveniles the height gained may not warrant the iatrogenic stiffness, complications, and additional operations. Surgeons and families should weigh these benefits and harms when choosing a treatment plan. Level of Evidence: Level III - retrospective comparative study.
A novel fluorescent sensor protein for detecting changes in airway surface liquid glucose concentration
Creators: name: Farrant, Matthew
name: Garnett, James P.
name: MacNevin, Christopher J.
name: Pickup, John C.
name: Khan, Faaizah
name: Baines, Deborah L.
name: Helassa, Nordine
name: Hahn, Klaus M.
name: Tarran, Robert
Publisher: name: The University of North Carolina at Chapel Hill University Libraries
Year: 2014

description: Both lung disease and elevation of blood glucose are associated with increased glucose concentration (from 0.4 to ~4.0 mM) in the airway surface liquid (ASL). This perturbation of ASL glucose makes the airway more susceptible to infection by respiratory pathogens. ASL is minute (~1 μl/cm2) and the measurement of glucose concentration in the small volume ASL is extremely difficult. Therefore, we sought to develop a fluorescent biosensor with sufficient sensitivity to determine glucose concentrations in ASL in situ. We coupled a range of environmentally sensitive fluorophores to mutated forms of a glucose/galactose-binding protein (GBP) including H152C and H152C/A213R and determined their equilibrium binding properties. Of these, GBP H152C/A213R–BADAN (Kd 0.86 ± 0.01 mM, Fmax/F0 3.6) was optimal for glucose sensing and in ASL increased fluorescence when basolateral glucose concentration was raised from 1 to 20 mM. Moreover, interpolation of the data showed that the glucose concentration in ASL was increased, with results similar to that using glucose oxidase analysis. The fluorescence of GBP H152C/A213R–BADAN in native ASL from human airway epithelial cultures in situ was significantly increased over time when basolateral glucose was increased from 5 to 20 mM. Overall our data indicate that this GBP is a useful tool to monitor glucose homoeostasis in the lung.
Recurrence of the Brownian motion in multidimensional semi-selfsimilar environments and Gaussian environments
Creators: name: Kusuoka, Seiichiro
name: Takahashi, Hiroshi
name: Tamura, Yozo
Publisher: name: arXiv
Year: 2014
Subjects: subject: Probability (math.PR)
subject: FOS: Mathematics

description: Asymptotic behavior of the one-dimensional Brownian motion in general random environments has been investigated by many researchers. However, many of the methods used in the argument are available only for the one-dimensional case. In this paper the multidimensional case of the problem is considered, and we obtain some sufficient conditions for recurrence of the multi-dimensional Brownian motion in random environments. By using the sufficient conditions we show that the recurrence of the Brownian motion in Gaussian environments under some conditions on the correlation functions.
description: To appear in Potential Analysis
Ca 2+ switches the effect of PS-containing membranes on Factor Xa from activating to inhibiting: implications for initiation of blood coagulation
Creators: name: Majumder, Rinku
name: Lentz, Barry R.
name: Koklic, Tilen
Publisher: name: The University of North Carolina at Chapel Hill University Libraries
Year: 2014

description: Calcium (Ca2+) plays a pivotal role in cellular and organismal physiology. The Ca2+ ion has an intermediate protein-binding affinity, thus it can serve as an on/off switch in regulation of different biochemical processes. The serum level of ionized Ca2+ is regulated with normal ionized Ca2+ being in the range from 1.10 to 1.29 mM. Hypocalcaemia (free Ca2+ < 1.1mM) in critically ill patients is commonly accompanied by hemostatic abnormalities, ranging from isolated thrombocytopenia to complex defects such as disseminated intravascular coagulation, commonly thought to be due to insufficient functioning of anticoagulation pathways. A small amount of Factor Xa (fXa) produced by Factor VIIa and exposed tissue factor is key to initiating blood coagulation by producing enough thrombin to induce later stages of coagulation. FXa must bind to phosphatidylserine (PS)-containing membranes to produce thrombin at a physiologically significant rate. In this work, we show that overall fXa activity on PS-containing membranes is sharply regulated by a “Ca2+ switch” centered at 1.16 mM, below which fXa is active and above which fXa forms inactive dimers on PS-exposing membranes. Our data lead to a mathematical model that predicts the variation of fXa activity as a function of both calcium and membrane concentrations. Because the critical Ca2+ concentration is at the lower end of the normal plasma ionized Ca2+ concentration range, we propose a new regulatory mechanism by which local Ca2+ concentration switches fXa from an intrinsically active form to a form requiring its cofactor (fVa) to achieve significant activity.
Individual and cumulative measures of knee joint load associate with T2 relaxation times of knee cartilage in young, uninjured individuals: A pilot study
Creators: name: Wellsandt, E.
name: Dudley, A.T.
name: Tao, M.A.
name: Sajja, B.R.
name: Michaud, K.
name: Emory, J.
name: Manzer, M.N.
name: Golightly, Y.M.
Publisher: name: Elsevier B.V.
Year: 2021

description: Background: Articular cartilage structure and chondrocyte health are sensitive and reliant on dynamic joint loading during activities. The purpose of this pilot study was to determine the association between measures of individual and cumulative knee joint loading with T2 relaxation times in the knee cartilage of young individuals without knee injury. Methods: Twelve participants (17–30 years old) without history of knee injury or surgery completed MRI, physical activity (PA), and biomechanical gait testing. T2 relaxation times were calculated in the cartilage within the patella and lateral and medial compartments. Accelerometry was used to measure mean daily step counts, minutes of PA, and % sedentary time over 7 days. Vertical ground reaction force, external knee joint moments and peak knee flexion angle were measured during stance phase of gait using three-dimensional motion capture. Cumulative knee joint loading was calculated as daily step count by external knee joint moment impulse. The relationship between measures of knee joint loading and T2 relaxation times was assessed using Pearson correlations. Results: Higher T2 relaxation times in the femoral and tibial cartilage were consistently correlated to greater body mass, daily step counts, moderate and vigorous PA, and peak knee joint moments (r = 0.10–0.84). Greater cumulative knee flexion and adduction loading was associated with higher T2 relaxation times in the femoral and tibial cartilage (r = 0.16–0.65). Conclusion: Preliminary findings suggest that individual loading factors and cumulative knee joint loading are associated with higher T2 relaxation times in the articular cartilage of young, healthy knees.
Inhomogeneous broadening of optical transitions of 87Rb atoms in an optical nanofiber trap
Creators: name: Lee, J.
name: Grover, J. A.
name: Hoffman, J. E.
name: Orozco, L. A.
name: Rolston, S. L.
Publisher: name: arXiv
Year: 2014
Subjects: subject: Atomic Physics (physics.atom-ph)
subject: Optics (physics.optics)
subject: Quantum Physics (quant-ph)
subject: FOS: Physical sciences

description: We experimentally demonstrate optical trapping of 87Rb atoms using a two-color evanescent field around an optical nanofiber. In our trapping geometry, a blue-detuned traveling wave whose polarization is nearly parallel to the polarization of a red-detuned standing wave produces significant vector light shifts that lead to broadening of the absorption profile of a near-resonant beam at the trapping site. A model that includes scalar, vector, and tensor light shifts of the probe transition $5S_{1/2}$-$5P_{3/2}$ from the trapping beams, weighted by the temperature-dependent position of the atoms in the trap, qualitatively describes the observed asymmetric profile and explains differences with previous experiments that used Cs atoms. The model provides a consistent way to extract the number of atoms in the trap.
description: 6 pages, 4 figures
Phosphatidylserine and FVa regulate FXa structure
Creators: name: Quinn-Allen, Mary Ann
name: Kane, William H.
name: Lentz, Barry R.
name: Majumder, Rinku
name: Srivasatava, Kinshuk Raj
Publisher: name: The University of North Carolina at Chapel Hill University Libraries
Year: 2014

description: Human coagulation factor Xa (FXa) plays a key role in blood coagulation by activating prothrombin to thrombin on “stimulated” platelet membranes in the presence of its cofactor factor Va (FVa). Phosphatidylserine (PS) exposure on activated platelet membranes promotes prothrombin activation by FXa by allosterically regulating FXa. To identify the structural basis of this allosteric regulation, we used fluorescence resonance energy transfer (FRET) to monitor changes in FXa length in response 1] to soluble PS (dicaproyl-phosphatidylserine; C6PS), 2] to PS membranes, and 3] to FVa in the presence of C6PS and membranes. We incorporated a FRET pair with donor (fluorescein) at the active site and acceptor (Alexa fluor 555) at FXa N-terminus near the membrane. The results demonstrated that FXa structure changes upon binding of C6PS to two sites, a regulatory site (Reg site) at the N-terminus (previously identified as involving the Gla and EGFN domains) and a presumptive protein-recognition site in the catalytic domain (Prot site). Binding of C6PS to the regulatory site increased the inter-probe distance by ~ 3 Å, while saturation of both sites further increased the distance by ~ 6.4 Å. FXa binding to a membrane produced a smaller length increase (~1.4 Å), indicating that FXa has a somewhat different structure on a membrane than when bound to C6PS in solution. However, when both FVa2 (a FVa glycoform) and either C6PS or PS-containing membranes bound to FXa, the overall change in length was comparable (~ 5.6–5.8 Å), indicating that C6PS and PS-containing membranes in conjunction with FVa2 have comparable regulatory effects on FXa. We conclude that the similar functional regulation of FXa by C6PS or membranes in conjunction with FVa2 correlates with similar structural regulation. The results demonstrate the usefulness of FRET in analyzing structure-function relationships in FXa and in the FXa.FVa2 complex.
Quantifying cumulative anticholinergic and sedative drug load among US Medicare Beneficiaries
Creators: name: Gnjidic, D.
name: Lund, J.L.
name: Golightly, Y.M.
name: Pepin, M.J.
name: Bailey, J.C.
name: Hanson, L.C.
name: Stürmer, T.
name: Naumann, R.B.
name: Shmuel S.
name: Pate, V.
Publisher: name: John Wiley and Sons Ltd
Year: 2021

description: Purpose: Medications with anticholinergic and sedative properties are widely used among older adults despite strong evidence of harm. The drug burden index (DBI), a pharmacological screening tool, measures these properties across drug classes, and higher DBI drug exposure (DBI > 1) has been associated with certain physical function-related adverse events. Our aim was to quantify mean daily DBI drug exposure among older adults in the United States (US). Methods: We screened medications for DBI properties and operationalized the DBI for US Medicare claims. We then conducted a retrospective cohort study of a 20% random, nationwide sample of 4 137 384 fee-for-service Medicare beneficiaries aged 66+ years (134 757 039 person-months) from January 2013 to December 2016. We measured the monthly distribution based on mean daily DBI, categorized as (a) >0 vs 0 (any use) and (b) 0, 0 < DBI ≤ 1, 1 < DBI ≤ 2, and DBI > 2, and examined temporal trends. We described patient-level factors (eg, demographics, healthcare use) associated with high (>2) vs low (0 < DBI≤1) DBI drug exposure. Results: The distribution of the mean daily DBI, aggregated at the month-level, was: 58.1% DBI = 0, 29.0% 0 < DBI≤1, 9.3% 1 < DBI≤2, and 3.7% DBI > 2. Predictors of high monthly DBI drug exposure (DBI > 2) included certain indicators of increased healthcare use (eg, high number of drug claims), white race, younger age, frailty, and a psychosis diagnosis code. Conclusions: The predictors of high DBI drug exposure can inform discussions between patients and providers about medication appropriateness and potential de-prescribing. Future Medicare-based studies should assess the association between the DBI and adverse events. © 2020 John Wiley & Sons Ltd
The Influence of Indonesian History on Qur'anic Interpretation: Insights from Gadamerian Hermeneutics
Creators: name: Bukhori Abdul Shomad
name: Munirul Abidin
name: Anwar Mujahidin
name: Ahkmad Fatoni
name: Bambang Irawan
Publisher: name: Zenodo
Year: 2024
Subjects: Hermeneutic, Gadamer, Qur'anic Interpretation, History, Indonesia.

description: Abstract

This article examines the profound influence of Indonesian history on the interpretation of the Qur'an within the Indonesian context, employing a Gadamerian hermeneutical framework. Through a detailed analysis of historical events, cultural evolutions, and religious discourse in Indonesia, we explore how Gadamer's concepts of "fusion of horizons" and "historical consciousness" provide insightful lenses for understanding the dynamic interplay between the Qur'an's sacred texts and Indonesian societal norms and values. The study highlights the role of historical experiences, including colonialism, nationalism, and modernization, in shaping the interpretative approaches adopted by Indonesian Muslims. Using qualitative research methods, we delve into case studies that illustrate the localized interpretations of the Qur'an, revealing a unique blend of Islamic teachings with indigenous traditions and contemporary issues. The findings underscore the significance of historical context in Qur'anic interpretation, suggesting that Indonesian Islam exemplifies a distinctive model of religious understanding that bridges the gap between tradition and modernity. This investigation not only contributes to the broader discourse on Islamic hermeneutics but also offers a critical perspective on the interrelation between history and religious interpretation in a Gadamerian framework, emphasizing the dialogical process of understanding that transcends temporal and cultural boundaries.
Methylation of the Gpat2 promoter regulates transient expression during mouse spermatogenesis
Creators: name: Cattaneo, E. R.
name: Pellon-Maison, M.
name: Garcia-Fabiani, M. B.
name: Lacunza, E.
name: Coleman, R. A.
name: Montanaro, M. A.
name: Gonzalez-Baro, M. R.
Publisher: name: The University of North Carolina at Chapel Hill University Libraries
Year: 2015

description: Spermatogenesis is a highly regulated process that involves both mitotic and meiotic divisions, as well as cellular differentiation to yield mature spermatozoa from undifferentiated germinal stem cells. Although Gpat2 was originally annotated as encoding a glycerol-3-phosphate acyltransferase by sequence homology to Gpat1, GPAT2 is highly expressed in testis but not in lipogenic tissues and is not up-regulated during adipocyte differentiation. New data show that GPAT2 is required for the synthesis of piRNAs (piwi-interacting RNAs), a group of small RNAs that protect the germ cell genome from retrotransposable elements. In order to understand the relationship between GPAT2 and its role in the testis, we focused on Gpat2 expression during the first wave of mouse spermatogenesis. Gpat2 expression was analysed by qPCR (quantitative real-time PCR), in situ hybridization, immunohistochemistry and Western blotting. Gpat2 mRNA content and protein expression were maximal at 15 dpp (days post-partum) and were restricted to pachytene spermatocytes. To achieve this transient expression, both epigenetic mechanisms and trans-acting factors are involved. In vitro assays showed that Gpat2 expression correlates with DNA demethylation and histone acetylation and that it is up-regulated by retinoic acid. Epigenetic regulation by DNA methylation was confirmed in vivo in germ cells by bisulfite sequencing of the Gpat2 promoter. Consistent with the initiation of meiosis at 11 dpp, methylation decreased dramatically. Thus, Gpat2 is expressed at a specific stage of spermatogenesis, consistent with piRNA synthesis and meiosis I prophase, and its on–off expression pattern responds predominantly to epigenetic modifications.
The mucolipidosis IV Ca2+ channel TRPML1 (MCOLN1) is regulated by the TOR kinase
Creators: name: Diaz, M. C. H.
name: Major, M. B.
name: Forsberg, L. J.
name: Brenman, J. E.
name: Yan, F.
name: Sexton, J. Z.
name: Onyenwoke, R. U.
Publisher: name: The University of North Carolina at Chapel Hill University Libraries
Year: 2015

description: Autophagy is a complex pathway regulated by numerous signalling events that recycles macromolecules and may be perturbed in lysosomal storage disorders (LSDs). During autophagy, aberrant regulation of the lysosomal Ca2+ efflux channel TRPML1 [transient receptor potential mucolipin 1 (MCOLN1)], also known as MCOLN1, is solely responsible for the human LSD mucolipidosis type IV (MLIV); however, the exact mechanisms involved in the development of the pathology of this LSD are unknown. In the present study, we provide evidence that the target of rapamycin (TOR), a nutrient-sensitive protein kinase that negatively regulates autophagy, directly targets and inactivates the TRPML1 channel and thereby functional autophagy, through phosphorylation. Further, mutating these phosphorylation sites to unphosphorylatable residues proved to block TOR regulation of the TRPML1 channel. These findings suggest a mechanism for how TOR activity may regulate the TRPML1 channel.
Analysis of proton and neutron pair breakings: High-spin structures of $^{124-127}$Te isotopes
Creators: name: Kumar, Vikas
name: Srivastava, P. C.
name: Ermamatov, M. J.
name: Morales, Irving O.
Publisher: name: arXiv
Year: 2014
Subjects: subject: Nuclear Theory (nucl-th)
subject: FOS: Physical sciences

description: In the present work recently available experimental data for high-spin states of four nuclei, $^{124}_{\ 52}$Te, $^{125}_{\ 52}$Te, $^{126}_{\ 52}$Te, and $^{127}_{\ 52}$Te have been interpreted using state-of-the-art shell model calculations. The calculations have been performed in the $50-82$ valence shell composed of $1g_{7/2}$, $2d_{5/2}$, $1h_{11/2}$, $3s_{1/2}$, and $2d_{3/2}$ orbitals. We have compared our results with the available experimental data for excitation energies and transition probabilities, including high-spin states. The results are in reasonable agreement with the available experimental data. The wave functions, particularly, the specific proton and neutron configurations which are involved to generate the angular momentum along the yrast lines are discussed. We have also estimated overall contribution of three-body forces in the energy level shifting. Finally, results with modified effective interaction are also reported.
description: 21 pages, 10 figures, 1 table, accepted for publication in Nuclear Physics A
Antiaggregatory activity in human platelets of potent antagonists of the P2Y1 receptor
Creators: name: Tchilibon, Susanna
name: Lecchi, Anna
name: Cattaneo, Marco
name: Joshi, Bhalchandra V.
name: Besada, Pedro
name: Lombardi, Rossana
name: Harden, T. Kendall
name: Jacobson, Kenneth A.
name: Bischofberger, Norbert
name: Ohno, Michihiro
Publisher: name: The University of North Carolina at Chapel Hill University Libraries
Year: 2004

description: Activation of the P2Y1 nucleotide receptor in platelets by ADP causes changes in shape and aggregation, mediated by activation of phospholipase C (PLC). Recently, MRS2500 (2-iodo-N6-methyl-(N)-methanocarba-2′-deoxyadenosine-3′,5′-bisphosphate) was introduced as a highly potent and selective antagonist for this receptor. We have studied the actions of MRS2500 in human platelets and compared these effects with the effects of two acyclic nucleotide analogues, a bisphosphate MRS2298 and a bisphosphonate derivative MRS2496, which act as P2Y1 receptor antagonists, although less potently than MRS2500. Improved synthetic methods for MRS2500 and MRS2496 were devised. The bisphosphonate is predicted to be more stable in general in biological systems than phosphate antagonists due to the non-hydrolyzable C–P bond. MRS2500 inhibited the ADP-induced aggregation of human platelets with an IC50 value of 0.95 nM. MRS2298 and MRS2496 also both inhibited the ADP-induced aggregation of human platelets with IC50 values of 62.8 nM and 1.5 μM, respectively. A similar order of potency was observed for the three antagonists in binding to the recombinant human P2Y1 receptor and in inhibition of ADP-induced shape change and ADP-induced rise in intracellular Ca2+. No substantial antagonism of the pathway linked to the inhibition of cyclic AMP was observed for the nucleotide derivatives, indicating no interaction of these three P2Y1 receptor antagonists with the proaggregatory P2Y12 receptor, which is also activated by ADP. Thus, all three of the bisphosphate derivatives are highly selective antagonists of the platelet P2Y1 receptor, and MRS2500 is the most potent such antagonist yet reported.
Structure activity and molecular modeling analyses of ribose- and base-modified uridine 5′-triphosphate analogues at the human P2Y2 and P2Y4 receptors
Creators: name: Tchilibon, Susanna
name: Gao, Zhan-Guo
name: Harden, T. Kendall
name: Ivanov, Andrei A.
name: Costanzi, Stefano
name: Jacobson, Kenneth A.
name: Besada, Pedro
name: Maddileti, Savitri
Publisher: name: The University of North Carolina at Chapel Hill University Libraries
Year: 2006

description: With the long-term goal of developing receptor subtype-selective high affinity agonists for the uracil nucleotide-activated P2Y receptors we have carried out a series of structure activity and molecular modeling studies of the human P2Y2 and P2Y4 receptors. UTP analogues with substitutions in the 2′-position of the ribose moiety retained capacity to activate both P2Y2 and P2Y4 receptors. Certain of these analogues were equieffective for activation of both receptors whereas 2′-amino-2′-deoxy-UTP exhibited higher potency for the P2Y2 receptor and 2′-azido-UTP exhibited higher potency for the P2Y4 receptor. 4-Thio substitution of the uracil base resulted in a UTP analogue with increased potency relative to UTP for activation of both the P2Y2 and P2Y4 receptors. In contrast, 2-thio substitution and halo- or alkyl substitution in the 5-position of the uracil base resulted in molecules that were 3–30-fold more potent at the P2Y2 receptor than P2Y4 receptor. 6-Aza-UTP was a P2Y2 receptor agonist that exhibited no activity at the P2Y4 receptor. Stereoisomers of UTPαS and 2′-deoxy-UTPαS were more potent at the P2Y2 than P2Y4 receptor, and the R-configuration was favored at both receptors. Molecular docking studies revealed that the binding mode of UTP is similar for both the P2Y2 and P2Y4 receptor binding pockets with the most prominent dissimilarities of the two receptors located in the second transmembrane domain (V90 in the P2Y2 receptor and I92 in the P2Y4 receptor) and the second extracellular loop (T182 in the P2Y2 receptor and L184 in the P2Y4 receptor). In summary, this work reveals substitutions in UTP that differentially affect agonist activity at P2Y2 versus P2Y4 receptors and in combination with molecular modeling studies should lead to chemical synthesis of new receptor subtype-selective drugs.
Causal Inference by Identification of Vector Autoregressive Processes with Hidden Components
Creators: name: Geiger, Philipp
name: Zhang, Kun
name: Gong, Mingming
name: Janzing, Dominik
name: Schölkopf, Bernhard
Publisher: name: arXiv
Year: 2014
Subjects: subject: Machine Learning (stat.ML)
subject: FOS: Computer and information sciences

description: A widely applied approach to causal inference from a non-experimental time series $X$, often referred to as "(linear) Granger causal analysis", is to regress present on past and interpret the regression matrix $\hat{B}$ causally. However, if there is an unmeasured time series $Z$ that influences $X$, then this approach can lead to wrong causal conclusions, i.e., distinct from those one would draw if one had additional information such as $Z$. In this paper we take a different approach: We assume that $X$ together with some hidden $Z$ forms a first order vector autoregressive (VAR) process with transition matrix $A$, and argue why it is more valid to interpret $A$ causally instead of $\hat{B}$. Then we examine under which conditions the most important parts of $A$ are identifiable or almost identifiable from only $X$. Essentially, sufficient conditions are (1) non-Gaussian, independent noise or (2) no influence from $X$ to $Z$. We present two estimation algorithms that are tailored towards conditions (1) and (2), respectively, and evaluate them on synthetic and real-world data. We discuss how to check the model using $X$.
A cross-institutional analysis of the effects of broadening trainee professional development on research productivity
Creators: name: Hall, J.D.
name: Dominguez, I.
name: Mathur, A.
name: Baas, T.
name: Layton, R.L.
name: Petrie, K.A.
name: Wiesen, C.A.
name: Chow, C.S.
name: Singh, H.
name: Bolgioni, A.F.
name: Bowden, B.
name: Van Wart, A.
name: Stayart, C.A.
name: Fruman, D.A.
name: Holmquist, C.E.
name: Brennwald, P.J.
name: Arneman, D.
name: Hyman, L.E.
name: Chalkley, R.
name: Brandt, P.D.
name: Alder, J.
name: Gould, K.L.
name: Brown, A.M.
name: Varvayanis, S.S.
name: Golightly, Y.M.
name: Schreiber, B.M.
Publisher: name: Public Library of Science
Year: 2021

description: PhD-trained scientists are essential contributors to the workforce in diverse employment sectors that include academia, industry, government, and nonprofit organizations. Hence, best practices for training the future biomedical workforce are of national concern. Complementing coursework and laboratory research training, many institutions now offer professional training that enables career exploration and develops a broad set of skills critical to various career paths. The National Institutes of Health (NIH) funded academic institutions to design innovative programming to enable this professional development through a mechanism known as Broadening Experiences in Scientific Training (BEST). Programming at the NIH BEST awardee institutions included career panels, skill-building workshops, job search workshops, site visits, and internships. Because doctoral training is lengthy and requires focused attention on dissertation research, an initial concern was that students participating in additional complementary training activities might exhibit an increased time to degree or diminished research productivity. Metrics were analyzed from 10 NIH BEST awardee institutions to address this concern, using time to degree and publication records as measures of efficiency and productivity. Comparing doctoral students who participated to those who did not, results revealed that across these diverse academic institutions, there were no differences in time to degree or manuscript output. Our findings support the policy that doctoral students should participate in career and professional development opportunities that are intended to prepare them for a variety of diverse and important careers in the workforce.
An insight into the pharmacophores of phosphodiesterase-5 inhibitors from synthetic and crystal structural studies
Creators: name: Ke, Hengming
name: Chen, Gong
name: Wang, Huanchen
name: Robinson, Howard
name: Cai, Jiwen
name: Wan, Yiqian
Publisher: name: The University of North Carolina at Chapel Hill University Libraries
Year: 2008

description: Selective inhibitors of cyclic nucleotide phosphodiesterase-5 (PDE5) have been used as drugs for treatment of male erectile dysfunction and pulmonary hypertension. An insight into the pharmacophores of PDE5 inhibitors is essential for development of second generation of PDE5 inhibitors, but has not been completely illustrated. Here we report the synthesis of a new class of the sildenafil derivatives and a crystal structure of the PDE5 catalytic domain in complex with 5-(2-ethoxy-5-(sulfamoyl)-3-thienyl)-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo[4,3-d] pyrimidin-7-one (12). Inhibitor 12 induces conformational change of the H-loop (residues 660–683), which is different from any of the known PDE5 structures. The pyrazolopyrimidinone groups of 12 and sildenafil are well superimposed, but their sulfonamide groups show a positional difference of as much as 1.5 Å. The structure-activity analysis suggests that a small hydrophobic pocket and the H-loop of PDE5 are important for the inhibitor affinity, in addition to two common elements for binding of almost all the PDE inhibitors: the stack against the phenylalanine and the hydrogen bond with the invariant glutamine. However, the PDE5-12 structure does not provide a full explanation to affinity changes of the inhibitors. Thus alternatives such as conformational change of the M-loop are open and further structural study is required.
High-Intensity Interval Training for Knee Osteoarthritis: A Pilot Study
Creators: name: Allen, K.D.
name: Alvarez, C.
name: Blue, M.N.M.
name: Nelson, A.E.
name: Golightly, Y.M.
name: Smith-Ryan, A.E.
Publisher: name: John Wiley and Sons Inc
Year: 2021

description: Objective: To assess the feasibility and changes in outcomes of a 12-week high-intensity interval training (HIIT) program in individuals with symptomatic knee osteoarthritis (OA). Methods: The single-arm trial included 29 participants (mean ± SD age 63 ± 7 years; 66% women; 66% obese). Measures of participant flow, adherence, and tolerability were collected. Pain, function, and balance were assessed at baseline, 6 weeks, and 12 weeks using the Western Ontario and McMaster Universities Osteoarthritis Index, 20-m fast-paced walk test, 30-second chair-stand test, stair-climb test, timed up and go test, and single leg stance. Cardiorespiratory fitness, strength, and body composition were evaluated using peak oxygen consumption (VO2peak), isometric knee extensor/flexor strength, and dual-energy x-ray absorptiometry, respectively. HIIT was completed two times/week (cycling or treadmill) and consisted of 10 repetitions of 1-minute bouts at 90% VO2peak, with 1-minute rest periods. Separate multivariable-adjusted linear mixed models were fit for each outcome with fixed effects of time, age, sex, body mass index, and random effects of baseline values to estimate mean changes and 95% confidence intervals (CIs) between baseline and 12-week assessments. Results: Recruitment aligned with the anticipated enrollment rate, adherence was 70%, and no adverse events were reported. At 12 weeks, improvements were observed for most outcomes, with notable mean changes for the 20-m fast-paced walk (−1.13 [95% CI −1.61 to −0.64] seconds), 30-second chair-stand (2.6 [1.8-3.4] stands), and VO2peak (0.14 [0.03-0.24] liters/minute). Conclusion: In this 12-week pilot study, HIIT improved multiple aspects of health in individuals with knee OA; larger studies are needed.
The oxysterol-binding protein superfamily: new concepts and old proteins
Creators: name: Villasmil, Michelle L.
name: Mousley, Carl J.
name: Bankaitis, Vytas A.
Publisher: name: The University of North Carolina at Chapel Hill University Libraries
Year: 2012

description: The Kes1 OSBP (oxysterol-binding protein) is a key regulator of membrane trafficking through the TGN (trans-Golgi network) and endosomal membranes. We demonstrated recently that Kes1 acts as a sterol-regulated rheostat for TGN/endosomal phosphatidylinositol 4-phosphate signalling. Kes1 utilizes its dual lipid-binding activities to integrate endosomal lipid metabolism with TORC1 (target of rapamycin complex 1)-dependent proliferative pathways and transcriptional control of nutrient signalling.
The Prevalence of Knee Symptoms, Radiographic, and Symptomatic Osteoarthritis at Four Time Points: The Johnston County Osteoarthritis Project, 1999-2018
Creators: name: Callahan, L.F.
name: Murphy, L.B.
name: Helmick, C.G.
name: Alvarez, C.
name: Renner, J.B.
name: Golightly, Y.M.
name: Cleveland, R.J.
name: Jordan, J.M.
name: Schwartz, T.A.
name: Hu, D.
name: Arbeeva, L.
name: Nelson, A.E.
Publisher: name: John Wiley and Sons Inc
Year: 2021

description: Objective: To describe point prevalence of knee symptoms, radiographic knee osteoarthritis (rKOA), severe rKOA, and symptomatic rKOA at four time points in the longitudinal, population-based Johnston County Osteoarthritis Project (JoCo OA). Methods: Data were from 2573 JoCo OA participants with up to 18 years of follow-up (1999-2018) and standardized fixed-flexion knee radiographs read by a single, reliable expert musculoskeletal radiologist. The four outcomes were 1) self-reported knee symptoms, defined by “On most days, do you have pain, aching, or stiffness in your right/left knee?”; 2) rKOA, defined as a Kellgren-Lawrence grade (KLG) of 2 to 4); 3) severe rKOA, defined as a KLG of 3 or 4; and 4) symptomatic rKOA, defined as both symptoms and rKOA in the same joint. Weighted prevalence estimates and 95% confidence intervals (CIs) were generated overall and by age group, sex, race, and body mass index (BMI). Results: Most recently (2017-2018, T4), the overall prevalence (percentage) of knee symptoms, rKOA, severe rKOA, and symptomatic rKOA was 41% (95% CI: 35-47%), 61% (95% CI: 56-67%), 35% (95% CI: 30-40%), and 30% (95% CI: 24-35%), respectively. From time point T1 to T4, prevalence increased for rKOA, severe rKOA, and symptomatic rKOA but not for knee symptoms. The prevalence of both severe rKOA (17-39%) and symptomatic rKOA (23-30%) was consistently higher among women. The prevalence of all outcomes was higher among those with higher BMI and among Black participants at all time points, particularly rKOA (35-69%) and severe rKOA (22-46%). Conclusion: These updated estimates demonstrate a large and increasing burden of knee OA, particularly among women and Black individuals.
Using anchoring motifs for the computational design of protein–protein interactions
Creators: name: Jacobs, Timothy M.
name: Kuhlman, Brian
Publisher: name: The University of North Carolina at Chapel Hill University Libraries
Year: 2013

description: The computer-based design of protein-protein interactions is a challenging problem because large desolvation and entropic penalties must be overcome by the creation of favorable hydrophobic and polar contacts at the target interface. Indeed, many computationally designed interactions fail to form when tested in the laboratory. Here, we highlight strategies our laboratory has been pursuing to make interface design more tractable. Our general approach has been to make use of structural motifs found in native proteins that are predisposed to interact with a particular binding geometry, and then further bolster these anchor points with favorable hydrophobic contacts. We describe the use of three different anchor points – β-strand pairing, metal binding, and the docking of an α-helix into a groove – to successfully design new interfaces. In several cases high- resolution crystal structures show that the design models closely match the experimental structure. Additionally, we have tested the use of buried hydrogen bond networks as a source of affinity and specificity at interfaces. In these cases the designed complexes did not form, highlighting the challenges associated with designing buried polar interactions.
Protzia flagellum (Lundblad 1934
Creators: name: Pešić, Vladimir
name: Chatterjee, Tapas
name: Bordoloi, Sabitry
Publisher: name: Zenodo
Year: 2010
Subjects: Biodiversity
Taxonomy
Animalia
Arthropoda
Arachnida
Trombidiformes
Protziidae
Protzia

description: Protzia flagellum (Lundblad, 1934)
Records from the study area: Kashmir—“ Calonyx flagellum “ Lundblad (1934); Prasad (1974).
Habitat: Fast flowing mountain streams.
Distribution: India.
description: Published as part of Pešić, Vladimir, Chatterjee, Tapas & Bordoloi, Sabitry, 2010, A checklist of the water mites (Acari: Hydrachnidia) of India, with new records and description of one new species, pp. 1-54 in Zootaxa 2617 (1) on page 7, DOI: 10.11646/zootaxa.2617.1.1, http://zenodo.org/record/197964