gebhart/patrepeval huggingface dataset:
Abstract PR02: Mechanisms of NT5C2 activating mutations driving thiopurine resistance in relapsed lymphoblastic leukemia (2017)

Abstract Activating mutations in cytosolic 5'-nucleotidase II (NT5C2) drive resistance to 6-mercaptopurine (6-MP) in relapsed acute lymphoblastic leukemia (ALL). These gain-of function alleles encode proteins with increased nucleotidase activity, yet their specific molecular mechanisms are poorly understood. Allosteric activation of NT5C2 is primarily mediated by a marked conformational change in the helix A region, which reconfigures the catalytic center for substrate access and catalysis. Here we demonstrate that constitutively active NT5C2 mutant proteins (K359Q and L375F) adopt active helix A region structures in the absence of allosteric activator. Moreover, crystallographic, structural modeling, genetic, and functional antibody analyses identify a switch-off mechanism mediated by the dynamic mobilization of Asp407 in the tip region of the arm segment which, guided by positively charged residues located in the surface of a basic inter-monomeric cavity exposed upon allosteric activation, turns off NT5C2 by interacting with and disrupting the helical conformation of helix A. Loss of this regulatory mechanism in NT5C2 mutants involving the tip region of the arm segment and the inter-monomeric cavity drives increased nucleotidase activity and allosteric response. Finally, increased allosteric activation by the Q523X mutation results from loss of the NT5C2 C-terminal acidic tail segment, which promotes a closed inactive state in basal conditions. These results uncover dynamic mechanisms responsible for NT5C2 regulation targeted by chemotherapy resistance-driving NT5C2 mutations, with important implications for the development of NT5C2 inhibitor therapies. This abstract is also being presented as Poster 05. Citation Format: Chelsea L. Dieck, Gannie Tzoneva, Farhad Forouhar, Zachary Carpenter, Marta Sanchez-Martin, Alberto Ambesi-Impiombato, Renate Kirschner-Schwabe, Scott Lew, Jayaraman Seetharaman, Liang Tong, Adolfo Ferrando. Mechanisms of NT5C2 activating mutations driving thiopurine resistance in relapsed lymphoblastic leukemia [abstract]. In: Proceedings of the Second AACR Conference on Hematologic Malignancies: Translating Discoveries to Novel Therapies; May 6-9, 2017; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(24_Suppl):Abstract nr PR02.
Polyethyleneimine‐poly(ethylene glycol)‐star‐copolymers as efficient and biodegradable vectors for mammalian cell transfection (2013)

Abstract High molecular weight (MW) polyethyleneimine (PEI) has been successfully used for the transfection of a broad variety of cell lines. In contrast to low MW PEI, which exhibits low transfection efficiencies but also low cytotoxicity, high MW PEI‐mediated transfection achieves much higher efficiencies but at the cost of cell viability; therefore its use in commercial scale transfection and clinical application is limited. In this work we address this problem by constructing biodegradable high MW PEI mimics built from low MW PEI building blocks. The end‐groups of small 5‐arm star polyethylene glycol (PEG) prepolymers were decorated with linear oligo‐ethyleneimine (OEI)/PEI arms of various MW via azomethine linkages. The resultant PEI‐PEG‐star‐copolymers were investigated for their ability to complex plasmid DNA. Polymer/DNA complexes were characterized using techniques such as dynamic light scattering and transmission electron microscopy. Having established their cytotoxicity limits, they were tested as gene delivery vehicles for the transfection of suspension adapted Chinese hamster ovary (CHO‐S) cells under serum‐free conditions and adherent human embryonic kidney cells (HEK293T) in serum containing medium. Our PEI‐PEG‐star‐copolymers showed a reduced cytotoxicity compared to high MW PEI while maintaining the ability to complex plasmid DNA and transfect mammalian cells, with significant transfection efficiencies. The effects of the optimum parameters on the transfection of mammalian cells using such novel polymers are discussed. © 2013 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 102A: 2137–2146, 2014.
Beta-2-Microglobulin Levels in the Cerebrospinal Fluid: Their Value as a Disease Marker (1991)

The usefulness of measuring beta 2-microglobulin levels in the cerebrospinal fluid (CSF) in neurological diseases is discussed and the relevant literature is reviewed in this article. An elevation of this protein in the CSF is particularly indicative of disease activity in multiple sclerosis, neuro-Behçet's disease, sarcoidosis, acquired immunodeficiency syndrome-dementia complex and meningeal metastasis of malignant tumors, especially the meningeal dissemination of acute leukemia and malignant lymphoma.
Bringing the Jury to the Scene of the Crime: Memory and Decision-Making in a Simulated Crime Scene (2021)

This paper investigates the use of immersive virtual reconstructions as an aid for jurors during a courtroom trial. The findings of a between-participant user study on memory and decision-making are presented in the context of viewing a simulated hit-run-death scenario. Participants listened to the opening statement of a prosecutor and a defence attorney before viewing the crime scene in Virtual Reality (VR) or as still images. We compare the effects on cognition and usability of using VR over images presented on a screen. We found several significant improvements, including that VR led to more consistent decision-making among participants. This shows that VR could provide a promising solution for the court to present crime scenes when site visitations are not possible.
Flaxseed enhances the beneficial effect of low-dose estrogen therapy at reducing bone turnover and preserving bone microarchitecture in ovariectomized rats (2014)

Our previous research showed greatest protection to vertebral bone mineral density and strength in ovariectomized (OVX) rats when lignan- and α-linolenic acid-rich flaxseed (FS) is combined with low-dose estrogen therapy (LD) compared with either treatment alone. This study determined the effects of combined FS+LD on serum and tissue markers of bone turnover and microarchitecture to explain our previous findings. Three-month-old OVX rats were randomized to negative control (NEG), FS, LD or FS+LD for 2 or 12 weeks, meaningful time points for determining effects on markers of bone metabolism and bone structure, respectively. Ground FS was added to the AIN-93M diet (100 g/kg diet) and LD (0.42 μg 17β-estradiol/(kg body weight·day)) was delivered by subcutaneous implant. Sham rats were included as positive control. Bone formation (e.g., osteocalcin), bone resorption (e.g., tartrate-resistant acid phosphatase-5β (TRAP-5β)), as well as osteoprotegerin (OPG) and receptor activator of nuclear factor κ-B ligand (RANKL) were analyzed from the 2-week study by commercial assays (serum) and (or) histology (vertebra). Vertebral bone microarchitecture was measured from the 12-week study using microcomputed tomography. In serum, FS+LD and LD induced lower TRAP-5β and osteocalcin, and higher OPG and OPG/RANKL ratio versus NEG and FS (p < 0.05). In vertebrae, FS+LD induced higher OPG and lower osteocalcin versus NEG (p < 0.01) and did not differ from LD and FS. FS+LD improved bone microarchitecture versus NEG, FS, and LD (p < 0.05). In conclusion, FS+LD protects bone tissue because of a reduction in bone turnover. However, elucidating the distinctive action of FS+LD on bone turnover compared with LD requires further investigation.
Cyclic AMP Response Element-Binding Protein and the Catalytic Subunit of Protein Kinase A Are Present in F9 Embryonal Carcinoma Cells but Are Unable To Activate the Somatostatin Promoter (1992)

The cyclic AMP (cAMP) response elements (CREs) of the somatostatin and vasoactive intestinal peptide (VIP) promoters contain binding sites for CRE-binding protein (CREB) that are essential for cAMP-regulated transcription. Using F9 embryonal carcinoma cells, we show that the somatostatin and VIP promoters exhibit a differentiation-dependent cAMP response, demonstrating that these promoters are regulated by transcription factors that become active during differentiation. Lack of cAMP responsiveness of the somatostatin promoter in undifferentiated cells is not due to the absence of known positive-acting factors (the catalytic subunit of protein kinase A [cPKA] and CREB) or a general inhibition of protein kinase A activity. Since overexpression of exogenous cPKA and CREB is sufficient to activate the somatostatin promoter in undifferentiated cells, these findings suggest that a negative factor(s) represses endogenous cPKA and CREB. In contrast to their effects on somatostatin, exogenous CREB and cPKA do not activate the VIP promoter. Thus, despite coregulation during differentiation and the ability to bind CREB, the somatostatin and VIP promoters are not coordinately activated by CREB in undifferentiated F9 cells.
Fabrication of biomolecular devices via supramolecular contact-based approaches (2009)

This tutorial review provides an outlook on contact-based fabrication methods suitable for biomolecular platforms. Contact-based methods have emerged in response to serial and expensive fabrication techniques that built devices in a serial way, typically point by point or region by region. The review surveys the biological applications of microcontact printing and affinity contact printing. There is a special focus on DNA printing methods harnessing the supramolecular interactions between two complementary DNA strands.
Design of Power-Transmitting Hydraulic Hose with Integrated Controller Area Network and Life-Sensing Capability (2013)

The goal of this project is to design and test a hydraulic hose and fitting assembly that hasthe ability to transmit electrical power as well as SAE J1939 CAN bus signal. The intendedapplications included mobile machinery, automotive, aerospace, manufacturing, and processequipment. The benefits of this approach to power and signal transmission included improvedrobustness and durability, reduction in parts and faster machine assembly times. Multiple conceptualdesigns have been generated, including sending current through the existing steel reinforcing layersof the hose, or utilizing a dedicated wire or wires that are embedded in the outer rubber layer or arewrapped around the hose and encased with and additional sheath. Each design will be evaluatedaccording to SAE standards J1939, J343, and J1405, which specify testing procedures for thephysical ability of the hose and the requirements for CAN Bus signal protocol.
Practical aspects of visual recognition for indoor mobile positioning (2013)

Visual recognition based positioning requires complex image processing algorithms like feature detection, description, grouping and matching, which need considerable processing power from mobile devices. Many algorithms for feature detection have been developed from which some became de-facto solutions for many visual recognition scenarios. Novel techniques have since been published for feature description, grouping and matching. Although the applicability of these techniques for indoor mobile positioning is a subject of recent, ongoing research, only a few papers discuss the peculiarities of mobile visual imaging considering recent technical developments and usability aspects. For a visual recognition based indoor positioning application not only do we need to consider the quality of known algorithms, but we also have to take into account the whole set of boundary conditions, like processing capabilities, memory availability, battery capacity and quality of visual recording of the mobile devices and overall system communication capabilities. In this paper we investigate some of these aspects together through a real visual recognition system and present simulation results to support the usability of feature detection algorithms in mobile environments.
Preparation of Palladium Metal Intercalated between Graphite Layers with Low Palladium Loading for Cinnamaldehyde Hydrogenation (2021)

Abstract Spherical palladium nanoparticles between graphite layers were prepared by the intercalation of palladium chloride followed by its reduction between graphite layers. The palladium particles intercalated between graphite layers were more active for cinnamaldehyde hydrogenation to hydrocinnamaldehyde and hydrocinnamyl alcohol in n-heptane solvent than those supported on graphite surface.
Beat-by-Beat Cardiomyocyte T-Tubule Deformation Drives Tubular Content Exchange (2020)

Our data confirm the existence of an advective component to TT content exchange. This points toward a novel mechanism of cardiac autoregulation, whereby the previously implied increased propensity for TT luminal concentration imbalances at high electrical stimulation rates would be countered by elevated advection-assisted diffusion at high mechanical beating rates. The relevance of this mechanism in health and during pathological remodeling (eg, cardiac hypertrophy or failure) forms an exciting target for further research.
Screening for late neonatal vitamin K deficiency by acarboxyprothrombin in dried blood spots. (1987)

Acarboxyprothrombin (protein induced by vitamin K absence or antagonist-II (PIVKA-II] concentrations in dried blood spots were determined in 19,029 infants at about 1 month of age as an indicator of vitamin K deficiency. We observed 51 cases with raised blood concentrations of PIVKA-II (greater than 4 AU/ml), nine of whom showed very high concentrations (greater than 20 AU/ml). For infants who did not receive vitamin K prophylaxis at birth, the incidence of the PIVKA-II test yielding positive results was significantly higher in those solely breast fed (0.51%) compared with those fed formula milk (0.18%). Among solely breast fed infants, the incidence of a very high result of the PIVKA-II test was 0.14% in those who had not received vitamin K prophylaxis at birth, 0.04% in those who received 2 mg orally, and 0.03% in those who received 2 mg orally plus a further dose of 2-4 mg orally at 7 days. Thus vitamin K prophylaxis at birth did not completely prevent vitamin K deficiency at 1 month. We administered vitamin K therapeutically to all infants whose PIVKA-II test yielded a positive result at 1 month. Only one infant with a positive result developed late neonatal intracranial haemorrhage.
The Effects of Active Therapeutic Exercises on the Electromyographic Activity of Lumbopelvic Muscles during Prone Hip Extension in Patients with Chronic Non-Specific Low Back Pain (2014)

Introduction: LBP is one of the most common health issues throughout the world and has multiple causes which one of them is the defect in motor patterns. This study compared the effectiveness of stability, general and mixed exercises on the electromyographic activity of ipsilateral erector spinae muscle (IES), contralateral erector spinae muscle (CES), gluteus maximus (GM) and medial hamstring (MH) during prone hip extension (PHE) in patients with nonspecific chronic low back pain (NSCLBP). Methods: The study used an interventional quasi-experimental design. Thirty patients with NSCLBP between the ages of 20 to 40 years were randomly divided into 3 groups (each with ten patients) including stability, general and mixed groups. The study was conducted in Spring and Summer of 2014 in Amir Physical Clinic in Isfahan. MVEA of the muscles was measured using surface electromyography (EMG) prior and after exercises during PHE. Exercises were done for 10 sessions and 3 times per week. The obtained data by SPSS (version 22) and using the Kolmogorov- Smirnov test, Independent t–test Paired t test and ANCOVA were analyzed. Results: MVEA of GM (P=0.036) significantly increased in the group who practiced with mixed exercises. Also‚ the exercises decreased MVEA of IES‚ MH and CES. Besides, this decrease for IES (P=0.024) was significant but for MH (P=0.973) and CES (P=0.111) were not. However, the statistical results did not show any significance among any two and or all three groups. Conclusion: The findings of this study revealed that mixed exercises are more effective than stability and general exercises on the EMG activity of lumbo- pelvic muscles and could alter the electrical activity pattern of these muscles.
Multiomic study of skin, peripheral blood, and serum: is serum proteome a reflection of disease process at the end-organ level in systemic sclerosis? (2021)

Abstract Background Serum proteins can be readily assessed during routine clinical care. However, it is unclear to what extent serum proteins reflect the molecular dysregulations of peripheral blood cells (PBCs) or affected end-organs in systemic sclerosis (SSc). We conducted a multiomic comparative analysis of SSc serum profile, PBC, and skin gene expression in concurrently collected samples. Methods Global gene expression profiling was carried out in skin and PBC samples obtained from 49 SSc patients enrolled in the GENISOS observational cohort and 25 unaffected controls. Levels of 911 proteins were determined by Olink Proximity Extension Assay in concurrently collected serum samples. Results Both SSc PBC and skin transcriptomes showed a prominent type I interferon signature. The examination of SSc serum profile revealed an upregulation of proteins involved in pro-fibrotic homing and extravasation, as well as extracellular matrix components/modulators. Notably, several soluble receptor proteins such as EGFR, ERBB2, ERBB3, VEGFR2, TGFBR3, and PDGF-Rα were downregulated. Thirty-nine proteins correlated with severity of SSc skin disease. The differential expression of serum protein in SSc vs. control comparison significantly correlated with the differential expression of corresponding transcripts in skin but not in PBCs. Moreover, the differentially expressed serum proteins were significantly more connected to the Well-Associated-Proteins in the skin than PBC gene expression dataset. The assessment of the concordance of between-sample similarities revealed that the molecular profile of serum proteins and skin gene expression data were significantly concordant in patients with SSc but not in healthy controls. Conclusions SSc serum protein profile shows an upregulation of profibrotic cytokines and a downregulation of soluble EGF and other key receptors. Our multilevel comparative analysis indicates that the serum protein profile in SSc correlates more closely with molecular dysregulations of skin than PBCs and might serve as a reflection of disease severity at the end-organ level.
Human endothelial and foetal femur-derived stem cell co-cultures modulate osteogenesis and angiogenesis (2016)

These studies demonstrate a differential skeletal response of early foetal skeletal cells, when co-cultured with endothelial cells and the potential of co-culture models for bone repair. The differential effect of VEGF supplementation on markers of angiogenesis and osteogenesis in co-cultures and organ cultures, demonstrate the importance of the intricate temporal coordination of osteogenic and angiogenic processes during bone formation and implications therein for effective approaches to bone regenerative therapies.
Association of E-cadherin germ-line alterations with prostate cancer. (2001)

In our recent cancer registry-based study, the incidence of gastric carcinoma was increased up to 5-fold in male relatives of early-onset prostate cancer (PCA) patients. This association may reflect the influence of genetic factors predisposing individuals to both tumor types. Germ-line mutations of the CDH1 gene at 16q have recently been associated with familial gastric cancer. Furthermore, two genome-wide linkage studies of PCA recently reported positivity at 16q. We therefore identified families and individual patients with both gastric and PCA and investigated whether the CDH1 gene mutations were involved in cancer predisposition in these cases. Fifteen of the 180 Finnish hereditary PCA families (8.3%) had one or more gastric cancer cases. No truncating or splice site CDH1 mutations were identified by PCR single-strand conformational polymorphism in these families or in eight individual patients who had both prostate and gastric cancer. However, a novel S270A missense mutation in exon 6 of the CDH1 gene was seen in a single family with four prostate and two gastric cancers. A large-scale population-based survey indicated a higher prevalence of S270A among both familial PCA cases (3.3%; n = 120; P = 0.01) and unselected PCA patients (1.5%; n = 472; P = 0.12) as compared with blood donors serving as population controls (0.5%; n = 923). We conclude that individual rare mutations and polymorphisms in the CDH1 gene, such as S270A, may contribute to the onset of PCA and warrant further investigations in other populations. However, the CDH1 gene does not appear to explain the link between prostate and gastric cancer.
Mice Null for Sox18 Are Viable and Display a Mild Coat Defect (2000)

We have previously shown that Sox18 is expressed in developing vascular endothelium and hair follicles during mouse embryogenesis and that point mutations in Sox18 are the underlying cause of cardiovascular and hair follicle defects in ragged (Ra) mice. Here we describe the analysis of Sox18(-/-) mice produced by gene targeting. Despite the profound defects seen in Ra mice, Sox18(-/-) mice have no obvious cardiovascular defects and only a mild coat defect with a reduced proportion of zigzag hairs. A reduction in the amount of pheomelanin pigmentation in hair shafts was also observed; later-forming hair follicles showed a reduced subapical pheomelanin band, giving Sox18(-/-) mice a slightly darker appearance than Sox18(+/+) and Sox18(+/-) siblings. Sox18(-/-) mice are viable and fertile and show no difference in the ability to thrive relative to littermates. Because of the mild effect of the mutation on the phenotype of Sox18(-/-) mice, we conclude that the semidominant nature of the Ra mutations is due to a trans-dominant negative effect mediated by the mutant SOX18 proteins rather than haploinsufficiency as has been observed for other SOX genes. Due to the similarity of SOX18 to other subgroup F SOX proteins, SOX7 and -17, and the overlap in expression of these genes, functional redundancy amongst these SOX proteins could also account for the mild phenotype of Sox18(-/-) mice.
The effect of non‐quantal acetylcholine release on quantal miniature currents at mouse diaphragm. (1993)

1. The amplitude and exponential decay time constant of miniature endplate currents (MEPCs) were measured in mouse diaphragms treated with anti-cholinesterase under conditions known to modulate non-quantal acetylcholine (ACh) release. 2. Anti-cholinesterase prolonged MEPC decay and the extent of this initial prolongation was not influenced by non-quantal release. When non-quantal release was present, the decays of MEPCs became increasingly faster over several hours. This increased decay did not occur in the absence of non-quantal release. 3. Potentiation of the non-quantal release by zero Mg2+ and 1 x 10(-5) M choline, on the other hand, led to acceleration of MEPC shortening. 4. Increase of temperature from 15 to 26 degrees C and the presence of the desensitization-promoting drug proadifen (5 x 10(-6) M) accelerated the rate of MEPC shortening. 5. These observations are consistent with increased receptor desensitization due to non-quantal release. Repetitive binding of ACh to postsynaptic receptors which prolongs the time course of MEPC in anti-cholinesterase-treated endplates leads to progressive desensitization in the presence of non-quantal release and to the subsequent shortening of the quantal responses.