gebhart/patrepeval huggingface dataset:
Dual-regulated Lentiviral Vector for Gene Therapy of X-linked Chronic Granulomatosis (2014)

Regulated transgene expression may improve the safety and efficacy of hematopoietic stem cell (HSC) gene therapy. Clinical trials for X-linked chronic granulomatous disease (X-CGD) employing gammaretroviral vectors were limited by insertional oncogenesis or lack of persistent engraftment. Our novel strategy, based on regulated lentiviral vectors (LV), targets gp91(phox) expression to the differentiated myeloid compartment while sparing HSC, to reduce the risk of genotoxicity and potential perturbation of reactive oxygen species levels. Targeting was obtained by a myeloid-specific promoter (MSP) and posttranscriptional, microRNA-mediated regulation. We optimized both components in human bone marrow (BM) HSC and their differentiated progeny in vitro and in a xenotransplantation model, and generated therapeutic gp91(phox) expressing LVs for CGD gene therapy. All vectors restored gp91(phox) expression and function in human X-CGD myeloid cell lines, primary monocytes, and differentiated myeloid cells. While unregulated LVs ectopically expressed gp91(phox) in CD34(+) cells, transcriptionally and posttranscriptionally regulated LVs substantially reduced this off-target expression. X-CGD mice transplanted with transduced HSC restored gp91(phox) expression, and MSP-driven vectors maintained regulation during BM development. Combining transcriptional (SP146.gp91-driven) and posttranscriptional (miR-126-restricted) targeting, we achieved high levels of myeloid-specific transgene expression, entirely sparing the CD34(+) HSC compartment. This dual-targeted LV construct represents a promising candidate for further clinical development.
Interactions between NKG2x Immunoreceptors and HLA-E Ligands Display Overlapping Affinities and Thermodynamics (2005)

The NKG2x/CD94 family of C-type lectin-like immunoreceptors (x = A, B, C, E, and H) mediates surveillance of MHC class Ia cell surface expression, often dysregulated during infection or tumorigenesis, by recognizing the MHC class Ib protein HLA-E that specifically presents peptides derived from class Ia leader sequences. In this study, we determine the affinities and interaction thermodynamics between three NKG2x/CD94 receptors (NKG2A, NKG2C, and NKG2E) and complexes of HLA-E with four representative peptides. Inhibitory NKG2A/CD94 and activating NKG2E/CD94 receptors bind HLA-E with indistinguishable affinities, but with significantly higher affinities than the activating NKG2C/CD94 receptor. Despite minor sequence differences, the peptide presented by HLA-E significantly influenced the affinities; HLA-E allelic differences had no effect. These results reveal important constraints on the integration of opposing activating and inhibitory signals driving NK cell effector functions.
Using the CATH domain database to assign structures and functions to the genome sequences (2000)

The CATH database of protein structures contains approximately 18000 domains organized according to their (C)lass, (A)rchitecture, (T)opology and (H)omologous superfamily. Relationships between evolutionary related structures (homologues) within the database have been used to test the sensitivity of various sequence search methods in order to identify relatives in Genbank and other sequence databases. Subsequent application of the most sensitive and efficient algorithms, gapped blast and the profile based method, Position Specific Iterated Basic Local Alignment Tool (PSI-BLAST), could be used to assign structural data to between 22 and 36 % of microbial genomes in order to improve functional annotation and enhance understanding of biological mechanism. However, on a cautionary note, an analysis of functional conservation within fold groups and homologous superfamilies in the CATH database, revealed that whilst function was conserved in nearly 55% of enzyme families, function had diverged considerably, in some highly populated families. In these families, functional properties should be inherited far more cautiously and the probable effects of substitutions in key functional residues carefully assessed.
MEME SUITE: tools for motif discovery and searching (2009)

The MEME Suite web server provides a unified portal for online discovery and analysis of sequence motifs representing features such as DNA binding sites and protein interaction domains. The popular MEME motif discovery algorithm is now complemented by the GLAM2 algorithm which allows discovery of motifs containing gaps. Three sequence scanning algorithms--MAST, FIMO and GLAM2SCAN--allow scanning numerous DNA and protein sequence databases for motifs discovered by MEME and GLAM2. Transcription factor motifs (including those discovered using MEME) can be compared with motifs in many popular motif databases using the motif database scanning algorithm TOMTOM. Transcription factor motifs can be further analyzed for putative function by association with Gene Ontology (GO) terms using the motif-GO term association tool GOMO. MEME output now contains sequence LOGOS for each discovered motif, as well as buttons to allow motifs to be conveniently submitted to the sequence and motif database scanning algorithms (MAST, FIMO and TOMTOM), or to GOMO, for further analysis. GLAM2 output similarly contains buttons for further analysis using GLAM2SCAN and for rerunning GLAM2 with different parameters. All of the motif-based tools are now implemented as web services via Opal. Source code, binaries and a web server are freely available for noncommercial use at http://meme.nbcr.net.
In vitro cytotoxicity against fresh human tumors and P388 leukemia predicts the differential in vivo activity of a series of anthracene anticancer drugs (1991)

To date, random anticancer drug screening has proven to be relatively inefficient and non-specific with respect to selecting active compounds for most tumor types (except for leukemia/lymphoma). Although large numbers of compounds from diverse sources were evaluated for many years in the P388 mouse leukemia model, only a few clinically useful drugs have been identified by this in vivo screening method. Thus, there is intense interest in the development of more effective in vitro screening models for new anticancer drugs. In the present paper we have compared the discriminating power for fresh human tumors from patients, human tumor cell lines developed from 11 patients and murine P388 leukemia in tumor colony forming assays as indicators of cytotoxicity for a series of anthracene antitumor agents. Two of a series of 21 novel bisantrene analogs, R6 (N,N1-bis[2-(dimethylamino)ethyl]-9,10-anthracene-bis(methylamine)) and R26 (N,N1-bis(1-ethyl-3-piperidinyl)-9,10-anthracene-bis(methylamine] produced significant cytotoxicity against the 11 human tumor cell lines and were therefore selected for additional in vitro and in vivo studies. R26 was specifically selected for further testing since it had similar in vitro potency as mitoxantrone, but showed no cross-resistance against mitoxantrone-resistant WiDr colon or doxorubicin-resistant 8226 myeloma cell lines. In contrast to the cell line data, only of the 22 fresh human tumors showed significant in vitro sensitivity (i.e. less than 50% survival of tumor colony forming units) to either R6 or R26 tested at high concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)
Synthesis, Characterization, and Cu2+Coordination Studies of a 3-Hydroxy-4-pyridinone Aza Scorpiand Derivative (2016)

The synthesis, acid-base behavior, and Cu(2+) coordination chemistry of a new ligand (L1) consisting of an azamacrocyclic core appended with a lateral chain containing a 3-hydroxy-2-methyl-4(1H)-pyridinone group have been studied by potentiometry, cyclic voltammetry, and NMR and UV-vis spectroscopy. UV-vis and NMR studies showed that phenolate group was protonated at the highest pH values [log K = 9.72(1)]. Potentiometric studies point out the formation of Cu(2+) complexes of 1:2, 2:2, 4:3, 1:1, and 2:1 Cu(2+)/L1 stoichiometries. UV-vis analysis and electrochemical studies evidence the implication of the pyridinone moieties in the metal coordination of the 1:2 Cu(2+)/L1 complexes. L1 shows a stronger chelating ability than the reference chelating ligand deferiprone. While L1 shows no cytotoxicity in HeLa and ARPE-19 human cell lines (3.1-25.0 μg/mL), it has significant antioxidant activity, as denoted by TEAC assays at physiological pH. The addition of Cu(2+) diminishes the antioxidant activity because of its coordination to the pyridinone moiety phenolic group.
Structural basis for CARM1 inhibition by indole and pyrazole inhibitors (2011)

CARM1 (co-activator-associated arginine methyltransferase 1) is a PRMT (protein arginine N-methyltransferase) family member that catalyses the transfer of methyl groups from SAM (S-adenosylmethionine) to the side chain of specific arginine residues of substrate proteins. This post-translational modification of proteins regulates a variety of transcriptional events and other cellular processes. Moreover, CARM1 is a potential oncological target due to its multiple roles in transcription activation by nuclear hormone receptors and other transcription factors such as p53. Here, we present crystal structures of the CARM1 catalytic domain in complex with cofactors [SAH (S-adenosyl-L-homocysteine) or SNF (sinefungin)] and indole or pyazole inhibitors. Analysis of the structures reveals that the inhibitors bind in the arginine-binding cavity and the surrounding pocket that exists at the interface between the N- and C-terminal domains. In addition, we show using ITC (isothermal titration calorimetry) that the inhibitors bind to the CARM1 catalytic domain only in the presence of the cofactor SAH. Furthermore, sequence differences for select residues that interact with the inhibitors may be responsible for the CARM1 selectivity against PRMT1 and PRMT3. Together, the structural and biophysical information should aid in the design of both potent and specific inhibitors of CARM1.
Empirical filter estimation for subpixel interpolation and matching (2002)

We study the low-level problem of predicting pixel intensities after subpixel image translations. This is a basic subroutine for image warping and super-resolution, and it has a critical influence on the accuracy of subpixel matching by image correlation. Rather than using traditional frequency-space filtering theory or ad hoc interpolators such as splines, we take an empirical approach, finding optimal subpixel interpolation filters by direct numerical optimization over a large set of training examples. The training set is generated by subsampling larger images at different translations, using subsamplers that mimic the spatial response functions of real pixels. We argue that this gives realistic results, and design filters of various different parametric forms under traditional and robust prediction error metrics. We systematically study the performance of the resulting filters, paying particular attention to the influence of the underlying image sampling regime and the effects of aliasing ("jaggies"). We summarize the results and give practical advice for obtaining subpixel accuracy.
Motor Neuron Gene Therapy: Lessons from Spinal Muscular Atrophy for Amyotrophic Lateral Sclerosis (2017)

Spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS) are severe nervous system diseases characterized by the degeneration of lower motor neurons. They share a number of additional pathological, cellular, and genetic parallels suggesting that mechanistic and clinical insights into one disorder may have value for the other. While there are currently no clinical ALS gene therapies, the splice-switching antisense oligonucleotide, nusinersen, was recently approved for SMA. This milestone was achieved through extensive pre-clinical research and patient trials, which together have spawned fundamental insights into motor neuron gene therapy. We have thus tried to distil key information garnered from SMA research, in the hope that it may stimulate a more directed approach to ALS gene therapy. Not only must the type of therapeutic (e.g., antisense oligonucleotide vs. viral vector) be sensibly selected, but considerable thought must be applied to the <i>where</i>, <i>which</i>, <i>what</i>, and <i>when</i> in order to enhance treatment benefit: to where (cell types and tissues) must the drug be delivered and how can this be best achieved? Which perturbed pathways must be corrected and can they be concurrently targeted? What dosing regime and concentration should be used? When should medication be administered? These questions are intuitive, but central to identifying and optimizing a successful gene therapy. Providing definitive solutions to these quandaries will be difficult, but clear thinking about therapeutic testing is necessary if we are to have the best chance of developing viable ALS gene therapies and improving upon early generation SMA treatments.
ChemInform Abstract: REARRANGEMENTS OF ORGANOMETALLIC COMPOUNDS. XVII. SYNTHESIS OF LACTONES VIA THE TITANIUM‐CATALYZED HYDROMAGNESIATION OF ALKENOLS (1979)

Abstract Die durch Addition von Vinyl‐ oder Alkylgrignard‐Verbindungen an Aldehyde oder Ketone erhaltenen Alkohole (I) und (V) lassen sich in Gegenwart eines Titanocen‐Katalysators zu Zwischenprodukten des Typs (II) umsetzen, deren Carbonylierung die 7‐ und ö‐Lactone (III) und (VI) in guten Ausbeuten liefert.
Urinary N-Acetyl-β-(D)-Glucosaminidase Activity and Kidney Injury Molecule-1 Level Are Associated with Adverse Outcomes in Acute Renal Failure (2007)

The role of urinary biomarkers of kidney injury in the prediction of adverse clinical outcomes in acute renal failure (ARF) has not been well described. The relationship between urinary N-acetyl-beta-(D)-glucosaminidase activity (NAG) and kidney injury molecule-1 (KIM-1) level and adverse clinical outcomes was evaluated prospectively in a cohort of 201 hospitalized patients with ARF. NAG was measured by spectrophotometry, and KIM-1 was measured by a microsphere-based Luminex technology. Mean Acute Physiology, Age, Chronic Health Evaluation II (APACHE II) score was 16, 43% had sepsis, 39% required dialysis, and hospital mortality was 24%. Urinary NAG and KIM-1 increased in tandem with APACHE II and Multiple Organ Failure scores. Compared with patients in the lowest quartile of NAG, the second, third, and fourth quartile groups had 3.0-fold (95% confidence interval [CI] 1.3 to 7.2), 3.7-fold (95% CI 1.6 to 8.8), and 9.1-fold (95% CI 3.7 to 22.7) higher odds, respectively, for dialysis requirement or hospital death (P < 0.001). This association persisted after adjustment for APACHE II, Multiple Organ Failure score, or the combined covariates cirrhosis, sepsis, oliguria, and mechanical ventilation. Compared with patients in the lowest quartile of KIM-1, the second, third, and fourth quartile groups had 1.4-fold (95% CI 0.6 to 3.0), 1.4-fold (95% CI 0.6 to 3.0), and 3.2-fold (95% CI 1.4 to 7.4) higher odds, respectively, for dialysis requirement or hospital death (P = 0.034). NAG or KIM-1 in combination with the covariates cirrhosis, sepsis, oliguria, and mechanical ventilation yielded an area under the receiver operator characteristic curve of 0.78 (95% CI 0.71 to 0.84) in predicting the composite outcome. Urinary markers of kidney injury such as NAG and KIM-1 can predict adverse clinical outcomes in patients with ARF.
Nonablative Remodeling: A 14-Month Clinical Ultrasound Imaging and Profilometric Evaluation of a 1540 nm Er:Glass Laser (2002)

This study demonstrated that irradiation with a 1540 nm Er:glass laser emitting in a pulsed mode and coupled with an efficient cooling system increased dermal thickness, reduced the anisotropy of the skin, and improved clinical aspects. The lack of adverse effects within the 14 months confirmed that this procedure was safe. Overall the stability of the results many months after the treatment was remarkable.
Demonstration of the Power of Inter-Disciplinary Integration to Beat Field Development Challenges in a Complex Brown Field-South Oman (2010)

Abstract An integrated understanding of static and dynamic issues is essential to generate an appropriate life cycle FDP. This abstract will highlight the power of such integration. First pass dynamic modeling gave very poor history match results. The model significantly under produced the historical gross volumes. Sensitivity analysis on the permeability multiplier, Kv/Kh, viscosity and relative permeability curves were utilized to improve the history match, however, the improvement was limited. Careful investigation showed that the main reason for the poor history match was the underestimation of permeability in apparently low porosity intervals. These previously unrecognized flow units also contributed to a high vertical heterogeneity. Further integration and analysis of various petrophysical data, combined with reservoir performance behavior, suggested that these additional flow units were conglomeratic intervals of different gravel sizes. These intervals are characterized by reduced bulk porosity because of the presence of low porosity pebbles in the otherwise highly permeable sandy matrix. Following this re-interpretation, a new realization of the conceptual depositional model, that incorporates the new litho-facies, was constructed. The static inputs were re-visited; however, due to the lack of core data, identification of the permeability range of the new litho-facies was complicated. This forced maximum utilization of the basic static/dynamic data and analogues. Analysis of borehole rugosity, oil saturation, reservoir performance and pressure data strengthened the adopted subsurface concept model. A recent core, taken from this reservoir, revealed the presence of conglomerates comprising hard clasts cemented by unconsolidated sands and thereby finally confirmed the interpretation. The updated models, with minor fine-tuning in dynamic parameters, showed a step change in the history match. This outcome confirmed the presence of high permeable facies despite the low porosity reading at these intervals. It can be concluded that the vertical heterogeneity, which is often overlooked, can cause complex issues in history match process. However, the better understanding of these features, through multidisciplinary approach, is the key to drive the right solution. Moreover, maximum utilization of the basic data can paint a picture beyond its anticipated frame. Despite the lack of core data, compiling the subsurface data through multidisciplinary integration provides a powerful tool to mitigate subsurface uncertainties.
Glycine-Rich Antifreeze Proteins from Snow Fleas (2005)

We purified antifreeze proteins from winter-active snow fleas, Hypogastrura harveyi. These 6.5- and 15.7-kilodalton thermolabile proteins are glycine-rich (45% of the residues), and the short isoform is composed of the tripeptide repeat Gly-X-X. This makes them very different from other antifreeze proteins, including two from insects, suggesting independent adaptation to freezing environments.
Analysis of bHLH and MYB domain proteins: species‐specific regulatory differences are caused by divergent evolution of target anthocyanin genes (1998)

The regulatory anthocyanin loci, an1, an2, an4 and an11 of Petunia hybrida, and r and c1 from Zea mays, control transcription of different sets of target genes. Both an2 and c1 encode a MYB-type protein. This study reports the isolation of a P. hybrida gene, jaf13, encoding a basic helix-loop-helix protein that, on the basis of sequence homology and intron/exon structure, represents the P. hybrida orthologue of the Z. mays r genes. Ectopic expression of an2 and jaf13 is sufficient for activation of the dihydroflavonol 4-reductase-A (dfrA) promoter and enhanced pigment accumulation in P. hybrida. This indicates that an2 and jaf13 play a key role in determining the tissue-specific expression pattern of structural genes. However, because chalcone synthase (chs) and flavanone-3-hydroxylase (f3h) are not activated, the pattern of pigmentation is not fundamentally altered. Expression of an2 in Z. mays complements a mutation in pl, a c1 paralogue, indicating that an2 activates a wider set of target genes in this host. Transient expression assays in Z. mays and P. hybrida tissues showed that C1 and R or AN2 and JAF13 can activate the promoter of the c2 gene, encoding Z. mays CHS, but not the chsA promoter from P. hybrida. These results indicate that regulatory anthocyanin genes are conserved between species and that divergent evolution of the target gene promoters is responsible for the species-specific differences in regulatory networks.
أثر تطبيق حوكمة المؤسسات على تنافسيتها – دراسة ميدانية لعينة من المؤسسات العمومية الاقتصادية بولاية سكيكدة – (2016)

هدفت الدراسة إلى إيجاد العلاقة بين تطبيق الحوكمة في المؤسسات العمومية الاقتصادية الجزائرية بولاية سكيكدة وقدرتها التنافسية. ولتحقيق هذا الهدف أجرى الباحث دراسة ميدانية لعينة شملت الفئات التالية: عضو مجلس إدارة، مدير تنفيذي، رئيس دائرة المحاسبة والمالية، ومدقق داخلي لست مؤسسات عمومية اقتصادية بولاية سكيكدة، تنشط في قطاعات مختلفة. بناء على استمارة مهيكلة شملت محاور الدراسة، وزعت على فئات العينة. بينت نتائج الدراسة الميدانية أنه لا توجد علاقة ارتباط ذات معنوية إحصائية بين أبعاد مجلس الإدارة، الإفصاح والشفافية، والتدقيق والرقابة الداخلية وإدارة المخاطر، وتنافسية المؤسسات محل الدراسة، في حين توجد علاقة ارتباط متوسطة ذات معنوية إحصائية بين بعد أصحاب المصالح وتنافسية المؤسسات محل الدراسة.
[Interactions of insulin with dipalmitoylphosphatidylcholine liposomes]. (2000)

Amphiphilic, example insulin, may disturb the intact membrane of liposome through the interaction either hydrophobic or hydrophilic. The attention should be paid to the entrapment process of peptides into liposomes.
The structure of aggrecan fragments in human synovial fluid. evidence that aggrecanase mediates cartilage degradation in inflammatory joint disease, joint injury, and osteoarthritis (1993)

The aggrecan fragments present in joint fluids from patients with various inflammatory arthritides, joint injury, or OA result from a predominant cleavage of the human aggrecan core protein at the glutamate 373-alanine 374 bond within the interglobular domain, between the G1 and G2 domains. The consistent pattern of fragments seen on SDS-PAGE and the single predominant N-terminal sequence suggest a common degradative mechanism of aggrecan in these different joint conditions. The identity of the proteolytic agent (aggrecanase), however, remains unknown. These results appear to have important implications with regard to the development of therapies to protect cartilage from degradation in patients with joint disease.
A new class of bispecific antibodies to redirect T cells for cancer immunotherapy (2013)

Various constructs of bispecific antibodies (bsAbs) to redirect effector T cells for the targeted killing of tumor cells have shown considerable promise in both preclinical and clinical studies. The single-chain variable fragment (scFv)-based formats, including bispecific T-cell engager (BiTE) and dual-affinity re-targeting (DART), which provide monovalent binding to both CD3 on T cells and to the target antigen on tumor cells, can exhibit rapid blood clearance and neurological toxicity due to their small size (~55 kDa). Herein, we describe the generation, by the modular DOCK-AND-LOCK™) (DNL™) method, of novel T-cell redirecting bispecific antibodies, each comprising a monovalent anti-CD3 scFv covalently conjugated to a stabilized dimer of different anti-tumor Fabs. The potential advantages of this design include bivalent binding to tumor cells, a larger size (~130 kDa) to preclude renal clearance and penetration of the blood-brain barrier, and potent T-cell mediated cytotoxicity. These prototypes were purified to near homogeneity, and representative constructs were shown to provoke the formation of immunological synapses between T cells and their target tumor cells in vitro, resulting in T-cell activation and proliferation, as well as potent T-cell mediated anti-tumor activity. In addition, in vivo studies in NOD/SCID mice bearing Raji Burkitt lymphoma or Capan-1 pancreatic carcinoma indicated statistically significant inhibition of tumor growth compared with untreated controls.