gebhart/patrepeval huggingface dataset:
Functional characterization of the common c.-32-13T>G mutation of GAA gene: identification of potential therapeutic agents (2013)

Glycogen storage disease type II is a lysosomal storage disorder due to mutations of the GAA gene, which causes lysosomal alpha-glucosidase deficiency. Clinically, glycogen storage disease type II has been classified in infantile and late-onset forms. Most late-onset patients share the leaky splicing mutation c.-32-13T>G. To date, the mechanism by which the c.-32-13T>G mutation affects the GAA mRNA splicing is not fully known. In this study, we demonstrate that the c.-32-13T>G mutation abrogates the binding of the splicing factor U2AF65 to the polypyrimidine tract of exon 2 and that several splicing factors affect exon 2 inclusion, although the only factor capable of acting in the c.-32-13 T>G context is the SR protein family member, SRSF4 (SRp75). Most importantly, a preliminary screening using small molecules described to be able to affect splicing profiles, showed that resveratrol treatment resulted in a significant increase of normal spliced GAA mRNA, GAA protein content and activity in cells transfected with a mutant minigene and in fibroblasts from patients carrying the c-32-13T>G mutation. In conclusion, this work provides an in-depth functional characterization of the c.-32-13T>G mutation and, most importantly, an in vitro proof of principle for the use of small molecules to rescue normal splicing of c.-32-13T>G mutant alleles.
Mosquito records from the Republic of Niger, with reference to the construction of the new 'Trans-Sahara Highway'. (1981)

Construction of a new, fully-tarred 'Trans-Sahara Highway' from the coast of Algeria to Nigeria is well advanced. Information on the distribution of anopheline and culicine mosquitoes collected in Niger during a survey in August and September, 1979 is presented and discussed. Particular reference is made to the dangers of West African malaria vectors being transported north along the Highway as traffic increases. The vector species, Anopheles arabiensis, was found as far north as Agadez (17 degrees N).
Non-nucleoside reverse transcriptase inhibitor resistance among patients failing a nevirapine plus protease inhibitor-containing regimen (2000)

The failure of a nevirapine plus PI-containing regimen is associated with nevirapine resistance in most patients, with the most common mutation occurring at amino acid residue 181. Although there is a high degree of cross-resistance among NNRTI, nearly one third of resistant isolates carrying the single Y181C mutation remain susceptible to efavirenz.
D8/17 Expression on B Lymphocytes in Anorexia Nervosa (2002)

A larger study is needed to determine whether D8/17 serves as a marker for susceptibility to a type of anorexia nervosa.
Intravascular activation of complement and acute lung injury. Dependency on neutrophils and toxic oxygen metabolites. (1982)

Intravascular activation of the complement system with cobra venom factor results in acute lung injury, which has been quantitated by increases in lung vascular permeability. Cobra venom factor preparations devoid of phospholipase A2 activity retain full lung-damaging capacity. The lung injury is associated with the preceding appearance of chemotactic activity in the serum coincident with the development of a profound neutropenia. The chemotactic activity is immunochemically related to human C5a. Morphologic studies have revealed discontinuities in the endothelial cell lining of lung alveolar capillaries, damage and/or destruction of endothelial cells in these areas, plugging of pulmonary capillaries with neutrophils that are in direct contact with vascular basement membrane, the presence of fibrin in alveolar spaces and in areas adjacent to damaged endothelial cells, and intraalveolar hemorrhage. Lung injury is dramatically attenuated in animals that have been previously neutrophil depleted. Teh intravenous injection of superoxide dismutase or catalase also provides significant protection from the pulmonary damage. Very little protection from the pulmonary damage. Very little protection is afforded by pretreatment of rats with antihistamine. These studies suggest that intravascular activation of the complement system leads to neutrophil aggregation and activation, intrapulmonary capillary sequestration of neutrophils, and vascular injury, which may be related to production of toxic oxygen metabolites by complement-activated neutrophils.
Comparative Analysis of Adeno-Associated Virus Capsid Stability and Dynamics (2013)

Icosahedral viral capsids are obligated to perform a thermodynamic balancing act. Capsids must be stable enough to protect the genome until a suitable host cell is encountered yet be poised to bind receptor, initiate cell entry, navigate the cellular milieu, and release their genome in the appropriate replication compartment. In this study, serotypes of adeno-associated virus (AAV), AAV1, AAV2, AAV5, and AAV8, were compared with respect to the physical properties of their capsids that influence thermodynamic stability. Thermal stability measurements using differential scanning fluorimetry, differential scanning calorimetry, and electron microscopy showed that capsid melting temperatures differed by more than 20°C between the least and most stable serotypes, AAV2 and AAV5, respectively. Limited proteolysis and peptide mass mapping of intact particles were used to investigate capsid protein dynamics. Active hot spots mapped to the region surrounding the 3-fold axis of symmetry for all serotypes. Cleavages also mapped to the unique region of VP1 which contains a phospholipase domain, indicating transient exposure on the surface of the capsid. Data on the biophysical properties of the different AAV serotypes are important for understanding cellular trafficking and is critical to their production, storage, and use for gene therapy. The distinct differences reported here provide direction for future studies on entry and vector production.
Inhibition of CD40 expression and CD40‐mediated dendritic cell function by tumor‐derived IL‐10 (2002)

As CD40 plays a key role in both antitumor immunity and DC maturation, we have studied the regulation of its expression during DC hematopoiesis (dendropoiesis) in vitro and in vivo in the tumor microenvironment. Using MC38 colon adenocarcinoma tumor models, we have demonstrated that DCs generated in vitro from bone marrow precursors obtained from tumor-bearers have significantly lower expression of CD40 molecules compared to DCs generated from tumor-free mice. Furthermore, CD40 expression on DCs isolated from the spleens of tumor-bearing mice was also significantly reduced, suggesting that tumor-derived factors inhibit CD40 expression on DCs during dendropoiesis both in vitro and in vivo. Interestingly, CD40 ligation on DCs generated from tumor-bearers did not result in inducible expression of IL-12 protein or IL-12 p40 mRNA. However, Staphylococcus aureus-induced IL-12 production by DCs was not altered in tumor-bearers, confirming that inhibition of IL-12 production by DCs generated in vitro from tumor-bearing mice was due to reduced expression of CD40 on DCs. We have also shown that MC38 tumor cells produce IL-10 and that exogenous IL-10 causes downregulation of CD40 expression on DCs. In addition, endogenous IL-10 produced by colon carcinoma cells inhibited CD40-dependent IL-12 production by DCs since tumor-induced inhibition of IL-12 production was abrogated by neutralizing anti-IL-10 antibody. Finally, systemic administration of FLT3L and/or CD40L reversed CD40 and IL-12 (p40) deficiency of DCs in tumor-bearing mice in vivo. These findings thus demonstrate that tumor-derived factors, including IL-10, inhibit CD40 expression on DCs and DC precursors and suppress their maturation and function.
Vitamins E and C in the Prevention of Cardiovascular Disease in Men (2008)

clinicaltrials.gov Identifier: NCT00270647.
An Introduction to Array Logic (1975)

After a discussion of the reasons for choosing to implement logic in array form, a detailed description of the nature of array logic is given. Topics specifically discussed include general array structures and implementation, influence of decoder partitioning, design of logic arrays, output phase, “split” variables, feedback in logic arrays, and reconfiguration.
Effective Diverting on Horizontal Wells in the Austin Chalk (1993)

ABSTRACT Most horizontal wells in the Austin Chalk have been completed as open hole laterals since the advent of horizontal drilling. The laterals range in length from 500 to 6000 ft. This horizontal configuration makes stimulating the entire length of the lateral zone extremely difficult. Natural fractures in the Austin Chalk and the horizontal profile preclude the use of conventional hydraulic fracturing techniques. Horizontal wells have been successfully stimulated with large volumes of treated slickwater at high rates alternately staging diverter and hydrochloric acid volumes. Wax buttons and beads have been successfully applied to divert these treatments in the open hole laterals. Wax provides effective diverting while the melting point and solubility provide ease of cleanup. This product can be manufactured in any shape or size and is a non-hazardous material. This paper will analyze case histories of 63 wells (Table 1) stimulated over a two-year period in the Brazos and Burleson County areas (Fig. 1) of the Giddings Field. The effectiveness of the wax diverting beads will be demonstrated by Realtime Computer Analysis.1 Pre and post-production levels microresistivity logs for wellbore analysis and radioactive tracer logs2 will demonstrate wax diverters contribute significantly to the stimulation of these wells. Selection of an effective diverting agent to optimize the slickwater fracture stimulation has evolved from treatments utilizing graded salt, benzoic acid, paraformaldehyde and naphthalene to the current use of wax beads. Product availability, solubility in hydrocarbons, cost and the lower concentrations required to achieve diversion make wax the diverter of choice for horizontal well slickwater treatments.
Imagery of local defects in multilayer components by short coherence length interferometry (2002)

We propose to image local defects inside multidielectric optical components by using a special configuration Linnik interference microscope, along with a CCD camera and a dedicated detection, to extract the amplitude scattered by the defects in the interference image. The use of a short coherence length source allows one to obtain interference only from a thin slice (~1microm) within the observed object. The object is tilted to permit the use of a dark-field configuration to enhance the defect contrast. We describe the experimental setup and the detection scheme. Images that exhibit local point defects on the interfaces of various multilayer optical components (laser mirrors) are presented.
Porous Silicon Nanoparticle Delivery of Tandem Peptide Anti‐Infectives for the Treatment of Pseudomonas aeruginosa Lung Infections (2017)

There is an urgent need for new materials to treat bacterial infections. In order to improve antibacterial delivery, an anti-infective nanomaterial is developed that utilizes two strategies for localization: i) a biodegradable nanoparticle carrier to localize therapeutics within the tissue, and ii) a novel tandem peptide cargo to localize payload to bacterial membranes. First, a library of antibacterial peptides is screened that combines a membrane-localizing peptide with a toxic peptide cargo and discovers a tandem peptide that displays synergy between the two domains and is able to kill Pseudomonas aeruginosa at sub-micromolar concentrations. To apply this material to the lung, the tandem peptide is loaded into porous silicon nanoparticles (pSiNPs). Charged peptide payloads are loaded into the pores of the pSiNP at ≈30% mass loading and ≈90% loading efficiency using phosphonate surface chemistry. When delivered to the lungs of mice, this anti-infective nanomaterial exhibits improved safety profiles over free peptides. Moreover, treatment of a lung infection of P. aeruginosa results in a large reduction in bacterial numbers and markedly improves survival compared to untreated mice. Collectively, this study presents the selection of a bifunctional peptide-based anti-infective agent and its delivery via biodegradable nanoparticles for application to an animal model of lung infection.
Transition in Specification of Embryonic Metazoan DNA Replication Origins (1995)

In early Xenopus embryos, in which ribosomal RNA genes (rDNA) are not transcribed, rDNA replication initiates and terminates at 9- to 12-kilobase pair intervals, with no detectable dependence on specific DNA sequences. Resumption of ribosomal RNA (rRNA) synthesis at late blastula and early gastrula is accompanied by a specific repression of replication initiation within transcription units; the frequency of initiation within intergenic spacers remains as high as in early blastula. These results demonstrate that for rRNA genes, circumscribed zones of replication initiation emerge in intergenic DNA during the time in metazoan development when the chromatin is remodeled to allow gene transcription.
Bacterial load in relation to vacuum‐assisted closure wound therapy: A prospective randomized trial (2004)

Vacuum-assisted closure has become a new technique in the challenging management of contaminated, acute, and chronic wounds. Although promising clinical results have been described, scientific proof to substantiate the mechanism of action of this therapy is scarce. In the present study, we examined whether the positive effect on wound healing found in vacuum-assisted closure-treated wounds could be explained by an effect on the bacterial load. Fifty-four patients who needed open wound management before surgical closure were included in this study. Wounds were randomized to either vacuum-assisted closure therapy (n= 29) or treatment by conventional moist gauze therapy (n= 25). Healing was characterized by development of a clean granulating wound bed ("ready for surgical therapy") and reduction of wound surface area. To quantify bacterial load, biopsies were collected. No significant difference was found in time needed to reach "ready for surgical therapy" comparing both therapies. Wound surface area reduction was significantly larger in vacuum-assisted closure-treated wounds: 3.8 +/- 0.5 percent/day (mean +/- SEM) compared to conventional-treated wounds (1.7 +/- 0.6 percent/day; p < 0.05). The total quantitative bacterial load was generally stable in both therapies. However, nonfermentative gram negative bacilli showed a significant decrease in vacuum-assisted closure-treated wounds (p < 0.05), whereas Staphylococcus aureus showed a significant increase in vacuum-assisted closure-treated wounds (p < 0.05). In conclusion, this study shows a positive effect of vacuum-assisted closure therapy on wound healing, expressed as a significant reduction of wound surface area. However, this could not be explained by a significant quantitative reduction of the bacterial load.
Pig Cloning by Microinjection of Fetal Fibroblast Nuclei (2000)

Pig cloning will have a marked impact on the optimization of meat production and xenotransplantation. To clone pigs from differentiated cells, we microinjected the nuclei of porcine (Sus scrofa) fetal fibroblasts into enucleated oocytes, and development was induced by electroactivation. The transfer of 110 cloned embryos to four surrogate mothers produced an apparently normal female piglet. The clonal provenance of the piglet was indicated by her coat color and confirmed by DNA microsatellite analysis.
Ferroelectric and antiferroelectric low molar mass organosiloxane liquid crystals (1998)

Abstract The present paper is a study of the ferroelectric and antiferroelectric behaviour in low molar mass organosiloxane liquid crystal materials classed as mono-mesogens (AB type) and bi-mesogens (ABA type). A systematic study of series of materials all based on the same chiral mesogenic moiety is presented. The mesogen is a biphenylyl benzoate with a halogen X attached laterally to the benzoate ring which is closest to the chiral centre. Three homologous series, where the halogen is either fluorine, chlorine or bromine, are investigated. The number of silicon atoms in the linkage or end group is varied between two and nine. It is found that the materials have a broad (40 C) ferroelectric or antiferroelectric phase with a high P s (90nC cm2). The siloxane moiety forces the tilt angle to a temperature independent value close to 45. The antiferroelectric order is observed only in bi-mesogens with an odd number of silicon atoms in the siloxane link. The antiferroelectric order is attributed to the conformation of the molecule rather than to antiferroelectric interactions between layers.
The crystal structures of the psychrophilic subtilisin S41 and the mesophilic subtilisin Sph reveal the same calcium‐loaded state (2008)

We determine and compare the crystal structure of two proteases belonging to the subtilisin superfamily: S41, a cold-adapted serine protease produced by Antarctic bacilli, at 1.4 A resolution and Sph, a mesophilic serine protease produced by Bacillus sphaericus, at 0.8 A resolution. The purpose of this comparison was to find out whether multiple calcium ion binding is a molecular factor responsible for the adaptation of S41 to extreme low temperatures. We find that these two subtilisins have the same subtilisin fold with a root mean square between the two structures of 0.54 A. The final models for S41 and Sph include a calcium-loaded state of five ions bound to each of these two subtilisin molecules. None of these calcium-binding sites correlate with the high affinity known binding site (site A) found for other subtilisins. Structural analysis of the five calcium-binding sites found in these two crystal structures indicate that three of the binding sites have two side chains of an acidic residue coordinating the calcium ion, whereas the other two binding sites have either a main-chain carbonyl, or only one acidic residue side chain coordinating the calcium ion. Thus, we conclude that three of the sites are of high affinity toward calcium ions, whereas the other two are of low affinity. Because Sph is a mesophilic subtilisin and S41 is a psychrophilic subtilisin, but both crystal structures were found to bind five calcium ions, we suggest that multiple calcium ion binding is not responsible for the adaptation of S41 to low temperatures.
Effect of an electronic nicotine delivery device (e cigarette) on desire to smoke and withdrawal, user preferences and nicotine delivery: randomised cross-over trial (2010)

The 16 mg Ruyan V8 ENDD alleviated desire to smoke after overnight abstinence, was well tolerated and had a pharmacokinetic profile more like the Nicorette inhalator than a tobacco cigarette. Evaluation of the ENDD for longer-term safety, potential for long-term use and efficacy as a cessation aid is needed. Trial registration No.12607000587404, Australia and New Zealand Clinical Trials Register.
An Introduction to Intertask Transfer for Reinforcement Learning (2011)

Transfer learning has recently gained popularity due to the development of algorithms that can successfully generalize information across multiple tasks. This article focuses on transfer in the context of reinforcement learning domains, a general learning framework where an agent acts in an environment to maximize a reward signal. The goals of this article are to (1) familiarize readers with the transfer learning problem in reinforcement learning domains, (2) explain why the problem is both interesting and difficult, (3) present a selection of existing techniques that demonstrate different solutions, and (4) provide representative open problems in the hope of encouraging additional research in this exciting area.
VEGF localisation in diabetic retinopathy (1998)

This study supports a circumstantial role for VEGF in the pathogenesis of both the preclinical and proliferative stages of diabetic retinopathy.
In vitro and in vivo antitumor effects of murine monoclonal antibody NCC-ST-421 reacting with dimeric Le(a) (Le(a)/Le(a)) epitope. (1991)

A murine monoclonal antibody (MAb), NCC-ST-421 (IgG3), was raised by using a human gastric cancer xenograft St-4 as immunogen. Immunization was achieved by transferring immunocompetent normal BALB/c mouse spleen cells into BALB/c-nu/nu mice bearing St-4 tumors. Hybridomas were produced from spleen cells of the mice after rejection of the tumors and were screened for preferential reactivity with cancers on formalin-fixed paraffin sections, as described previously for establishment of MAb NCC-ST-439 (M. Watanabe et al., Jpn. J. Cancer Res., 76: 43-52, 1985). The immunobiological and immunochemical properties of the new MAb NCC-ST-421 are described here. The MAb is essentially directed to a structure with dimeric Le(a) (V4III4Fuc2Lc6Cer) epitope (Gal beta 1----3[Fuc alpha 1----4]GlcNAc beta 1----3Gal beta 1----3[Fuc alpha 1----4]GlcNAc beta 1----3Gal beta 1----4Glc beta 1----1 Cer). It cross-reacts with Le(a) but does not show any effect on Le(a)-positive RBC in vitro or on Le(a)-positive tissue loci in vivo. ST-421 strongly induced antibody-dependent cellular cytotoxicity using human peripheral blood leukocytes as effector cells with a variety of human tumor cells, using the short-term 51Cr release assay. It also showed striking complement-dependent cytotoxicity with a human complement source and was able to produce lysis of a variety of human cancer cell lines, supporting its observed ability to cause cytotoxic suppression of tumor growth in nude mice. In another series of experiments, i.p. injection of ST-421 completely inhibited growth of human tumor xenografts in nu/nu mice, and this inhibitory activity was closely dependent on expression of the dimeric Le(a) antigen on the cell surface. While Le(a) antigen was expressed in the kidneys of nu/nu mice, infusion of ST-421 in these mice did not cause histological change in kidney tissue. This finding suggests that the MAb does not damage normal cells or tissues which contain cross-reacting Le(a) antigen. These results demonstrate that ST-421 exerts a significant antitumor effect in vitro as well as in vivo, does not affect Le(a) antigen expressed on normal tissues, and therefore has potential application in therapy of certain types of human cancer which express the dimeric Le(a) antigen.
Compensatory signals associated with the activation of human GC 5′ splice sites (2011)

GC 5' splice sites (5'ss) are present in ∼1% of human introns, but factors promoting their efficient selection are poorly understood. Here, we describe a case of X-linked agammaglobulinemia resulting from a GC 5'ss activated by a mutation in BTK intron 3. This GC 5'ss was intrinsically weak, yet it was selected in >90% primary transcripts in the presence of a strong and intact natural GT counterpart. We show that efficient selection of this GC 5'ss required a high density of GAA/CAA-containing splicing enhancers in the exonized segment and was promoted by SR proteins 9G8, Tra2β and SC35. The GC 5'ss was efficiently inhibited by splice-switching oligonucleotides targeting either the GC 5'ss itself or the enhancer. Comprehensive analysis of natural GC-AG introns and previously reported pathogenic GC 5'ss showed that their efficient activation was facilitated by higher densities of splicing enhancers and lower densities of silencers than their GT 5'ss equivalents. Removal of the GC-AG introns was promoted to a minor extent by the splice-site strength of adjacent exons and inhibited by flanking Alu repeats, with the first downstream Alus located on average at a longer distance from the GC 5'ss than other transposable elements. These results provide new insights into the splicing code that governs selection of noncanonical splice sites.