gebhart/patrepeval huggingface dataset:
Human and Murine Phenotypes Associated with Defects in Cation-Chloride Cotransport (2002)

The diuretic-sensitive cotransport of cations with chloride is mediated by the cation-chloride cotransporters, a large gene family encompassing a total of seven Na-Cl, Na-K-2Cl, and K-Cl cotransporters, in addition to two related transporters of unknown function. The cation-chloride cotransporters perform a wide variety of physiological roles and differ dramatically in patterns of tissue expression and cellular localization. The renal-specific Na-Cl cotransporter (NCC) and Na-K-2Cl cotransporter (NKCC2) are involved in Gitelman and Bartter syndrome, respectively, autosomal recessive forms of metabolic alkalosis. The associated phenotypes due to loss-of-function mutations in NCC and NKCC2 are consistent, in part, with their functional roles in the distal convoluted tubule and thick ascending limb, respectively. Other cation-chloride cotransporters are positional candidates for Mendelian human disorders, and the K-Cl cotransporter KCC3, in particular, may be involved in degenerative peripheral neuropathies linked to chromosome 15q14. The characterization of mice with both spontaneous and targeted mutations of several cation-chloride cotransporters has also yielded significant insight into the physiological and pathophysiological roles of several members of the gene family. These studies implicate the Na-K-2Cl cotransporter NKCC1 in hearing, salivation, pain perception, spermatogenesis, and the control of extracellular fluid volume. Targeted deletion of the neuronal-specific K-Cl cotransporter KCC2 generates mice with a profound seizure disorder and confirms the central role of this transporter in modulating neuronal excitability. Finally, the comparison of human and murine phenotypes associated with loss-of-function mutations in cation-chloride cotransporters indicates important differences in physiology of the two species and provides an important opportunity for detailed physiological and morphological analysis of the tissues involved.
New chroman-4-one/thiochroman-4-one derivatives as potential anticancer agents (2017)

The synthesis of 3-[3/4-(2-aryl-2-oxoethoxy)arylidene]chroman/thiochroman-4-one derivatives (<b>1</b>-<b>34</b>) and evaluation of their anticancer activities were aimed in this work. Final compounds were obtained in multistep synthesis reactions using phenol/thiophenol derivatives as starting materials. For anticancer activity evaluation, all compounds were offered to National Cancer Institute (NCI), USA and selected ones were tested against sixty human tumor cell lines derived from nine neoplastic diseases. The activity results were evaluated according to the drug screening protocol of the institute. Compounds containing thiochromanone skeleton exhibited higher anticancer activity.
Expression, Cross-Linking, and Characterization of Recombinant Chitin Binding Resilin (2009)

Resilin is a polymeric rubber-like protein secreted by insects to specialized cuticle regions, in areas where high resilience and low stiffness are required. Resilin binds to the cuticle polysaccharide chitin via a chitin binding domain and is further polymerized through oxidation of the tyrosine residues resulting in the formation of dityrosine bridges and assembly of a high-performance protein--carbohydrate composite material. We describe the mechanical, structural and biochemical function of chitin binding recombinant Drosophila melanogaster resilin. Various resilin constructs were cloned including the full length gene enabling Ni-NTA purification, as well as heat and salt precipitation for rapid and efficient purification. The binding isotherms and constants (K(d), B(max)) of resilin to chitin via its chitin binding domain were determined and displayed high affinity to chitin, implying its important role in the assembly of the resilin-chitin composite. The structural and elastic properties were investigated using Fourier transform infrared spectroscopy, circular dichroism, and atomic force microscopy with peroxidase cross-linked solid resilin materials. Generally, little structural organization was found by these biophysical methods, suggesting structural order was not induced by the dityrosine cross-links. Further, the elastomeric properties found from the full length protein compared favorably with the shorter resilin generated previously from exon 1. The unusual elastomeric behavior of this protein suggests possible utility in biomaterials applications.
An elevation of cytosolic protein phosphorylation modulates trimeric G-protein regulation of secretory vesicle formation from the trans-Golgi network. (1994)

The role of protein phosphorylation in the formation of secretory vesicles from the trans-Golgi network (TGN) and in the regulation of this process by TGN-associated trimeric G-proteins was investigated, using a previously established and a novel cell-free system derived from the neuroendocrine cell line PC12. In the absence of exogenous activators of trimeric G-proteins, okadaic acid, an inhibitor of protein serine/threonine phosphatase types 1, 2A, and PPX, had no significant effect on secretory vesicle formation as reconstituted in a postnuclear supernatant. However, okadaic acid antagonized the inhibition of secretory vesicle formation which occurred upon activation of trimeric G-proteins by either aluminum fluoride or guanosine 5'-3-O-(thio)-triphosphate (GTP gamma S). Microcystin-LR, a protein phosphatase inhibitor structurally distinct from okadaic acid, also antagonized the trimeric G-protein-mediated inhibition of secretory vesicle formation but, in contrast to okadaic acid, alone was sufficient to stimulate this process. The antagonistic effect of the phosphatase inhibitors was abolished by a broad spectrum protein kinase inhibitor, staurosporine, which alone, however, did not affect vesicle formation. The effect of okadaic acid was promoted by activators of protein kinase C (phorbol myristate acetate) and protein kinase A (cyclic AMP). To investigate the subcellular localization of the phosphoprotein that is involved in the antagonistic effect of protein phosphatase inhibitors, a novel cell-free system was established which reconstitutes the formation of secretory vesicles from TGN membranes supplemented with cytosol. Using this cell-free system, the relevant phosphoprotein was found to reside in the cytosol. In conclusion, our results suggest that serine/threonine protein phosphorylation is not required for secretory vesicle formation from the TGN but modulates, via a cytosolic phosphoprotein, the regulation of this process by TGN-associated trimeric G-proteins.
Amino acid substitutions in genetic variants of human serum albumin and in sequences inferred from molecular cloning. (1987)

The structural changes in four genetic variants of human serum albumin were analyzed by tandem high-pressure liquid chromatography (HPLC) of the tryptic peptides, HPLC mapping and isoelectric focusing of the CNBr fragments, and amino acid sequence analysis of the purified peptides. Lysine-372 of normal (common) albumin A was changed to glutamic acid both in albumin Naskapi, a widespread polymorphic variant of North American Indians, and in albumin Mersin found in Eti Turks. The two variants also exhibited anomalous migration in NaDodSO4/PAGE, which is attributed to a conformational change. The identity of albumins Naskapi and Mersin may have originated through descent from a common mid-Asiatic founder of the two migrating ethnic groups, or it may represent identical but independent mutations of the albumin gene. In albumin Adana, from Eti Turks, the substitution site was not identified but was localized to the region from positions 447 through 548. The substitution of aspartic acid-550 by glycine was found in albumin Mexico-2 from four individuals of the Pima tribe. Although only single-point substitutions have been found in these and in certain other genetic variants of human albumin, five differences exist in the amino acid sequences inferred from cDNA sequences by workers in three other laboratories. However, our results on albumin A and on 14 different genetic variants accord with the amino acid sequence of albumin deduced from the genomic sequence. The apparent amino acid substitutions inferred from comparison of individual cDNA sequences probably reflect artifacts in cloning or in cDNA sequence analysis rather than polymorphism of the coding sections of the albumin gene.
Evidence that Pregnancy Specific Glycoproteins Regulate T-Cell Function and Inflammatory Autoimmune Disease During Pregnancy (2005)

The capacity of the pregnancy state to regulate T-cell function is well documented. A consequence of this regulation is that many T-cell mediated autoimmune disorders, including multiple sclerosis (MS) are suppressed during pregnancy. The suppression of MS during pregnancy is more potent than the currently available treatments for this disease. Thus, the study of immunoregulatory factors of pregnancy could potentially result in the discovery of novel MS treatments. The regulation of T-cell function during pregnancy is likely the result of significant hormonal changes and may well involve immunoregulatory proteins derived from the placenta. Pregnancy specific glycoproteins (PSGs) are the most abundant placentally derived glycoproteins in the maternal serum. The levels of PSGs are highest during the third trimester of pregnancy, a time marked by the most profound suppression of MS disease attacks. Recent studies by our laboratories, and others, suggest that PSGs regulate T-cell function. We propose this regulation occurs by two distinct, but complementary mechanisms. PSGs may regulate T-cell function by (1) directly signaling tetraspanins present on the cell surface and by (2) regulating T-cell function indirectly through signaling of tetraspanins expressed by macrophages and dendritic cells. In this report, we will review evidence implicating PSGs as important immunoregulatory proteins and discuss our recent findings regarding the mechanisms by which PSGs regulate T-cell function.
Silicon Photodiodes for Low Penetration Depth Beams such as DUV/VUV/EUV Light and Low-Energy Electrons (2011)

for achieving exceptional photodiode performance that surpasses that of other existing technologies on points such as internal/external quantum efficiency, dark current, uniformity and degradation of responsivity. At the same time the B-layer process is fully compatible with Si front-end technology, and these photodiodes readily lend themselves to detector integration schemes that allow low parasitic resistance and capacitance as well as on-chip integration with other electronic elements. These properties have lead to a fast qualification for production of several types of B-layer photodiode detectors for industrial applications. Three examples of such applications are described in Section 4: -vacuum ultraviolet (VUV) detectors This includes the deep ultraviolet (DUV) wavelength of 193 nm used in advanced lithography systems (Sarubbi et al., 2008a); -extreme ultraviolet (EUV) detectors (Sarubbi et al., 2008b) for detecting light at a wavelength of 13.5 nm. This is essentially soft X-rays that have an attenuation length of 700 nm in Si. This wavelength has been chosen for use in future advanced lithography tools; -low-energy electrons that for energies around 500 eV have ranges in Si below ~ 10 nm (aki et al., 2010b). Particularly the application in Scanning Electron Microscopes (SEMs) is explored here.
67. Protective Immunity Against Yersinia pestis in Mice Immunized with an Ad-Based Vaccine Vector Expressing the Y. pestis F1 and V Antigens (2005)

The aerosol form of the bacterium Yersinia pestis causes the pneumonic plague, an extremely virulent and rapidly fatal disease that develops within days post-infection. In the context of a bioterror threat, an effective anti-plague vaccine must elicit rapid, robust and long acting protective immunity after a single dose. At present, no plague vaccines are available for use in the USA. Two subunits of Y. pestis, fraction 1 (F1) and V antigen have been identified as vaccine candidates based on: (1) F1 antigen is a temperature-regulated capsular protein of Y. pestis with anti-phagocytic activity in the host; (2) V antigen has local anti-inflammatory effects and influences the function of important virulence factors such as the Yersinia outer membrane proteins (Yops). It is known that protective immunity against Y. pestis challenge can be induced by multiple immunizations with recombinant F1 and V proteins and immediate protection can be achieved by passive transfer of immune sera against these antigens. Based on the knowledge that adenovirus (Ad) gene transfer vectors act as adjuvants in eliciting host immunity against the transgene they carry, replication-defective Ad gene transfer vectors encoding either the Y. pestis V antigen or the F1 protein (AdsecV and AdsecF1, respectively) were constructed. The F1 and V antigen genes were synthesized by an overlap PCR strategy using mammalian preferred codons, and fused to the human Ig signal sequence for extracellular secretion. We tested the hypothesis that AdsecV and AdsecF1 can stimulate strong protective immune responses without a requirement for repeat administration. To test the efficacy of the vaccines, BALB/c mice were immunized with a single intramuscular administration of either vector at a dose of 108 to 1011 particles units (pu). Four wk after immunization, mice were challenged in a BSL3 experimental animal facility (n=10/group) by the intranasal route with 3103 cfu of the fully virulent Yersinia pestis strain, CO92. At challenge time, anti-V antigen IgG reciprocal titers from AdsecV–immunized mice (n=10/group) were 666137 (108 pu), 3045735 (109 pu), 97032193 (1010 pu), and 7611215914 (1011 pu). In contrast, anti-F1 antigen IgG reciprocal titers from AdsecF1-immunized mice (n=10/group) were much lower with 122 (108 pu), 9135 (109 pu), 1154138 (1010 pu), and 939157 (1011 pu). All (10/10) of the animals survived the Y. pestis challenge in the group vaccinated with 1011 pu AdsecV, and 40% (4/10) survived in the 1010 pu AdsecV dose, while in all the other experimental groups immunized with AdsecV and in the control groups the mice died within 2 to 5 days after challenge. No mice vaccinated with AdsecF1 survived the Y. pestis challenge. These observations suggest that an Ad-based vaccine encoding for the V antigen of Y. pestis (AdsecV) is an excellent candidate as a effective single dose vaccine against the plague.
Progressive familial intrahepatic cholestasis: diagnosis, management, and treatment (2018)

Progressive familial intrahepatic cholestasis (PFIC) is a group of autosomal recessive cholestatic liver diseases which are subgrouped according to the genetic defect, clinical presentation, laboratory findings and liver histology. Progressive liver fibrosis, cirrhosis, and end stage liver disease (ESLD) may eventually develop. PFIC was first described in Amish descendants of Jacob Byler, therefore it was originally called Byler disease. But it can be seen anywhere on the globe. This review summarizes the main features of the subtypes of the disease and discusses the current available diagnosis, conservative and surgical therapeutic options.
Towards a universal group BStreptococcusvaccine using multistrain genome analysis (2006)

Genomics has revolutionized the way in which novel vaccine candidates are identified for the development of efficacious vaccines. Reverse vaccinology, whereby all candidates of interest are identified by analysis of a pathogen's genome, enables characterization of many candidates simultaneously. It accelerates the initial steps of vaccine development and greatly increases the chances of obtaining reliable candidates or cocktails thereof. The availability of one or two genome sequences for any given pathogen provides access to strain-specific vaccine candidates but often fails to identify candidates that would confer general protection. The analysis of multiple genomes of group B Streptococcus revealed tremendous diversity and identified candidates that are not shared by all the strains sequenced, but provide general protection when combined.
A Wirelessly Controlled Smart Bandage with 3D‐Printed Miniaturized Needle Arrays (2020)

Chronic wounds are one of the most devastating complications of diabetes and are the leading cause of nontraumatic limb amputation. Despite the progress in identifying factors and promising in vitro results for the treatment of chronic wounds, their clinical translation is limited. Given the range of disruptive processes necessary for wound healing, different pharmacological agents are needed at different stages of tissue regeneration. This requires the development of wearable devices that can deliver agents to critical layers of the wound bed in a minimally invasive fashion. Here, for the first time, a programmable platform is engineered that is capable of actively delivering a variety of drugs with independent temporal profiles through miniaturized needles into deeper layers of the wound bed. The delivery of vascular endothelial growth factor (VEGF) through the miniaturized needle arrays demonstrates that, in addition to the selection of suitable therapeutics, the delivery method and their spatial distribution within the wound bed is equally important. Administration of VEGF to chronic dermal wounds of diabetic mice using the programmable platform shows a significant increase in wound closure, re-epithelialization, angiogenesis, and hair growth when compared to standard topical delivery of therapeutics.
A New Generation 18¾-in.—15,000-psi Subsea Wellhead System (1982)

ABSTRACT A new generation 18-3/4" 15,000 p.s.i. subsea wellhead system has been specifically designed for deep-water high-pressure use. It features: (1) a breech-block profiled housing to receive a matching seat when only 3 strings are required or a 16" casing hanger for a fourth string, (2) a new seal assembly with 3 metal-to -metal seals in series plus resilient backup, and (3) a single-trip running tool and method which sets the metal-to-metal and resilient seals at a pressure higher than the well pressure to be encountered. Design criteria were established from "scratch" to focus on actual wellhead requirements unbiased by conventional designs. Breech insert tests, based in many years' previous successful experience with breech-block connectors, involved both scale and full-size prototypes. Major development work on the new metal-to-metal seals involved models, finite-element analysis, and extensive testing.
Harp test structure to electrically determine size distributions of killer defects (1998)

To improve accuracy of electrically based measurements of defect densities and defect size distributions, we present a novel harp test structure (HTS). There, horizontal and vertical parallel lines will be placed inside a given boundary pad frame without using any additional active semiconductor devices. The enhanced two-dimensional (2D) permutation sequence provides that all neighborhood relationships of adjacent test structure lines are unique. This is the key to disentangle even multiple faults detected by fast digital measurements. For this reason, the number and size of individual defects will be extracted anywhere inside or in-between layers. Experimental results show, that not only optical measurements, but also electrical measurements at a harp test structure are sufficient to get a precise defect size distribution that enables size distribution modeling for yield prediction.
INHIBITION OF TUMOR GROWTH AND ANGIOGENESIS BY VITAMIN D3 AGENTS IN MURINE RENAL CELL CARCINOMA (1998)

These results suggest that VD agents may be effective as a treatment for renal cell carcinoma, especially when micrometastases are involved.
Asparagine Hydroxylation of the HIF Transactivation Domain: A Hypoxic Switch (2002)

The hypoxia-inducible factors (HIFs) 1alpha and 2alpha are key mammalian transcription factors that exhibit dramatic increases in both protein stability and intrinsic transcriptional potency during low-oxygen stress. This increased stability is due to the absence of proline hydroxylation, which in normoxia promotes binding of HIF to the von Hippel-Lindau (VHL tumor suppressor) ubiquitin ligase. We now show that hypoxic induction of the COOH-terminal transactivation domain (CAD) of HIF occurs through abrogation of hydroxylation of a conserved asparagine in the CAD. Inhibitors of Fe(II)- and 2-oxoglutarate-dependent dioxygenases prevented hydroxylation of the Asn, thus allowing the CAD to interact with the p300 transcription coactivator. Replacement of the conserved Asn by Ala resulted in constitutive p300 interaction and strong transcriptional activity. Full induction of HIF-1alpha and -2alpha, therefore, relies on the abrogation of both Pro and Asn hydroxylation, which during normoxia occur at the degradation and COOH-terminal transactivation domains, respectively.
Methotrexate resistance in relation to treatment outcome in childhood acute lymphoblastic leukemia (2015)

These findings emphasize the central role of MTX in ALL treatment thereby expanding our understanding of the molecular basis of clinical differences in treatment response between ALL individuals. In particular, the identification of patients that are potentially resistant to MTX at diagnosis may allow for tailoring novel treatment strategies to individual leukemia patients.
Genome Integration and Excision by a New Streptomyces Bacteriophage, ϕJoe (2016)

Bacteriophages are the source of many valuable tools for molecular biology and genetic manipulation. In <i>Streptomyces</i>, most DNA cloning vectors are based on serine integrase site-specific DNA recombination systems derived from phage. Because of their efficiency and simplicity, serine integrases are also used for diverse synthetic biology applications. Here, we present the genome of a new <i>Streptomyces</i> phage, ϕJoe, and investigate the conditions for integration and excision of the ϕJoe genome. ϕJoe belongs to the largest <i>Streptomyces</i> phage cluster (R4-like) and encodes a serine integrase. The <i>attB</i> site from <i>Streptomyces venezuelae</i> was used efficiently by an integrating plasmid, pCMF92, constructed using the ϕJoe <i>int-attP</i> locus. The <i>attB</i> site for ϕJoe integrase was occupied in several <i>Streptomyces</i> genomes, including that of <i>S. coelicolor</i>, by a mobile element that varies in gene content and size between host species. Serine integrases require a phage-encoded recombination directionality factor (RDF) to activate the excision reaction. The ϕJoe RDF was identified, and its function was confirmed <i>in vivo</i> Both the integrase and RDF were active in <i>in vitro</i> recombination assays. The ϕJoe site-specific recombination system is likely to be an important addition to the synthetic biology and genome engineering toolbox.<b>IMPORTANCE</b><i>Streptomyces</i> spp. are prolific producers of secondary metabolites, including many clinically useful antibiotics. Bacteriophage-derived integrases are important tools for genetic engineering, as they enable integration of heterologous DNA into the <i>Streptomyces</i> chromosome with ease and high efficiency. Recently, researchers have been applying phage integrases for a variety of applications in synthetic biology, including rapid assembly of novel combinations of genes, biosensors, and biocomputing. An important requirement for optimal experimental design and predictability when using integrases, however, is the need for multiple enzymes with different specificities for their integration sites. In order to provide a broad platform of integrases, we identified and validated the integrase from a newly isolated <i>Streptomyces</i> phage, ϕJoe. ϕJoe integrase is active <i>in vitro</i> and <i>in vivo</i> The specific recognition site for integration is present in a wide range of different actinobacteria, including <i>Streptomyces venezuelae</i>, an emerging model bacterium in <i>Streptomyces</i> research.