gebhart/patrepeval huggingface dataset:
Brown Adipose Tissue: Function and Physiological Significance (2004)

The function of brown adipose tissue is to transfer energy from food into heat; physiologically, both the heat produced and the resulting decrease in metabolic efficiency can be of significance. Both the acute activity of the tissue, i.e., the heat production, and the recruitment process in the tissue (that results in a higher thermogenic capacity) are under the control of norepinephrine released from sympathetic nerves. In thermoregulatory thermogenesis, brown adipose tissue is essential for classical nonshivering thermogenesis (this phenomenon does not exist in the absence of functional brown adipose tissue), as well as for the cold acclimation-recruited norepinephrine-induced thermogenesis. Heat production from brown adipose tissue is activated whenever the organism is in need of extra heat, e.g., postnatally, during entry into a febrile state, and during arousal from hibernation, and the rate of thermogenesis is centrally controlled via a pathway initiated in the hypothalamus. Feeding as such also results in activation of brown adipose tissue; a series of diets, apparently all characterized by being low in protein, result in a leptin-dependent recruitment of the tissue; this metaboloregulatory thermogenesis is also under hypothalamic control. When the tissue is active, high amounts of lipids and glucose are combusted in the tissue. The development of brown adipose tissue with its characteristic protein, uncoupling protein-1 (UCP1), was probably determinative for the evolutionary success of mammals, as its thermogenesis enhances neonatal survival and allows for active life even in cold surroundings.
Oral Insulin Reloaded (2014)

Optimal coverage of insulin needs is the paramount aim of insulin replacement therapy in patients with diabetes mellitus. To apply insulin without breaking the skin barrier by a needle and/or to allow a more physiological provision of insulin are the main reasons triggering the continuous search for alternative routes of insulin administration. Despite numerous attempts over the past 9 decades to develop an insulin pill, no insulin for oral dosing is commercially available. By way of a structured approach, we aim to provide a systematic update on the most recent developments toward an orally available insulin formulation with a clear focus on data from clinical-experimental and clinical studies. Thirteen companies that claim to be working on oral insulin formulations were identified. However, only 6 of these companies published new clinical trial results within the past 5 years. Interestingly, these clinical data reports make up a mere 4% of the considerably high total number of publications on the development of oral insulin formulations within this time period. While this picture clearly reflects the rising research interest in orally bioavailable insulin formulations, it also highlights the fact that the lion's share of research efforts is still allocated to the preclinical stages.
Chemical composition of lavender essential oil and its antioxidant activity and inhibition against rhinitis-related bacteria (2010)

In this study we assessed the chemical composition, antioxidant and antibacterial activities of Lavender essential oil. The antioxidant and antibacterial capacity of test sample was assayed by a linoleic acid system and conventional method of bacterial growth inhibition. The results demonstrated that the essential oil consisted of 1,5-Dimethyl-1-vinyl-4-hexenyl but yrate as the most abundant component (43.73%), followed by 1,3,7-Octatriene, 3,7-dimethyl- (25.10%), Eucalyptol (7.32%), and Camphor (3.79%). Lavender essential oil display the stronger antioxidant activity against lipid peroxidation in a linoleic acid model system and good antibacterial activity against four rhinitis-related bacteria including staphylococcus aureus,Micrococcus ascoformans, Proteus vulgaris and Escherichia coli.

	 

	Key words: Antibacterial, Lavender; antioxidant, essential oil, extraction, rhinitis.
Mapping applications to the RaPiD configurable architecture (2002)

The goal of the RaPiD (Reconfigurable Pipelined Datapath) architecture is to provide high performance configurable computing for a range of computationally-intensive applications that demand special-purpose hardware. This is accomplished by mapping the computation into a deep pipeline using a configurable array of coarse-grained computational units. A key feature of RaPiD is the combination of static and dynamic control. While the underlying computational pipelines are configured statically, a limited amount of dynamic control is provided which greatly increases the range and capability of applications that can be mapped to RaPiD. This paper illustrates this mapping and configuration for several important applications including a FIR filter, 2-D DCT, motion estimation, and parametric curve generation; it also shows how static and dynamic control are used to perform complex computations.
Stabilization and humanization of a single-chain Fv antibody fragment specific for human lymphocyte antigen CD19 by designed point mutations and CDR-grafting onto a human framework (2009)

A single-chain Fv (scFv) fragment derived from the murine antibody 4G7, specific for human lymphocyte CD19, was engineered for stability and expression in Escherichia coli in view of future use as a therapeutic protein. We compared two orthogonal knowledge-based procedures. In one approach, we designed a mutant with 14 single amino-acid substitutions predicted to correct destabilizing residues in the 4G7-wt sequence to create 4G7-mut. In the second variant, the murine CDRs were grafted to the human acceptor framework huVkappa3-huV(H)3, with 11 additional point mutations introduced to obtain a better match between CDR graft and acceptor framework, to arrive at 4G7-graft. Compared to 4G7-wt, 4G7-mut showed greater thermodynamic stability in guanidinium chloride-induced equilibrium denaturation experiments and somewhat greater stability in human serum. The loop graft maintained the comparatively high stability of the murine loop donor, but did not improve it further. Our analysis indicates that this is due to subtle strain introduced between CDRs and framework, mitigating the otherwise highly favorable properties of the human acceptor framework. This slight strain in the loop graft is also reflected in the binding affinities for CD19 on leukemic cells of 8.4 nM for 4G7-wt, 16.4 nM for 4G7-mut and 30.0 nM for 4G7-graft. This comparison of knowledge-based mutation and loop-grafting-based approaches will be important, when moving molecules forward to therapeutic applications.
Staphylococcus aureus Infections: Epidemiology, Pathophysiology, Clinical Manifestations, and Management (2015)

Staphylococcus aureus is a major human pathogen that causes a wide range of clinical infections. It is a leading cause of bacteremia and infective endocarditis as well as osteoarticular, skin and soft tissue, pleuropulmonary, and device-related infections. This review comprehensively covers the epidemiology, pathophysiology, clinical manifestations, and management of each of these clinical entities. The past 2 decades have witnessed two clear shifts in the epidemiology of S. aureus infections: first, a growing number of health care-associated infections, particularly seen in infective endocarditis and prosthetic device infections, and second, an epidemic of community-associated skin and soft tissue infections driven by strains with certain virulence factors and resistance to β-lactam antibiotics. In reviewing the literature to support management strategies for these clinical manifestations, we also highlight the paucity of high-quality evidence for many key clinical questions.
Molecular basis for CD40 signaling mediated by TRAF3 (2000)

Tumor necrosis factor receptors (TNFR) are single transmembrane-spanning glycoproteins that bind cytokines and trigger multiple signal transduction pathways. Many of these TNFRs rely on interactions with TRAF proteins that bind to the intracellular domain of the receptors. CD40 is a member of the TNFR family that binds to several different TRAF proteins. We have determined the crystal structure of a 20-residue fragment from the cytoplasmic domain of CD40 in complex with the TRAF domain of TRAF3. The CD40 fragment binds as a hairpin loop across the surface of the TRAF domain. Residues shown by mutagenesis and deletion analysis to be critical for TRAF3 binding are involved either in direct contact with TRAF3 or in intramolecular interactions that stabilize the hairpin. Comparison of the interactions of CD40 with TRAF3 vs. TRAF2 suggests that CD40 may assume different conformations when bound to different TRAF family members. This molecular adaptation may influence binding affinity and specific cellular triggers.
HAI‐2 is epigenetically downregulated in human hepatocellular carcinoma, and its Kunitz domain type 1 is critical for anti‐invasive functions (2008)

Pharmacological demethylation-based gene expression profile analysis is a useful tool to identify epigenetically silenced tumour suppressor genes. HGF activator inhibitor 2 (HAI-2), a serine protease inhibitor, has been identified as one of the candidate tumour suppressor genes in human hepatocellular carcinoma (HCC) with this technique. In this study, we aimed to characterise the epigenetic status and tumour suppressive function of HAI-2 in HCC. We validated that HAI-2 expression was either absent or low in most of the HCC cell lines tested, and 5-Aza-2'-deoxycytidine treatment significantly restored its expression in 9 (75%) of these 12 cell lines. HAI-2 was found to be frequently underexpressed in human HCCs (p < 0.001). With bisulphite DNA sequencing and methylation-specific PCR, we found that the promoter of the HAI-2 gene was frequently hypermethylated in both HCC cell lines and human HCCs. Ectopic expression of HAI-2 significantly inhibited cell migration and invasiveness of HCC cells in vitro and suppressed tumourigenicity in vivo. In addition, we also provided the first evidence that HAI-2 mediated its tumour suppressor function via the Kunitz domain 1 (KD-1), as KD-1 but not KD-2 inactivating mutant abolished its anti-tumour invasiveness in vitro. Our findings suggest that HAI-2 is a candidate tumour suppressor gene that is frequently hypermethylated and underexpressed in human HCCs, and the KD-1 domain of HAI-2 is the key region responsible for its anti-invasive function.
New Naturally Occurring Amino Acids (1983)

Abstract The majority of the 500 or so naturally occurring amino acids known today were discovered during the last 30 years, for example during the search for new antibiotics in the culture media of microorganisms, or as components of the antibiotics in fungi, seeds, in numerous plants and fruits, and in the body fluids of animals. Some 240 of these amino acids occur free in nature, some only as intermediates in metabolism. This article provides an overview of the developments that have taken place in this area since 1956 when the last review appeared. Summary accounts are presented, dealing with new unsaturated amino acids, cyclopropane‐ and cyclobutane‐amino acids, heterocyclic amino acids, halogen‐containing amino acids sulfur‐, selenium‐ and phosphorus‐containing amino acids as well as aliphatic amino acids. In a few cases, e. g. betalamic acid and muscaflavin, the biosynthesis is described in detail.
Pet-1, a novel ETS domain factor that can activate neuronal nAchR gene transcription (1998)

We report a cDNA clone prepared from adrenal chromaffin-derived PC12 cell RNA that encodes a novel ETS-domain factor, Pet-1. The deduced primary structure of Pet-1 is composed of 340 amino acids and the encoded polypeptide has a predicted molecular mass of 35.4 kD. The pattern of Pet-1 gene expression in the neonatal rat is highly restricted and suggests that Pet-1 functions primarily in the nervous system. Adrenal gland expresses the highest level of Pet-1 among the tissues examined. In situ hybridization indicates that Pet-1 is expressed in the adrenal medulla but not the adrenal cortex. Slightly weaker Pet-1 hybridization is detected in brain and low levels are detectable in intestine and eye. Pet-1 can bind specifically to a PEA3 ETS DNA-binding motif and can modulate transcription of synthetic promoter constructs in a sequence-specific manner. We recently identified a neural cell-type specific enhancer, beta43', within the 3'-untranslated exon of the neuronal nicotinic acetylcholine receptor (nAchR) beta4 subunit gene. Similar to Pet-1, the beta4 gene is also expressed in PC12 cells. The presence of putative ETS-domain binding sites in the beta43' enhancer led us to hypothesize that members of the ets gene family activate neuronal nAchR genes. Cotransfection assays show that Pet-1 can activate reporter gene transcription in a beta43' enhancer-dependent and cell type-dependent manner. Our results lead us to hypothesize that Pet-1 acts as a transcriptional regulator of downstream target genes involved in cholinergic neurotransmission.
Pre-Existent Adenovirus Antibody Inhibits Systemic Toxicity and Antitumor Activity of CN706 in the Nude Mouse LNCaP Xenograft Model: Implications and Proposals for Human Therapy (2000)

Pre-existent humoral antibody to adenovirus potentially confounds human clinical trials involving intravascular administration of adenovirus. Using the LNCaP prostate cancer xenograft model in BALB/c nu/nu mice and the prostate-specific attenuated replication-competent adenovirus (ARCATM) CN706, we developed an animal model that systematically controls both the dose of intravascularly administered adenovirus and the titer of the pre-existent anti-Ad5 antibody, and then measures the virus-induced toxicity as well as antitumor activity. We prepared hyperimmune sera to adenovirus in rabbits, passively injected the purified rabbit anti-Ad5 antibody into tumor-bearing mice, and established measurable humoral anti-Ad5 antibody titers. CN706 was intravenously injected into the tail vein of animals 24 hr after passive anti-Ad5 antibody administration. In the absence of pre-existent antibody, the lethal dose (LD100) for BALB/c nu/nu mice was 2.5x10(11) CN706 particles, whereas 1x10(11) CN706 particles was not lethal. However, in the presence of a 1:80 pre-existent titer of Ad5 neutralizing antibody (NAb), intravenous injection of 5x10(11) CN706 particles was no longer lethal. In addition, pre-existent antibody also prevented antitumor activity in a dose-dependent manner: 1x 10(11) CN706 particles prevented LNCaP xenograft tumor progression, but antitumor activity was eliminated by a pre-existent 1:80 NAb titer. These results led us to propose transient removal of pre-existent adenovirus antibody by immunoapheresis. An affinity column of cloned virus capsid proteins was constructed that was able to specifically remove adenovirus antibody from human clinical serum samples. A 5-min disposable immunoassay was also developed to monitor the level of pre-existent antibody in sera before and after immunoapheresis. Clinically, this approach may enable controlled clinical studies of intravenously administered adenovirus in patients with pre-existent anti-adenovirus antibody.
SUMOylation of Tissue Transglutaminase as Link between Oxidative Stress and Inflammation (2009)

Cystic fibrosis (CF) is a monogenic disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. CF is characterized by chronic bacterial lung infections and inflammation, and we have previously reported that tissue transglutaminase (TG2), a multifunctional enzyme critical to several diseases, is constitutively up-regulated in CF airways and drives chronic inflammation. Here, we demonstrate that the generation of an oxidative stress induced by CFTR-defective function leads to protein inhibitor of activated STAT (PIAS)y-mediated TG2 SUMOylation and inhibits TG2 ubiquitination and proteasome degradation, leading to sustained TG2 activation. This prevents peroxisome proliferator-activated receptor (PPAR)gamma and IkBalpha SUMOylation, leading to NF-kappaB activation and to an uncontrolled inflammatory response. Cellular homeostasis can be restored by small ubiquitin-like modifier (SUMO)-1 or PIASy gene silencing, which induce TG2 ubiquitination and proteasome degradation, restore PPARgamma SUMOylation, and prevent IkBalpha cross-linking and degradation, thus switching off inflammation. Manganese superoxide dismutase overexpression as well as the treatment with the synthetic superoxide dismutase mimetic EUK-134 control PIASy-TG2 interaction and TG2 SUMOylation. TG2 inhibition switches off inflammation in vitro as well as in vivo in a homozygous F508del-CFTR mouse model. Thus, TG2 may function as a link between oxidative stress and inflammation by driving the decision as to whether a protein should undergo SUMO-mediated regulation or degradation. Targeting TG2-SUMO interactions might represent a new option to control disease evolution in CF patients as well as in other chronic inflammatory diseases, neurodegenerative pathologies, and cancer.
Chemical and serological studies with an iodine-containing synthetic immunological determinant 4-hydroxy-3-iodo-5-nitrophenylacetic acid (NIP) and related compounds. (1966)

The synthesis and properties of 4-hydroxy-3-iodo-5-nitrophenylacetic acid (NIP) and several related compounds are described. Conjugates of NIP with proteins are prepared from the azide, synthesized from commercial 4-hydroxy-phenylacetic acid. Sera from rabbits and mice immunized with NIP—ovalbumin or NIP—chicken serum globulin bind N(131)IP-containing compounds, as judged from precipitation of radioactivity by salting-out of immunoglobulins. Homogeneous binding is obtained with N(131)IP—polylysine, N(131)IP—ε-amino-n-caproic acid (N(131)IP—aminocap), and other structurally related haptens; non-homogeneous binding is obtained with N(131)IP—bovine serum albumin. Binding to salt-precipitated immunoglobulin of N(131)IP—aminocap, the hapten of choice for this purpose, provides an assay for antibody measurable at concentrations down to at least M(-9) serum binding capacity (∼0.1 μg antibody/ml). Structurally related compounds and NIP—protein conjugates competitively inhibit binding of N(131)IP—aminocap. The inhibitions indicate that the iodine contained in NIP, but not the carrier protein, contributes significantly to the binding site.
Human plasma R-type vitamin B12-binding proteins. II. The role of transcobalamin I, transcobalamin III, and the normal granulocyte vitamin B12-binding protein in the plasma transport of vitamin B12. (1975)

The normal human granulocyte vitamin B12-binding protein, transcobalamin I, and transcobalamin III, have been labeled with 125I-labeled N-succinimidyl 3-(4-hydroxyphenyl)propionate and utilized for plasma clearance studies performed with rabbits. Both moieties of 125I-labeled granulocyte vitamin B12-binding protein-[57Co]vitamin B12 were cleared rapidly from the plasma (is less than 90% by 5 min) by the liver. After 30 min, the bulk of the 125I reappeared in the plasma in small molecular weight (less than 1000) form and was rapidly excreted in the urine. After 60 min the bulk of the [57Co]vitamin B12 reappeared in the plasma bound to rabbit transcobalamin II and was subsequently taken up by a variety of tissues. Approximately 15% of the 125I-labeled granulocyte vitamin B12-binding protein-[57Co-a1vitamin B12 was excreted intact into the bile during the period from 10 to 80 min after injection. The hepatic uptake of the protein-vitamin B12 complex was blocked by the prior injection of desialyzed fetuin but not by native fetuin. Similar results were obtained with 125I-labeled transcobalamin III-[57Co]vitamin B12. Approximately 90% of both moieties of 125I-labeled transcobalamin I-[57Co]vitamin B12 had prolonged plasma survivals similar to that of 125I-labeled bovine serum albumin. After treatment with neuraminadase, both moieties of the 125I-labeled transcobalamin I-[57Co]vitamin B12 complex were cleared rapidly from the plasma by the liver in a manner that was indistinguishable from that observed in the case of untreated granulocyte vitamin B12-binding protein and transcobalamin III. These observations indicate that desialyzed transcobalamin I and the native forms of the granulocyte vitamin B12-binding protein and transcobalamin III are cleared from plasma by the mechanism elucidated by Ashwell and Morell (Ashwell, G., and Morell A. G. (1974) Adv. Enzymol. 41, 99-128) that is capable of clearing a wide variety of asialoglycoproteins. These observations have implications concerning the function of the human R-type vitamin B12-binding proteins, the nature of the enterohepatic circulation of vitamin B12, the biological significance of the mechanism described by Ashwell and Morell, and the etiology of the increased plasma concentration of human R-type protein that occurs frequently in chronic myelogenous leukemia and occasionally in hepatocellular carcinoma and other solid tumors.
Phage display of intact domains at high copy number: A system based on SOC, the small outer capsid protein of bacteriophage T4 (1996)

Peptides fused to the coat proteins of filamentous phages have found widespread applications in antigen display, the construction of antibody libraries, and biopanning. However, such systems are limited in terms of the size and number of the peptides that may be incorporated without compromising the fusion proteins' capacity to self-assemble. We describe here a system in which the molecules to be displayed are bound to pre-assembled polymers. The polymers are T4 capsids and polyheads (tubular capsid variants) and the display molecules are derivatives of the dispensable capsid protein SOC. In one implementation, SOC and its fusion derivatives are expressed at high levels in Escherichia coli, purified in high yield, and then bound in vitro to separately isolated polyheads. In the other, a positive selection vector forces integration of the modified soc gene into a soc-deleted T4 genome, leading to in vivo binding of the display protein to progeny virions. The system is demonstrated as applied to C-terminal fusions to SOC of (1) a tetrapeptide; (2) the 43-residue V3 loop domain of gp120, the human immunodeficiency virus type-1 (HIV-1) envelope glycoprotein; and (3) poliovirus VP1 capsid protein (312 residues). SOC-V3 displaying phage were highly antigenic in mice and produced antibodies reactive with native gp120. That the fusion protein binds correctly to the surface lattice was attested in averaged electron micrographs of polyheads. The SOC display system is capable of presenting up to approximately 10(3) copies per capsid and > 10(4) copies per polyhead of V3-sized domains. Phage displaying SOC-VP1 were isolated from a 1:10(6) mixture by two cycles of a simple biopanning procedure, indicating that proteins of at least 35 kDa may be accommodated.
Hierarchical Assembly of Model Cell Surfaces:  Synthesis of Mucin Mimetic Polymers and Their Display on Supported Bilayers (2007)

Molecular level analysis of cell-surface phenomena could benefit from model systems comprising structurally defined components. Here we present the first step toward bottom-up assembly of model cell surfaces-the synthesis of mucin mimetics and their incorporation into artificial membranes. Natural mucins are densely glycosylated O-linked glycoproteins that serve numerous functions on cell surfaces. Their large size and extensive glycosylation makes the synthesis of these biopolymers impractical. We designed synthetically tractable glycosylated polymers that possess rodlike extended conformations similar to natural mucins. The glycosylated polymers were end-functionalized with lipid groups and embedded into supported lipid bilayers where they interact with protein receptors in a structure-dependent manner. Furthermore, their dynamic behavior in synthetic membranes mirrored that of natural biomolecules. This system provides a unique framework with which to study the behavior of mucin-like macromolecules in a controlled, cell surface-mimetic environment.