gebhart/patrepeval huggingface dataset:
DNA immunization inrelB-deficient mice discloses a role for dendritic cells in IgM  →   IgG1 switchin vivo (1998)

A single intraspleen inoculation of plasmid DNA coding for an immunoglobulin heavy chain gene initiates immunity and establishes immunologic memory against the antigenic determinants of transgenic immunoglobulins, somatic transgene immunization. During priming mice produce IgM but not IgG1 antibodies. Since IgM --> IgG1 class switch occurs spontaneously during the primary immune response to protein antigens we investigated possible mechanisms for failure of spontaneous isotype switch in vivo in this model of immunity. We found that inoculation of plasmid DNA in the form of a chimeric gene coding for granulocyte-macrophage colony-stimulating factor (GM-CSF) was able to drive IgG1 class switch readily after priming. Since GM-CSF activates cells of the dendritic lineage we tested the possibility that dendritic cells (DC) may be involved in regulating IgM --> IgG1 switch. To this end we used bone marrow chimeras constructed from mice carrying the null mutation for the relB member of the NF-kappaB/Rel family as these mice lack bone marrow-derived mature DC. RelB (-/-) mice and (-/-) bone marrow chimeras inoculated with DNA/GM-CSF did not produce IgG1 antibodies during the primary immune response. Since relB (-/-) bone marrow chimeras lack DC of donor origin but possess resident follicular dendritic cells we conclude that Ig class switch in vivo is regulated by the function of interdigitating dendritic cells (IDC). Thus, IDC may contribute to the qualitative aspects of the emerging immune response.
Transgenesis by means of blastocyst-derived embryonic stem cell lines. (1986)

This study demonstrates that blastocyst-derived embryonic stem cells (ES cells) can be used as a vehicle for transgenesis. The method is nearly as efficient as other methods, and the introduced neomycin phosphotransferase (neo) gene is stably transmitted through several generations with no apparent loss in G418 resistance. An important factor contributing to the efficiency of this process is the rigorous selection, before blastocyst injection, of genetically transformed cells for in vitro developmental pluripotency. One of the advantages of the ES cell route to transgenesis is that it provides investigators with the opportunity to screen for the desired genetic alterations before reintroducing the ES cells into the animal.
Electrostatic Self-Assembly of PEG Copolymers onto Porous Silica Nanoparticles (2008)

A critical requirement toward the clinical use of nanocarriers in drug delivery applications is the development of optimal biointerfacial engineering procedures designed to resist biologically nonspecific adsorption events. Minimization of opsonization increases blood residence time and improves the ability to target solid tumors. We report the electrostatic self-assembly of polyethyleneimine-polyethylene glycol (PEI-PEG) copolymers onto porous silica nanoparticles. PEI-PEG copolymers were synthesized and their adsorption by self-assembly onto silica surfaces were investigated to achieve a better understanding of structure-activity relationships. Quartz-crystal microbalance (QCM) study confirmed the rapid and stable adsorption of the copolymers onto silica-coated QCM sensors driven by strong electrostatic interactions. XPS and FT-IR spectroscopy were used to analyze the coated surfaces, which indicated the presence of dense PEG layers on the silica nanoparticles. Dynamic light scattering was used to optimize the coating procedure. Monodisperse dispersions of the PEGylated nanoparticles were obtained in high yields and the thin PEG layers provided excellent colloidal stability. In vitro protein adsorption tests using 5% serum demonstrated the ability of the self-assembled copolymer layers to resist biologically nonspecific fouling and to prevent aggregation of the nanoparticles in physiological environments. These results demonstrate that the electrostatic self-assembly of PEG copolymers onto silica nanoparticles used as drug nanocarriers is a robust and efficient procedure, providing excellent control of their biointerfacial properties.
The effect of condensed tannins inLotus pedunculatuson the digestion and metabolism of methionine, cystine and inorganic sulphur in sheep (1993)

Two experiments were conducted with sheep fed on fresh Lotus pedunculatus containing 50-55 g condensed tannin (CT)/kg dry matter. Effects of CT were assessed by comparing control sheep (CT operating) with sheep receiving a continuous intraruminal infusion of polyethylene glycol (PEG) to bind and inactivate CT. Digestion of methionine and cystine was determined using a continuous intraruminal infusion of indigestible markers, whilst plasma irreversible loss (IRL) of methionine, cystine and inorganic sulphate was determined using 35S labelling. The proportion of microbial non-NH3-N (NAN) in whole rumen digesta NAN and the IRL of reducible S from the rumen were determined using a continuous intraruminal infusion of (NH4)2(35)SO4. The proportion of microbial NAN in whole rumen digesta NAN (0.44 v. 0.71) and the IRL of reducible S from the rumen (0.84 v. 2.49 g S/d) were lower in control than PEG sheep. PEG sheep lost 30% of ingested methionine and cystine across the rumen, whereas the control sheep lost no methionine and cystine across the rumen. Apparent absorption of methionine from the small intestine was 27% higher in control than PEG sheep, but both groups had a similar apparent absorption of cystine. The apparent digestibility of cystine in the small intestine was lower in control (0.42) than PEG (0.53) sheep, whereas the apparent digestibility of methionine was similar (0.78) for both groups. CT had no effect on plasma methionine IRL, but markedly increased the IRL of cystine (39.8 v. 22.4 mumol/min) and reduced the IRL of plasma inorganic sulphate (35.9 v. 50.2 mumol/min). A three-pool model comparing interconversions between the three plasma metabolites showed that CT increased the flow of cystine to body synthetic reactions (36.5 v. 17.3 mumol/min). This was due to trans-sulphuration of methionine to cystine being greater in control than in PEG sheep, whilst the oxidation of both methionine and cystine were reduced in control sheep. It was concluded that CT reduced the proteolysis of forage protein and the degradation of S amino acids to inorganic sulphide in the rumen, resulting in increased net absorption of methionine and increased utilization of cystine for body synthetic reactions in sheep with a high capacity for wool growth (and, hence, high cystine requirement).
Immunoglobulin transgenes as targets for somatic hypermutation (1998)

This review describes studies on somatic hypermutation of immunoglobulin genes that were started in the mid-80s in collaboration with Ralph Brinster. Almost all of the experiments were carried out using Ig transgenes as targets for the somatic mutation mechanism. Ig transgenes can be very good targets of somatic mutation, despite many different transgene integration sites. Thus, the required cis-acting elements must be present within the approximately 10 kb of the transgene. Only the Ig variable region and its proximate flanks are mutated, not the constant region in unmanipulated sequences. Several Ig gene enhancers are permissive for somatic mutation and they do not have to be associated with the Ig promoter they normally interact with. However, the mutation process does seem to be specific for Ig genes. No mutations were found in several housekeeping genes isolated from cells that had very high levels of somatic hypermutation of their Ig genes. This suggests that the Ig enhancers provide the lg gene specificity. An exception is the Bcl-6 gene, encoding a transcription factor, which was found to be mutated in normal human memory B cells. When the transcriptional promoter that is located upstream of the variable region is duplicated upstream of the constant region, this region is mutated as well. This suggests a transcription coupled model in which a mutator factor associates with the RNA polymerase at the initiation of transcription, travels with the polymerase during elongation, and causes mutations during polymerase pausing. Our recent data with an artificial substrate for somatic mutation suggest that the mutations are increased by increased stability of the secondary structures in the nascent RNA, and the specific nucleotides that are mutated are due to preferences of a mutator factor.
Genetics and Cytogenetics of Multiple Myeloma (2004)

Much has been learned regarding the biology and clinical implications of genetic abnormalities in multiple myeloma. Because of recent advances in the field, an International Workshop was held in Paris in february of 2003. This summary describes the consensus recommendations arising from that meeting with special emphasis on novel genetic observations. For instance, it is increasingly clear that translocations involving the immunoglobin heavy-chain locus are important for the pathogenesis of one-half of patients. As a corollary, it also clear that the remaining patients, lacking IgH translocations, have hyperdiploidy as the hallmark of their disease. Several important genetic markers are associated with a shortened survival such as chromosome 13 monosomy, hypodiploidy, and others. The events leading the transformation of the monoclonal gammopathy of undetermined significance (MGUS) to myeloma are still unclear. One of the few differential genetic lesions between myeloma and MGUS is the presence of ras mutations in the latter. Gene expression platforms are capable of detecting many of the genetic aberrations found in the clonal cells of myeloma. Areas in need of further study were identified. The study of the genetic aberrations will likely form the platform for targeted therapy for the disease.
Oral Phosphate Supplementation Corrects Hypophosphatemia and Normalizes Plasma FGF23 and 25-Hydroxyvitamin D3 Levels in Women with Chronic Metabolic Acidosis (2009)

The CMA-induced hypophosphatemia was likely to initiate a negative feedback response, thereby leading to reduction in the plasma levels of hyperphosphaturic hormones, FGF23 and PTH. An increase in the plasma 1,25(OH) (2)D (3) level, despite diminishing 25(OH)D (3) storage pool, may help enhance the intestinal phosphate absorption. Oral phosphate supplementation abolished the effects of CMA on FGF23 and 25(OH)D (3) levels, suggesting that the plasma phosphate concentration is the primary regulator of the plasma levels of these hormones during CMA.
Cytochrome P450 CYP2D6. (1999)

Altered expression of CYP2D6 (debrisoquine hydroxylase), resulting from genetic polymorphism at the CYP2D6 gene locus, is responsible for pronounced interindividual variation in the metabolism of many clinically important drugs. Although CYP2D6 substrates are structurally diverse, most are small molecules that interact with the protein via an electrostatic interaction between a basic nitrogen which is common to the majority of CYP2D6 substrates and an aspartic acid residue in the active site of the protein. As CYP2D6 substrates have a wide range of pharmacological functions, any variation in CYP2D6 expression can have profound clinical consequences. CYP2D6 activity can be determined both by phenotyping methods with a variety of probe drugs and by genotyping methods where PCR-based techniques are used to investigate the inheritance of individual CYP2D6 alleles. Allele frequencies have been shown to vary widely between populations of different racial origin. For example, the PM genotype is particularly rare in Orientals. The inheritance of certain CYP2D6 allelic variants has been associated with altered susceptibility to Parkinson's disease and several types of cancer.
Learnings from a qualitative study into counselling supervision: Listening to supervisor and supervisee (2004)

This paper draws on the authors' recent experience of piloting qualitative research into helpful and hindering events in supervision using interpersonal process recall with three supervisor‐supervisee dyads. This paper presents in some detail the findings from one dyad. The authors draw on their experience of the research to raise questions relating to ethics and methodology and the implications for practice are considered.
Toxicity associated with boronophenylalanine and cranial neutron irradiation (1995)

Abstract Boron neutron capture therapy (BNCT) involves administration of a tumor selective boron compound followed by neutron irradiation directed at the target organ. Several studies have shown antitumor activity in animal models with BNCT using the amino acid analog boronophenylalanine (BPA). This study investigates the pharmacological toxicity of BPA in rabbits and the acute (14 days) and subacute (100 days) radiotoxicity of cranial BNCT with BPA in normal mice. To assess the toxicity of BPA alone the drug was administered orally in either a single dose of 5,000 mg/kg or 5 divided doses of 1,000 mg/kg/day to rabbits which were subsequently sacrificed at 2.5 or 4.5 weeks. To study the radiotoxic effects of BNCT mice were given BPA orally followed by cranial irradiation with a thermal neutron beam 3 hr later, with resulting brain doses ranging from 1,100 to 2,750 cGy‐Eq [compound‐relative biological effectiveness (C‐RBE) of 1.3 for 10 B, 3.2 for neutrons, and 1.0 for gammas]. Mice were sacrificed 14 or 100 days after irradiation to study acute and subacute radiation toxicity, respectively. BPA alone demonstrated no discernible toxicity at the doses and schedules administered. BNCT resulted in a dose‐independent acute dilatation of the cerebral ventricles and mild cerebral atrophy. No neurologic deterioration could be detected in animals exposed to 2,200 cGy‐Eq or lower but acute clinical morbidity was evident at 2,750 cGy‐Eq, possibly related to non‐neural toxicity. Mice exposed to a dose of 2,750 cGy‐Eq to the brain also presented with moderately severe gastrointestinal toxicity consisting of epithelial hyperplasia or atrophy and necrosis. Animals exposed to lower doses showed no significant gastrointestinal radiotoxicity. All animals sacrificed at 100 days that received 2,200 cGy‐Eq developed bilateral posterior subcapsular cataracts. Lower doses had a minimal ocular toxic effect. It is concluded that there was no discernible toxicity from BPA administration at daily doses 10 times higher than those required for proposed therapeutic applications. Single‐fraction BNCT irradiations to the head showed significant ocular toxicity with a threshold between 1,650 and 2,200 cGy‐Eq; gastrointestinal toxicity with a threshold between 2,200 and 2,750 cGy‐Eq; and neural toxicity with a threshold ≦l,100 cGy‐Eq for histopathologic lesions. © 1995 Wiley‐Liss, Inc.
Substituted 3-phenyltropane analogs of cocaine: synthesis, inhibition of binding at cocaine recognition sites, and positron emission tomography imaging (1993)

It is now accepted that (-)-cocaine binds to specific recognition sites associated with monoamine transporters in the mammalian brain. In this study, several analogs of 3 beta-phenyltropane-2 beta-carboxylic acid methyl ester were prepared and their potency for inhibiting the binding of [3H]-3 beta-(4-fluorophenyl)tropane-2 beta-carboxylic acid methyl ester to primate caudate-putamen was evaluated. The synthesis and binding affinity of 3 beta-(3,4- dichlorophenyl)tropane-2 beta-carboxylic acid methyl ester, one of the most potent cocaine congeners yet reported, is presented. The feasibility of synthesizing high-affinity ligands for cocaine recognition sites and their suitability as PET imaging ligands for cocaine receptors in vivo is demonstrated.
Dephosphorylation of phosphopeptides by calcineurin (protein phosphatase 2B) (1994)

38 (6-32 residues) enzymically phosphorylated synthetic peptides have been assayed as substrates for calcineurin, a Ca2+/calmodulin-dependent protein phosphatase (PP-2B) belonging to the family of Ser/Thr-specific enzymes but also active on phosphotyrosine residues. Many peptides reproduce, with suitable modifications, naturally occurring phosphoacceptor sites. While protein phosphatases 2A and 2C are also very active on short phosphopeptides, an extended N-terminal stretch appears to be a necessary, albeit not sufficient, condition for an optimal dephosphorylation, comparable to that of protein substrates, of both phosphoseryl and phosphotyrosyl peptides by calcineurin. This finding corroborates the view that higher-order structure is an important determinant for the substrate specificity of calcineurin. However, a number of shorter peptides are also appreciably dephosphorylated by this enzyme, their efficiency as substrates depending on local structural features. All the peptides that are appreciably dephosphorylated by calcineurin contain basic residue(s) on the N-terminal side. A basic residue located at position -3 relative to the phosphorylated residue plays a particularly relevant positive role in determining the dephosphorylation of short phosphopeptides. Acidic residue(s) adjacent to the C-terminal side of the phosphoamino acid are conversely powerful negative determinants, preventing the dephosphorylation of otherwise suitable peptide substrates. However, calcineurin displays an only moderate preference for phosphothreonyl peptides which are conversely strikingly preferred over their phosphoseryl counterparts by the other classes of Ser/Thr-specific protein phosphatases. Moreover calcineurin does not perceive as a strong negative determinant the motif Ser/Thr-Pro in peptides where this motif prevents dephosphorylation by the other classes of Ser/Thr protein phosphatases. Whenever tested on phosphotyrosyl peptides, calcineurin exhibits a specificity which is strikingly different from that of T-cell protein tyrosine phosphatase, a bona fide protein tyrosine phosphatase. In particular while the latter enzyme is especially active toward a number of phosphopeptides reproducing the phosphoacceptor sites of src products and of calmodulin whose N-terminal moieties are predominantly acidic, the artificial substrate phospho-angiotensin II, bearing an arginine residue at position -2, is far preferred by calcineurin over all phosphotyrosyl peptides of similar size. Collectively taken these results show that the specificity of calcineurin, rather than resting on a given consensus sequence, is determined by a variety of primary and higher-order structural features conferring to it an overall selectivity that is different from those of any other known protein phosphatase.
Rod Photoreceptor Function Predicts Blood Vessel Abnormality in Retinopathy of Prematurity (2007)

The rods may instigate the vascular abnormalities that are the clinical hallmark of ROP.
Impact of diet in shaping gut microbiota revealed by a comparative study in children from Europe and rural Africa (2010)

Gut microbial composition depends on different dietary habits just as health depends on microbial metabolism, but the association of microbiota with different diets in human populations has not yet been shown. In this work, we compared the fecal microbiota of European children (EU) and that of children from a rural African village of Burkina Faso (BF), where the diet, high in fiber content, is similar to that of early human settlements at the time of the birth of agriculture. By using high-throughput 16S rDNA sequencing and biochemical analyses, we found significant differences in gut microbiota between the two groups. BF children showed a significant enrichment in Bacteroidetes and depletion in Firmicutes (P < 0.001), with a unique abundance of bacteria from the genus Prevotella and Xylanibacter, known to contain a set of bacterial genes for cellulose and xylan hydrolysis, completely lacking in the EU children. In addition, we found significantly more short-chain fatty acids (P < 0.001) in BF than in EU children. Also, Enterobacteriaceae (Shigella and Escherichia) were significantly underrepresented in BF than in EU children (P < 0.05). We hypothesize that gut microbiota coevolved with the polysaccharide-rich diet of BF individuals, allowing them to maximize energy intake from fibers while also protecting them from inflammations and noninfectious colonic diseases. This study investigates and compares human intestinal microbiota from children characterized by a modern western diet and a rural diet, indicating the importance of preserving this treasure of microbial diversity from ancient rural communities worldwide.
Considering B7-CD28 as a family through sequence and structure (2019)

With the emergence of immuno-oncology, new therapeutic agents that modulate immune activation and regulation are being used to treat cancer patients with durable response. It is well known that following T-cell receptor (TCR) activation, many co-receptors can augment or suppress the TCR signal, and therapeutically targeting these co-receptors has proven effective. The B7-CD28 family is comprised of such immune-regulatory receptors, and antibodies against its members programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) have revolutionized cancer treatment. These therapies promote an immune response against tumor cells, which demonstrated better long-term survival and tolerability compared to traditional cancer treatments. In this review we describe the history of the expanding B7-CD28 family, and by comparison of sequence and structure reveal that it is a non-traditional family. The family has grown to include proteins that share low sequence identity, generally grouped by regulation of immune response, which utilize the common immunoglobulin fold. This low level of commonality has provided additional challenges to the drug discovery process as the mechanisms and therapeutic potency between family members can vary greatly. Impact statement Immunotherapy as a field has dramatically expanded in the last decade in the area of oncology with efficacy demonstrated by PD-1, PD-L1, and CTLA-4 blockade. With all three “checkpoint blockade” receptors being in the B7-CD28 family, there has been increased interest in targeting other members in this family due to redundancy in immune regulation, i.e., the combination of therapeutic agents targeting multiple co-inhibitory receptors may yield additional antitumor efficacy. Therefore significant resources are being dedicated to developing additional B7-CD28 treatment options.
Systems chemistry (2007)

The study of complex mixtures of interacting synthetic molecules has historically not received much attention from chemists, even though research into complexity is well established in the neighbouring fields. However, with the huge recent interest in systems biology and the availability of modern analytical techniques this situation is likely to change. In this tutorial review we discuss some of the incentives for developing systems chemistry and we highlight the pioneering work in which molecular networks are making a splash. A distinction is made between networks under thermodynamic and kinetic control. The former include dynamic combinatorial libraries while the latter involve pseudo-dynamic combinatorial libraries, oscillating reactions and networks of autocatalytic and replicating compounds. These studies provide fundamental insights into the organisational principles of molecular networks and how these give rise to emergent properties such as amplification and feedback loops, and may eventually shed light on the origin of life. The knowledge obtained from the study of molecular networks should ultimately enable us to engineer new systems with properties and functions unlike any conventional materials.