gebhart/patrepeval huggingface dataset:
Clonal diversity in the B cell repertoire of patients with X-linked agammaglobulinemia. (1989)

Ig protein and mRNA expression was examined in a collection of 18 monoclonal EBV-transformed B cell lines derived from five patients with X-linked agammaglobulinemia (XLA). A diversity of H and L chain isotypes were synthesized by these lines: the majority (12 lines) expressed mu kappa chains, while mu lambda (two lines), gamma kappa (one), gamma lambda (one), delta lambda (one), and alpha kappa (one) isotype expression was also observed. For all the mu kappa-producing XLA B cell lines, the mu and kappa mRNA transcripts were of native size, and sequence analysis across the regions of VHDJH and V kappa J kappa gene joining showed that Ig gene rearrangements occurred in a typical manner. A variety of VHDJH and V kappa J kappa gene rearrangements were observed, not only within the set of mu kappa+ XLA B cells as a whole, but also among the cell lines derived from single patients. Southern blot analysis for genomic Ig H chain gene rearrangements was done to fully assess the extent of clonal heterogeneity among multiple mu kappa+ XLA B cell lines derived from two patients; all the B cell lines possessed distinct gene rearrangement patterns demonstrating their clonal unrelatedness. Our findings indicate that the B cell repertoire in individual XLA patients is clonally diverse and that it is unlikely that the defect in B cell differentiation in XLA is the result of inefficient or ineffective rearrangement of Ig H or L chain genes. Rather, this study provides support for the idea that the XLA defect relates to a more generalized cellular function, such as regulating the proliferation and/or clonal expansion of cells of the B lymphoid lineage.
Concerted evolution of duplicate fla genes in Campylobacter (2000)

Campylobacters have two similar copies (flaA and flaB) of their flagellin gene. It has been hypothesized that the two copies can serve for antigenic phase variation. Analysis of polymorphisms within aligned multiple DNA sequences of the Campylobacter flagellin genes revealed high pairwise homoplasy indexes between flaB/flaB pairs that were not observed between any flaA/flaA pairings or flaA/flaB pairings. Thus it seems there are constraints on the sequence of flaB that distinguish it from flaA. Nevertheless, segments of the two genes that are highly variable between strains are conserved between the flaA and flaB copies of the genes within a strain. The patterns of synonymous and non-synonymous differences suggest that one segment of the flagellin sequence is under selective pressure at the amino acid sequence level. Another segment of the protein is maintained within a strain by conversion or recombination. Comparisons of strict consensus amino acid sequences did not reveal any motifs that are uniquely FlaA or FlaB, but there are differences between FlaA and FlaB in those amino acids available for post-translational modification. The observed pattern of concerted evolution of portions of a structural gene is an unusual finding in bacteria and should be searched for with other duplicated genes. Concerted evolution was unexpected for genes involved in phase variation since it minimizes the antigenic repertoire that can be expressed by a single clone in the face of the host immune response.
Combined ultrasound and MR imaging to guide focused ultrasound therapies in the brain (2013)

Several emerging therapies with potential for use in the brain, harness effects produced by acoustic cavitation--the interaction between ultrasound and microbubbles either generated during sonication or introduced into the vasculature. Systems developed for transcranial MRI-guided focused ultrasound (MRgFUS) thermal ablation can enable their clinical translation, but methods for real-time monitoring and control are currently lacking. Acoustic emissions produced during sonication can provide information about the location, strength and type of the microbubble oscillations within the ultrasound field, and they can be mapped in real-time using passive imaging approaches. Here, we tested whether such mapping can be achieved transcranially within a clinical brain MRgFUS system. We integrated an ultrasound imaging array into the hemisphere transducer of the MRgFUS device. Passive cavitation maps were obtained during sonications combined with a circulating microbubble agent at 20 targets in the cingulate cortex in three macaques. The maps were compared with MRI-evident tissue effects. The system successfully mapped microbubble activity during both stable and inertial cavitation, which was correlated with MRI-evident transient blood-brain barrier disruption and vascular damage, respectively. The location of this activity was coincident with the resulting tissue changes within the expected resolution limits of the system. While preliminary, these data clearly demonstrate, for the first time, that it is possible to construct maps of stable and inertial cavitation transcranially, in a large animal model, and under clinically relevant conditions. Further, these results suggest that this hybrid ultrasound/MRI approach can provide comprehensive guidance for targeted drug delivery via blood-brain barrier disruption and other emerging ultrasound treatments, facilitating their clinical translation. We anticipate that it will also prove to be an important research tool that will further the development of a broad range of microbubble-enhanced therapies.
Preparation of SF5 Aromatics by Vicarious Nucleophilic Substitution Reactions of Nitro(pentafluorosulfanyl)benzenes with Carbanions (2011)

Vicarious nucleophilic substitutions (VNS) of hydrogen in 1-nitro-4-(pentafluorosulfanyl)benzene with carbanions provide 2-substituted 1-nitro-4-(pentafluorosulfanyl)benzenes in good to high yields. VNS of 1-nitro-3-(pentafluorosulfanyl)benzene gives a mixture of 6- and 4-substituted 1-nitro-3-(pentafluorosulfanyl)benzenes in 85:15 to >98:2 ratio and good to high yields. In basic media, the VNS reactions lead to the formation of carbanions that can be alkylated by alkyl halides affording the corresponding alkylated products in moderate yields. Transformation of primary products to substituted (pentafluorosulfanyl)anilines and 3- or 4-substituted (pentafluorosulfanyl)benzenes is also described.
Enrichment of Cell‐Targeting and Population‐Specific Aptamers by Fluorescence‐Activated Cell Sorting (2008)

A class above: In a sophisticated approach to the systematic evolution of ligands by exponential enrichment (SELEX) of cell-type-specific nucleic acid aptamers, the title technique was combined with the use of combinatorial nucleic acid libraries to target a defined subpopulation within composite mixtures of cells (see picture). The ssDNA library after 10 selection cycles bound vital Burkitt lymphoma cells more effectively than the starting library.
ZC3H12A/MCPIP1/Regnase‐1‐related endonucleases: An evolutionary perspective on molecular mechanisms and biological functions (2017)

The mammalian Zc3h12a/MCPIP1/Regnase-1, an extensively studied regulator of inflammatory response, is the founding member of a ribonuclease family, which includes proteins related by the presence of the so-called Zc3h12a-like NYN domain. Recently, several related proteins have been described in Caenorhabditis elegans, allowing comparative evaluation of molecular functions and biological roles of these ribonucleases. We discuss the structural features of these proteins, which endow some members with ribonuclease (RNase) activity while others with auxiliary or RNA-independent functions. We also consider their RNA specificity and highlight a common role for these proteins in cellular defense, which is remarkable considering the evolutionary distance and fundamental differences in cellular defense mechanisms between mammals and nematodes.
Manual of Stem Cell and Bone Marrow Transplantation (2009)

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Role of the Ubiquitin-Proteasome Pathway in Regulating Abundance of the Cyclin-Dependent Kinase Inhibitor p27 (1995)

The p27 mammalian cell cycle protein is an inhibitor of cyclin-dependent kinases. Both in vivo and in vitro, p27 was found to be degraded by the ubiquitin-proteasome pathway. The human ubiquitin-conjugating enzymes Ubc2 and Ubc3 were specifically involved in the ubiquitination of p27. Compared with proliferating cells, quiescent cells exhibited a smaller amount of p27 ubiquitinating activity, which accounted for the marked increase of p27 half-life measured in these cells. Thus, the abundance of p27 in cells is regulated by degradation. The specific proteolysis of p27 may represent a mechanism for regulating the activity of cyclin-dependent kinases.
A comprehensive, non-invasive visualization of primordial germ cell development in mice by the Prdm1 -mVenus and Dppa3 -ECFP double transgenic reporter (2008)

The ability to monitor the development of a given cell lineage in a non-invasive manner by fluorescent markers both in vivo and in vitro provides a great advantage for the analysis of the lineage of interest. To date, a number of transgenic or knock-in mouse strains, in which developing germ cells are marked with fluorescent reporters, have been generated. We here describe a novel double transgenic reporter mouse strain that expresses membrane-targeted Venus (mVenus), a brighter variant of yellow fluorescent protein (YFP), under the control of Prdm1 (Blimp1) regulatory elements and enhanced cyan fluorescent protein (ECFP) under the control of Dppa3 (Stella/Pgc7). The double transgenic strain unambiguously marked Prdm1 expression in the lineage-restricted precursors of primordial germ cells (PGCs) in the proximal epiblast at embryonic day (E) 6.25 and specifically illuminated Prdm1- and Dppa3-positive migrating PGCs after E8.5. The double transgenic reporter also precisely recapitulated dynamic embryonic expression of Prdm1 outside the germ cell lineage. Moreover, we derived ES cells that bore both transgenes. These cells made a robust contribution both to the germ and somatic cell lineages in chimeras with accurate Prdm1-mVenus and Dppa3-ECFP expression. The transgenic strain and the ES cells will serve as valuable experimental materials not only for analyzing the origin and properties of the germ cell lineage in vivo, but also for establishing a culture system to efficiently induce proper germ cells with temporally coordinated Prdm1 and Dppa3 expression in vitro.
Intracellular Targeting Using Bispecific Antibodies (2003)

The technological development and application of bispecific antibodies for biological research have advanced steadily since the idea of creating hybrid reagents with dual specificity was first promulgated by Nisonoff and Rivers (1). It was realized that appropriately designed bispecific antibodies could provide a unique means for selectively delivering biologically active agents onto the surface of target cells so that they could ultimately be internalized (2-7). Hybrid constructs developed in my laboratory used a specific antibody to reversibly bind the effector molecule within its combining site, whereas the second antibody or ligand component accurately targeted the complex to selected sites on the cell membrane Fig. 1). Those target receptor sites, along with the attached hybrid antibody complex, are subsequently taken inside the cell via receptor-mediated endocytosis. Cytotoxic drugs and toxins were chosen for delivery via the bispecific reagent because the entry of these potent molecules into target cells is signaled by an easily measured intracellular activity (2-7). Fig. 1. Intracellular delivery of effector molecules using bispecific antibodies. A bifunctional carrier is constructed by linking a monoclonal anti-effector antibody to a monoclonal cell-targeting antibody. A noncovalent complex forms when the effector is added and binds to its specific antibody-combining sites. The targeting antibody directs this preformed complex to a distinct receptor site on the cell membrane. Alternatively, cells can be pretreated with the bispecific antibody, allowing the empty combining sites of the cell-bound reagent to be filled by subsequently added effector molecules. Surface-localized complexes quickly enter cells via a receptor-mediated endocytosis pathway. Escape of the effector from the cell vesicle system and passage into the cytosol is achieved but occurs slowly (∼24 h).
Agouti regulation of intracellular calcium: role in the insulin resistance of viable yellow mice. (1995)

Several dominant mutations at the agouti locus in the mouse cause a syndrome of marked obesity, hyperinsulinemia, and insulin resistance. Although it is known that the agouti gene is expressed in an ectopic manner in these mutants, the precise mechanism by which the agouti gene product mediates these effects is unclear. Since intracellular Ca2+ is believed to play a role in mediating insulin action and dysregulation of Ca2+ flux is observed in diabetic animals and humans, we examined the status of intracellular Ca2+ in mice carrying the dominant agouti allele, viable yellow (Avy). We show here that in mice carrying this mutation, the intracellular free calcium concentration ([Ca2+]i) is elevated in skeletal muscle, and the degree of elevation is closely correlated with the degree to which the mutant traits are expressed in individual animals. Moreover, we demonstrate that the agouti gene product is capable of inducing increased [Ca2+]i in cultured and freshly isolated skeletal muscle myocytes from wild-type mice. Based on these findings, we present a model in which we propose that the agouti polypeptide promotes insulin resistance in mutant animals through its ability to increase [Ca2+]i.
Tumor Necrosis Factor-induced Microtubule Stabilization Mediated by Hyperphosphorylated Oncoprotein 18 Promotes Cell Death (2000)

Tumor necrosis factor (TNF)-induced cell death in the fibrosarcoma cell line L929 occurs independently of caspase activation and cytochrome c release. However, it is dependent on mitochondria and is characterized by increased production of reactive oxygen intermediates that are essential to the death process. To identify signaling molecules involved in this TNF-induced, reactive oxygen intermediate-dependent cell death pathway, we performed a comparative study by two-dimensional gel electrophoresis of phosphoproteins from a mitochondria-enriched fraction derived from TNF-treated and control cells. TNF induced rapid and persistent phosphorylation of the phosphorylation-responsive regulator of the microtubule (MT) dynamics, oncoprotein 18 (Op18). By using induced overexpression of wild type Op18 and phosphorylation site-deficient mutants S25A/S38A and S16A/S63A in L929 cells, we show that TNF-induced phosphorylation on each of the four Ser residues of Op18 promotes cell death and that Ser(16) and Ser(63) are the primary sites. This hyperphosphorylation of Op18 is known to completely turn off its MT-destabilizing activity. As a result, TNF treatment of L929 cells induced elongated and extremely tangled microtubules. These TNF-induced changes to the MT network were also observed in cells overexpressing wild type Op18 and, to a lesser extent, in cells overexpressing the S25A/S38A mutant. No changes in the MT network were observed upon TNF treatment of cells overexpressing the S16A/S63A mutant, and these cells were desensitized to TNF-induced cell death. These findings indicate that TNF-induced MT stabilization is mediated by hyperphosphorylation of Op18 and that this promotes cell death. The data suggest that Op18 and the MT network play a functional role in transduction of the cell death signal to the mitochondria.
"Partly Folded" State, a New Equilibrium State of Protein Molecules: Four-State Guanidinium Chloride-Induced Unfolding of .beta.-Lactamase at Low Temperature (1994)

Guanidinium chloride- (GdmCl-) induced unfolding of beta-lactamase has been investigated by a combination of size-exclusion chromatography (SEC-FPLC) and usual optical methods. It has been shown that at low temperatures this protein unfolds through two equilibrium intermediates. The first of these intermediates is the molten globule state, while the other (which we have called a "partly folded" state) is less compact than the molten globule but much more compact than the unfolded state. It also preserves a substantial part of secondary structure of the native or molten globule state. We suggest that this new "partly folded" state of a protein molecule can be the equilibrium counterpart of the first kinetic intermediate of protein folding, formed within a few milliseconds, i.e., after the "burst" stage of folding.
Function of the retinoic acid receptors (RARs) during development: (I) Craniofacial and skeletal abnormalities in RAR double mutants (1994)

Numerous congenital malformations have been observed in fetuses of vitamin A-deficient (VAD) dams [Wilson, J. G., Roth, C. B., Warkany, J., (1953), Am. J. Anat. 92, 189-217]. Previous studies of retinoic acid receptor (RAR) mutant mice have not revealed any of these malformations [Li, E., Sucov, H. M., Lee, K.-F., Evans, R. M., Jaenisch, R. (1993) Proc. Natl. Acad. Sci. USA 90, 1590-1594; Lohnes, D., Kastner, P., Dierich, A., Mark, M., LeMeur, M., Chambon, P. (1993) Cell 73, 643-658; Lufkin, T., Lohnes, D., Mark, M., Dierich, A., Gorry, P., Gaub, M. P., Lemeur, M., Chambon, P. (1993) Proc. Natl. Acad. Sci. USA 90, 7225-7229; Mendelsohn, C., Mark, M., Dollé, P., Dierich, A., Gaub, M.P., Krust, A., Lampron, C., Chambon, P. (1994a) Dev. Biol. in press], suggesting either that there is a considerable functional redundancy among members of the RAR family during ontogenesis or that the RARs are not essential transducers of the retinoid signal in vivo. In order to discriminate between these possibilities, we have generated a series of RAR compound null mutants. These RAR double mutants invariably died either in utero or shortly after birth and presented a number of congenital abnormalities, which are reported in this and in the accompanying study. We describe here multiple eye abnormalities which are found in various RAR double mutant fetuses and are similar to those previously seen in VAD fetuses. Interestingly, we found further abnormalities not previously reported in VAD fetuses.(ABSTRACT TRUNCATED AT 250 WORDS)
Structure and Function of Toll Receptors and Their Ligands (2007)

The Toll family of class I transmembrane receptors recognizes and responds to diverse structures associated with pathogenic microorganisms. These receptors mediate initial responses in innate immunity and are required for the development of the adaptive immune response. Toll receptor signaling pathways are also implicated in serious autoimmune diseases such as endotoxic shock and thus are important therapeutic targets. In this review we discuss how microbial structures as different as nucleic acids and lipoproteins can be recognized by the extracellular domains of Toll receptors. We review recent evidence that the mechanism of signal transduction is complex and involves sequential changes in the conformation of the receptor induced by binding of the ligand. Finally, we assess the emerging area of cross talk in the Toll pathways. Recent work suggests that signaling through TLR4 in response to endotoxin is modified by inputs from at least two other pathways acting through beta2 integrins and protein kinase Cepsilon.
Atypical Antipsychotic Use in the Treatment of Psychosis in Primary Care (2000)

Atypical antipsychotics are a class of novel agents increasingly employed for the treatment of psychotic disorders. The pharmacodynamic properties of the atypicals appear to impact a broader spectrum of psychotic symptoms than had been appreciated with older generation antipsychotics. In addition, the atypical agents appear to have a reduced risk of neurologic side effects compared with conventional antipsychotic use. Both of these features enhance the appeal of the atypical antipsychotics and may be associated with enhanced patient compliance. The atypical antipsychotics appear to be effective for schizophrenia as well as other psychotic disorders, including schizoaffective disorder and mood disorders with psychotic features. Consequently, atypical antipsychotics are now considered to be the first-line treatment for schizophrenia, with the exception of clozapine, which is considered a second-line agent because of risks associated with its use. This review will discuss the literature on atypical antipsychotic efficacy in psychotic disorders. Issues related to antipsychotic use, dosing, adverse effects, and drug interactions are also discussed.
Sequential Learning for Adaptive Critic Design: An Industrial Control Application (2006)

This paper investigates the feasibility of applying reinforcement learning (RL) concepts to industrial process optimisation. A model-free action-dependent adaptive critic design (ADAC), coupled with sequential learning neural network training, is proposed as an online RL strategy suitable for both modelling and controller optimisation. The proposed strategy is evaluated on data from an industrial grinding process used in the manufacture of disk drives. Comparison with a proprietary control system shows that the proposed RL technique is able to achieve comparable performance without any manual intervention
Sorptive Removal of Cesium-137 and Strontium-90 from Water by Unconventional Sorbents. I. Usage of Bauxite Wastes (Red Muds) (1995)

Bauxite wastes of alumina manufacture, i.e., red muds, have been tested for radiocesium and strontium removal from water. The red muds were water-washed, acid-, and heat-treated before usage to produce hydrous oxide like sorbents. Surface treatment of the sorbent was benefical for 137s uptake, while heat-treatment was detrimental to the -SOH surface sites responsible for high 90Sr affinity. Fractionation of the sorbent with respect to apparent grain size did not produce significant differences in the sorption efficiency. The distribution coefficients vs. equilibrium activity in solution showed a maximum with Cs, and a gradual decrease trend with Sr. The solution activity vs. adsorption data were fitted to B.E. T. (essentially types IV-V) isotherms for Cs and B.E. T.-Langmuir isotherms for Sr. Desorption, temperature-, pH-, and ionic strength-dependence tests revealed that the primary mode of sorption for both cations is specific adsorption while the secondary mode is ion exchange. A rise in pH favours the ion- exchange sorption of Sr while the specific adsorption of Cs is negatively affected. Competitive adsorption of an inert electrolyte, i.e., NaCl, severely hinders Cs sorption, while Sr sorption on water-washed red mud is not significantly affected.