gebhart/patrepeval huggingface dataset:
Impact of freezing on pH of buffered solutions and consequences for monoclonal antibody aggregation (2009)

Freezing of biologic drug substance at large scale is an important unit operation that enables manufacturing flexibility and increased use-period for the material. Stability of the biologic in frozen solutions is associated with a number of issues including potentially destabilizing pH changes. The pH changes arise from temperature-associated change in the pK(a)s, solubility limitations, eutectic crystallization, and cryoconcentration. The pH changes for most of the common protein formulation buffers in the frozen state have not been systematically measured. Sodium phosphate buffer, a well-studied system, shows the greatest change in pH when going from +25 to -30 degrees C. Among the other buffers, histidine hydrochloride, sodium acetate, histidine acetate, citrate, and succinate, less than 1 pH unit change (increase) was observed over the temperature range from +25 to -30 degrees C, whereas Tris-hydrochloride had an approximately 1.2 pH unit increase. In general, a steady increase in pH was observed for all these buffers once cooled below 0 degrees C. A formulated IgG2 monoclonal antibody in histidine buffer with added trehalose showed the same pH behavior as the buffer itself. This antibody in various formulations was subject to freeze/thaw cycling representing a wide process (phase transition) time range, reflective of practical situations. Measurement of soluble aggregates after repeated freeze-thaw cycles shows that the change in pH was not a factor for aggregate formation in this case, which instead is governed by the presence or absence of noncrystallizing cryoprotective excipients. In the absence of a cryoprotectant, longer phase transition times lead to higher aggregation.
MicroInspector: a web tool for detection of miRNA binding sites in an RNA sequence (2005)

Regulation of post-transcriptional gene expression by microRNAs (miRNA) has so far been validated for only a few mRNA targets. Based on the large number of miRNA genes and the possibility that one miRNA might influence gene expression of several targets simultaneously, the quantity of ribo-regulated genes is expected to be much higher. Here, we describe the web tool MicroInspector that will analyse a user-defined RNA sequence, which is typically an mRNA or a part of an mRNA, for the occurrence of binding sites for known and registered miRNAs. The program allows variation of temperature, the setting of energy values as well as the selection of different miRNA databases to identify miRNA-binding sites of different strength. MicroInspector could spot the correct sites for miRNA-interaction in known target mRNAs. Using other mRNAs, for which such an interaction has not yet been described, we discovered frequently potential miRNA binding sites of similar quality, which can now be analysed experimentally. The MicroInspector program is easy to use and does not require specific computer skills. The service can be accessed via the MicroInspector web server at http://www.imbb.forth.gr/microinspector.
Niemann–Pick disease type C (2003)

Niemann-Pick disease type C (NPC) is an autosomal recessive neurovisceral lipid storage with a wide spectrum of clinical phenotypes. At the cellular level, the disorder is characterized by accumulation of unesterified cholesterol and glycolipids in the lysosomal/late endosomal system. Approximatively 95% of patients have mutations in the NPC1 gene (mapped at 18q11) which encodes a large membrane glycoprotein primarily located to late endosomes. The remainder have mutations in the NPC2 gene (mapped at 14q24.3) which encodes a small soluble lysosomal protein with cholesterol-binding properties. The identical biochemical patterns observed in NPC1 and NPC2 mutants suggest that the two proteins function in a coordinate fashion. Identification of mutations revealed a complex picture of molecular heterogeneity, allowing genotype - phenotype correlations for both genes and providing insights into structure - function relationships for the NPC1 protein. Although a whole body of evidence suggests that the NPC1 and NPC2 proteins are involved in the cellular postlysosomal/late endosomal transport of cholesterol, glycolipids and other cargo, their precise functions and relationship remain unclear and are currently the subject of intense investigation. These studies, conducted in various models, should ultimately lead to a better understanding of the pathophysiology of NPC and new therapeutic approaches.
T-cell epitopes within the complementarity-determining and framework regions of the tumor-derived immunoglobulin heavy chain in multiple myeloma (2003)

The idiotypic structure of the monoclonal immunoglobulin (Ig) in multiple myeloma (MM) might be regarded as a tumor-specific antigen. The present study was designed to identify T-cell epitopes of the variable region of the Ig heavy chain (VH) in MM (n = 5) using bioinformatics and analyze the presence of naturally occurring T cells against idiotype-derived peptides. A large number of human-leukocyte-antigen (HLA)-binding (class I and II) peptides were identified. The frequency of predicted epitopes depended on the database used: 245 in bioinformatics and molecular analysis section (BIMAS) and 601 in SYFPEITHI. Most of the peptides displayed a binding half-life or score in the low or intermediate affinity range. The majority of the predicted peptides were complementarity-determining region (CDR)-rather than framework region (FR)-derived (52%-60% vs 40%-48%, respectively). Most of the predicted peptides were confined to the CDR2-FR3-CDR3 "geographic" region of the Ig-VH region (70%), and significantly fewer peptides were found within the flanking (FR1-CDR1-FR2 and FR4) regions (P <.01). There were 8- to 10-amino acid (aa) long peptides corresponding to the CDRs and fitting to the actual HLA-A/B haplotypes that spontaneously recognized, albeit with a low magnitude, type I T cells (interferon gamma), indicating an ongoing major histocompatibility complex (MHC) class I-restricted T-cell response. Most of those peptides had a low binding half-life (BIMAS) and a low/intermediate score (SYFPEITHI). Furthermore, 15- to 20-aa long CDR1-3-derived peptides also spontaneously recognized type I T cells, indicating the presence of MHC class II-restricted T cells as well. This study demonstrates that a large number of HLA-binding idiotypic peptides can be identified in patients with MM. Such peptides may spontaneously induce a type I MHC class I- as well as class II-restricted memory T-cell response.
Umbrella Sampling Simulations of Biotin Carboxylase: Is a Structure with an Open ATP Grasp Domain Stable in Solution? (2009)

Biotin carboxylase is a homodimer that utilizes ATP to carboxylate biotin. Studies of the enzyme using X-ray crystallography revealed a prominent conformational change upon binding ATP. To determine the importance of this closing motion, the potential of mean force with the closure angle as a reaction coordinate was calculated using molecular dynamics simulations and umbrella sampling for a monomer of Escherichia coli biotin carboxylase in water with restraints to simulate attachment to a surface. The result suggests that the most stable state for the enzyme is a closed state different from both the ATP-bound and open state X-ray crystallography structures. There is also a significant motion of a region near the dimer interface not predicted by considering only open and closed configurations, which may have implications for the dynamics and activity of the dimer.
Anti-vascular endothelial growth factor therapy for ocular neovascular disease (2007)

Newer anti-VEGF therapies have shown unprecedented efficacy in treating age related macular degeneration with many patients experiencing improvement in vision. Ongoing trials will help guide their use in age related macular degeneration and expand their indications to many other blinding diseases.
Disorder-associated mutations lead to functional inactivation of neuroligins (2004)

Autism is a neuro-developmental syndrome that affects 0.1-0.5% of the population. It has been proposed that alterations in neuronal circuitry and/or neuronal signaling are responsible for the behavioral and cognitive aberrations in autism patients. However, the cellular basis of such alterations is unknown. Recently, point mutations in a family of neuronal cell adhesion molecules called neuroligins have been linked to autism-spectrum disorders and mental retardation. We investigated the consequences of these disease-associated mutations on neuroligin function. We demonstrate that the point mutation at arginine 451 and a nonsense mutation at aspartate 396 of neuroligin-3 and -4 (NL3 and NL4), respectively, result in intracellular retention of the mutant proteins. Over-expression of wild-type NL3 and NL4 proteins in hippocampal neurons stimulates the formation of presynaptic terminals, whereas the disease-associated mutations result in a loss of this synaptic function. Our findings suggest that the previously identified mutations in neuroligin genes are likely to be relevant for the neuro-developmental defects in autism-spectrum disorders and mental retardation since they impair the function of a synaptic cell adhesion molecule.
17β-Estradiol Antagonizes Effects of 1α,25-Dihydroxyvitamin D3 on Interleukin-6 Production and Osteoclast-Like Cell Formation in Mouse Bone Marrow Primary Cultures* (1997)

In mouse bone marrow primary cultures, the formation of osteoclast-like, i.e. tartrate-resistant acid phosphatase (TRAP)- and calcitonin receptor-positive multinucleated cells (MNC), when induced by 1alpha,25-dihydroxyvitamin D3 (1alpha,25(OH)2D3), can be suppressed by 17beta-estradiol (17beta-E2), whereas 17alpha-E2 is without any effect. 17beta-E2, above 10(-11) M, significantly reduced 1alpha,25(OH)2D3-mediated TRAP+ MNC formation in cultured bone marrow cells from both female and male mice. The estrogen at 10(-8) M suppressed the peak response to the vitamin D sterol by 50%. 17beta-E2 significantly suppressed basal and 1alpha,25(OH)2D3-stimulated cellular production of interleukin (IL)-6. IL-6 alone, although bone marrow cells in hormone-free culture produced appreciable amounts of the cytokine, did not induce any TRAP+ MNC. Therefore, the changes in IL-6 production induced by the hormones could not be the sole determinant for the extent of TRAP+ MNC formation. However, the stimulatory effect of 1alpha,25(OH)2D3 on osteoclastogenesis nevertheless can be significantly reduced by a neutralizing monoclonal anti-IL-6 antibody. In the presence of 10(-8) M 17beta-E2, the anti-IL-6 monoclonal antibody does not achieve any further suppression of 1alpha,25(OH)2D3-related osteoclast-like cell formation. Our data suggest that induction of osteoclastogenesis by 1alpha,25(OH)2D3 is partially dependent on IL-6 signaling and can be modulated by 17beta-E2 through interference with IL-6 receptor activation, in addition to inhibition of IL-6 production by marrow stromal cells.
Direct activation of full-length proapoptotic BAK (2013)

Proapoptotic B-cell lymphoma 2 (BCL-2) antagonist/killer (BAK) and BCL-2-associated X (BAX) form toxic mitochondrial pores in response to cellular stress. Whereas BAX resides predominantly in the cytosol, BAK is constitutively localized to the outer mitochondrial membrane. Select BCL-2 homology domain 3 (BH3) helices activate BAX directly by engaging an α1/α6 trigger site. The inability to express full-length BAK has hampered full dissection of its activation mechanism. Here, we report the production of full-length, monomeric BAK by mutagenesis-based solubilization of its C-terminal α-helical surface. Recombinant BAK autotranslocates to mitochondria but only releases cytochrome c upon BH3 triggering. A direct activation mechanism was explicitly demonstrated using a liposomal system that recapitulates BAK-mediated release upon addition of BH3 ligands. Photoreactive BH3 helices mapped both triggering and autointeractions to the canonical BH3-binding pocket of BAK, whereas the same ligands crosslinked to the α1/α6 site of BAX. Thus, activation of both BAK and BAX is initiated by direct BH3-interaction but at distinct trigger sites. These structural and biochemical insights provide opportunities for developing proapoptotic agents that activate the death pathway through direct but differential engagement of BAK and BAX.
Handbook of Clinical Neurology, Headache VolumeHandbook of Clinical Neurology, Headache Volumeedited by NappiGiuseppeMoskowitzMichael 825 pp., Elsevier Edinburgh, 2011, $330 (2012)

Handbook of Clinical Neurology, Headache Volume edited by Giuseppe Nappi, Michael Moskowitz 825 pp., Elsevier Edinburgh, 2011, $330

The current third series of the Handbook of Neurology now includes a volume on headache, as a successor to earlier volumes on headache in the first and second series. This seems very appropriate, as the editors point out in the foreword that at least 40% of neurologic consultations are triggered by headache-related problems. The update is timely, as the last Handbook volume on headache was published in 1985, over 25 years ago.

At 825 pages, …
Classification of mutations at the human, hprt-locus in T-lymphocytes of bus maintenance workers by multiplex-PCR and reverse transcriptase-PCR analysis (1995)

Polymerase chain reaction (PCR)-based screening methods were used to classify mutations arising in vivo at the hypoxanthine guanine phosphoribosyl-transferase (hprt) locus in small samples of human T-lymphocyte clones (< 5 x 10(4) cells) from 29 bus maintenance workers exposed to diesel exhaust, and 14 control individuals. All subjects were healthy, non-smoking males. Among 462 T-cell mutants studied by multiplex-PCR of genomic DNA, only 12 (2.6%) deletions were found: three total deletions, five partial exon deletions and four mutants with one or two exons deleted. Point mutations were classified in 323 mutants using reverse transcriptase-PCR amplification: 74 (22.9%) of these had splice site mutations and 241 (74.6%) had coding errors. Splice mutation was more frequent among the garage workers (24.8%) as compared to the controls (19.5%), possibly reflecting a polycyclic aromatic hydrocarbon-specific mutation induction in these workers. Our results also show that both gene deletion and splice mutation at the hprt-locus in T-cells of healthy non-smokers could be less frequent than previously reported.
QUIKTRAK: a unique new AVL system (2003)

This automatic vehicle location system developed and installed in Australia features a low-cost on-vehicle component, and offers high system performance in terms of location capacity and accuracy. The added ability to transfer data to and from the vehicle enables many applications in fleet management and security to be realized. The system has been designed to provide coverage over an area of some 2000 km/sup 2/ with an accuracy of approximately 30 m. It has the capability to support many independent users and many thousands of vehicles. The current tracking capacity is 30000 locations per hour. Spread-spectrum phase-multilateration techniques provide accurate locations on moving vehicles in the severe multipath environment encountered in heavily built-up areas.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
Dopamine Transporter Brain Imaging to Assess the Effects of Pramipexole vs Levodopa on Parkinson Disease Progression (2002)

Patients initially treated with pramipexole demonstrated a reduction in loss of striatal [(123)I]beta-CIT uptake, a marker of dopamine neuron degeneration, compared with those initially treated with levodopa, during a 46-month period. These imaging data highlight the need to further compare imaging and clinical end points of PD progression in long-term studies.
Hormone phage: An enrichment method for variant proteins with altered binding properties (1990)

Human growth hormone (hGH), a 191 residue protein containing two disulfide bonds, was fused to the carboxyl-terminal domain of the gene III protein, a minor coat protein exposed at one end of the filamentous phage M13. The gene fusion was cloned into a plasmid containing origins of replication for Escherichia coli and filamentous phage and was packaged into phagemid particles upon infection by an M13KO7 helper phage. Transcription of the hGH-gene III fusion was controlled so that usually no more than one copy of the fusion protein was displayed along with the four copies of the wild-type gene III protein. The hGH-gene III fusion protein was properly folded, as judged by reactivity with six hGH monoclonal antibodies whose epitopes are sensitive to the folded conformation of hGH. Moreover, the hGH-gene III phagemid particles were enriched over 5000-fold from non-hGH phage, and 8-fold from a mutant hGH phagemid following a single hGH-specific elution step from hGH receptor-coated beads. The hGH phagemid should be useful for isolating new receptor binding mutants of hGH. More generally, this expression system may allow other large proteins with discontinuous binding epitopes to be displayed, and binding selections applied to their mutated gene III fusions on filamentous phage.
Superconductor-semiconductor-superconductor planar junctions of aluminium on δ-doped gallium-arsenide (1997)

We have fabricated and characterized planar superconductor-semiconductor-superconductor (S-Sm-S) junctions with a high quality (i.e. low barrier) interface between an n/sup ++/ modulation doped conduction layer in MBE grown GaAs and in situ deposited Al electrodes. The Schottky barrier at the S-Sm interface was compensated by inserting several Si /spl delta/-doped layers above the conduction layer and close to the surface of the GaAs heterostructure. Below 1.2 K, the transition temperature of Al, the dc I-V curves of such S-Sm-S junctions with a wide and short GaAs channel exhibited the classic features of S-N-S junctions including subharmonic energy gap structure (SGS) and excess current (EC) due to Andreev reflections at the interfaces.
Tetranortriterpenoids from Melia azadirachta L. (1967)

D. Lavie and M. K. Jain, Chem. Commun. (London), 1967, 278 DOI: 10.1039/C19670000278
Granulocyte colony-stimulating factor "mobilized" peripheral blood progenitor cells accelerate granulocyte and platelet recovery after high-dose chemotherapy (1993)

Hematopoietic growth factors have been used to accelerate engraftment after bone marrow transplantation and to "mobilize" peripheral blood progenitor cells (PBPC). We report on the data in 85 consecutive patients with Hodgkin's disease who were treated in a single institution using different methods to obtain PB progenitor cells. Use of granulocyte colony-stimulating factor for mobilization resulted in a significantly accelerated time to recovery of granulocytes (10 days v 12 days, P < .01) when compared with "nonmobilized" PBPC recipients. Similarly, use of mobilized PBPC resulted in a significantly accelerated time to platelet engraftment (13 days v 30 days, P < .001) when compared with "nonmobilized" recipients. Moreover, there was a statistically significant difference in total costs in favor of the group receiving "mobilized" PBPC.
Effects of growth hormone and insulin-like growth factor-I on colony formation of rabbit epiphyseal chondrocytes at different stages of maturation (1987)

The effect of human GH (hGH) and insulin-like growth factor-I (IGF-I) on colony formation of rabbit epiphyseal tibial chondrocytes at different stages of maturation was studied in suspension culture. The epiphyseal growth plate from the proximal tibia of 8-week-old male rabbits was dissected and divided into three different (proximal, intermediate and distal) zones, each zone representing an enrichment of chondrocytes from the germinative, proliferative and hypertrophic cell layers respectively. Chondrocytes from these three zones were isolated by collagenase digestion and cultured in the presence of 10% (v/v) newborn calf serum in suspension stabilized with 0.5% (w/v) agarose for 14 days. The colonies were classified according to diameter and the number of colonies was estimated as a function of colony size (distribution of cloning efficiency). Cell clusters with a diameter of 56 micron or more were classified as colonies. The cloning efficiency (number of colonies formed per 1000 seeded cells) was 10.1 +/- 0.7 and 6.0 +/- 0.8 for chondrocytes isolated from the proximal and intermediate zones respectively. Insulin-like growth factor-I (25-200 ng/ml) increased the number of colonies in chondrocytes isolated from the proximal zone (122 +/- 9.0-156 +/- 8.4%; control value, 100%) and from the intermediate zone (136 +/- 14.0-191 +/- 29%). Low concentrations of hGH (10-40 ng/ml) stimulated colony formation in chondrocytes isolated from the proximal zone (125 +/- 6.4-137 +/- 7.9%) whereas a high concentration of hGH (160 ng/ml) was ineffective. Chondrocytes isolated from the intermediate zone showed no response to low concentrations of hGH (10-20 ng/ml).(ABSTRACT TRUNCATED AT 250 WORDS)
Use of adoptive transfer of T‐cell antigen‐receptor‐transgenic T cells for the study of T‐cell activation in vivo (1997)

Adoptive transfer of TCR-transgenic T cells uniformly expressing an identifiable TCR of known peptide/MHC specificity can be used to monitor the in vivo behavior of antigen-specific T cells. We have used this system to show that naive T cells are initially activated within the T-cell zones of secondary lymphoid tissue to proliferate in a B7-dependent manner. If adjuvants or inflammatory cytokines are present during this period, enhanced numbers of T cells accumulate, migrate into B-cell-rich follicles, and acquire the capacity to produce IFN-gamma and help B cells produce IgG2a. If inflammation is absent, most of the initially activated antigen-specific T cells disappear without entering the follicles, and the survivors are poor producers of IL-2 and IFN-gamma. Our results indicate that inflammatory mediators play a key role in regulating the anatomic location, clonal expansion, survival and lymphokine production potential of antigen-stimulated T cells in vivo.
The inflammasome activating caspase 1 mediates fibrosis and myofibroblast differentiation in systemic sclerosis (2011)

Innate immune signaling contributes to SSc fibrosis via activation of the inflammasome and caspase 1. These results suggest that inflammasome activation may play an important role in the pathogenesis of SSc.
Objectively recognizing human activity in body-worn sensor data with (more or less) deep neural networks (2017)

This thesis concerns the application of different artificial neural network architectures on the classification of multivariate accelerometer time series data into activity classes such as sitting, lying down, running, or walking. There is a strong correlation between increased health risks in children and their amount of daily screen time (as reported in questionnaires). The dependency is not clearly understood, as there are no such dependencies reported when the sedentary (idle) time is measured objectively. Consequently, there is an interest from the medical side to be able to perform such objective measurements. To enable large studies the measurement equipment should ideally be low-cost and non-intrusive. The report investigates how well these movement patterns can be distinguished given a certain measurement setup and a certain network structure, and how well the networks generalise to noisier data. Recurrent neural networks are given extra attention among the different networks, since they are considered well suited for data of sequential nature. Close to state-of-the-art results (95% weighted F1-score) are obtained for the tasks with 4 and 5 classes, which is notable since a considerably smaller number of sensors is used than in the previously published results. Another contribution of this thesis is that a new labeled dataset with 12 activity categories is provided, consisting of around 6 hours of recordings, comparable in number of samples to benchmarking datasets. The data collection was made in collaboration with the Department of Public Health at Karolinska Institutet.