gebhart/patrepeval huggingface dataset:
Hippocampal neurogenesis: Opposing effects of stress and antidepressant treatment (2006)

The hippocampus is one of several limbic brain structures implicated in the pathophysiology and treatment of mood disorders. Preclinical and clinical studies demonstrate that stress and depression lead to reductions of the total volume of this structure and atrophy and loss of neurons in the adult hippocampus. One of the cellular mechanisms that could account for alterations of hippocampal structure as well as function is the regulation of adult neurogenesis. Stress exerts a profound effect on neurogenesis, leading to a rapid and prolonged decrease in the rate of cell proliferation in the adult hippocampus. In contrast, chronic antidepressant treatment up-regulates hippocampal neurogenesis, and could thereby block or reverse the atrophy and damage caused by stress. Recent studies also demonstrate that neurogenesis is required for the actions of antidepressants in behavioral models of depression. This review discusses the literature that has lead to a neurogenic hypothesis of depression and antidepressant action, as well as the molecular and cellular mechanisms that underlie the regulation of adult neurogenesis by stress and antidepressant treatment.
Streptococcus pneumoniae Surface Protein PcpA Elicits Protection against Lung Infection and Fatal Sepsis (2008)

Previous studies have suggested that pneumococcal choline binding protein A (PcpA) is important for the full virulence of Streptococcus pneumoniae, and its amino acid sequence suggests that it may play a role in cellular adherence. PcpA is under the control of a manganese-dependent regulator and is only expressed at low manganese concentrations, similar to those found in the blood and lungs. PcpA expression is repressed under high manganese concentrations, similar to those found in secretions. In this study, we have demonstrated that PcpA elicits statistically significant protection in murine models of pneumonia and sepsis. In the model of pneumonia with each of four challenge strains, statistically fewer S. pneumoniae cells were recovered from the lungs of mice immunized with PcpA and alum versus mice immunized with alum only. The immunizations reduced the median CFU by 4- to 400-fold (average of 28-fold). In the model of sepsis using strain TIGR4, PcpA expression resulted in shorter times to become moribund and subcutaneous immunization with PcpA increased survival times of mice infected with wild-type PcpA-expressing pneumococci.
Cross-comparison of Protein Recognition of Sialic Acid Diversity on Two Novel Sialoglycan Microarrays (2012)

Background: Various glycan microarrays are currently widely used, but systematic cross-comparisons are lacking. Results: We compare and contrast two sialoglycan microarrays using a variety of sialic acid-binding proteins. Conclusion: Diverse array formats can strengthen the quality of information, but differences between arrays may be observed. Significance: Glycan arrays with similar glycan structures cannot be simply assumed to give similar results.
Identification of active peptide sequences in the carboxyl-terminal cell binding domain of human thrombospondin-1. (1992)

Thrombospondin (TS) mediates attachment, spreading, and motility of several cell types through at least four cell binding domains: the amino-terminal heparin binding domain, the type I repeats containing the CSVTCG sequence, the RGDA sequence in the last of the type III calcium binding repeats and the carboxyl-terminal cell or platelet binding domain (CBD). The attachment of human melanoma cells (G361) to the COOH-terminal domain is independent of the RGDA sequence and is inhibited by the monoclonal antibody C6.7. To define the cell binding site(s) within this 212-residue COOH-terminal domain, we have synthesized eight overlapping peptides (seven 30-mers and a final 37-mer) representing the entire sequence of the CBD. Several of these peptides are insoluble in aqueous buffers at high concentration. Cell adhesion assays have been devised which employ covalent coupling of peptides in chaotropic solvents to chemically derivatized plastic 96-well plates. Three synthetic peptides, two of which are nonadjacent in the linear sequence, are potent attachment factors for G361 cells. C6.7 blocks adhesion to one of these peptides, whereas sulfated glycoconjugates inhibit adhesion of cells to all three. Polyclonal antibodies raised against the peptides inhibit cell adhesion to the peptides, the recombinant CBD, and to intact TS. The peptides GRGDSP and VTCG are not inhibitory. These sites are thus independent from the type I repeats and the RGDA sequence of TS. Each of the active peptides inhibits cell attachment to the other active peptides as well as to the CBD and to intact TS. This mutual inhibition suggests that the peptides share a common cellular receptor which may contain an associated glycoconjugate chain. These data indicate that the COOH-terminal cell binding domain of TS contains at least two peptide sequences which contribute to the attachment of a wide variety of cells.
Repolarization alternans: implications for the mechanism and prevention of sudden cardiac death (2003)

For nearly 100 years, beat to beat alternation of T wave amplitude, termed T wave alternans (TWA), has been closely linked to electrical instability in the heart. TWA is now established among the strongest markers of susceptibility to sudden cardiac death. Since computer technology allows for detection of very subtle yet clinically significant TWA during standard exercise testing, TWA has been used increasingly as a noninvasive clinical tool for identifying and treating patients at risk for sudden cardiac death. The observation of TWA hastening ventricular tachyarrhythmias in an extraordinary variety of clinical and experimental conditions suggest potential universality of TWA in the pathophysiological mechanism of sudden death. High resolution optical mapping studies have shown that TWA arises from alternans of repolarization at the level of the ventricular myocyte. Cellular alternans is likely due to the actions of one or more ionic currents and is closely related to, if not directly dependent on, the kinetics of intracellular calcium cycling. Impairment in calcium cycling at the cellular and sub-cellular levels has been implicated in the mechanism of cellulcar alternans. Importantly, spatially discordant alternans between cells is most likely a consequence of heterogeneities of electrophysiological properties between cells which span the ventricular wall, serving to amplify spatial heterogeneities of repolarization, and forming a substrate for reentrant excitation. Through this mechanism, TWA is linked directly and mechanistically to the pathogenesis of arrhythmias. Although available data would suggest that TWA is certainly closely related to a mechanism of arrhythmogenesis, and is a strong marker of clinical risk, the precise sequence of events which triggers sudden cardiac death, and the potential role of TWA in this process remains elusive.
In vivo recombination and the production of hybrid genes (1992)

In vivo recombination between homologous genes is increasingly being favoured as a means of generating proteins with altered and novel specificities. The typical procedure requires the cloning of two related genes on a single replicative plasmid of Escherichia coli and the selection or screening of recombinants. Up to now the recombination process between the cloned genes was generally thought to involve the recA function and the availability of free ends in the DNA molecule to be recombined. Our results show that neither is necessary. Recombinants are obtained by simply growing the bacteria that host the plasmid carrying the two cloned genes.
Caspases and neurodegeneration: on the cutting edge of new therapeutic approaches (2000)

Unregulated apoptosis underlies many pathological conditions, including neurodegenerative diseases. In this review, we focus on the role of cysteine aspartate-specific proteases (caspase) activity in Huntington disease (HD) and Alzheimer disease (AD) as two representative neurodegenerative disorders that normally manifest in mid- to late-life. Caspases appear to be involved in the molecular pathology of HD by directly cleaving huntingtin and generating toxic protein fragments containing the polyglutamine tract, and by being recruited and activated by polyglutamine-containing aggregates composed mainly of truncated huntingtin fragments. Several proteins involved in AD, including beta-amyloid precursor protein (APP) and presenilins (PSs), are also cleaved by caspases. For APP, caspase cleavage may contribute to toxicity by generating toxic fragments or by shifting APP processing toward an amyloidogenic pathway. For PSs, caspase cleavage disables antiapoptotic functions attributed to PS C-terminal fragments. These observations suggest that caspases actively contribute to the molecular pathogenesis of these diseases and support the development of caspase inhibitors as potential therapeutic approaches for chronic neurodegenerative disorders.
Investigation of Growth Hormone Releasing Hormone Receptor Structure and Activity Using Yeast Expression Technologies (1997)

Growth hormone releasing hormone (GHRH) is the positive regulator of growth hormone synthesis and secretion in the anterior pituitary. The peptide confers activity by binding to a seven transmembrane domain G protein-coupled receptor. Signal transduction proceeds through subsequent G alpha s stimulation of adenylyl cyclase. To investigate ligand/receptor and receptor/G protein associations, the human GHRH receptor was expressed in a modified S. cerevisiae strain which allows for facile measurement of receptor activity by cell prototrophy mediated by a reporter gene coupled to the yeast pheromone response pathway. GHRH-dependent signal activation in this system required the substitution of yeast G alpha protein with proteins containing C-terminal regions of G alpha s. A D60G variant (analogous to the little mouse mutation) of the receptor failed to respond to agonist. In parallel studies, GHRH29 and the N-terminal extracellular region of the receptor were expressed as Gal4 fusion proteins in a 2-hybrid assay. A specific interaction between these proteins was readily observed. The D60G mutation was engineered into the receptor fusion protein. This protein failed to interact with the ligand fusion, confirming the specificity of the association between unmodified proteins. These two yeast expression technologies should prove invaluable in additional structure/activity analyses of this ligand/receptor pair as well as other peptide ligands and receptors.
‘Non-specific’ binding. The problem, and a solution (1985)

The concept of 'non-specific' binding, as it relates to studies of the binding of hormones to their receptors, is reviewed. It is concluded that the most widely used operational definition, namely binding that is not displaceable by an excess of unlabelled ligand, is often inaccurate, resulting either in overestimation of the number of high-affinity receptors and underestimation of the affinity of a given hormone for its receptor, or in a curvilinear Scatchard plot suggesting (artifactually) the presence of negative co-operativity or multiple classes of binding sites. The general use of an alternative approach to non-specific binding, in which the non-specific component is assessed from an analysis of total binding, is advocated. The superiority of this approach is illustrated with data on the binding of high-density lipoproteins to their receptors.
Association of high tissue TMB and atezolizumab efficacy across multiple tumor types. (2018)

12000 Background: PD-L1 expression has limitations as a biomarker for checkpoint immunotherapy (CI). Prior atezolizumab (atezo) monotherapy studies suggest improved efficacy in high tissue tumor mutational burden (tTMB-H) cohorts. We report a large retrospective analysis associating tTMB with neoantigen load (NAL) and CI efficacy across multiple studies, tumor types and lines of therapy. Methods: Tissue TMB was evaluated by the FoundationOne (F1) assay across 7 atezo monotherapy studies: NSCLC n= 342 (FIR, BIRCH, POPLAR, OAK), metastatic urothelial carcinoma (mUC) n=400 (IMvigor210, 211), and other advanced solid tumors n=245 (PCD4989g). Pooled data yielded a biomarker evaluable population (BEP) of 987 patients (pts); 175 (17.7%) had TMB-H defined as ≥16 mutations/megabase (mut/Mb). Efficacy endpoints were overall response rate (ORR) and duration of response (DoR). Survival analysis is ongoing. Neoantigen load (NAL) was calculated by whole-exome sequencing (WES) and RNA-Seq. Results: tTMB was associated with efficacy across tumor types and lines of therapy. In the BEP, ORR was 16.4% (95% CI 14.2, 18.9), vs. 29.7% (95% CI 23.1, 37.1) in tTMB-H (≥16 mut/Mb, N=175), and 13.5% (95% CI 11.3, 16.1) in tTMB-Low (<16 mut/Mb, N=812). DoR benefit was also observed: median DoR=29.0 mths (95% CI 18.6, NA) in tTMB-H vs. 16.6 mths (95% CI 13.8, 23.1) in BEP and 13.8 mths (95% CI 12.5, 17.4) in tTMB-Low cohorts. This association was not seen in control cohorts of randomized studies OAK, POPLAR, and IMvigor211. Pooled ORR in controls was 14.9% in BEP, 14.4% in tTMB-H and 15.1% in tTMB-Low. Survival analysis by tTMB is ongoing. tTMB-H also identified a population independent of PD-L1 status. tTMB by F1 was positively correlated with WES-based NAL in mUC (Pearson=0.85, N=218) and NSCLC (Pearson=0.78, N=70). NAL was associated with atezo ORR in mUC (p=2.7 x 10-9). Conclusions: High tTMB (≥16 mut/Mb) is associated with improved atezo response and DoR across NSCLC, mUC and melanoma and lines of therapy. tTMB-H by F1 may serve as a surrogate biomarker for NAL and may complement PD-L1 expression in providing predictive value. Ongoing studies are prospectively evaluating both tissue TMB and blood-based TMB for efficacy with CI. Clinical trial information: NCT02008227 NCT01903993 NCT02031458 NCT01846416 NCT02951767 NCT02302807 NCT01375842.
Graphene‐based Materials: Graphene and Graphene Oxide: Synthesis, Properties, and Applications (Adv. Mater. 35/2010) (2010)

Abstract There is intense interest in graphene in fields such as physics, chemistry, and materials science, among others. Interest in graphene's exceptional physical properties, chemical tunability, and potential for applications has generated thousands of publications and an accelerating pace of research, making review of such research timely. Here is an overview of the synthesis, properties, and applications of graphene and related materials (primarily, graphite oxide and its colloidal suspensions and materials made from them), from a materials science perspective.
Mapping the determinants of human immunodeficiency virus 2 for infectivity, replication efficiency, and cytopathicity. (1993)

Human immunodeficiency virus 2 (HIV-2) ISY and the newly derived HIV-2KR are infectious molecular clones that yield viruses differing markedly in their abilities to infect and/or induce syncytia in various T- and monocytoid-cell lines. Chimeric viruses were constructed from these two viral genomes to localize the genetic determinants of some of these properties. Envelope sequences, particularly those spanning the CD4 binding site, appear to be critical for the ability of HIV-2KR to infect MOLT-4 clone 8 and SupT1 cells and to efficiently infect the H9 cell line. On the other hand, multiple determinants may contribute to cytopathicity (gp41 and nef) in H9 cells and replication efficiency in monocytic (THP-1) cells.
Quantifying surface-to-reservoir electromagnetics for waterflood monitoring in a Saudi Arabian carbonate reservoir (2013)

ABSTRACT We modeled surface-to-borehole controlled-source electromagnetics to assess the sensitivity of electromagnetic fields to the detection and evolution of the waterfront position in a Saudi Arabian carbonate reservoir. We studied a test well drilled for research purposes at the edge of the current waterfront. The 3D reservoir saturations were obtained by using a black oil simulator and later converted to resistivity using Archie’s empirical relation. The anisotropic overburden model was derived from the upscaling of triaxial resistivity logs acquired from the surface to reservoir depth in the well. The modeling study was performed by the combination of 3D finite-element time-domain and 3D finite-difference frequency-domain methods using surface galvanic sources in radial and transverse polarization modes with borehole receivers. Results indicated that the electric-field components have the largest sensitivity to static reservoir resistivity distributions and to the time-lapse resistivity changes. The vertical component of the electric field, in particular, showed the largest sensitivity to reservoir changes and obtained the best spatial resolution after inversion. A comparative analysis of the noise floor achievable in a vertical well by existing electromagnetic sensors versus the strength of the field changes over a two-year time-lapse scenario indicated that the electric field is the only electromagnetic component showing a magnitude of the change above the estimated noise floor. The obtained results suggested that the detection and monitoring of waterflooding around producing wells is feasible within the sensitivity offered by current borehole sensing technology using a surface-to-borehole acquisition configuration. In this framework, the combination of multicomponent electric and magnetic sensors deployed in vertical and horizontal wells would provide enhanced resolution for the reservoir properties by enabling a better description of anisotropic effects.
Development of a Preclinical Model for Hormonal Therapy of Human Endometrial Carcinomas (1993)

Endometrial carcinoma is the most common gynaecological malignancy. Progestins are widely used in the treatment of advanced and metastatic disease with about 20-40% response rate. Attempts to develop a predictive test for progestin-sensitivity of endometrial cancers are plagued by the problems of steroid receptor instability and the heterogeneous distribution of progesterone receptor. Successful development of a nude mouse model for human endometrial carcinoma has permitted a detailed investigation of the biological behaviour, hormonal modulation and resistance to progestin therapy. Use of this preclinical model should enhance our understanding of the hormonal mechanisms and lead to improved rational treatment strategies for this malignancy.
Citrus Pectin:  Characterization and Inhibitory Effect on Fibroblast Growth Factor−Receptor Interaction (2001)

This study was undertaken to characterize the pectin from four citrus species and to determine their in vitro inhibitory activities on the binding of fibroblast growth factor (FGF) to the FGF receptor (FGFR). Pectin from various parts of lemon, grapefruit, tangerine, and orange were isolated and characterized. Tangerine had the highest pectin content among the four citrus species. Segment membrane contained as much as or more pectin than flavedo/albedo. Anhydrogalacturonic content was highest in pectin from segment membrane of tangerine and flavedo/albedo of grapefruit. Lemon pectin contained the highest methoxyl content (MC), and grapefruit contained the largest proportion of lower molecular weight (<10000 Da) pectin. Tangerine contained the highest neutral sugar in both flavedo/albedo and segment membrane. The interdependency of heparin on factor-receptor interaction provides a means for identifying new antagonists of growth factor activity and thus for treatment of various diseases. These results showed that pectin significantly inhibited the binding of FGF-1 to FGFR1 in the presence of 0.1 microg/mL heparin. The pectin from the segment membrane of lemon was the most potent inhibitor. The inhibition activity was significantly correlated with sugar content, MC, and size of pectin. Kinetic studies revealed a competitive nature of pectin inhibition with the heparin, a crucial component of the FGF signal transduction process. The observation that the heparin-dependent biological activity of FGF signal transduction is antagonized by citrus pectin should be further investigated for the use of these pectins as anti-growth factor agents for potential health benefits.
The Immunological Function of iGb3 (2006)

The mechanistic studies on immune recognition of carbohydrates have been paved by the synergized advances in identifying the precise sugar structures recognized by the immune system, in analyzing the cellular and humoral components bearing the receptors for glycoconjugates, and production of the biological relevant carbohydrate epitopes by synthetic chemistry. In our current studies on natural antigenic glycolipids, we have found that the activation as well as the development of natural killer T cells (NKT) is guided by the information provided by glycolipid metabolism pathways in antigen presenting cells (APC). Based on genetic data and cellular immunological assays, we propose a neutral glycosphingolipid isoglobotrihexosylceramide, iGb3, as one of the candidates recognized by NKT cells under patho-physiological conditions such as cancer and auto-immune disease. New immunotherapy approaches might be explored by interfering with glycolipid metabolism or by directly supplementing rationally designed glycolipids.
Understanding intrinsic characteristics and system implications of flash memory based solid state drives (2009)

Flash Memory based Solid State Drive (SSD) has been called a "pivotal technology" that could revolutionize data storage systems. Since SSD shares a common interface with the traditional hard disk drive (HDD), both physically and logically, an effective integration of SSD into the storage hierarchy is very important. However, details of SSD hardware implementations tend to be hidden behind such narrow interfaces. In fact, since sophisticated algorithms are usually, of necessity, adopted in SSD controller firmware, more complex performance dynamics are to be expected in SSD than in HDD systems. Most existing literature or product specifications on SSD just provide high-level descriptions and standard performance data, such as bandwidth and latency. In order to gain insight into the unique performance characteristics of SSD, we have conducted intensive experiments and measurements on different types of state-of-the-art SSDs, from low-end to high-end products. We have observed several unexpected performance issues and uncertain behavior of SSDs, which have not been reported in the literature. For example, we found that fragmentation could seriously impact performance -- by a factor of over 14 times on a recently announced SSD. Moreover, contrary to the common belief that accesses to SSD are uncorrelated with access patterns, we found a strong correlation between performance and the randomness of data accesses, for both reads and writes. In the worst case, average latency could increase by a factor of 89 and bandwidth could drop to only 0.025MB/sec. Our study reveals several unanticipated aspects in the performance dynamics of SSD technology that must be addressed by system designers and data-intensive application users in order to effectively place it in the storage hierarchy.
Azide: A Unique Dipole for Metal‐Free Bioorthogonal Ligations (2010)

Covalently bound azide on a (small) organic molecule or a (large) biomolecular structure has proven an important handle for bioconjugation. Azides are readily introduced, small, and stable, yet undergo smooth ligation with a range of reactive probes under mild conditions. In particular, the potential of azides to undergo metal-free reactions with strained unsaturated systems has inspired the development of an increasing number of reactive probes, which are comprehensively summarized here. For each individual probe, the synthetic preparation is described, together with reaction kinetics and the full range of applications, from materials science to glycoprofiling. Finally, a qualitative and quantitative comparison of azido-reactive probes is provided.