gebhart/patrepeval huggingface dataset:
Quantitative Spatial Profiling of Immune Populations in Pancreatic Ductal Adenocarcinoma Reveals Tumor Microenvironment Heterogeneity and Prognostic Biomarkers (2022)

Quantitative image analysis of PDAC specimens reveals intertumoral and intratumoral heterogeneity of immune populations and identifies spatial immune architectures that are significantly associated with disease prognosis.
structural characterization of the interaction between the C-terminal domain of the influenza polymerase PA subunit and an optimized small peptide inhibitor (2020)

Influenza viruses can cause severe respiratory infections in humans, leading to nearly half a million deaths worldwide each year. Improved antiviral drugs are needed to address the threat of development of novel pandemic strains. Current therapeutic interventions target three key proteins in the viral life cycle: neuraminidase, the M2 channel and RNA-dependent-RNA polymerase. Protein-protein interactions between influenza polymerase subunits are potential new targets for drug development. Using a newly developed assay based on AlphaScreen technology, we screened a peptide panel for protein-protein interaction inhibitors to identify a minimal PB1 subunit-derived peptide that retains high inhibition potential and can be further modified. Here, we present an X-ray structure of the resulting decapeptide bound to the C-terminal domain of PA polymerase subunit from pandemic isolate A/California/07/2009 H1N1 at 1.6 Å resolution and discuss its implications for the design of specific, potent influenza polymerase inhibitors.
Appraisal theories for emotion classification in text (2020)

Over the last years the automated classification of emotions from text has become an interesting topic in natural language processing with many applications. Theories from psychological studies on emotions have been widely utilized to support the task of the automated assignment of emotions to textual content. Most commonly used theories are the fundamental emotions theory like proposed by Paul Ekman and the dimensional model of affect proposed by Albert Mehrabian and James Russell. However, these theories ignore other psychological theories, namely the cognitive appraisal theories, which explain emotions as a response to an individual interpretation of a given situation. Such appraisal theories have only been minorly used in the attempt to improve performance of emotion classification. In addition, there are no datasets annotated with appraisal dimensions. This work filled this gap by annotating a dataset with appraisal dimensions. Further, this work conducted several experiments in which classification models utilized these appraisal annotations. Although this work was not able to show a clear improvement in a real-world setting, the results show that appraisal dimensions have the potential to improve the performance of classifiers, which predict emotions from text.
Indium-Induced Addition of Bromomethylacrylates to Phthaloyl-Protected Amino Aldehydes (2002)

The indium-mediated reaction of phthaloyl-protected α-amino aldehydes 1-4 with methyl 2-(bromomethyl)acrylate in aqueous solvents was investigated. The homoallyl alcohols 5-8 were formed in 72-89% yields, the anti-isomers being the major diastereoisomers (dr 45:55-18:82). Acid-catalyzed esterification (H2SO4 in Et2O) led to α-methylene γ-butyrolactones 9,10 with yields ranging from 88 to 99%. Conjugate addition of cyanide and thiophenolate led to the addition products with improved selectivities compared with additions to carbamate-protected substrates. During the conjugate addition of a cuprate, a trapping of the intermediate enolate by a phthaloyl carbonyl group occurred, leading to tetracycle 11 in 57% yield. The configuration of all diastereo­isomers could be established by three X-ray crystallographic analyses and by NMR spectroscopy.
Challenges and recommendations to improve the installability and archival stability of omics computational tools (2019)

Developing new software tools for analysis of large-scale biological data is a key component of advancing modern biomedical research. Scientific reproduction of published findings requires running computational tools on data generated by such studies, yet little attention is presently allocated to the installability and archival stability of computational software tools. Scientific journals require data and code sharing, but none currently require authors to guarantee the continuing functionality of newly published tools. We have estimated the archival stability of computational biology software tools by performing an empirical analysis of the internet presence for 36,702 omics software resources published from 2005 to 2017. We found that almost 28% of all resources are currently not accessible through uniform resource locators (URLs) published in the paper they first appeared in. Among the 98 software tools selected for our installability test, 51% were deemed "easy to install," and 28% of the tools failed to be installed at all because of problems in the implementation. Moreover, for papers introducing new software, we found that the number of citations significantly increased when authors provided an easy installation process. We propose for incorporation into journal policy several practical solutions for increasing the widespread installability and archival stability of published bioinformatics software.
Role of hypoxia and extracellular matrix‐integrin binding in the modulation of angiogenic growth factors secretion by retinal pigmented epithelial cells (1999)

The retinal pigmented epithelium (RPE) is a monolayer of polarized cells located between retinal photoreceptors and blood vessels of the choroid. The basal surface of RPE cells rests on Bruch's membrane, a complex extracellular matrix structure which becomes abnormal in several disease processes, including age-related macular degeneration (AMD). Ruptures or abnormalities in Bruch's membrane are frequently accompanied by choroidal neovascularization. Disturbed interaction of RPE cells with their extracellular matrix (ECM) could play a role in this process. The present study was undertaken to examine the complex interactions between hypoxia, integrin, and ECM in the regulation of RPE functions. Antibody blocking experiments demonstrated that RPE cell adhesion to vitronectin is mediated primarily through αvβ5 and adhesion to fibronectin occurs through α5β1. RPE adhesion to immobilized laminin demonstrated highest level of non-RGD-mediated adhesion as compared to that with collagen IV or the RGD matrices such as vitronectin (αvβ5) , fibronectin (α5β1), or thrombospondin (α5β1 + αvβ5). Addition of soluble vitronectin, or fibrinogen to RPE cell cultures resulted in a small to moderate increase in VEGF and FGF2 in the media, while each of these growth factors was dramatically increased after addition of thrombospondin 1 (TSP1). In contrast, soluble fibronectin resulted in differential upregulation of VEGF but not FGF2. Similarly, immobilized TSP1 resulted in differential greater upregulation in VEGF but not FGF2 release from RPE as compared to other ECMs under either normoxic or hypoxic conditions. Additionally, Hypoxia resulted in a time-dependent increase in VEGF, but not FGF2 release in the media. RPE cells grown on TSP1-coated plates showed increased VEGF and FGF2 in their media compared to cells grown on plates coated with type IV collagen, laminin, vitronectin, or fibronectin. The TSP1-induced increase in secretion of growth factors was partially blocked by anti-α5β1, anti-αvβ3, and anti-αvβ5 antibodies indicating that it may be mediated in part by TSP1 binding to those integrins. These data suggest that alterations in oxygen levels (hypoxia/ischemia) and ECM of RPE cells, a prominent feature of AMD, can cause increased secretion of angiogenic growth factors that might contribute to the development of choroidal neovascularization. These data also suggest the potential modulatory role of VEGF release from RPE by ECM and αvβ5 and α5β1 integrins. J. Cell. Biochem. 74:135–143, 1999. © 1999 Wiley-Liss, Inc.
High-dimensional Causal Mediation Analysis with a Large Number of Mediators Clumping at Zero to Assess the Contribution of the Microbiome to the Risk of Bacterial Pathogen Colonization in Older Adults (2019)

Background: Causal mediation analysis is conducted in biomedical research with the goal of investigating causal mechanisms that consist of both direct causal pathways between the treatment and outcome variables and intermediate causal pathways through mediators. Recently, this type of analysis has been applied in the context of bioinformatics; however, it encounters the obstacle of high-dimensional and semi-continuous mediators with clumping at zero. Methods: In this article, we develop a methodology to conduct high-dimensional causal mediation analysis with a modeling framework that involves (i) a nonlinear model for the outcome variable, (ii) two-part models for semi-continuous mediators with clumping at zero, and (iii) sophisticated variable-selection techniques using machine learning. We conducted simulations and investigated the performance of the proposed method. It is shown that the proposed method can provide reliable statistical information on the causal effects with high-dimensional mediators. The method is adopted to assess the contribution of the intestinal microbiome to the risk of bacterial pathogen colonization in older adults from US nursing homes. Conclusions: The proposed high-dimensional causal mediation analysis with nonlinear models is an innovative and reliable approach to conduct causal inference with high-dimensional mediators.
BAsE-Seq: a method for obtaining long viral haplotypes from short sequence reads (2014)

We present a method for obtaining long haplotypes, of over 3 kb in length, using a short-read sequencer, Barcode-directed Assembly for Extra-long Sequences (BAsE-Seq). BAsE-Seq relies on transposing a template-specific barcode onto random segments of the template molecule and assembling the barcoded short reads into complete haplotypes. We applied BAsE-Seq on mixed clones of hepatitis B virus and accurately identified haplotypes occurring at frequencies greater than or equal to 0.4%, with >99.9% specificity. Applying BAsE-Seq to a clinical sample, we obtained over 9,000 viral haplotypes, which provided an unprecedented view of hepatitis B virus population structure during chronic infection. BAsE-Seq is readily applicable for monitoring quasispecies evolution in viral diseases.
New Insights into Podocyte Biology in Glomerular Health and Disease (2017)

Podocyte and glomerular research is center stage for the development of improved preventive and therapeutic strategies for chronic progressive kidney diseases. Held April 3-6, 2016, the 11th International Podocyte Conference took place in Haifa and Jerusalem, Israel, where participants from all over the world presented their work on new developments in podocyte research. In this review, we briefly highlight the advances made in characterizing the mechanisms involved in podocyte development, metabolism, acquired injury, and repair, including progress in determining the roles of genetic variants and microRNA in particular, as well as the advances made in diagnostic techniques and therapeutics.
Assessing Immune-Related Adverse Events of Efficacious Combination Immunotherapies in Preclinical Models of Cancer (2016)

New combination immunotherapies are displaying both efficacy and immune-related adverse events (irAE) in humans. However, grade 3/4 irAEs occur in a high proportion, which can lead to discontinuation of treatment and can result in fatalities if not promptly treated. Prolonged T regulatory cell (Treg) depletion in tumor-bearing Foxp3-DTR mice using diphtheria toxin (DT) mirrored the spectrum of antitumor responses and severity of irAEs that can occur in ipilimumab/nivolumab-treated patients. In contrast, transient Treg depletion or anti-CTLA-4/PD-1 therapy had equivalent effects in mice, lowering the immune tolerance threshold and allowing irAEs to be more easily induced following treatment with additional immunomodulatory antibodies. Transient Treg depletion of DT in combination with anti-PD-1 or anti-TIM-3 monoclonal antibodies had a high therapeutic window compared with DT plus anti-CD137. In contrast, DT plus anti-CD137-treated mice developed severe irAEs similar to grade 3/4 clinical symptoms. These irAEs appeared because of an infiltration of activated proliferating effector T cells in the tissues producing IFNγ and TNF; however, TNF blockade decreased irAEs severity without impacting on tumor growth. Cancer Res; 76(18); 5288-301. ©2016 AACR.
Electromagnetic properties of carbon-based nanocomposites: The effect of filler and resin characteristics (2010)

Carbon nanostructures such as carbon nanotubes and most recently discovered graphenes can be included in very low weight percentages in a polymer matrix to create new lightweight nanocomposites with improved electrical, electromagnetic and mechanical performances. The present study shows the effect of the filler type and concentration, and of the characteristics of the thermosetting resin, on both the effective complex permittivity and the effective conductivity of the nanocomposites at radio-frequency. Three different types of fillers are considered: commercially available multi-wall carbon nanotubes and nickel-coated microfibers, and graphene nanoplatelets produced in our lab. The results show that it is possible to produce nanocomposites with tailored electromagnetic properties, i.e. with controlled dielectric constant and effective conductivity at the same time, by properly selecting the type of matrix used, considering the characteristics of the nanofiller.
Adaptive transmission scheme using dynamic aggregation and fragmentation in WLAN MAC (2014)

Transmission Opportunity (TXOP) which is specified in the IEEE 802.11e enables a Wi-Fi station to transmit multiple frames consecutively. In this paper, we propose an adaptive transmission scheme based on the Dynamic Aggregation and Fragmentation (DAF) algorithm. With real-time scheduling and adaptive TXOP allocation being the main focus of the suggested adaptive transmission scheme, optimum transmission parameters are also calculated and used under different Bit Error Rate (BER) conditions. The suggested transmission scheme works in synchronous with the DAF scheme which focuses mainly on efficient use of TXOP and minimizing retransmissions by adjusting the frame and fragment size dynamically. Analytical model for the scheme is developed to evaluate the throughput, delay performance, and stability with respect to different traffic classes and scenarios, and proved with NS-3 simulator. The simulation result shows that there is significant throughput improvement keeping the delay minimum with the scheme while ensuring long term fairness and performance stability to channel conditions and underlying physical rates.
Right ventricular dysfunction and its relationships to otherhemodynamic variables in patients with chronic heart failure (2002)

Right ventricular dysfunction and its relationships to other
hemodynamic variables in patients with chronic heart failure
Comparative Utility of Mineralized Collagen as an Osteoinductive Material (2017)

In prior work we have studied the mineralization of collagen, in the absence of other non-collagenous proteins, by nucleation and precipitation of calcium phosphates. 1 In this article we describe the results of an in vivo experiment with this mineralized collagen. The experiment is designed to test the material as a potential substitute for autograft bone and for delivering bone growth factors like BMPs (bone morphogenic proteins) to foster bone formation. Collagenous matrix 2 and demineralized bone 3–5 are being used for delivering such bone inducing growth factors. Other bio-active matrices being considered are polylactide-glycolide co-polymers, 6 fibrin, 7 porous hydroxyapatite, 8 tricalcium phosphate 9 and other calcium-rich minerals. 10,11 The overall objective of this study is the evaluation of mineralized collagen, nanophase composite of collagen and hydroxyapatite, for its osteoconductivity and its ability to express the incorporated bone morphogenic protein-2 (BMP-2) in vivo. Further these properties of mineralized collagen are compared with other bioactive matrices: [a] type-I collagen, [b] polylactide glycolide (1:1) co-polymer, and [c] fibrin glue. The results of the study demonstrate that mineralized collagen may serve as a substitute for autograft bone and for the delivery of BMP-2.
Ischemia/reperfusion injury of the ascending colon in ponies: a correlative study utilizing microvascular histopathology and corrosion casting. (1993)

Volvulus of the ascending colon (ACV) in the horse results in microvascular injury and necrosis of the intestinal mucosa. This study investigated the site and type of microvascular injury which occurs within the mucosa and submucosa following ACV. Histopathology of volvulus treated ponies demonstrated mucosal necrosis with microvascular hemorrhage and thrombosis. Thrombi occurred within the subepithelial capillaries and edema and hemorrhage developed throughout the mucosa and submucosa. Vascular casts allowed 3-D viewing of samples obtained from the entire pelvic flexure and demonstrated two distinct microvascular changes: 1) disruption of the colonic glandular capillary network occurred concomitantly with the mucosal injury, and 2) extensive endothelial leakage from the submucosal microvasculature contributes to edema formation. Thus, microcorrosion casting of the equine pelvic flexure provided an effective means to characterize the location and severity of vascular leakage and visualize the extent and severity of injury to the capillary network not easily depicted by histopathology. Microvascular casting in conjunction with routine histopathology provided additional information on the pathomorphologic changes in this model of ischemia/reperfusion injury.
TRPC channels are not required for graded persistent activity in entorhinal cortex neurons (2019)

Adaptive behavior requires the transient storage of information beyond the physical presence of external stimuli. This short-lasting form of memory involves sustained ("persistent") neuronal firing which may be generated by cell-autonomous biophysical properties of neurons or/and neural circuit dynamics. A number of studies from brain slices reports intrinsically generated persistent firing in cortical excitatory neurons following suprathreshold depolarization by intracellular current injection. In layer V (LV) neurons of the medial entorhinal cortex (mEC) persistent firing depends on the activation of cholinergic muscarinic receptors and is mediated by a calcium-activated nonselective cation current (I<sub>CAN</sub> ). The molecular identity of this conductance remains, however, unknown. Recently, it has been suggested that the underlying ion channels belong to the canonical transient receptor potential (TRPC) channel family and include heterotetramers of TRPC1/5, TRPC1/4, and/or TRPC1/4/5 channels. While this suggestion was based on pharmacological experiments and on effects of TRP-interacting peptides, an unambiguous proof based on TRPC channel-depleted animals is pending. Here, we used two different lines of TRPC channel knockout mice, either lacking TRPC1-, TRPC4-, and TRPC5-containing channels or lacking all seven members of the TRPC family. We report unchanged persistent activity in mEC LV neurons in these animals, ruling out that muscarinic-dependent persistent activity depends on TRPC channels.
Supplementary Figures Legends from Combined MEK and PI3K Inhibition in a Mouse Model of Pancreatic Cancer (2023)

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Emeritus Professor of Plant Biotechnology at the University of Nottingham (2022)

"Emeritus Professor of Plant Biotechnology at the University of Nottingham." The Journal of Horticultural Science and Biotechnology, 97(1), p. 2
PINE: An Automation Tool to Extract and Visualize Protein-Centric Functional Networks (2020)

Recent surges in mass spectrometry-based proteomics studies demand a concurrent rise in speedy and optimized data processing tools and pipelines. Although several stand-alone bioinformatics tools exist that provide protein-protein interaction (PPI) data, we developed Protein Interaction Network Extractor (PINE) as a fully automated, user-friendly, graphical user interface application for visualization and exploration of global proteome and post-translational modification (PTM) based networks. PINE also supports overlaying differential expression, statistical significance thresholds, and PTM sites on functionally enriched visualization networks to gain insights into proteome-wide regulatory mechanisms and PTM-mediated networks. To illustrate the relevance of the tool, we explore the total proteome and its PTM-associated relationships in two different nonalcoholic steatohepatitis (NASH) mouse models to demonstrate different context-specific case studies. The strength of this tool relies in its ability to (1) perform accurate protein identifier mapping to resolve ambiguity, (2) retrieve interaction data from multiple publicly available PPI databases, and (3) assimilate these complex networks into functionally enriched pathways, ontology categories, and terms. Ultimately, PINE can be used as an extremely powerful tool for novel hypothesis generation to understand underlying disease mechanisms.
The important role of CNS facilitation and inhibition for chronic pain (2013)

Multiple studies have demonstrated that the pain experience among individuals is highly variable. Even under circumstances where the tissue injuries are similar, individual pain experiences may vary drastically. However, this individual difference in pain sensitivity is not only related to sensitivity of peripheral pain receptors, but also to variability in CNS pain processing. Peripheral impulses derived from tissue receptors undergo modification in dorsal horn neurons that can either result in inhibition or facilitation of pain. Such influences are particularly apparent in inflammation where not only peripheral, but also central, pain modulatory mechanisms can significantly increase nociceptive pain. Emotional state, level of anxiety, attention and distraction, memories, stress, fatigue and many other factors can either increase or reduce the pain experience. Increasing evidence suggests that 'bottom-up' and 'top-down' modulatory circuits within the spinal cord and brain play an important role in pain processing, which can profoundly affect the experience of pain.
Reward Motivation Accelerates the Onset of Neural Novelty Signals in Humans to 85 Milliseconds (2009)

The neural responses that distinguish novel from familiar items in recognition memory tasks are remarkably fast in both humans and nonhuman primates. In humans, the earliest onsets of neural novelty effects emerge at about approximately 150-200 ms after stimulus onset. However, in recognition memory studies with nonhuman primates, novelty effects can arise at as early as 70-80 ms. Here, we address the possibility that this large species difference in onset latencies is caused experimentally by the necessity of using reward reinforcement to motivate the detection of novel or familiar items in nonhuman primates but not in humans. Via magnetoencephalography in humans, we show in two experiments that the onset of neural novelty signals is accelerated from approximately 200 ms to approximately 85 ms if correct recognition memory for either novel or familiar items is rewarded. Importantly, this acceleration is independent of whether the detection of the novel or the familiar scenes is rewarded. Furthermore, this early novelty effect contributed to memory retrieval because neural reward responses, which were contingent upon novelty detection, followed approximately 100 ms later. Thus, under the contextual influence of reward motivation, behaviorally relevant novelty signals emerge much faster than previously held possible in humans.