gebhart/patrepeval huggingface dataset:
Bacteriological profiling of diphenylureas as a novel class of antibiotics against methicillin-resistant Staphylococcus aureus (2017)

Bacterial resistance to antibiotics remains an imposing global public health challenge. Of the most serious pathogens, methicillin-resistant Staphylococcus aureus (MRSA) is problematic given strains have emerged that exhibit resistance to several antibiotic classes including β-lactams and agents of last resort such as vancomycin. New antibacterial agents composed of unique chemical scaffolds are needed to counter this public health challenge. The present study examines two synthetic diphenylurea compounds 1 and 2 that inhibit growth of clinically-relevant isolates of MRSA at concentrations as low as 4 µg/mL and are non-toxic to human colorectal cells at concentrations up to 128 μg/mL. Both compounds exhibit rapid bactericidal activity, completely eliminating a high inoculum of MRSA within four hours. MRSA mutants exhibiting resistance to 1 and 2 could not be isolated, indicating a low likelihood of rapid resistance emerging to these compounds. Bacterial cytological profiling revealed the diphenylureas exert their antibacterial activity by targeting bacterial cell wall synthesis. Both compounds demonstrate the ability to resensitize vancomycin-resistant Staphylococcus aureus to the effect of vancomycin. The present study lays the foundation for further investigation and development of diphenylurea compounds as a new class of antibacterial agents.
A Qualitative Model of the Differentiation Network in Chondrocyte Maturation: A Holistic View of Chondrocyte Hypertrophy (2016)

Differentiation of chondrocytes towards hypertrophy is a natural process whose control is essential in endochondral bone formation. It is additionally thought to play a role in several pathophysiological processes, with osteoarthritis being a prominent example. We perform a dynamic analysis of a qualitative mathematical model of the regulatory network that directs this phenotypic switch to investigate the influence of the individual factors holistically. To estimate the stability of a SOX9 positive state (associated with resting/proliferation chondrocytes) versus a RUNX2 positive one (associated with hypertrophy) we employ two measures. The robustness of the state in canalisation (size of the attractor basin) is assessed by a Monte Carlo analysis and the sensitivity to perturbations is assessed by a perturbational analysis of the attractor. Through qualitative predictions, these measures allow for an in silico screening of the effect of the modelled factors on chondrocyte maintenance and hypertrophy. We show how discrepancies between experimental data and the model's results can be resolved by evaluating the dynamic plausibility of alternative network topologies. The findings are further supported by a literature study of proposed therapeutic targets in the case of osteoarthritis.
Multi-Label Learning With Fused Multimodal Bi-Relational Graph (2014)

The problem of multi-label image classification using multiple feature modalities is considered in this work. Given a collection of images with partial labels, we first model the association between different feature modalities and the images labels. These associations are then propagated with a graph diffusion kernel to classify the unlabeled images. Towards this objective, a novel Fused Multimodal Bi-relational Graph representation is proposed, with multiple graphs corresponding to different feature modalities, and one graph corresponding to the image labels. Such a representation allows for effective exploitation of both feature complementariness and label correlation. This contrasts with previous work where these two factors are considered in isolation. Furthermore, we provide a solution to learn the weight for each image graph by estimating the discriminative power of the corresponding feature modality. Experimental results with our proposed method on two standard multi-label image datasets are very promising.
Performance of time delay estimation in a cognitive radar (2017)

A cognitive radar adapts the transmit waveform in response to changes in the radar and target environment. In this work, we analyze the recently proposed sub-Nyquist cognitive radar wherein the total transmit power in a multi-band cognitive waveform remains the same as its full-band conventional counterpart. For such a system, we derive lower bounds on the mean-squared-error (MSE) of a single-target time delay estimate. We formulate a procedure to select the optimal bands, and recommend distribution of the total power in different bands to enhance the accuracy of delay estimation. In particular, using Cramér-Rao bounds, we show that equi-width subbands in cognitive radar always have better delay estimation than the conventional radar. Further analysis using Ziv-Zakai bound reveals that cognitive radar performs well in low signal-to-noise (SNR) regions.
Simultaneous measurement of temperature and refractive index using focused ion beam milled Fabry-Perot cavities in optical fiber micro-tips (2016)

Optical fiber micro-tips are promising devices for sensing applications in small volume and difficult to access locations, such as biological and biomedical settings. The tapered fiber tips are prepared by dynamic chemical etching, reducing the size from 125 μm to just a few μm. Focused ion beam milling is then used to create cavity structures on the tapered fiber tips. Two different Fabry-Perot micro-cavities have been prepared and characterized: a solid silica cavity created by milling two thin slots and a gap cavity. A third multi-cavity structure is fabricated by combining the concepts of solid silica cavity and gap cavity. This micro-tip structure is analyzed using a fast Fourier transform method to demultiplex the signals of each cavity. Simultaneous measurement of temperature and external refractive index is then demonstrated, presenting sensitivities of - 15.8 pm/K and -1316 nm/RIU, respectively.
Direct inhibition of the Notch transactivation complex with stapled peptides in T-ALL (2008)

2547 The Notch signaling pathway is a highly conserved regulator of diverse biological processes including cellular differention, proliferation and death. Activation of Notch1 receptors results in cleavage and release of an intracellular domain (ICN1). Following translocation to the nucleus, ICN1 forms a ternary complex with the transcriptional repressor CSL bound to cognate DNA. This event triggers a repressor-to-activator switch, as an interfacial groove recruits the Mastermind-Like (MAML1) co-activator protein. Activating mutations in NOTCH1 are found in more than 50% of T-Cell Acute Lymphoblastic Leukemia (T-ALL) cases, promoting protein stability and establishing a direct link to disease pathogenesis. Despite efforts to inhibit the pathway with inhibitors of gamma-secretase, intervention at this step appears to impart growth inhibitory effects in only a subset of T-ALL cell lines, a result that has recently been explained in part by mutations in ubiquitin-ligases affecting protein turnover. Therefore, direct inhibitors of ICN1 function are highly desirable. Drawing upon insights afforded by the resolved crystal structure of the DNA-bound transactivation complex, we have designed synthetically constrained peptides predicted to disrupt complex assembly. Specifically, we have synthesized a series of hydrocarbon stapled alpha-helical peptides based on short stretches of the MAML protein (SAHMs) predicted to engage the composite ICN1:CSL interface. Direct, high-affinity binding to purified components of the Notch complex has been confirmed using surface plasmon resonance. Intracellular association with ICN1 and CSL has been established using bidirectional affinity chromatography and immunoblotting. SAHM1 induces a dose-dependent knockdown of endogenous Notch1 target genes including HES1, HEY1 and cMYC in T-ALL cell lines. Remarkably, inhibition of Notch signaling by SAHM1 induces apoptosis and selective cytotoxicity at 48 hours in a panel of T-ALL cell lines with known mutations in NOTCH1. Supporting an on-target mechanism of action, we have prepared a mutant analogue of SAHM1 containing a two-residue rearrangement (SAHM1D). SAHM1D possesses reduced binding affinity for the Notch complex by SPR and ligand affinity chromatography. Despite comparable intracellular access, SAHM1D lacks both transcriptional and cytotoxic effects on cultured T-ALL cell lines in vitro. Efficacy studies have also been performed in vivo using a novel murine model of T-ALL harboring clinically relevant mutations in NOTCH1. Remarkably, ex-vivo treatment with a single dose of SAHM1 prior to inoculation significantly reduces spleen weight and extends life when compared to vehicle alone. In summary, we report here the design, biochemical characterization and translational rationale supporting the first direct inhibitor of the Notch transactivation complex in T-ALL.
Toward Serotonin Fluorescent False Neurotransmitters: Development of Fluorescent Dual Serotonin and Vesicular Monoamine Transporter Substrates for Visualizing Serotonin Neurons (2017)

Ongoing efforts in our laboratories focus on design of optical reporters known as fluorescent false neurotransmitters (FFNs) that enable the visualization of uptake into, packaging within, and release from individual monoaminergic neurons and presynaptic sites in the brain. Here, we introduce the molecular probe FFN246 as an expansion of the FFN platform to the serotonergic system. Combining the acridone fluorophore with the ethylamine recognition element of serotonin, we identified FFN54 and FFN246 as substrates for both the serotonin transporter and the vesicular monoamine transporter 2 (VMAT2). A systematic structure-activity study revealed the basic structural chemotype of aminoalkyl acridones required for serotonin transporter (SERT) activity and enabled lowering the background labeling of these probes while maintaining SERT activity, which proved essential for obtaining sufficient signal in the brain tissue (FFN246). We demonstrate the utility of FFN246 for direct examination of SERT activity and SERT inhibitors in 96-well cell culture assays, as well as specific labeling of serotonergic neurons of the dorsal raphe nucleus in the living tissue of acute mouse brain slices. While we found only minor FFN246 accumulation in serotonergic axons in murine brain tissue, FFN246 effectively traces serotonin uptake and packaging in the soma of serotonergic neurons with improved photophysical properties and loading parameters compared to known serotonin-based fluorescent tracers.
Basal forebrain parvalbumin neurons mediate arousals from sleep induced by hypercarbia or auditory stimuli (2019)

SUMMARY Brief arousals from sleep in patients with sleep apnea and other disorders prevent restful sleep, and contribute to cognitive, metabolic and physiologic dysfunction. Little is currently known about which neural systems mediate these brief arousals, hindering the development of treatments. The basal forebrain (BF) receives inputs from many nuclei of the ascending arousal system. These inputs include the brainstem parabrachial neurons which promote arousal in response to elevated blood carbon dioxide levels, as seen in sleep apnea. Optical inhibition of the terminals of parabrachial neurons in the BF impairs cortical arousals to hypercarbia, but which cell types within the BF mediate cortical arousals in response to hypercarbia or other sensory stimuli is unknown. Here using optogenetic techniques in mice, we show that BF parvalbumin (PV) neurons fulfill several criteria for a system mediating brief arousals from sleep. Optical stimulation of BF PV neurons during the light period, when mice normally sleep, caused rapid transitions to wakefulness and increased wake bout durations. Unlike many other ascending arousal systems, arousals induced by stimulation of BF PV neurons were brief, resulting in only a small (13.6%) increase in the total amount of wakefulness. Bilateral optical inhibition of BF PV neurons increased the latency to arousal produced by hypercarbia or auditory stimuli. Thus, BF PV neurons are an important component of the brain circuitry which generates brief arousals from sleep in response to internal and external sensory stimuli.
Medical image search and retrieval using local binary patterns and KLT feature points (2008)

In the medical domain, experts usually look at specific anatomical structures to identify the cause of a pathology, and therefore they can largely benefit from automated tools that retrieve relevant slice(s) from a patient's image volume in diagnosis. Accordingly, this paper introduces a novel search and retrieval work for finding relevant slices in brain MR (magnetic resonance) volumes. As intensity is non-standard in MR we explore performance of two complementary intensity invariant features, local binary patterns and Kanade-Lucas-Tomasi feature points, their extended versions with spatial context, and a simple edge descriptor with spatial context. Experiments on real and simulated data showed that the local binary patterns with spatial context is fast, highly accurate, and robust to geometric deformations and intensity variations.
Abstract 3720: TACH101, a first-in-class inhibitor of KDM4 histone lysine demethylase for the treatment of diffuse large B-cell lymphoma (2022)

Abstract Background: Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma (NHL) in the US accounting for about 22% of newly diagnosed cases of B-cell NHL. It is considered to be more aggressive and to have worse prognosis due to low response to existing treatments. KDM4 is a family of histone demethylases that can drive tumor growth by regulating transcription, cell cycle, and DNA replication/repair. Overexpression of KDM4 alters post-translational histone modification and is associated with many types of cancer, including DLBCL. TACH101 is a novel, potent small molecule inhibitor of KDM4 that is being developed for treatment of advanced cancers, including DLBCL. Methods: TACH101 was evaluated in vitro and in vivo using cancer cell lines and patient-derived organoid (PDO) and xenograft (PDX) models of DLBCL. Results: TACH101 is a reversible, α-ketoglutarate competitive, selective and potent inhibitor of KDM4 isoforms A-D with IC50 values &amp;lt; 0.100 μM for all four isoforms. An initial screen using a 301-cell line panel showed that DLBCL cell lines are sensitive to TACH101 (IC50 &amp;lt; 10 nM). In an additional panel of DLBCL cell lines, TACH101 inhibited proliferation in a dose-dependent manner in all DLBCL cell lines, independent of molecular subtype, with mean IC50’s of 0.03 ± 0.01 μM in ABC DLBCL cell lines (n=6); 0.02 ± 0.01 μM in GCB DLBCL cell lines (n=7) and 0.02 ± 0.01 μM in PMBL DLBCL cell lines (n=2). In OCI-LY19 DLBCL xenografts in vivo, TACH101 was well tolerated and inhibited tumor growth by 55% to 100%, depending on dosing regimen (either QD or BID following a 3 days on/4 days off schedule). In PK studies, TACH101 exhibited low clearance, moderate volume of distribution, and good oral bioavailability in mouse, rat, and dog. Moreover, treatment with TACH101 resulted in little or no inhibitory effects on CYP enzymes. Toxicity studies in rats and dogs identified potential target tissues and provided safety guidance for the use of TACH101 in human studies. Conclusions: The KDM4 inhibitor, TACH101, had compelling activity in preclinical DLBCL models, suggesting that TACH101 could be an effective therapy for DLBCL. Preparations to advance the drug into clinical trials are underway. Citation Format: Frank Perabo, Chandtip Chandhasin, Sanghee Yoo, Joselyn Del Rosario, Young K. Chen, Ellen Filvaroff, Jeffrey A. Stafford, Stephen Quake, Michael F. Clarke. TACH101, a first-in-class inhibitor of KDM4 histone lysine demethylase for the treatment of diffuse large B-cell lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3720.
Active Memory Networks for Language Modeling (2018)

Making predictions of the following word given the back history of words may be challenging without meta-information such as the topic.Standard neural network language models have an implicit representation of the topic via the back history of words.In this work a more explicit form of topic representation is used via an attention mechanism.Though this makes use of the same information as the standard model, it allows parameters of the network to focus on different aspects of the task.The attention model provides a form of topic representation that is automatically learned from the data.Whereas the recurrent model deals with the (conditional) history representation.The combined model is expected to reduce the stress on the standard model to handle multiple aspects.Experiments were conducted on the Penn Tree Bank and BBC Multi-Genre Broadcast News (MGB) corpora, where the proposed approach outperforms standard forms of recurrent models in perplexity.Finally, N-best list rescoring for speech recognition in the MGB3 task shows word error rate improvements over comparable standard form of recurrent models.
Sortase A Substrate Specificity in GBS Pilus 2a Cell Wall Anchoring (2011)

Streptococcus agalactiae, also referred to as Group B Streptococcus (GBS), is one of the most common causes of life-threatening bacterial infections in infants. In recent years cell surface pili have been identified in several Gram-positive bacteria, including GBS, as important virulence factors and promising vaccine candidates. In GBS, three structurally distinct types of pili have been discovered (pilus 1, 2a and 2b), whose structural subunits are assembled in high-molecular weight polymers by specific class C sortases. In addition, the highly conserved housekeeping sortase A (SrtA), whose main role is to link surface proteins to bacterial cell wall peptidoglycan by a transpeptidation reaction, is also involved in pili cell wall anchoring in many bacteria. Through in vivo mutagenesis, we demonstrate that the LPXTG sorting signal of the minor ancillary protein (AP2) is essential for pilus 2a anchoring. We successfully produced a highly purified recombinant SrtA (SrtA(ΔN40)) able to specifically hydrolyze the sorting signal of pilus 2a minor ancillary protein (AP2-2a) and catalyze in vitro the transpeptidation reaction between peptidoglycan analogues and the LPXTG motif, using both synthetic fluorescent peptides and recombinant proteins. By contrast, SrtA(ΔN40) does not catalyze the transpeptidation reaction with substrate-peptides mimicking sorting signals of the other pilus 2a subunits (the backbone protein and the major ancillary protein). Thus, our results add further insight into the proposed model of GBS pilus 2a assembly, in which SrtA is required for pili cell wall covalent attachment, acting exclusively on the minor accessory pilin, representing the terminal subunit located at the base of the pilus.
On the origin of a potential clearance marker: The contribution of enlarged perivascular fluid diffusion to a 7T IVIM interstitial fluid proxy (2023)

Between the parenchymal and microvascular diffusion components, a third, intermediate component can be derived with cerebral IVIM. Its fraction ( f int ) seems a promising biomarker for altered cerebral clearance function. f int has been suggested to both be driven by fluid diffusivity within enlarged perivascular spaces (ePVS) and interstitial fluid between parenchymal cells. Using 7T MRI, this study determined a higher f int within the ePVS (through segmented masks) compared to surrounding non-ePVS tissue. Thereby, this study illustrates the contribution of ePVS fluid diffusivity to f int and highlights the ability to specifically assess ePVS fluid diffusion using a non-invasive MRI method.
Organocatalytic Desymmetrization of Meso‐Aziridines Via Asymmetric Intramolecular Rearrangement (2021)

Abstract Herein we report the first organocatalytic method for the desymmetrization of meso ‐aziridines that does not require the use of an external nucleophilic reagent. The process was designed upon a base promoted rearrangement of bicyclic meso ‐cyclopentanone aziridines, that progresses in intramolecular fashion to provide densely functionalized cyclic ketones, key intermediates for the preparation of Active Pharmaceutical Ingredients. The key enantio‐determining step proceeded under the catalysis of a bifunctional thiourea organocatalyst. The process provides an entry to a class of highly functionalized chiral amines, 4‐aminocyclopentenones, not accessible with previous desymmetrization methods. The ambiphilic nature of the products makes them versatile synthetic intermediates in the preparation of natural products and popular antiviral nucleoside inhibitors, for example abacavir.
Changes in refraction over 10 years in an adult population: the Beaver Dam Eye study. (2002)

Significant changes in spherical equivalent in adults occur over a 10-year period. Younger people became more hyperopic, whereas older people became more myopic. These data provide evidence of a longitudinal change in refraction in adults, which may explain the refractive patterns observed in cross-sectional studies.
Distinct signal transduction in mouse CD4+ and CD8+ splenic T cells after CD28 receptor ligation. (1995)

Current evidence suggests that recognition of Ag/MHC by the TCR alone is insufficient to lead to T cell proliferation or effector function. For a Th cell to produce sufficient IL-2 to allow autocrine-driven clonal expansion, there is a requirement for so-called "costimulatory" or "accessory" signals in addition to TCR ligation by Ag/MHC. Although the first signal delivered by TCR ligation has been well characterized, information regarding the biochemical nature of second signals is limited. In the present report, using a newly generated mAb specific for CD28, signal transduction by the CD28 receptor has been studied in mouse splenic T cells. When freshly isolated splenic T cells were assessed, cross-linking of CD28 by mAb did not induce increases in intracellular calcium concentration were assessed, cross-linking of CD28 by mAb did not induce increases in intracellular calcium concentration whereas TCR cross-linking was able to induce calcium mobilization. In contrast, when T cells were activated by phorbol ester treatment or by in vitro culture, CD28 ligation was able to induce calcium mobilization in 60 to 70% of splenic T cells. Unexpectedly, the CD28-induced calcium response was mainly limited to T cells of the CD4+ subset, whereas both CD4+ and CD8+ T cell subsets showed increases in [Ca2+]i of similar magnitude after CD3 epsilon ligation. The temporal nature of the CD28-induced signal was also different from TCR-induced calcium mobilization. CD28-induced signals were delayed in onset and sustained in duration in contrast to TCR signals that had short latency and brief duration. Differential expression of CD28 on the surface of activated CD4+ or CD8+ T cells did not appear to account for the differences in signal transduction between the two T cell subsets. The preferential responsiveness of the CD4+ T cell population to CD28-induced signaling was also observed in downstream events such as the induction of IL-2R, CD69 expression, and in cellular proliferation. These results indicate that the costimulatory signal delivered by CD28 may have fundamentally different biochemical properties in CD4 and CD8 T cell subsets, and therefore the functional role of CD28 may differ in these T cell subsets.