gebhart/patrepeval huggingface dataset:
Common genetic variants contribute to risk of rare severe neurodevelopmental disorders (2018)

There are thousands of rare human disorders caused by a single deleterious, protein-coding genetic variant 1 . However, patients with the same genetic defect can have different clinical presentation 2–4 , and some individuals carrying known disease-causing variants can appear unaffected 5 . What explains these differences? Here, we show in a cohort of 6,987 children with heterogeneous severe neurodevelopmental disorders expected to be almost entirely monogenic that 7.7% of variance in risk is attributable to inherited common genetic variation. We replicated this genome wide common variant burden by showing that it is over-transmitted from parents to children in an independent sample of 728 trios from the same cohort. Our common variant signal is significantly positively correlated with genetic predisposition to fewer years of schooling, decreased intelligence, and risk of schizophrenia. We found that common variant risk was not significantly different between individuals with and without a known protein-coding diagnostic variant, suggesting that common variant risk is not confined to patients without a monogenic diagnosis. In addition, previously published common variant scores for autism, height, birth weight, and intracranial volume were all correlated with those traits within our cohort, suggesting that phenotypic expression in individuals with monogenic disorders is affected by the same variants as the general population. Our results demonstrate that common genetic variation affects both overall risk and clinical presentation in disorders typically considered to be monogenic.
PD-1 up-regulation on CD4 + T cells promotes pulmonary fibrosis through STAT3-mediated IL-17A and TGF-β1 production (2018)

Pulmonary fibrosis is a progressive inflammatory disease with high mortality and limited therapeutic options. Previous genetic and immunologic investigations suggest common intersections between idiopathic pulmonary fibrosis (IPF), sarcoidosis, and murine models of pulmonary fibrosis. To identify immune responses that precede collagen deposition, we conducted molecular, immunohistochemical, and flow cytometric analysis of human and murine specimens. Immunohistochemistry revealed programmed cell death-1 (PD-1) up-regulation on IPF lymphocytes. PD-1<sup>+</sup>CD4<sup>+</sup> T cells with reduced proliferative capacity and increased transforming growth factor-β (TGF-β)/interleukin-17A (IL-17A) expression were detected in IPF, sarcoidosis, and bleomycin CD4<sup>+</sup> T cells. PD-1<sup>+</sup> T helper 17 cells are the predominant CD4<sup>+</sup> T cell subset expressing TGF-β. Coculture of PD-1<sup>+</sup>CD4<sup>+</sup> T cells with human lung fibroblasts induced collagen-1 production. Strikingly, ex vivo PD-1 pathway blockade resulted in reductions in TGF-β and IL-17A expression from CD4<sup>+</sup> T cells, with concomitant declines in collagen-1 production from fibroblasts. Molecular analysis demonstrated PD-1 regulation of the transcription factor STAT3 (signal transducer and activator of transcription 3). Chemical blockade of STAT3, using the inhibitor STATTIC, inhibited collagen-1 production. Both bleomycin administration to PD-1 null mice or use of antibody against programmed cell death ligand 1 (PD-L1) demonstrated significantly reduced fibrosis compared to controls. This work identifies a critical, previously unrecognized role for PD-1<sup>+</sup>CD4<sup>+</sup> T cells in pulmonary fibrosis, supporting the use of readily available therapeutics that directly address interstitial lung disease pathophysiology.
Movie Map for Virtual Exploration in a City (2021)

This paper introduces our work on a Movie Map, which will enable users to explore a given city area using 360° videos. Visual exploration of a city is always needed. Nowadays, we are familiar with Google Street View (GSV) that is an interactive visual map. Despite the wide use of GSV, it provides sparse images of streets, which often confuses users and lowers user satisfaction. Forty years ago, a video-based interactive map was created - it is well-known as Aspen Movie Map. Movie Map uses videos instead of sparse images and seems to improve the user experience dramatically. However, Aspen Movie Map was based on analog technology with a huge effort and never built again. Thus, we renovate the Movie Map using state-of-the-art technology. We build a new Movie Map system with an interface for exploring cities. The system consists of four stages; acquisition, analysis, management, and interaction. After acquiring 360° videos along streets in target areas, the analysis of videos is almost automatic. Frames of the video are localized on the map, intersections are detected, and videos are segmented. Turning views at intersections are synthesized. By connecting the video segments following the specified movement in an area, we can watch a walking view along a street. The interface allows for easy exploration of a target area. It can also show virtual billboards in the view.
ChemInform Abstract: Anode Catalysts for Direct Hydrazine Fuel Cells: From Laboratory Test to an Electric Vehicle. (2014)

Abstract Nanocrystalline Ni 87 Zn 13 main phase plus varying amounts of a minor ZnO phase as a highly active electrocatalyst for hydrazine hydrate (HH) fuel cell applications are prepared by ball milling of the metal nitrates and carbon black (500 rpm, 2.5 h) followed by thermal reduction in 7% H 2 /N 2 (450 °C, 4 h).
INDIRECT RECOGNITION OF DONOR CLASS I PEPTIDES INDUCES AND ACCELERATES CARDIAC ALLOGRAFT VASCULOPATHY IN THE MINIATURE SWINE. (2000)

Lee, Richard S.; Yamada, Kazuhiko; Maloney, Michaella; Houser, Stuart; Womer, Karl L.; Sayegh, Mohamed H.; Madsen, Joren C. Author Information
Stiction-free cantilevers with rounded cross-section (2005)

In this work, we developed a novel anti-stiction structure with rounded cross section which dramatically prevented stiction by reducing the Laplace pressure force and contact areas effectively. Also structure with rounded cross-section was more effective in reducing stiction because of the increased rigidity. We demonstrated a 6/spl mu/m-suspended 1/spl mu/m-thick metal cantilever with 60/spl mu/m in width and 1,000/spl mu/m in length successfully released in the conventional wet releasing process for the beam with rounded cross-section, while the length was limited to 125/spl mu/m for the beam with rectangular cross-section.
P10.04.A The development of a potent, tumour-specific heptamethine cyanine dye-palbociclib conjugate with novel mechanisms of action for the treatment of glioblastoma (2022)

Abstract Background Glioblastoma is the most common and aggressive primary brain tumour in adults. The development of anti-cancer agents for brain tumours is challenged by the blood-brain barrier and the resistance conferred by the local tumour microenvironment. Heptamethine cyanine dyes (HMCDs) are a class of near-infrared fluorescence compounds that have recently emerged as promising agents for drug delivery Material and Methods We conjugated palbociclib, a cyclin-dependent kinase 4/6 inhibitor to the HMCD, MHI 148 for the treatment of GBM. Patient-derived GBM cell lines were established from surgically resected biopsy GBM tissue. Results High-throughput drug screening revealed an almost 100-fold increase in cytotoxicity of the palbociclib-MHI 148 conjugate compared to palbociclib alone. Moreover, the palbociclib-MHI 148 conjugate was synergistic with radiation, but not with temozolomide. Further analysis revealed the palbociclib-MHI 148 conjugate was superior to other cyclin-dependent kinase inhibitors in vitro. The shift of palbociclib from cytostatic to cytotoxic when conjugated to MHI 148 prompted further investigation. We revealed that palbociclib-MHI 148-dependent inhibition of cell-cycle progression resulted in increased DNA damage. This preceded increased transcription of key extrinsic apoptosis genes and caused a time-dependent upregulation of TNFR1 endocytosis-dependent cell death signalling. Notably, inhibition of endocytosis and siRNA knockdown of TNFR1 prevented palbociclib-MHI 148-induced cell death. Conclusion: These results highlight a novel mechanism of action of palbociclib when conjugated to MHI-148 that induced autocrine-driven TNFR1-mediated apoptosis. In addition, we highlight the potential application of HMCDs in repurposing tyrosine kinase inhibitors, to overcome the current limitations preventing the expansion of second-line treatment options for GBM.
T-Rex: Optimizing Pattern Search on Time Series (2023)

Pattern search is an important class of queries for time series data. Time series patterns often match variable-length segments with a large search space, thereby posing a significant performance challenge. The existing pattern search systems, for example, SQL query engines supporting MATCH_RECOGNIZE, are ineffective in pruning the large search space of variable-length segments. In many cases, the issue is due to the use of a restrictive query language modeled on time series points and a computational model that limits search space pruning. We built T-ReX to address this problem using two main building blocks: first, a MATCH_RECOGNIZE language extension that exposes the notion of segment variable and adds new operators, lending itself to better optimization; second, an executor capable of pruning the search space of matches and minimizing total query time using an optimizer. We conducted experiments using 5 real-world datasets and 11 query templates, including those from existing works. T-ReX outperformed an optimized NFA-based pattern search executor by 6x in median query time and an optimized tree-based executor by 19X.
Fast track to the neocortex: A memory engram in the posterior parietal cortex (2018)

Models of systems memory consolidation postulate a fast-learning hippocampal store and a slowly developing, stable neocortical store. Accordingly, early neocortical contributions to memory are deemed to reflect a hippocampus-driven online reinstatement of encoding activity. In contrast, we found that learning rapidly engenders an enduring memory engram in the human posterior parietal cortex. We assessed microstructural plasticity via diffusion-weighted magnetic resonance imaging as well as functional brain activity in an object-location learning task. We detected neocortical plasticity as early as 1 hour after learning and found that it was learning specific, enabled correct recall, and overlapped with memory-related functional activity. These microstructural changes persisted over 12 hours. Our results suggest that new traces can be rapidly encoded into the parietal cortex, challenging views of a slow-learning neocortex.
New quinoxalinone inhibitors targeting secreted phospholipase A2 and α-glucosidase (2017)

Elevated blood glucose and increased activities of secreted phospholipase A2 (sPLA2) are strongly linked to coronary heart disease. In this report, our goal was to develop small heterocyclic compound that inhibit sPLA2. The title compounds were also tested against α-glucosidase and α-amylase. This array of enzymes was selected due to their implication in blood glucose regulation and diabetic cardiovascular complications. Therefore, two distinct series of quinoxalinone derivatives were synthesised; 3-[N'-(substituted-benzylidene)-hydrazino]-1H-quinoxalin-2-ones 3a-f and 1-(substituted-phenyl)-5H-[1,2,4]triazolo[4,3-a]quinoxalin-4-ones 4a-f. Four compounds showed promising enzyme inhibitory effect, compounds 3f and 4b-d potently inhibited the catalytic activities of all of the studied proinflammatory sPLA2. Compound 3e inhibited α-glucosidase (IC<sub>50</sub> = 9.99 ± 0.18 µM); which is comparable to quercetin (IC<sub>50</sub> = 9.93 ± 0.66 µM), a known inhibitor of this enzyme. Unfortunately, all compounds showed weak activity against α-amylase (IC<sub>50</sub> > 200 µM). Structure-based molecular modelling tools were utilised to rationalise the SAR compared to co-crystal structures with sPLA2-GX as well as α-glucosidase. This report introduces novel compounds with dual activities on biochemically unrelated enzymes mutually involved in diabetes and its complications.
Overcoming Temozolomide Resistance in Glioblastoma via Enhanced NAD+ Bioavailability and Inhibition of Poly-ADP-Ribose Glycohydrolase (2022)

Glioblastoma multiforme (GBM) is an incurable brain cancer with an average survival of approximately 15 months. Temozolomide (TMZ) is a DNA alkylating agent for the treatment of GBM. However, at least 50% of the patients treated with TMZ show poor response, primarily due to elevated expression of the repair protein O<sup>6</sup>-methylguanine-DNA methyltransferase (MGMT) or due to defects in the mismatch repair (MMR) pathway. These resistance mechanisms are either somatic or arise in response to treatment, highlighting the need to uncover treatments to overcome resistance. We found that administration of the NAD<sup>+</sup> precursor dihydronicotinamide riboside (NRH) to raise cellular NAD<sup>+</sup> levels combined with PARG inhibition (PARGi) triggers hyperaccumulation of poly(ADP-ribose) (PAR), resulting from both DNA damage-induced and replication-stress-induced PARP1 activation. Here, we show that the NRH/PARGi combination enhances the cytotoxicity of TMZ. Specifically, NRH rapidly increases NAD<sup>+</sup> levels in both TMZ-sensitive and TMZ-resistant GBM-derived cells and enhances the accumulation of PAR following TMZ treatment. Furthermore, NRH promotes hyperaccumulation of PAR in the presence of TMZ and PARGi. This combination strongly suppresses the cell growth of GBM cells depleted of MSH6 or cells expressing MGMT, suggesting that this regimen may improve the efficacy of TMZ to overcome treatment resistance in GBM.
Novel Mutation inPTHLHRelated to Brachydactyly Type E2 Initially Confused with Unclassical Pseudopseudohypoparathyroidism (2018)

Among them, we identified a defect in parathyroid hormone like hormone (PTHLH), encoding the PTH-related protein, to be disease-causative. Herein, we report a family affected with brachydactyly type E2 caused by a novel PTHLH mutation, which was confused with PPHP with unclassical genetic penetrance.
A plasmonic chip-based bio/chemical hybrid sensing system for the highly sensitive detection of C-reactive protein (2015)

A synthetic polymer ligand-grafted plasmonic chip was fabricated and demonstrated a highly sensitive detection of C-reactive protein (CRP) by grating-coupled surface plasmon field-enhanced fluorescence. Poly(2-methacryloyloxyethyl-phosphorylcholine) was used as a CRP-specific polymer ligand layer and was grafted onto the plasmonic chip using surface-initiated controlled/living radical polymerization (limit of detection: ca. 10 pM).
Efficacy of intravitreal injection of bevacizumab for severe retinopathy of prematurity: a pilot study (2008)

There results suggest that intravitreal injection of bevacizumab seems to be associated with reduced neovascularisation without apparent ocular or systemic adverse effects, and is thus beneficial for treating severe ROP that is refractory to conventional laser therapy.
Multi-modal Alignment using Representation Codebook (2022)

Aligning signals from different modalities is an important step in vision-language representation learning as it affects the performance of later stages such as cross-modality fusion. Since image and text typically reside in different regions of the feature space, directly aligning them at instance level is challenging especially when features are still evolving during training. In this paper, we propose to align at a higher and more stable level using cluster representation. Specifically, we treat image and text as two "views" of the same entity, and encode them into a joint vision-language coding space spanned by a dictionary of cluster centers (codebook). We contrast positive and negative samples via their cluster assignments while simultaneously optimizing the cluster centers. To further smooth out the learning process, we adopt a teacher-student distillation paradigm, where the momentum teacher of one view guides the student learning of the other. We evaluated our approach on common vision language benchmarks and obtain new SoTA on zero-shot cross modality retrieval while being competitive on various other transfer tasks.
A Bayesian approach to estimate biodynamic model parameters: bioaccumulation of PCB 153 by the freshwater crustacean Gammarus fossarum (2018)

The first step to evaluate the effects of contamination on organisms is to study toxicokinetics. The bioaccumulation of contaminants by aquatic species is a variable phenomenon, since it depends on the characteristics of the environment, the properties of the contaminants and the species. Different toxicokinetic models have been developed to describe the accumulation of contaminants in aquatic food webs. In these models, the organism is often considered as a single compartment: the bioaccumulation is then described as the balance between uptake and elimination processes. The absorption process can involve both dissolved or trophic route. The diet of aquatic organisms is known to be an important route of bioaccumulation of contaminants. The elimination process includes excretion, metabolism and dilution by growth. To date, there are few models focusing on persistent organic contaminants. Furthermore, estimating models' parameters is generally done through a frequentist approach in two steps: first by estimating parameter(s) related to depuration and then estimating parameter(s) related to accucumulation. The problem by doing this is that depuration during the accumulation phase is neglected, while this process occurs in the two phases. The aim of our study is to propose a Bayesian framework to estimate the parameters of a biodynamic model together by considering simultaneously accumulation and depuration data. The posterior distribution obtained for all parameter will enable a more accurate assessment of bioaccumulation uncertainty. We illustrate our approach with the freshwater benthic invertebrate Gammarus fossarum exposed for 7 days to a sediment spiked with PCB153 and transferred to a clean media for 7 more days. The PCB153 concentrations in Gammarus fossarum increased from an initial concentration of 0.32 to 12.36 ng.g-1 ww (wet weight) at the end of accumulation step. When gammarids were transferred into a clean media, the PCB153 concentration in organisms decreased to 6.41 ng.g-1 ww at day 14. The bioaccumulation model assuming first-order kinetics was fitted to the data using Bayesian inference. The inference process quickly converged and thin posterior distributions were obtained for each parameter, meaning that data brough enough information to estimate preciselly each parameter. The median model predictions and their 95% credibility intervals showed a good fit of the model to the data.
Anisamide-Decorated pH-Sensitive Degradable Chimaeric Polymersomes Mediate Potent and Targeted Protein Delivery to Lung Cancer Cells (2015)

In spite of their high potency and specificity, few protein drugs have advanced to the clinical settings due to lack of safe and efficient delivery vehicles. Here, novel anisamide-decorated pH-sensitive degradable chimaeric polymersomes (Anis-CPs) were designed, prepared, and investigated for efficient and targeted delivery of apoptotic protein, granzyme B (GrB), to lung cancer cells. Anis-CPs were readily prepared with varying Anis surface densities from anisamide end-capped poly(ethylene glycol)-b-poly(2,4,6- trimethoxybenzylidene-1,1,1-tris(hydroxymethyl)ethane methacrylate)-b-poly(acrylic acid) (Anis-PEG-PTTMA-PAA) and PEG-PTTMA-PAA copolymers. Using cytochrome C (CC) as a model protein, Anis-CPs displayed high protein loading efficiencies (40.5-100%) and loading contents (up to 16.8 wt %). CC-loaded Anis-CPs had narrow distribution (PDI 0.04-0.13) and small sizes ranging from 152 to 171 nm, which increased with increasing CC contents. Notably, the release of proteins from Anis-CPs was accelerated under mildly acidic conditions, due to the hydrolysis of acetal bonds in PTTMA. MTT assays showed that GrB-loaded Anis-CPs (GrB-Anis-CPs) displayed high targetability to sigma receptor overexpressing cancer cells such as H460 and PC-3 cells. For example, GrB-Anis-CPs exhibited increasing antitumor efficacy to H460 cells with increasing Anis contents from 0 to 80%. The antitumor activity of GrB-Anis-CPs was significantly reduced upon pretreating H460 cells with haloperidol (a competitive antagonist). Notably, the half-maximal inhibitory concentrations (IC50) of GrB-Anis70-CPs were determined to be 6.25 and 5.94 nM for H460 and PC-3 cells, respectively, which were 2-3 orders of magnitude lower than that of chemotherapeutic drugs, such as paclitaxel. Flow cytometry studies demonstrated that GrB-Anis70-CPs induced widespread apoptosis of H460 cells. The confocal laser scanning microscopy (CLSM) experiments using FITC-labeled CC-loaded Anis-CPs confirmed fast internalization and intracellular protein release into H460 cells. GrB-Anis-CPs with high potency and specificity are particularly interesting for targeted therapy of lung cancers.
Human Fallopian tubal epithelial cells in vitro:establishment of polarity and potential role of intracellular calcium and extracellular ATP in fluid secretion (1996)

A pure population of human Fallopian tubal epithelial cells has been isolated by enzyme digestion, grown in primary culture and used to explore the biochemical basis of oviduct fluid secretion. Confluence was achieved in 3-7 days. Immunocytochemical labelling for cytokeratins indicated that the cells were epithelial in nature and formed extensive desmosomal contacts, producing a polarized layer in culture. By growing the cells on collagen-impregnated filters, a small transepithelial electrical potential difference could be recorded, with the apical side of the cells negative with respect to the basal side. In addition, the consumption of glucose and the appearance of lactate were greater on the basal than on the apical side of the cells. Because intracellular Ca2+ ([Ca2+]i) is well established as a signal transduction agent in epithelial fluid secretion, the effect of a wide range of agonists on [Ca2+]i in isolated tubal epithelial cells was studied using Fura-2. The only agent which induced a change in [Ca2+]i was extracellular ATP. The transients induced were dependent on both intracellular and extracellular calcium. ATP added to the basal side of the cells of the polarized layer induced a transient increase in the potential difference. The data are consistent with a potential role for extracellular ATP in the regulation of human tubal fluid formation.