gebhart/patrepeval huggingface dataset:
Establishment of subcellular fractionation techniques to monitor the intracellular fate of polymer therapeutics I. Differential centrifugation fractionation B16F10 cells and use to study the intracellular fate of HPMA copolymer–doxorubicin (2006)

Polymer therapeutics are being designed for lysosomotropic, endosomotropic and transcellular drug delivery. Their appropriate intracellular routing is thus crucial for successful use. For example, polymer-anticancer drug conjugates susceptible to lysosomal enzyme degradation will never deliver their drug payload unless they encounter the appropriate activating enzymes. Many studies use confocal microscopy to monitor intracellular fate, but there is a pressing need for more quantitative methods able to define intracellular compartmentation over time. Only then will it be possible to optimise the next generation of polymer therapeutics for specific applications. The aim of this study was to establish a subcellular fractionation method for B16F10 murine melanoma cells and subsequently to use it to define the intracellular trafficking of N-(2-hydroxyproplylmethacrylamide) (HPMA) copolymer-bound doxorubicin (PK1). Free doxorubicin was used as a reference. The cell cracker method was used to achieve cell breakage and optimised to reproducibly achieve approximately 90% breakage efficiency. This ensured that subsequent subcellular fractionation experiments were representative for the whole cell population. To characterise the subcellular fractions obtained by differential centrifugation, DNA (nuclei), succinate dehydrogenase (mitochondria), N-acetyl-beta-glucosaminidase (lysosomes), alkaline phosphatase (plasma membrane) and lactate dehydrogenase (cytosol) were selected as markers and their assay was carefully validated. The relative specific activity (RSA) of the fractions obtained from B16F10 cells were: nuclei (2.2), mitochondria (4.1), lysosomes (3.7) and cytosol (2.5). When used to study the intracellular distribution at non-toxic concentrations of PK1 and doxorubicin, time-dependent accumulation of PK1 in lysosomes was evident and the expected nuclear localisation of free doxorubicin was seen. Live cell fluorescence microscopy and confocal co-localisation studies gave qualitative corroboration of these results, but by using this method, we were unable to accurately define organelle localisation. In conclusion, the B16F10 subcellular fractionation method developed here provides a useful tool to allow comparison of the intracellular trafficking of other polymer conjugates.
Investigations on stimulation of lac transcription in vivo in Escherichia coli by cAMP analogues (1984)

The ability of 24 systematically modified analogues of adenosine 3',5'-monophosphate (cAMP) to enhance the synthesis of beta-galactosidase in glucose-repressed Escherichia coli strains KNBL 1001 and cpd- Crookes has been investigated. The properties of the analogues in comparison with cAMP are, with only two exceptions, alike in both strains. Two analogues, 7-deazaadenosine 3',5'-monophosphate (i.e. tubercidin 3',5'-monophosphate) and (Rp)-adenosine 3',5'-monothionophosphate, exhibit higher biological activity than cAMP. The latter analogue is 50-fold more active in both strains. Three analogues showed activities comparable to cAMP, four analogues were less active and 12 analogues were unable to antagonize catabolite repression. Structure-activity correlations showed that the 2'OH-, 3'O-, 5'O-, the negative charge and the 6-amino group cannot be modified without losing biological activity in vivo, while the N-1 and N-7 in adenine are not essential. The interaction with the catabolite gene activator protein is stereoselective for an unmodified axial exocyclic oxygen. The results are compared to those obtained with cAMP analogues in E. coli in vitro and those obtained with the same analogues in protein-kinase systems and Dictyostelium species. The model of McKay et al. [McKay, D.B., Weber, J.T. and Steitz, T.A. (1982) J. Biol. Chem. 257, 9518-9524] proposed for distinct chemical interactions of cAMP with the catabolite gene activator protein is discussed and supplemented by additional hydrogen bond interactions.
Exploring physical and chemical properties in new multifunctional indium-, bismuth-, and zinc-based 1D and 2D coordination polymers (2017)

Main group element coordination polymers (MGE-CPs) are important compounds for the development of multifunctional materials. However, there has been a shortage of studies regarding their structural, optical, catalytic, mechanical, and antibacterial properties. This work presents an exhaustive study of a set of crystalline MGE-CPs obtained from bismuth and indium metals and iminodiacetate, 1,2,4,5-benzenetetracarboxylate, and 2,2'-bipyridine as building blocks. An in-depth topological analysis of the networks was carried out. Additionally, nanoindentation studies were performed on two representative low-dimensional compounds in order to find the relationships between their structural features and their intrinsic mechanical properties (hardness and elasticity). The solid-state photoluminescence (SSPL) properties were also studied in terms of excitation, emission, lifetimes values, and CIE chromaticites. Moreover, the heterogeneous catalytic activities of the compounds were evaluated with the cyanosilylation reaction using a set of carbonylic substrates under solvent-free conditions. Finally, the inhibitory effect of the Bi-CPs on the growth of microorganisms such as Escherichia coli, Salmonella enterica serovar Typhimurium, and Pseudomonas aeruginosa, which are associated with relevant infectious diseases, is reported.
Electroluminescence thermal quenching in alternating-current thin-film electroluminescent devices (2001)

Electroluminescence (EL) thermal quenching in alternating-current thin-film electroluminescent (ACTFEL) devices refers to a reduction in the luminance with increasing temperature, which is in excess to that of normal thermal quenching and is concomitant with a reduction in the transferred charge. A comparison of thermal quenching trends for ZnS:Mn, SrS:Ce, SrS:Cu,Ag, and multilayer SrS:Cu,Ag/SrS:Ce ACTFEL devices is presented. Respectively, ZnS:Mn; SrS:Cu and SrS:Cu,Ag; and SrS:Ce and multilayer SrS:Cu,Ag/SrS:Ce ACTFEL devices exhibit very little (normal), a large amount (of primarily EL), or a small amount (of primarily normal) thermal quenching. Insertion of one or more interface layers of SrS:Ce significantly reduces the extent of EL thermal quenching in a SrS:Cu,Ag ACTFEL device. Simulation suggests that SrS:Ce interface layers decrease the rate and displace the location of hole creation by band-to-band impact ionization away from the SrS:Cu,Ag layer, where hole trapping at Cu or Ag acceptor sites leads to EL thermal quenching via thermally activated annihilation of positive space charge due to thermionic emission of holes from Cu or Ag acceptor traps.
ChemInform Abstract: DIE SYNTH. VON TRANS‐3′‐METHYL‐NICOTIN (1972)

Abstract Aus 3‐Pyridinaldehyd (I) und Methylamin (II) entsteht die Schiffsche Base (III), die mit Bemsteinsäureanhydrid (IV) zu (Va) reagiert.
Facile Synthesis of Lactones from Silyl ω-Siloxycarboxylates Using p-Trifluoromethylbenzoic Anhydride and a Catalytic Amount of Active Lewis Acid (1993)

Abstract The lactonization of silyl ω-siloxycarboxylates is successfully carried out under mild conditions in good to high yields by using p-trifluoromethylbenzoic anhydride and a catalytic amount of active acidic species generated in situ from TiCl4 and AgClO4.
Application of spectrum analysis and neural-network classification to imaging for targeting and monitoring treatment of prostate cancer (2002)

Conventional B-mode ultrasound is the standard means of imaging the prostate for guiding prostate biopsies and planning brachytherapy of prostate cancer. Yet no imaging modality, including B-mode images, reliably shows cancerous lesions of the prostate. Tissue-typing imaging based on spectrum analysis of ultrasonic radio-frequency (RF) echo signals may be able to overcome the limitations of conventional imaging modalities for visualizing prostate tumors. Such tissue typing utilizes neural-networks, to classify tissue based on spectral-parameter and clinical-variable values. Tissue-type images based on these methods are intended to improve guidance of prostate biopsies and targeting of radiotherapy of prostate cancer. Two-dimensional images have been imported into instrumentation for real-time biopsy guidance and into commercial dose-planning software for brachytherapy planning. Three-dimensional renderings show locations and volumes of cancer foci.
GDNF receptor agonist supports dopamine neurons in vitro and protects their function in animal model of Parkinson’s (2019)

Abstract Motor symptoms of Parkinson’s disease (PD) are caused by degeneration and progressive loss of nigrostriatal dopamine neurons. Currently no cure for this disease is available. Existing drugs alleviate PD symptoms, but fail to halt neurodegeneration. Glial cell line-derived neurotrophic factor (GDNF) is able to protect and repair dopamine neurons in vitro and in animal models of PD, but its clinical use is complicated by pharmacokinetic properties. In the present study we demonstrate the ability of a small molecule agonist of GDNF receptor RET to support the survival of cultured dopamine neurons only when they express GDNF receptors. In addition, BT13 activates intracellular signaling cascades in vivo , stimulates release of dopamine and protect the function of dopaminergic neurons in a 6-hydroxydopamine (6-OHDA) rat model of PD. In contrast to GDNF, BT13 is able to penetrate through the blood-brain-barrier. Thus, BT13 serves as an excellent tool compound for the development of novel disease-modifying treatments against PD.
Supplementary Figure 1 from Aberrant Expression of Mucin Core Proteins and O-Linked Glycans Associated with Progression of Pancreatic Cancer (2023)

&lt;p&gt;PDF file - 248K, Supplementary Figure 1. (A) Simplified schematic of mucin type O-glycans analyzed in this report. Mucin-type O-linked glycans are initiated by the addition of an N-acetyl galactose sugar residue (the Tn epitope), which can be extended into the T antigen or core 3 structures, or Tn can be sialylated creating terminal STn that cannot be further extended. T antigen can be extended into core 2 structures that lead to the Lewis Blood Group antigens - LeX, SLeX, SLeC and sialyl Lewis A (the CA19-9 antigen, a widely utilized biomarker of adenocarcinoma progression). B &amp; C - Representative immunohistochemical results for comparison of expression of mucin core proteins, glycans, and glycopeptides taken at 200x magnification. (B) Serial sections of primary tumor from autopsy patient 3 stained for indicated antigens. (C) Serial sections of liver metastasis from autopsy patient 20 for same antigens seen in primary tumor.&lt;/p&gt;
Enhancing traditional process SCADA and historians for industrial &amp; commercial power systems with energy (via IEC 61850) (2014)

Coordination of large scale distributed measurement and control systems, such as Supervisory Control and Data Acquisition (SCADA) and other process control system implementations, require reliable and robust networks that can connect thousands of remote devices from multiple remote locations. Additionally, many heavy industries have ever increasing demands of their infrastructure to handle more network services and deliver a full spectrum of control and monitoring of thousands and even tens of thousands of points within their global business operations. This paper will outline a new novel method of providing a convergent use of the IEC 61850 protocol, within process control networks, to provide a more deterministic type of process control, monitoring and energy management. The benefits of real-time archiving of process values, process messages, Intelligent Electronic Device (lED) status and alarm data along with process batch data can be achieved in an advancement of traditional historian based systems. This new approach, providing traditional downtime reports and alarm summaries for maintenance purposes along with the added benefits of providing the opportunity for highly accurate and time synchronized energy consumption and energy balance data along with efficiency reports of various different production or process operations.
Width-Aware Fine-Grained Dynamic Supply Gating: A Design Methodology for Low-Power Datapath and Memory (2012)

With increasing contribution of leakage in total active power, run-time leakage control techniques are becoming extremely important. Supply gating provides an effective, low-overhead and technology scalable approach for active leakage reduction through the well-known "stacking effect". However, conventional supply gating approaches are typically coarse-grained in both space and time - i.e. are applied to large data path or memory blocks when an entire logic/memory block is idle for sufficiently long period. They suffer from limited applicability at run time. On the other hand, fine-grained supply gating is constrained primarily by the large wake-up delay and wake-up power overhead. In this paper, we propose a novel fine-grained width-aware dynamic supply gating (WADSG) approach to reduce both active leakage and redundant switching power in data path and embedded memory (e.g. L1/L2 cache). The approach exploits the abundance of narrow-width (NW) operands in general-purpose and embedded applications to "supply-gate" unused parts of integer execution units and memory blocks while they are in use. We introduce a novel levelized gating strategy to virtually eliminate the wake-up delay overhead. We employ the proposed WADSG approach to a super scalar processor. To reduce the wake-up power we use a width aware instruction issue policy. In case of L1 and L2 cache, we store the width information per "ways" of associative cache and supply-gate the most significant bits of the NW ways. We also propose a width-aware block allocation and replacement policy to maximize the number of NW ways. Simulation results for 45nm technology with Spec2k benchmarks show major savings (34.5%) in total processor power (considering both switching and active leakage power) with no performance impact. As a by-product, the proposed scheme also improves the thermal profile of both data path and memory.
Identifying Ethical Considerations for Machine Learning Healthcare Applications (2020)

Along with potential benefits to healthcare delivery, machine learning healthcare applications (ML-HCAs) raise a number of ethical concerns. Ethical evaluations of ML-HCAs will need to structure the overall problem of evaluating these technologies, especially for a diverse group of stakeholders. This paper outlines a systematic approach to identifying ML-HCA ethical concerns, starting with a conceptual model of the pipeline of the conception, development, implementation of ML-HCAs, and the parallel pipeline of evaluation and oversight tasks at each stage. Over this model, we layer key questions that raise value-based issues, along with ethical considerations identified in large part by a literature review, but also identifying some ethical considerations that have yet to receive attention. This pipeline model framework will be useful for systematic ethical appraisals of ML-HCA from development through implementation, and for interdisciplinary collaboration of diverse stakeholders that will be required to understand and subsequently manage the ethical implications of ML-HCAs.
Multi-Task Learning for Speaker Verification and Voice Trigger Detection (2020)

Automatic speech transcription and speaker recognition are usually treated as separate tasks even though they are interdependent. In this study, we investigate training a single network to perform both tasks jointly. We train the network in a supervised multi-task learning setup, where the speech transcription branch of the network is trained to minimise a phonetic connectionist temporal classification (CTC) loss while the speaker recognition branch of the network is trained to label the input sequence with the correct label for the speaker. We present a large-scale empirical study where the model is trained using several thousand hours of labelled training data for each task. We evaluate the speech transcription branch of the network on a voice trigger detection task while the speaker recognition branch is evaluated on a speaker verification task. Results demonstrate that the network is able to encode both phonetic and speaker information in its learnt representations while yielding accuracies at least as good as the baseline models for each task, with the same number of parameters as the independent models.
SPARC: Development of a Transgenic Pig Expressing mCherry and CRE Recombinase Fusion Proteins Under the Control of the Murine Choline Acetyltransferase Promoter (2021)

Pigs can serve as useful models for advancing the biomedical field due to anatomy and physiology that more closely resembles human anatomy and physiology compared to traditional rodent models. However, there is a paucity of porcine CRE‐driver lines available, limiting their utility for refined neural mapping and neural modulation studies. Here we describe the development of pigs with mCherry and CRE recombinase proteins expressed in cholinergic neurons. A 6,419 bp DNA fragment containing the Mus musculus choline acetyltransferase (ChAT) promoter was used to drive production of a mCherry–P2A–CRE recombinase fusion protein (mmChAT–mCherry–P2A–CRE). Linearized mm ChAT – mCherry – P2A – CRE plasmid DNA was introduced into male porcine fetal fibroblasts by electroporation. Positive colonies were selected with 400µg/mL G‐418 and screened for transgene insertion by PCR. Two colonies showing targeted insertion were used for somatic cell nuclear transfer and the resulting blastocysts were transferred to surrogate gilts. Two early pregnancies were established, and one of them went to term. Six Duroc‐Landrace male piglets were born by natural delivery. PCR analysis of genomic DNA showed that one piglet carried the transgene whereas the others were determined to be wild‐type. The transgenic piglet was phenotypically normal with no obvious difference in appearance compared to the wild‐type littermates. The piglet was euthanized at 7‐weeks of age for further characterization. Major tissues known to have cholinergic cell bodies and cholinergic innervation (hippocampus, cerebellum, spinal cord, basal ganglion, dorsal root ganglion, nodose ganglion, vagus nerve, trachea, bronchus, heart, bladder, duodenum and pancreas) were evaluated regarding mCherry and CRE recombinase mRNA presence. End‐point PCR revealed CRE recombinase mRNA in basal ganglion, nodose ganglion, dorsal root ganglion and heart. mCherry mRNA was found in bronchus homogenates. Studies are ongoing to confirm integration sites into the genome, and mCherry and CRE recombinase expression at the protein level in cholinergic neurons. If successful, this model will allow for simultaneous dissection of cholinergic circuit connectivity and control of neural activity through CRE‐mediated recombination.
Predictive Model Selection for Transfer Learning in Sequence Labeling Tasks (2020)

Transfer learning is a popular technique to learn a task using less training data and fewer compute resources. However, selecting the correct source model for transfer learning is a challenging task. We demonstrate a novel predictive method that determines which existing source model would minimize error for transfer learning to a given target. This technique does not require learning for prediction, and avoids computational costs of trial-and-error.
Design and Evaluation of a Multi-source Multi-destination Real-time Application on Content Centric Network (2018)

Multi-source multi-destination class of applications can range from interactive AR/VR games and high-definition video conferencing to non real-time file sharing applications; and also includes similar applications in other environments including IoT and data center. These applications require efficient synchronization among the end points with varying level of loss and delay tolerance. Also application specific requirements like throughput, end-to-end latency and mobility of end points impose even more stringency. IP based solutions often fail to meet these requirements due to lack of efficient multicast. In this paper we study this problem in the context of multi-party video conferencing system, and propose an information-centric solution based on content-centric networking (CCN). CCN, with its innate support for multicast delivery and service centricity, is used to deliver content and control state in a secure and reliable manner. We address the challenge of synchronizing participant states for a real-time experience through a media agnostic notification framework aided by service functions in the CCN network. Then, we implement a proof-of-concept testbed appropriate for this architecture and demonstrate its impact using scalability, QoE and reliability metrics.
The p85α Regulatory Subunit of Phosphoinositide 3-Kinase Potentiates c-Jun N-Terminal Kinase-Mediated Insulin Resistance (2007)

Insulin resistance is a defining feature of type 2 diabetes and the metabolic syndrome. While the molecular mechanisms of insulin resistance are multiple, recent evidence suggests that attenuation of insulin signaling by c-Jun N-terminal kinase (JNK) may be a central part of the pathobiology of insulin resistance. Here we demonstrate that the p85alpha regulatory subunit of phosphoinositide 3-kinase (PI3K), a key mediator of insulin's metabolic actions, is also required for the activation of JNK in states of insulin resistance, including high-fat diet-induced obesity and JNK1 overexpression. The requirement of the p85alpha regulatory subunit for JNK occurs independently of its role as a component of the PI3K heterodimer and occurs only in response to specific stimuli, namely, insulin and tunicamycin, a chemical that induces endoplasmic reticulum stress. We further show that insulin and p85 activate JNK by via cdc42 and MKK4. The activation of this cdc42/JNK pathway requires both an intact N terminus and functional SH2 domains within the C terminus of the p85alpha regulatory subunit. Thus, p85alpha plays a dual role in regulating insulin sensitivity and may mediate cross talk between the PI3K and stress kinase pathways.
Synonymous GATA2 mutations result in selective loss of mutated RNA and are common in patients with GATA2 deficiency (2020)

Deficiency of the transcription factor GATA2 is a highly penetrant genetic disorder predisposing to myelodysplastic syndromes (MDS) and immunodeficiency. It has been recognized as the most common cause underlying primary MDS in children. Triggered by the discovery of a recurrent synonymous GATA2 variant, we systematically investigated 911 patients with phenotype of pediatric MDS or cellular deficiencies for the presence of synonymous alterations in GATA2. In total, we identified nine individuals with five heterozygous synonymous mutations: c.351C>G, p.T117T (N = 4); c.649C>T, p.L217L; c.981G>A, p.G327G; c.1023C>T, p.A341A; and c.1416G>A, p.P472P (N = 2). They accounted for 8.2% (9/110) of cases with GATA2 deficiency in our cohort and resulted in selective loss of mutant RNA. While for the hotspot mutation (c.351C>G) a splicing error leading to RNA and protein reduction was identified, severe, likely late stage RNA loss without splicing disruption was found for other mutations. Finally, the synonymous mutations did not alter protein function or stability. In summary, synonymous GATA2 substitutions are a new common cause of GATA2 deficiency. These findings have broad implications for genetic counseling and pathogenic variant discovery in Mendelian disorders.