gebhart/patrepeval huggingface dataset:
High-throughput targeted long-read single cell sequencing reveals the clonal and transcriptional landscape of lymphocytes (2019)

High-throughput single-cell RNA sequencing is a powerful technique but only generates short reads from one end of a cDNA template, limiting the reconstruction of highly diverse sequences such as antigen receptors. To overcome this limitation, we combined targeted capture and long-read sequencing of T-cell-receptor (TCR) and B-cell-receptor (BCR) mRNA transcripts with short-read transcriptome profiling of barcoded single-cell libraries generated by droplet-based partitioning. We show that Repertoire and Gene Expression by Sequencing (RAGE-Seq) can generate accurate full-length antigen receptor sequences at nucleotide resolution, infer B-cell clonal evolution and identify alternatively spliced BCR transcripts. We apply RAGE-Seq to 7138 cells sampled from the primary tumor and draining lymph node of a breast cancer patient to track transcriptome profiles of expanded lymphocyte clones across tissues. Our results demonstrate that RAGE-Seq is a powerful method for tracking the clonal evolution from large numbers of lymphocytes applicable to the study of immunity, autoimmunity and cancer.
TGF-β1 promotes colorectal cancer immune escape by elevating B7-H3 and B7-H4viathe miR-155/miR-143 axis (2016)

Transforming growth factor-beta 1 (TGF-β1) suppresses T cell function, promoting tumor immune escape. Yet, whether the depression of TGF-β1 on T cell function is mediated by co-inhibitory molecules B7-H3 and B7-H4 remains largely unclear. Here, we demonstrated that TGF-β1 elevated the expression of miR-155 in colorectal cancer cells through SMAD3 and SMAD4. The upregulated miR-155 attenuated miR-143 by inhibiting its direct target, the transcription factor CEBPB. Consequently, the direct target genes of miR-143, B7-H3 and B7-H4, were augmented in the cytoplasm and membrane of tumor cells. Over-expression of B7-H3 and B7-H4 in HCT-116 cells induced T cells to secrete TGF-β1 and the immunosuppressive cytokines IL-2, IL-6, and IL-17. Restoration of miR-143 inhibited the growth of HCT-116 xenograft tumors in mice, and also repressed the expression of B7-H3 and B7-H4 in the tumors. Thus, this study reveals the mechanism by which TGF-β1 leads to T cell-mediated tumor evasion through an increase in B7-H3 and B7-H4 expression.
Toward the Second Generation of Optogenetic Tools (2010)

This mini-symposium aims to provide an integrated perspective on recent developments in optogenetics. Research in this emerging field combines optical methods with targeted expression of genetically encoded, protein-based probes to achieve experimental manipulation and measurement of neural systems with superior temporal and spatial resolution. The essential components of the optogenetic toolbox consist of two kinds of molecular devices: actuators and reporters, which respectively enable light-mediated control or monitoring of molecular processes. The first generation of genetically encoded calcium reporters, fluorescent proteins, and neural activators has already had a great impact on neuroscience. Now, a second generation of voltage reporters, neural silencers, and functionally extended fluorescent proteins hold great promise for continuing this revolution. In this review, we will evaluate and highlight the limitations of presently available optogenic tools and discuss where these technologies and their applications are headed in the future.
One hundred base pairs of 5' flanking sequence of a vaccinia virus late gene are sufficient to temporally regulate late transcription. (1985)

A vaccinia virus late gene coding for a major structural polypeptide of 11 kDa was sequenced. Although the 5' flanking gene region is very A+T rich, it shows little homology either to the corresponding region of vaccinia early genes or to consensus sequences characteristic of most eukaryotic genes. Three DNA fragments (100, 200, and 500 base pairs, respectively), derived from the flanking region and including the late gene mRNA start site, were inserted into the coding sequence of the vaccinia virus thymidine kinase (TK) early gene by homologous in vivo recombination. Recombinants were selected on the basis of their TK- phenotype. Cells were infected with the recombinant viruses and RNA was isolated at 1-hr intervals. Transcripts initiating either from the TK early promoter, or from the late gene promoter at its authentic position, or from the translocated late gene promoters within the early gene were detected by nuclease S1 mapping. Early after infection, only transcripts from the TK early promoter were detected. Later in infection, however, transcripts were also initiated from the translocated late promoters. This RNA appeared at the same time and in similar quantities as the RNA from the late promoter at its authentic position. No quantitative differences in promoter efficiency between the 100-, 200-, and 500-base-pair insertions were observed. We conclude that all necessary signals for correct regulation of late-gene expression reside within only 100 base pairs of 5' flanking sequence.
G protein mutations that alter the pheromone response in Saccharomyces cerevisiae. (1990)

The GPA1 gene of Saccharomyces cerevisiae encodes a G alpha protein that couples the membrane-bound pheromone receptors to downstream elements in the mating response pathway. We have isolated seven mutant alleles of GPA1 that confer pheromone resistance: G50D (a glycine-to-aspartate change at position 50), G322E, G322R, E355K, E364K, G470D, and an E364K-G470D double mutant. All of the mutations lie within large regions that are highly conserved between Gpa1 and four other G alpha proteins; four of the changes are located in domains with proposed functions. On the basis of a gentic analysis, the pheromone-unresponsive GPA1 alleles can be divided into two classes: those that encode constitutively activated proteins and those that encode proteins unable to respond to the upstream signal. Our results support the hypothesis that the activated form of Gpa1 stimulates adaptation to pheromone.
Improving broadcast news segmentation processing (2003)

We discuss techniques and results for automatically segmenting multimedia sources, with specific emphasis on broadcast news. We describe techniques that detect news events (e.g., start and stop, of stories or advertisements) using simple cues within and across multimedia streams (e.g., audio, video, text). In addition, we discuss a process for an evaluation and modification of our model using precision and recall metrics. Guided by our findings, we isolate multimedia cues that we consider critical in news story and advertisement segmentation. We also discuss ideas for improving segmentation beyond the methods described. Throughout the paper, we reference MITRE's Broadcast News Navigator (BNN) used to perform event segmentation.
Optimal network processor topologies for efficient packet processing (2005)

In this paper, we propose a novel strategy to determine the optimal network processor (NP) topology for the target application tasks. We partition network applications into different stages with the consideration of limited instruction memory of the processing elements (PEs). We develop a theoretical approach to determine an optimal topology of the PEs via multiple pipelines. The idea of multiple pipelining is to exploit the task/packet level parallelism and the pipelines are further optimized to achieve the maximum throughput and resource utilization. Simulation results verify our analytical model and demonstrate the robustness of our approach in different NP configurations.
USP9X controls DNA replication fork stability and the replication stress checkpoint through Claspin (2016)

Cells possess checkpoint pathways which are important for maintaining genome stability and preventing cancer. These signalling pathways include the ATR and CHK1 kinases which are activated in response to DNA damage or replication stress. Activation of CHK1 by ATR requires the mediator protein Claspin. Claspin also regulates the rate of fork progression during DNA replication. The levels of Claspin are cell cycle regulated and importantly Claspin is stabilised during S-phase. A growing number of ubiquitin ligases and deubiquitylating enzymes (DUBs) have been shown to affect Claspin stability, however how they cooperate in regulating Claspin levels remains unclear. In this thesis, I have characterised an affinity tagged overexpression system allowing for the induction of Claspin. I extensively optimised a purification protocol for this protein and using, SILAC, a quantitative proteomic approach, I identified several proteins that differentially co-purify with Claspin compared to control cells. Among these, I found a novel DUB, USP9X. I have confirmed by reciprocal immunoprecipitation experiments that it binds to Claspin. Using siRNA depletion and pharmacological inhibition strategies, I found that USP9X controls Claspin stability in an S-phase specific manner. I have also demonstrated that USP9X protects proteasome-dependent Claspin degradation. Using a DNA fiber spreading approach I have established that USP9X contributes to DNA replication fork stability. I have also established that USP9X contributes to the intra S-phase replication checkpoint response and the ability of a replication fork to recover following replication stress. Further still I have demonstrated that the depletion of USP9X leads to the spontaneous accumulation of DNA damage; however this damage can be significantly rescued with the simultaneous overexpression of Claspin. Therefore I propose that USP9X, through its role in the regulation of Claspin, is a novel player involved in the maintenance of genomic stability and in the DNA replication stress response pathway.
Forecasting with Mixed-Frequency Data (2012)

Abstract This article, which presents a regression framework that relates the quarterly macro variable (such as GDP growth) to higher-frequency variables in a relatively simple, parsimonious way, is organized as follows. Section 2 covers mixed data sampling (MIDAS) regressions. Section 3 covers so-called nowcasting, and the Kalman filter and its relationship with MIDAS regressions. The final section discusses volatility models using mixed frequencies.
BRANCH: boosting RNA-Seq assemblies with partial or related genomic sequences (2013)

Supplementary data are available at Bioinformatics online.
Child and Adolescent Mental Health and the Schools (2015)

Recently, a national priority has been set to improve mental health services for children and families. It has been identified in epidemiological literature that in the United States, an approximate 15% of youth meet diagnostic criteria for emotional or behavioral problems. Furthermore, less than one in every five children that present with such needs receive mental health services. Individual, family, and system barriers such as transportation, competing demands, and long waiting lists have negatively impacted access to mental health services. Therefore, the school system has become the “de facto” mental health system for children and adolescents, in part because of the significant time students spend at school. However, meeting the needs of students with behavioral or emotional problems within the school system poses its own challenges. Schools have reported being limited in their ability to deliver basic mental wellness to students due to the lack of available resources. Specifically, there is a shortage of school-employed mental health personnel and the ratio of student to mental health professional is two to three times larger than recommended. Expanded school mental health programs are partnered systems that utilize existing services and collaborate with community mental health (CMH) professionals at each level of the three-tiered system. This partnership enables CMH staff gain access to youth with emotional and behavioral problems, resulting in increased prevention and intervention services for students. Additionally, a coordinated effort such as student-transition services has an integral role of facilitating the process from the school system to postsecondary employment, training, and or additional education.
Antitumor Activity of an EpCAM/CD3-bispecific BiTE Antibody During Long-term Treatment of Mice in the Absence of T-cell Anergy and Sustained Cytokine Release (2009)

muS110 is a BiTE antibody bispecific for murine EpCAM (CD326) and murine CD3. MT110, its human-specific analog, is in a clinical phase 1 trial for treatment of patients with adenocarcinoma of the lung or gastrointestinal tract. Recent studies have shown a therapeutic window for muS110, have explored single-dose toxicity of muS110, and have found that a 1-week low-dose treatment dramatically increased the tolerability of mice to very high doses of muS110 (Cancer Immunol. Immunother. 2009;58:95-109). Here we analyzed the impact of long-term, high-dose treatment of mice with muS110 on antitumor activity and functionality of T cells. After an initial self-limiting cytokine release, the 1-week adaptation period effectively blunted further cytokine production in response to a subsequent high-dose treatment with muS110. The much-increased tolerability of mice adapted to muS110 was not because of anergy of T cells. T cells isolated from chronically muS110-treated mice fully retained their cytotoxic potential, proliferative capacity, and responsiveness to stimulation by either muS110 or anti-CD3/anti-CD28/interleukin-2 when compared with T cells from control mice. Unimpaired T-cell performance was also evident from the effective prevention of orthotopic 4T1 breast tumor outgrowth in mice treated long term with escalating doses of muS110. Finally, we show that muS110 and MT110 recognize orthologous epitopes on mouse and human EpCAM proteins, suggesting that the target-related safety profile of muS110 in mice may be predictive for MT110 in humans.
Gene Transfer In Vivo with DNA–Liposome Complexes: Safety and Acute Toxicity in Mice (1992)

DNA can be introduced into a variety of cell types after formation of liposomal complexes with cationic lipids. In this report, conditions have been established to optimize the production of DNA-liposome complexes that efficiently transfect cells. The safety and toxicity of this method of gene delivery have been assessed after in vivo administration, either by intravenous or direct intratumor injection. Nine to eleven days after intravenous injection, DNA was found primarily in heart and lung tissue by PCR analysis. No abnormalities were evident from histologic examination of tissue, examination of tissue-specific serum enzymes, routine biochemical parameters, or electrocardiographic monitoring. DNA-liposome complexes can therefore be used for the delivery of recombinant genes in vivo with minimal toxicity.
Cognitive Load During Problem Solving: Effects on Learning (1988)

Considerable evidence indicates that domain specific knowledge in the form of schemas is the primary factor distinguishing experts from novices in problem‐solving skill. Evidence that conventional problem‐solving activity is not effective in schema acquisition is also accumulating. It is suggested that a major reason for the ineffectiveness of problem solving as a learning device, is that the cognitive processes required by the two activities overlap insufficiently, and that conventional problem solving in the form of means‐ends analysis requires a relatively large amount of cognitive processing capacity which is consequently unavailable for schema acquisition. A computational model and experimental evidence provide support for this contention. Theoretical and practical implications are discussed.
Identification of a Member of the MAPKKK Family as a Potential Mediator of TGF-β Signal Transduction (1995)

The mitogen-activated protein kinase (MAPK) pathway is a conserved eukaryotic signaling module that converts receptor signals into various outputs. MAPK is activated through phosphorylation by MAPK kinase (MAPKK), which is first activated by MAPKK kinase (MAPKKK). A genetic selection based on a MAPK pathway in yeast was used to identify a mouse protein kinase (TAK1) distinct from other members of the MAPKKK family. TAK1 was shown to participate in regulation of transcription by transforming growth factor-beta (TGF-beta). Furthermore, kinase activity of TAK1 was stimulated in response to TGF-beta and bone morphogenetic protein. These results suggest that TAK1 functions as a mediator in the signaling pathway of TGF-beta superfamily members.
A new method for the simultaneous determination of surface tension and density of polymer melts (1999)

By employing a new strategy presented recently by Wulf etal., axisymmetric drop shape analysis (ADSA) can be used to determine simultaneously the surface tension and the density of polymer melts from sessile drops at elevated temperatures. This required the modification of the ADSA algorithm to replace the density by the mass of the drop as input parameter and the development of a closed high temperature chamber whose temperature can be precisely controlled. In addition, special sample holders for the formation of pendant and sessile drops at elevated temperatures were needed. Recently, their design has been improved, which is described in this paper. For a commercial epoxy resin (DER 664 UE), it is shown that measurements with sessile drops yield essentially the same surface tension values and temperature coefficients as with pendant drops. The densities determined with ADSA are comparable to independent PVT results.
Potassium channel dysfunction in fibroblasts identifies patients with Alzheimer disease. (1993)

Since memory loss is characteristic of Alzheimer disease (AD), and since K+ channels change during acquisition of memory in both molluscs and mammals, we investigated K+ channel function as a possible site of AD pathology and, therefore, as a possible diagnostic index as well. A 113-pS tetraethylammonium (TEA)-sensitive K+ channel was consistently absent from AD fibroblasts, while it was often present in young and aged control fibroblasts. A second (166-pS) K+ channel was present in all three groups. Elevated external potassium raised intracellular Ca2+ in all cases. TEA depolarized and caused intracellular Ca2+ elevation in young and aged control fibroblasts but not AD fibroblasts. The invariable absence of a 113-pS TEA-sensitive K+ channel and TEA-induced Ca2+ signal indicate K+ channel dysfunction in AD fibroblasts. These results suggest the possibility of a laboratory method that would diagnostically distinguish AD patients, with or without a family history of AD, from normal age-matched controls and also from patients with non-AD neurological and psychiatric disorders.
Cardiovascular disease, hypertension, and lipids (2003)

This report looks at Factors that increase the risk of developing cardiovascular heart disease (CHD) in diabetic patients. Diabetic patients, particularly those with type 2 diabetes or proteinuria, are at considerable risk of excessive morbidity and mortality from cardiovascular, cerebrovascular, and peripheral vascular disease leading to myocardial infarction, strokes, and amputations. Much effort must be given to reducing the risk factors that predispose to major atheromatous arterial disease. The many available measures add to the complexity of treating diabetic patients, especially those with type 2 diabetes.
Association of basonuclin with ability of keratinocytes to multiply and with absence of terminal differentiation. (1994)

Basonuclin is a protein possessing three pairs of zinc fingers and a nuclear localization signal. Expression of the gene is largely confined to keratinocytes of stratified squamous epithelia and hair follicles. In the epidermis and in stratified epidermal cultures, basonuclin is present in the nuclei of cells in or close to the basal layer but not in the nuclei of cells in more superficial layers. The Ki-67 protein, a nuclear marker for any stage of the multiplication cycle is present in only a subclass of basonuclin-containing cells. In cultured keratinocytes, the disappearance of basonuclin mRNA is associated with loss of colony-forming ability and the appearance of mRNA for involucrin, a protein characteristic of terminal differentiation. In hair follicles, the largest reservoir of basonuclin-containing cells is the outer root sheath, which contains precursors of differentiated cells of the hair shaft and of the epidermis. Basonuclin is not a cell cycle marker but is likely instead to be a regulatory molecular whose presence in the keratinocyte is linked to the maintenance of proliferative capacity and prevention of terminal differentiation.
Imidazolium Hydrogen Carbonates versus Imidazolium Carboxylates as Organic Precatalysts for N-Heterocyclic Carbene Catalyzed Reactions (2012)

Imidazolium-2-carboxylates (NHC-CO(2) adducts, 3) and (benz)imidazolium hydrogen carbonates ([NHC(H)][HCO(3)], 4) were independently employed as organic precatalysts for various molecular N-heterocyclic carbene (NHC) catalyzed reactions. NHC-CO(2) adducts were obtained by carboxylation in THF of related free NHCs (2), while the synthesis of [NHC(H)][HCO(3)] precursors was directly achieved by anion metathesis of imidazolium halides (1) using potassium hydrogen carbonate (KHCO(3)) in methanolic solution, without the need for the prior preparation of free carbenes. Thermogravimetric analysis (TGA) and TGA coupled with mass spectrometry (TGA-MS) of most [NHC(H)][HCO(3)] precursors 4 showed a degradation profile in stages, with either a concomitant or a stepwise release of H(2)O and CO(2), between 108 and 280 °C, depending on the nature of the azolium and substituents. In solution, NHC generation from both [NHC(H)][HCO(3)] salts and NHC-CO(2) adducts could be achieved at room temperature, most likely by a simple solvation effect. Both types of precursors proved efficient for organocatalyzed molecular reactions, including cyanosilylation, benzoin condensation, and transesterification reactions. The catalytic efficiencies of NHC-CO(2) adducts 3 were found to be approximately 3 times higher than those of their [NHC(H)][HCO(3)] counterparts 4.
Source routing in computer networks (1977)

As plans for network interconnection develop, the problems of internet routing and addressing become increasingly important. In one popular model of internet addressing, a hierarchical form of network and local (within network) address is used, with the source providing only the destination address while the intermediate network(s) and/or Gateways between networks take care of routing packets to that destination by various paths. This and related techniques requiring some form of routing table and knowledge at intermediate nodes are more fully discussed in [1,2,3]. This paper considers another technique for internet routing in which the source of internet packets specifies the complete internet route. When the entire route accompanies each internet packet, no routing decisions or tables are required at Gateways, but the packet format is complicated and overhead increases. In particular, the packet must carry a varying number of intermediate addresses depending on the path and destination [4]. This overhead may be reduced by setting up a fixed route with connection tables [1] when a connection is established.