Miracle-dz/UniFAR-FTUs huggingface dataset:
Primary structure of a 13 subunit of a-dendrotoxin-sensitive K+ channels from bovine brain

Voltage-dependent cation channls are large heterooligomeric proteins. Heterologous expression of cDNAs encoding the a subunits alone of K+, Na+, or Ca2+ channels produces functional multimeric proteins; however, coexpression of those for the latter two with their auxiliary proteins causes dramatic changes in the resultant membrane currents. Fast-activating, voltage-sensitive K+ channels from brain contain four a and 13 subunits, tightly associated in a 400-kDa complex; although molecular details of the a-subunit proteins have been determined, little is known about the f-subunit constituent. Proteolytic fragments of a 13 subunit from bovine a-dendrotoxin-sensitive neuronal K+ channels yielded nine different sequences. In the polymerase chain reaction, primers corresponding to two of these peptides amplified a 329-base-pair fragment in a AgtlO cDNA library from bovine brain; a full-length clone subsequently isolated encodes a protein of 367 amino acids (Mr 40,983). It shows no significant homology with any known protein. Unlike the channels' a subunits, the hydropathy profile of this sequence failed to reveal transmembrane domains. Several consensus phosphorylation motifs are apparent and, accordingly, the 13 subunit could be phosphorylated in the intact K+ channels. These results,
A PMLRAR (cid:97) transgene initiates murine acute promyelocytic leukemia

The malignant cells of acute promyelocytic leukemia (APL) contain a reciprocal chromosomal translocation that fuses the promyelocytic leukemia gene ( PML ) with the retinoic acid receptor (cid:97) gene ( RAR (cid:97) ). To test the hypothesis that the chimera PMLRAR (cid:97) plays a role in leukemogenesis, we expressed a PMLRAR (cid:97) cDNA in myeloid cells of transgenic mice. PMLRAR (cid:97) transgenic mice exhibited impaired neutrophil maturation early in life, which progressed at a low frequency over the course of several months to overt APL. Both the preleukemic state and the leukemia could be transplanted to nontransgenic mice, and the transplanted preleukemia could progress to APL. The APL recapitulated features of the human disease, including a response to retinoic acid. Retinoic acid caused the leukemic cells to differentiate in vitro and in vivo , eliciting remissions of both the preleukemic state and APL in mice. Our results demonstrate that PMLRAR (cid:97) impairs neutrophil differentiation and initiates the development of APL. The transgenic mice described here provide an apparently accurate model for human APL that includes clear evidence of tumor progression. The model should be useful for exploring the molecular pathogenesis of and the mechanisms of the therapeutic response to retinoic acid, as well as for preclinical studies of therapeutic regimens.
Nucleotide sequence and predicted amino acid sequence of a protein encoded in a small herpes simplex virus DNA fragment capable of trans-inducing a genes

The five a genes of herpes simplex virus 1 are the first set of genes to be expressed after infection. Previous studies have shown that a genes resident in eukaryotic cells are induced by infection with herpes simplex virus 1 or 2 but not by other herpesviruses and indicate that the a trans-inducing factor was a structural component of the virion. This factor induces genes linked to a bona fide promoter and containing at the 5' end a small sequence derived from the promoter- regulatory domains of a genes. We report the sequence of a small DNA fragment shown preViously to be capable of expressing the a trans-inducing factor in transient expression systems. The only gene encoded in its entirety in this fragment is predicted to specify a 479 amino acid protein with a Mr of 53,053. The precise termini of the 1.74-kilobase mRNA spec- ifyfing this protein were determined in our 5' and 3' S1 nuclease protection studies.
An Ultra-Low-Power Track-and-Hold Amplifier

The future of electronics is the Internet of Things (IoT) paradigm, where “always-on” devices and sensors monitor and transform everyday life. A plethora of applications (such as navigating drivers past road hazards or monitoring bridge and building stresses) employ this technology. These unattended ground-sensor applications require decade(s)long operational life-times without battery changes. Such electronics demand stringent performance specifications with only nano-Watt power levels. This thesis presents an ultra-low-power track-and-hold amplifier for such systems. It serves as the front-end of a SAR-ADC or the building block for equalizers or filters. This amplifier’s design attains exceptional hold times by mitigating switch subthreshold leakage and bulk leakage. Its novel transmission-gate topology achieves wide-swing performance. Though only consuming 100 pico-Watts, it achieves a precision of 7.6 effective number of bits (ENOB). The track-and-hold amplifier was designed in 130-nm CMOS.
Characteristics and outcomes of patients with multiple myeloma (MM) who develop therapy (t)-related myelodysplastic syndrome (MDS), t-chronic myelomonocytic leukemia (CMML), or t-acute myeloid leukemia (AML) patients underwent high-dose chemotherapy and autologous hematopoietic stem cell

Background— There has been significant improvement in the outcome of patients with MM. However, there has also been an increased risk of t-MN. Little is known about the characteristics and outcomes of patients with t-MN. Methods— Patients with MM treated at our institution between 1993 and 2011 were reviewed. We identified 47 patients who were diagnosed with t-MN. The primary objective of this study was to evaluate the time to develop t-MN their response to treatment and overall survival. Results— Median age of patients at diagnosis of MM was 65 years. Thirty two (68.0%) received initial treatment with conventional chemotherapeutic agents. Seven (14.9%) patients received treatment with novel agents such as lenalidomide, thalidomide or bortezomib. Eight (17.0%) patients were treated with a combination of novel and conventional agents. Twenty (42.6%) transplantation (auto-HCT). Median time from the diagnosis of MM to t-MN was 7 years 95%CI [5.0 – 28.0]. Thirty-three (70.2%) patients developed t-MDS, 11 (23.4%) t-AML, and 3 (6.4%) t-CMML. Median age at diagnosis of t-MN was 65 years. Twenty-six (78.8%) patients with t-MDS, nine (81.8%) patients with t-AML and one (33.3%) patients with t-CMML had complex/high risk cytogenetics. Median OS for all 47 patients after diagnosis of t-MN was 6.3 months 95%CI [4.0 – 8.7]. Conclusion— Development of t-MN in patients with MM is associated with poor outcomes. These patients in general have complex cytogenetic abnormalities, short CR and OS. Better understanding of disease biology and novel therapeutic approaches are warranted.
Rel/NF-KB Represses bcl-2 Transcription in pro-B Lym phocytes

The mechanisms controlling programmed cell death (PCD) during early B cell development are not well under­ stood. Members of both the Bcl-2 family of apoptosis-related proteins and the nuclear factor-kappa B/Rel (NF-KB/Rel) family of transcription factors are expressed differentially during B cell development. To date, however, no direct interactions between these two families have been demonstrated. The FL5.12 cell line represents a model for progenitor B cell development. Such cells reproducibly undergo PCD upon IL-3 withdrawal. The signal to enter the apoptotic pathway is mediated by a shift in the ratio of Bcl-2:Bax. While bax levels remain constant, bcl-2 transcription rate, steady-state mRNA, and protein levels decrease. Analysis of the bcl-2 promoter reveals 3 k B sites functionally able to bind k B factors from FL5.12 nuclear extracts. Cotransfection studies demonstrate that NF- k B factors can repress bcl-2 transcription and that site-directed mutagenesis of the k B motifs abolishes this repression. These studies suggest that NF- k B mediates PCD in pro-B cells through tran­ scriptional repression of the survival gene bcl-2 , thus shifting the bcl-2 :bax ratio in favor of death-promoting complexes. postcytokine withdrawal due, in part, to transcrip­ tional repression of its gene. We further demonstrate that the human bcl-2 promoter contains three putative NF- k B enhancer elements that associate with FL5.12 extracts in vitro. Assays of expression show that the bcl-2 promoter is repressed at early time points after cytokine withdrawal. This repression is alleviated when the k B sites are mutated. These results support the hypothesis that cytokine withdrawal-mediated NF- k B activity directly represses bcl-2 transcription, thereby promoting PCD in early lineage B cells.
RNA Polymerase II Elongation Complex: ELONGATION COMPLEXES PURIFIED USING AN ANTI-RNA ANTIBODY DO NOT CONTAIN INITIATION FACTOR α *

Gene expression in eukaryotes can be regulated by controlling the efficiency of transcript elongation by RNA polymerase II. The composition of the elongation complex is, however, poorly understood. Previous work has identified DNA sequences which block RNA polymerase II transcription and factors which stimulate RNA chain elongation. Here, I have purified elongation complexes arrested at discrete template locations. Complexes were rapidly and efficiently precipitated from in vitro transcription reactions using a monoclonal antibody that binds RNA. The isolated complexes remained transcriptionally active. This technique enables the facile manipulation of transcription elongation complexes. Using this approach, I show that transcription initiation factor α is not associated with a RNA polymerase II elongation complex. Since others have shown that α associates stoichiometrically with DNA, RNA polymerase II, and other required factors in an initiation complex, this work suggests that α departs from the transcription complex after nucleotides are required but before extensive RNA chain synthesis. In this regard α resembles the bacterial promoter-recognition factor σ .
The Molecular Basis of P-Thalamia in Thailand: Application to Prenatal Diagnosis

Summary To enable the prenatal diagnosis of 1-thalassemia by direct detection of the mutant 13-globin genes, we have determined the spectrum of mutations causing this disease in Thailand. The techniques employed included a combination of synthetic oligonucleotide probe hybridization, direct sequencing of genomic DNA enzymatically amplified by the polymerase chain reaction, and cloning and sequencing of the 3-globin genes. A total of 116 1-thalassemia genes from 78 Hb E/13-thalassemia patients and from 19 homozygous 13-thalassemia patients were analyzed, and the mutation was characterized in 112/116 (97%) of them. Eleven mutations were found, of which four (-CTTI7 in codon 41/42, AAG--TAG in codon 17, C-UT in position 654 of the IVS-2 region, and A-OG in position -28 upstream of the 3-globin gene) accounted for 83%; two previously undescribed mutations have been identified. The spectrum of 3-thalassemia mutations is similar to that reported among the Chinese. However, within the Thai population itself, patients with homozygous 13-thalassemia show a wider spread of mutations in comparison with the Hb E/13-thalassemia group, in whom the frameshift 41/42 mutation predominates at a frequency of 62%. This difference in distribution may reflect the difference in ethnic origin of the two groups. Characterization of these mutations should aid the planning of a prenatal diagnosis program for 3-thalassemia in Thailand.
Entry Generation for New Words by Analogy for Morphological Lexicons

Language software applications encounter new words, e.g., acronyms, technical terminology, loan words, names or compounds of such words. To add new words to a lexicon, we need to indicate their base form and inflectional paradigm. In this article, we evaluate a combination of corpus-based and lexicon-based methods for assigning the base form and inflectional paradigm to new words in Finnish, Swedish and English finite-state transducer lexicons. The methods have been implemented with the open-source Helsinki Finite-State Technology (Linden & al., 2009). As an entry generator often produces numerous suggestions, it is important that the best suggestions be among the first few, otherwise it may become more efficient to create the entries by hand. By combining the probabilities calculated from corpus data and from lexical data, we get a more precise combined model. The combined method has 77-81 % precision and 89-97 % recall, i.e. the first correctly generated entry is on the average found as the first or second candidate for the test languages. A further study demonstrated that a native speaker could revise suggestions from the entry generator at a speed of 300-400 entries per hour.
Assessing two D-dimer age-adjustment strategies to optimize CT utilization in ED evaluation of pulmonary embolism

Study Objective— Validate the sensitivity and specificity of two age adjustment strategies for D-dimer values in identifying patients at risk for pulmonary embolism (PE) compared to traditional D-dimer cutoff value (500ng/mL) to decrease inappropriate computed tomography pulmonary angiography (CTPA) utilization. Methods— This institutional review board-approved, HIPAA-compliant retrospective study included all adult emergency department (ED) patients evaluated for PE over a 32-month period (1/1/11–8/30/13). Only patients undergoing CTPA and D-dimer testing were included. We used a validated natural language processing algorithm to parse CTPA radiology reports and determine presence of acute PE. Outcome measures were sensitivity and specificity of two age-adjusted D-dimer cutoffs compared to the traditional cutoff. We used chi-square tests with proportional analyses to assess differences in traditional and age-adjusted (age × 10 ng/mL) D-dimer cutoffs, adjusting both by decade and by year. Results— A total 3,063 patients with suspected PE were evaluated by CTPA during the study period and 1,055 (34%) also received D-dimer testing. The specificity of age-adjusted D-dimer values was similar or higher for each age group studied compared to traditional cutoff, without significantly compromising sensitivity. Overall, had decade age-adjusted cutoffs been used, 37 Disclaimer: a file of an a our we the The copyediting, typesetting, and review of the its citable form. the production process may be discovered which could the and all legal disclaimers that to the pertain. CTPAs could have been avoided (19.6% of 189 patients aged >60 with Wells score ≤4); had yearly age-adjusted cutoffs been used, 52 CTPAs (18.2% of 286 patients aged >50 with Wells score ≤4) could have been avoided. Conclusion— Each age-adjusted D-dimer cutoff strategy for the evaluation of PE was associated with increased specificity and statistically insignificant decreased sensitivity when compared to the traditional D-dimer cutoff value.
Small Molecule MRP1 Inhibitor Reversan Increases the Therapeutic Index of Chemotherapy in Mouse Model of Neuroblastoma

The multidrug resistance-associated protein (MRP1) has been closely linked to poor treatment response in several cancers, most notably neuroblastoma. Homozygous deletion of the MRP1 gene in primary murine neuroblastoma tumors resulted in increased sensitivity to MRP1 substrate drugs (vincristine, etoposide, doxorubicin) compared to tumors containing both copies of wild-type MRP1, indicating that MRP1 plays a significant role in the drug resistance in this tumor type and defining this multidrug transporter as a target for pharmacological suppression. Cell-based readout system was created to functionally determine intracellular accumulation of MRP1 substrates using p53-responsive reporter as an indicator of drug-induced DNA damage. Screening of small molecule libraries in this readout system revealed pyrazolopyrimidines as a prominent structural class of potent MRP1 inhibitors. Reversan, the lead compound of this class, increased the efficacy of both vincristine and etoposide in murine models of neuroblastoma (syngeneic and human xenografts). As opposed to the majority of inhibitors of multidrug transporters, Reversan was not toxic by itself nor did it increase the toxicity of chemotherapeutic drug exposure in mice. Therefore, Reversan represents a new class of non-toxic MRP1 inhibitor, which may be clinically useful for the treatment of neuroblastoma and other MRP1 over-expressing drug refractory tumors by increasing their sensitivity to conventional chemotherapy.
Simplicity as a driving force in linguistic evolution

How did language come to have its characteristic structure? Many argue that by understanding those parts of our biological machinery relevant to language, we can explain why language is the way it is. If the hallmarks of language are simply properties of our biological machinery, elicited through the process of language acquisition, then such an explanatory route is adequate. As soon as we admit the possibility that knowledge of language is learned, in the sense that language acquisition is a process involving inductive generalisations, then an explanatory inadequacy arises. Any thorough explanation of the characteristic structure of language must now explain why the input to the language acquisition process has certain properties and not others. This thesis builds on recent work that proposes that the linguistic stimulus has certain structural properties that arise as a result of linguistic evolution. Here, languages themselves adapt to fit the task of learning: they reflect an accumulated structural residue laid down by previous generations of language users. Using computational models of linguistic evolution I explore the relationship be¬ tween language induction and generalisation based on a simplicity principle, and the linguistic evolution of compositional structures. The two main contributions of this thesis are as follows. Firstly, using a model of induction based on the minimum description length principle, I address the question of linguistic evolution resulting from a bias towards compression. Secondly, I carry out a thorough examination of the parameter space affecting the cultural transmission of language, and note that the conditions for linguistic evolution towards compositional structure correspond to (1) specific levels of semantic complexity, and (2), induction based on sparse language exposure.
Technical Advance Linker for Activation of T Cells (LAT), a Novel Immunohistochemical Marker for T Cells, NK Cells, Mast Cells, and Megakaryocytes Evaluation in Normal and Pathological Conditions

LAT (linker for activation of T cells) is an integral membrane protein of 36–38 kd that plays an important role in T cell activation. Using a rabbit polyclonal antibody generated against the cytosolic portion of LAT, we investigated the immunohistochemical expression of LAT in normal and pathological hematolymphoid tissues. LAT reacts with human T cells in paraffin sections, including decalcified bone marrow trephines. LAT appears early in T cells at the thymocyte stage and before TdT expression in embryos, and is expressed in peripheral lymphoid tissues, without restriction to any T cell subpopulations. In addition to T cells, natural killer (NK) cells (evaluated with flow cytometry), megakaryocytes and mast cells are also LAT-positive, whereas B cells and other myeloid and monocytic derived cells are negative. Tested on a total of 264 paraffin-embedded tissue biopsies, LAT reacted with the great majority (96.8%) of T/NK-cell neoplasms, covering the full range of T cell maturation. Although antibodies to both LAT and CD3 had a sim-ilarly high sensitivity in the staining of T/NK-cell lymphomas, when used in conjunction,
DNA Replication Timing, Genome Stability and Cancer

Normal cellular division requires that the genome be faithfully replicated to ensure that unaltered genomic information is passed from one generation to the next. DNA replication initiates from thousands of origins scattered throughout the genome every cell cycle; however, not all origins initiate replication at the same time. A vast amount of work over the years indicates that different origins along each eukaryotic chromosome are activated in early, middle or late S phase. This temporal control of DNA replication is referred to as the replication-timing program. The replication-timing program represents a very stable epigenetic feature of chromosomes. Recent evidence has indicated that the replication-timing program can influence the spatial distribution of mutagenic events such that certain regions of the genome experience increased spontaneous mutagenesis compared to surrounding regions. This influence has helped shape the genomes of humans and other multicellular organisms and can affect the distribution of mutations in somatic cells. It is also becoming clear that the replication-timing program is deregulated in many disease states, including cancer. Aberrant DNA replication timing is associated with changes in gene expression, changes in epigenetic modifications and an increased frequency of structural rearrangements. Furthermore, certain replication timing changes can directly lead to overt genomic instability and may explain unique mutational signatures that are present in cells that have undergone the recently described processes of “chromothripsis” and “kataegis”. In this review, we will discuss how the normal replication timing program, as well as how alterations to this program, can contribute to the evolution of the genomic landscape in normal and cancerous cells.
Estimates of Hepatic Glyceroneogenesis in Type 2 Diabetes in Humans

Background— Glyceroneogenesis, i.e. formation of triglyceride glycerol from pyruvate, is a critical component of triglyceride fatty acid cycling in-vivo. The quantitative contribution of glyceroneogenesis to triglyceride glycerol and its hormonal regulation have not been examined in humans. Methods— We have quantified the contribution of pyruvate to VLDL triglycerides in subjects with type II diabetes mellitus using the deuterium labeling of body water technique. Subjects with type II diabetes were studied before and after a six-month behavioral intervention therapy, during fasting and during a hyperinsulinemic normoglycemic clamp. Response to glucagon infusion was examined in five healthy subjects after an overnight fast. Results— Glyceroneogenesis contributed ∼ 54% to VLDL triglyceride glycerol in type II diabetes as compared with ∼ 12% contribution of plasma glucose. There was no effect of insulin plus glucose during hyperinsulinemic clamp on glyceroneogenesis, even following clinical interventions, when insulin sensitivity had improved. In healthy subjects, the contribution of triosephosphates to plasma VLDL triglycerides was ∼ 45%. Conclusion— Glyceroneogenesis, in contrast to glycolysis, is the predominant source of triglyceride-glycerol carbon for VLDL triglycerides in subjects with type II diabetes. The contribution of glyceroneogenesis to triglyceride-glycerol is not affected by short (4h) infusion of insulin in type