gebhart/patrepeval huggingface dataset:
Barth syndrome cardiomyopathy: targeting the mitochondria with elamipretide (2020)

Barth syndrome (BTHS) is a rare, X-linked recessive, infantile-onset debilitating disorder characterized by early-onset cardiomyopathy, skeletal muscle myopathy, growth delay, and neutropenia, with a worldwide incidence of 1/300,000-400,000 live births. The high mortality rate throughout infancy in BTHS patients is related primarily to progressive cardiomyopathy and a weakened immune system. BTHS is caused by defects in the TAZ gene that encodes tafazzin, a transacylase responsible for the remodeling and maturation of the mitochondrial phospholipid cardiolipin (CL), which is critical to normal mitochondrial structure and function (i.e., ATP generation). A deficiency in tafazzin results in up to a 95% reduction in levels of structurally mature CL. Because the heart is the most metabolically active organ in the body, with the highest mitochondrial content of any tissue, mitochondrial dysfunction plays a key role in the development of heart failure in patients with BTHS. Changes in mitochondrial oxidative phosphorylation reduce the ability of mitochondria to meet the ATP demands of the human heart as well as skeletal muscle, namely ATP synthesis does not match the rate of ATP consumption. The presence of several cardiomyopathic phenotypes have been described in BTHS, including dilated cardiomyopathy, left ventricular noncompaction, either alone or in conjunction with other cardiomyopathic phenotypes, endocardial fibroelastosis, hypertrophic cardiomyopathy, and an apical form of hypertrophic cardiomyopathy, among others, all of which can be directly attributed to the lack of CL synthesis, remodeling, and maturation with subsequent mitochondrial dysfunction. Several mechanisms by which these cardiomyopathic phenotypes exist have been proposed, thereby identifying potential targets for treatment. Dysfunction of the sarcoplasmic reticulum Ca<sup>2+</sup>-ATPase pump and inflammation potentially triggered by circulating mitochondrial components have been identified. Currently, treatment modalities are aimed at addressing symptomatology of HF in BTHS, but do not address the underlying pathology. One novel therapeutic approach includes elamipretide, which crosses the mitochondrial outer membrane to localize to the inner membrane where it associates with cardiolipin to enhance ATP synthesis in several organs, including the heart. Encouraging clinical results of the use of elamipretide in treating patients with BTHS support the potential use of this drug for management of this rare disease.
Peptide Brush Polymers for Efficient Delivery of a Gene Editing Protein to Stem Cells (2019)

The scarcity of effective means to deliver functional proteins to living cells is a central problem in biotechnology and medicine. Herein, we report the efficient delivery of an active DNA-modifying enzyme to human stem cells through high-density cell penetrating peptide brush polymers. Cre recombinase is mixed with a fluorophore-tagged polymer carrier and then applied directly to induced pluripotent stem cells or HEK293T cells. This results in efficient delivery of Cre protein as measured by activation of a genomically integrated Cre-mediated recombination reporter. We observed that brush polymer formulations utilizing cell penetrating peptides promoted Cre delivery but oligopeptides alone or oligopeptides displayed on nanoparticles did not. Overall, we report the efficient delivery of a genome-modifying enzyme to stem cells that may be generalizable to other, difficult-to-transduce cell types.
Molecular Cloning of the Chromosomal Breakpoint of B-Cell Lymphomas and Leukemias with the t(11;14) Chromosome Translocation (1984)

The chromosomal breakpoint of chronic lymphocytic leukemia (CLL) cells of the B-cell type carrying the translocated long arms of chromosomes 11 and 14 [t(11;14) (q13;q32)] was cloned. The breakpoint was found to be within the joining segment of the human heavy chain locus on the translocated long arm of chromosome 14. A probe that is specific for chromosome 11 and that maps immediately 5' to the breakpoint on the 14q+ chromosome was isolated. The probe detected a rearrangement of the homologous genomic DNA segment in the parental CLL cells and also in DNA from a diffuse large cell lymphoma with the t(11;14) translocation. This rearranged DNA segment was not present in Burkitt lymphoma cells with the t(8;14) translocation or in nonneoplastic human lymphoblastoid cells. The probe can thus be used to identify and characterize a gene located on band q13 of chromosome 11 that appears to be involved in the malignant transformation of human B cells carrying the t(11;14) translocation. This gene, named bcl -1, appears to be unrelated to any of the known retrovirus oncogenes described to date.
Protective Effects of Guizhi-Fuling-Capsules on Rat Brain Ischemia/Reperfusion Injury (2007)

Previous studies revealed that Guizhi-Fuling-Capsules (GZFLC), a traditional Chinese medical (Kampo) formulation composed of five kinds of medicinal plants, Cinnamomum cassia BLUME (Cinnamomi Cortex), Paeonia lactiflora PALL. (Peonies Radix), Paeonia suffruticosa ANDREWS (Moutan Cortex), Prunus persica BATSCH (Persicae Semen), and Poria cocos WOLF (Hoelen), exerts a protective effect against vascular injury and has a protective effect against glutamate- or nitro oxide-mediated neuronal damage. In the present study, the effect of GZFLC in a rat in vivo model of focal cerebral ischemia and reperfusion was investigated. Administration of GZFLC (0.3 and 0.9 g/kg, p.o.) after focal cerebral ischemia significantly decreased brain infarction and water contents in rats subjected to 2-h ischemia followed by 24-h reperfusion from 31.72 +/- 2.49%, 84.76 +/- 1.63% in the model group to 17.31 +/- 3.66%, 82.51 +/- 1.36% and 8.30 +/- 3.73%, 81.35 +/- 1.73%, respectively. Furthermore, analysis of inflammatory cytokines in ischemic brain showed that GZFLC treatment significantly down-regulated expressions of pro-inflammatory cytokines including interleukin (IL)-1beta and tissue necrosis factor-alpha and markedly up-regulated expressions of anti-inflammatory cytokines IL-10 and IL-10R both in mRNA and protein levels. The serum levels of these inflammatory cytokines were also regulated the same way. These results suggested that GZFLC may be beneficial for the treatment of brain ischemia-reperfusion injury partly due to its anti-inflammatory properties.
The site-specific recombination system of actinophage TG1 (2009)

Actinophage TG1 forms stable lysogens by integrating at a unique site on chromosomes of Streptomyces strains. The phage (attP(TG1)) and bacterial (attB(TG1)) attachment sites for TG1 were deduced from comparative genomic studies on the TG1-lysogen and nonlysogen of Streptomyces avermitilis. The attB(TG1) was located within the 46-bp region in the dapC gene (SAV4517) encoding the putative N-succinyldiaminopimelate aminotransferase. TG1-lysogens of S. avermitilis, however, did not demand either lysine or diaminopimelate for growth, indicating that the dapC annotation of S. avermitilis requires reconsideration. A bioinformatic survey of DNA databases using the fasta program for the attB(TG1) sequence extracted possible integration sites from varied streptomycete genomes, including Streptomyces coelicolor A3(2) and Streptomyces griseus. The gene encoding the putative TG1 integrase (int(TG1)) was located adjacent to the attP(TG1) site. TG1 integrase deduced from the int(TG1) gene was a protein of 619 amino acids having a high sequence similarity to phiC31 integrase, especially at the N-terminal catalytic region. By contrast, sequence similarities at the C-terminal regions crucial for the recognition of attachment sites were moderate or low. The site-specific recombination systems based on TG1 integrase were shown to work efficiently not only in Streptomyces strains but also in heterologous Escherichia coli.
Fibronectin domain engineering (2009)

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Chemical Engineering, 2009.
Broadband radial waveguide power amplifier using a spatial power combining technique (2009)

A broadband radial waveguide power amplifier has been designed and fabricated using a spatial power dividing/combining technique. A simple electromagnetic model of this power-dividing/combining structure has been developed. Analysis based on equivalent circuits gives the design formula for perfect power-dividing/combining circuits. The measured small-signal gain of the eight-device power amplifier is 12–16.5 dB over a broadband from 7 to 15 GHz. The measured maximum output power at 1-dB compression is 28.6 dBm at 10 GHz, with a power-combining efficiency of about 91%. Furthermore, the performance degradation of this power amplifier because of device failures has also been measured.
A Convolutional Neural Network Smartphone App for Real-Time Voice Activity Detection (2018)

This paper presents a smartphone app that performs real-time voice activity detection based on convolutional neural network. Real-time implementation issues are discussed showing how the slow inference time associated with convolutional neural networks is addressed. The developed smartphone app is meant to act as a switch for noise reduction in the signal processing pipelines of hearing devices, enabling noise estimation or classification to be conducted in noise-only parts of noisy speech signals. The developed smartphone app is compared with a previously developed voice activity detection app as well as with two highly cited voice activity detection algorithms. The experimental results indicate that the developed app using convolutional neural network outperforms the previously developed smartphone app.
Apolipoprotein E affects the central nervous system response to injury and the development of cerebral edema (2001)

Apolipoprotein E has been implicated in modifying neurological outcome after traumatic brain injury, although the mechanisms by which this occurs remain poorly defined. To investigate the role of endogenous apolipoprotein E following acute brain injury, noninvasive magnetic resonance imaging was performed on anesthetized mice following closed head injury. Effacement of the lateral ventricle was used as a radiographic surrogate for cerebral edema. At 24 hours following injury, apolipoprotein E-deficient animals had a greater degree of cerebral edema as compared to matched controls. In addition, the brains of apolipoprotein E-deficient animals had a significantly greater upregulation of tissue necrosis factor alpha messenger ribonucleic acid as compared to controls as early as 1-hr post injury. Thus, modulation of the endogenous central nervous system inflammatory response may be one mechanism by which apolipoprotein E affects outcome following acute brain injury.
Pharmacogenomics: A Tool to Prevent and Cure Coronary Heart Disease (2007)

Inflammation and genetics play an important role in the pathogenesis of coronary heart disease (CHD). This is supported by epidemiological studies which have thoroughly investigated the association between CHD and gene polymorphisms of the inflammatory molecules. Moreover, efforts to find elective therapy have not been rewarding and, despite the increasing appreciation of the role of genetics in CHD and myocardial infarction (MI) pathogenesis, pharmacogenomic approaches to uncover drug target have not been extensively explored. A critical search of published literature has suggested few inflammatory genes directly involved in the risk to develop CHD and MI. The selected genes are, the pro- and anti-inflammatory cytokines, Toll-like receptor 4 (TLR4), CD14, CCR5, cyclooxygenases (COXs) and lipoxygenases (LOXs). The associations between candidate gene polymorphisms and CHD/MI are difficult and complex as a consequence of pleiotropy, variations with age, selection due to the lethality of the disease, and interactions with other genes and environmental factors. However, current data indicate that screening for interleukin (IL)-6, IL-10, TLR4, CCR5, COX and LOX polymorphisms are likely to be a useful tool for CHD and MI risk assessment. What we believe is that dissecting out the influence of genetics polymorphism within the complex pathophysiology of CHD and MI will help to provide a more complete risk assessment and complement known classical cardiological risk factors. The detection of a risk profile will potentially allow both the early identification of individuals susceptible to disease and the possible discovery of potential targets for drug of lifestyle modification.
Mechanism of protein-guided folding of the active site U2/U6 RNA during spliceosome activation (2020)

Splicing machine shifts into gear Spliceosome activation involves extensive protein exchanges and RNA rearrangements that lead to the formation of a catalytically active U2/U6 RNA structure called B act . Previously, little was known about the pathway leading to the U2/U6 active site and how proteins aid in folding the U2/U6 RNA. Using cryo–electron microscopy to determine structures of two human pre-B act complexes, Townsend et al. uncovered an intricate cascade of coordinated structural changes involving mutually exclusive interactions that facilitate the directionality of the activation process. These structures reveal the assembly pathway of the U2/U6 catalytic RNA and the mechanism whereby proteins facilitate its folding. Science , this issue p. eabc3753
An Integrated Approach to a Portable and Low‐Cost Immunoassay for Resource‐Poor Settings (2004)

An integrated approach for detecting proteins that is low-cost, portable, battery-operated, and works under field conditions such as direct sunlight has been developed. The “POCKET immunoassay” uses commercially available components, and exhibits an analytical performance approaching that of established bench-top techniques. It may be appropriate for the diagnosis of infectious diseases, such as HIV/AIDS, in developing countries (see picture).
Salmonella typhimurium aroA, htrA, and aroD htrA mutants cause progressive infections in athymic (nu/nu) BALB/c mice (1997)

Athymic (nu/nu) BALB/c mice and their euthymic (nu/+) littermates were inoculated intravenously with live attenuated vaccine strains of Salmonella typhimurium. All strains caused progressive infections in the athymic mice but not in their euthymic littermates. Athymic mice given strain SL3261, an aroA derivative of SL1344, in doses between log 4.7 and 5.7 CFU were all severely ill and were killed by weeks 4 to 5. Athymic mice given log 4.7 CFU of a derivative of S. typhimurium C5 carrying a mutation in htrA, encoding a stress protein, were ill and were killed by week 7 in one experiment but survived to week 13 in another. Athymic mice given log 4.6 CFU of a C5 aroD htrA double mutant were ill and were killed at week 7. Athymic mice given SL3261 had high bacterial counts in the reticuloendothelial system at 4 weeks. Athymic mice given SL3261 or C5 htrA made immunoglobulin G3 (IgG3) (and to a lesser extent IgM) antibody to lipopolysaccharide (LPS), whereas euthymic mice made IgM, IgG1, IgG2a, IgG2b, and IgG3 anti-LPS antibodies. The results indicate that both aroA and htrA strains will produce slow, progressively lethal infections in athymic mice, that the htrA strain is more attenuated than the aroA strain as measured by time to death in this model, and that IgG3 anti-LPS antibody alone cannot suppress the progress of infections by very attenuated strains in athymic mice.
Bone Marrow Neovascularization, Plasma Cell Angiogenic Potential, and Matrix Metalloproteinase-2 Secretion Parallel Progression of Human Multiple Myeloma (1999)

To assess whether the progression of plasma cell tumors is accompanied by angiogenesis and secretion of matrix-degrading enzymes, bone marrow biopsy specimens from 20 patients with monoclonal gammopathy of undetermined significance (MGUS), 18 patients with nonactive multiple myeloma (MM), and 26 patients with active MM were evaluated for their angiogenic potential and matrix-metalloproteinase (MMP) production. A fivefold increase of the factor VIII+ microvessel area was measured by a planimetric method of point counting in the bone marrow of patients with active MM as compared with nonactive MM and MGUS patients (P <.01). When serum-free conditioned media (CM) of plasma cells isolated from the bone marrow of each patient were tested in vivo for their angiogenic activity in the chick embryo chorioallantoic membrane (CAM) assay, the incidence of angiogenic samples was significantly higher (P <. 01) in the active MM group (76%) compared with nonactive MM (33%) and MGUS (20%) groups. Moreover, a linear correlation (P <.01) was found between the extent of vascularization of the bone marrow of a given patient and the angiogenic activity exerted in the CAM assay by the plasma cells isolated from the same bone marrow. In vitro, a significantly higher fraction of the plasma cell CM samples from the active MM group stimulated human umbilical vein endothelial cell (HUVEC) proliferation (53%, P <.01), migration (42%, P <.05), and/or monocyte chemotaxis (38%, P <.05) when compared with nonactive MM and MGUS groups (ranging between 5% and 15% of the samples). Also, immunoassay of plasma cell extracts showed significantly higher (P <. 01) levels of the angiogenic basic fibroblast growth factor (FGF)-2 in the active MM patients than in nonactive MM and MGUS patients (153 +/- 59, 23 +/- 17, and 31 +/- 18 pg FGF-2/100 micrograms of protein, respectively). Accordingly, neutralizing anti-FGF-2 antibody caused a significant inhibition (ranging from 54% to 68%) of the biological activity exerted on cultured endothelial cells and in the CAM assay by plasma cell CM samples from active MM patients. Finally, in situ hybridization of bone marrow plasma cells and gelatin-zymography of their CM showed that active MM patients express significantly higher (P <.01) levels of MMP-2 mRNA and protein when compared with nonactive MM and MGUS patients, whereas MMP-9 expression was similar in all groups. Taken together, these findings indicate that the progression of plasma cell tumors is accompanied by an increase of bone marrow neovascularization. This is paralleled by an increased angiogenic and invasive potential of bone marrow plasma cells, which is dependent, at least in part, by FGF-2 and MMP-2 production. Induction of angiogenesis and secretion of MMPs by plasma cells in active disease may play a role in their medullary and extramedullary dissemination, raising the hypothesis that angiostatic/anti-MMP agents may be used for therapy of MM.
Accurate and simple calibration of DLP projector systems (2014)

Much work has been devoted to the calibration of optical cameras, and accurate and simple methods are now available which require only a small number of calibration targets. The problem of obtaining these parameters for light projectors has not been studied as extensively and most current methods require a camera and involve feature extraction from a known projected pattern. In this work we present a novel calibration technique for DLP Projector systems based on phase shifting profilometry projection onto a printed calibration target. In contrast to most current methods, the one presented here does not rely on an initial camera calibration, and so does not carry over the error into projector calibration. A radial interpolation scheme is used to convert features coordinates into projector space, thereby allowing for a very accurate procedure. This allows for highly accurate determination of parameters including lens distortion. Our implementation acquires printed planar calibration scenes in less than 1s. This makes our method both fast and convenient. We evaluate our method in terms of reprojection errors and structured light image reconstruction quality.
Use of cancer‐specific genomic rearrangements to quantify disease burden in plasma from patients with solid tumors (2010)

Detection of recurrent somatic rearrangements routinely allows monitoring of residual disease burden in leukemias, but is not used for most solid tumors. However, next-generation sequencing now allows rapid identification of patient-specific rearrangements in solid tumors. We mapped genomic rearrangements in three cancers and showed that PCR assays for rearrangements could detect a single copy of the tumor genome in plasma without false positives. Disease status, drug responsiveness, and incipient relapse could be serially assessed. In future, this strategy could be readily established in diagnostic laboratories, with major impact on monitoring of disease status and personalizing treatment of solid tumors.
Efficient Trans-Splicing in the Retina Expands the Utility of Adeno-Associated Virus as a Vector for Gene Therapy (2003)

Recombinant vectors based on adeno-associated virus (AAV) can efficiently transduce many different cell types, including cells of the retina, resulting in stable gene expression. A major shortcoming of this vector is its small packaging capacity. A trans-splicing approach, which reconstitutes gene expression from two independent AAV vectors, can be used to overcome the vector's packaging limitations. The efficiency of this system to date has been disappointing, and therefore its utility for therapeutic application limited. We demonstrate here that efficiency and cellular specificity of trans-splicing is dependent on selection of the appropriate AAV serotype. Efficiency of transgene expression resulting from trans-splicing in skeletal muscle approaches that obtained when delivering the intact transgene when using AAV2 vectors packaged with AAV5 capsids (AAV2/5). This expands the potential of AAV vectors for retinal gene therapy. The use of AAV2/5 also increases the efficiency of trans-splicing in photoreceptors. Selection of the appropriate AAV serotype is likely to affect efficiency of trans-splicing in other organ systems as well.
Intracellular targeting of the Yersinia YopE cytotoxin in mammalian cells induces actin microfilament disruption (1991)

Pathogenic Yersinia spp., including the etiological agent of plague, Y. pestis, all carry a common plasmid that encodes a number of essential virulence determinants, the Yop proteins. One of these, YopE, has been shown to be involved in the obstruction of the primary host defense by a molecular mechanism leading to inhibition of phagocytosis (R. Rosqvist, A. Forsberg, M. Rimpiläinen, T. Bergman, and H. Wolf-Watz, Mol. Microbiol. 4:657-667, 1990). Although the Yop proteins are secreted into the culture supernatant in vast amounts, in vitro studies of the function of the Yop proteins have so far been unsuccessful. We show that isolated Yop proteins indeed can cause cytotoxic effects in vitro if the proteins are introduced intracellularly into the eukaryotic cell. Isolated Yop proteins of Yersinia pseudotuberculosis were found to disrupt the microfilament structure when microinjected intracellularly into the host cell. In particular, YopE was demonstrated to be directly involved in the cytotoxic action, whereas YopD seems to have a critical role in translocating the YopE protein through the host cell membrane. These results elucidate the requirement for at least some of the Yop proteins to leave the pathogen during infection.