gebhart/patrepeval huggingface dataset:
A maturase-like subunit of the sequence-specific endonuclease endo.SceI from yeast mitochondria (1991)

Some yeast strains possess a sequence-specific endonuclease, Endo.SceI, which is a heterodimeric enzyme localized in mitochondria. The larger subunit (75 kDa) of Endo.SceI, encoded by a nuclear gene (ENS1), is transported from the cytosol into the mitochondria. In this study, we determined the partial amino acid sequence of the smaller subunit (50 kDa) of Endo.SceI. The determined sequence matched well the partial sequence deduced from a mitochondrial open reading frame (RF3). The RF3 locus is known to exhibit polymorphism since this reading frame in some yeast strains is supposed to encode a maturase-like protein, whereas in other strains, the frame is interrupted by GC clusters, which thus break the frame. Southern blot analysis of various yeast strains showed that the continuity of RF3 is correlated with the presence of Endo.SceI activity. These data indicate that the continuous RF3 sequence is a functional gene (ENS2) coding for the smaller subunit of Endo.SceI. The results of cytoduction, by which the continuous RF3 sequence was transferred into a yeast strain lacking mitochondrial DNA, confirmed this conclusion. This study suggests the involvement of Endo.SceI in genetic recombination of mitochondrial DNA.
A Versatile and Efficient Gene-Targeting System for Aspergillus nidulans (2005)

Abstract Aspergillus nidulans is an important experimental organism, and it is a model organism for the genus Aspergillus that includes serious pathogens as well as commercially important organisms. Gene targeting by homologous recombination during transformation is possible in A. nidulans, but the frequency of correct gene targeting is variable and often low. We have identified the A. nidulans homolog (nkuA) of the human KU70 gene that is essential for nonhomologous end joining of DNA in double-strand break repair. Deletion of nkuA (nkuAΔ) greatly reduces the frequency of nonhomologous integration of transforming DNA fragments, leading to dramatically improved gene targeting. We have also developed heterologous markers that are selectable in A. nidulans but do not direct integration at any site in the A. nidulans genome. In combination, nkuAΔ and the heterologous selectable markers make up a very efficient gene-targeting system. In experiments involving scores of genes, 90% or more of the transformants carried a single insertion of the transforming DNA at the correct site. The system works with linear and circular transforming molecules and it works for tagging genes with fluorescent moieties, replacing genes, and replacing promoters. This system is efficient enough to make genomewide gene-targeting projects feasible.
Decreased sAβPPβ, Aβ 38 , and Aβ 40 Cerebrospinal Fluid Levels in Frontotemporal Dementia (2011)

To improve the etiological diagnosis of neurodegenerative dementias like Alzheimer's disease (AD) or frontotemporal dementia (FTD), we evaluated the value of individual and combined measurements of the following relevant cerebrospinal fluid (CSF) biomarkers: Tau, 181p-Tau, Aβ38, Aβ40, Aβ42, sAβPPα, and sAβPPβ. This study conducted in two centers included patients with FTD (n = 34), AD (n = 52), as well as a control group of persons without dementia (CTRL, n = 42). Identical clinical criteria and pre-analytical conditions were used while CSF biomarkers were measured using commercial single and multiplex quantitative immunoassays. Thorough statistical analyses, including ROC curves, logistic regressions, and decision trees, were performed. We validated in AD the specific increase of p-Tau levels and the decrease of Aβ42 levels, two biological hallmarks of this disease. Tau concentrations were highest in AD and intermediate in FTD when compared to CTRL. The most interesting results were obtained by focusing on amyloid biomarkers as we found out in FTD a significant decrease of sAβPPβ, Aβ38, and Aβ40 levels. Aβ38 in particular was the most useful biomarker to differentiate FTD subjects from the CTRL population. Combining p-Tau and Aβ38 led us to correctly classifying FTD patients with sensitivity at 85% and specificity at 82%. Significant changes in amyloid biomarkers, particularly for Aβ38, are therefore seen in FTD. This could be quite useful for diagnosis purposes and it might provide additional evidence on the interrelationship between Tau and AβPP biology which understanding is essential to progress towards optimal therapeutic and diagnostic approaches of dementia.
Applying machine learning to automated segmentation of head and neck tumour volumes and organs at risk on radiotherapy planning CT and MRI scans (2016)

<ns4:p>Radiotherapy is one of the main ways head and neck cancers are treated; radiation is used to kill cancerous cells and prevent their recurrence.</ns4:p> <ns4:p>Complex treatment planning is required to ensure that enough radiation is given to the tumour, and little to other sensitive structures (known as organs at risk) such as the eyes and nerves which might otherwise be damaged. This is especially difficult in the head and neck, where multiple at-risk structures often lie in extremely close proximity to the tumour. It can take radiotherapy experts four hours or more to pick out the important areas on planning scans (known as segmentation).</ns4:p> <ns4:p>This research will focus on applying machine learning algorithms to automatic segmentation of head and neck planning computed tomography (CT) and magnetic resonance imaging (MRI) scans at University College London Hospital NHS Foundation Trust patients. Through analysis of the images used in radiotherapy DeepMind Health will investigate improvements in efficiency of cancer treatment pathways.</ns4:p>
A genetically engineered human IgG mutant with enhanced cytolytic activity (1992)

A mutant chimeric anti-5-dimethylaminonaphthalene-1-sulfonyl human Ig gamma that exhibited augmented effector function was constructed. Utilizing directed mutagenesis, a serine residue near the carboxyl terminus of the human IgG1 H chain (Ser444) was replaced by a cysteine. Novel intermolecular disulfide bonds between Cys444 residues linked pairs of Ig "tail-to-tail" to form covalent dimers ((H2L2)2). These dimers were 200-fold more efficient, compared with monomeric human IgG1, at antibody-dependent complement-mediated cytolysis of hapten-bearing erythrocytes. The ability to enhance the cytolytic activity of an mAb by genetic engineering may be of value in immunotherapy.
Detection and characterization of hibernating myocardium (2002)

Since Tennant and Wiggers observed that coronary occlusion caused a reduction in cardiac contractile function, a lot has been written about the concept of hibernating myocardium. Known as the 'smart heart', hibernating myocardium is characterized by a persistent ventricular myocardial dysfunction with preserved viability, which improves with the relief of the ischaemia; this chronic downregulation in contractile function being a protective mechanism to reduce oxygen demand and thus ensure myocyte survival. This improvement usually results in an enrichment in the quality of life as well as enhanced ventricular function. In fact, it has been observed that the cardiac event rate in patients with viable dysfunctional left ventricular segments who are medically treated, is higher than the event rate in patients with comparable viability who are revascularized. Different degrees of histological alteration have been seen in hibernating myocardium, ranging from cellular de-differentiation (fetal phenotype) to cellular degeneration. Cellular de-differentiation has been associated with repetitive stunning. On the other hand, cellular degeneration (with more extensive fibrosis) has been associated with chronic low myocardial blood flow and a longer time to recovery after revascularization. These histological patterns may suggest an evolution from cellular de-differentiation to degeneration, which ends in scar formation if no revascularization is performed. In fact, several studies have described the clinical value of identifying and revascularizing hibernating segments as early as possible, to minimize fibrosis and morbidity from adverse events. Detection of hibernating myocardium still remains an important clinical problem. Imaging modalities to assess myocardial viability must differentiate potentially functional tissue from myocardium with no potential for functional recovery. These techniques fall into three broad categories: ventricular function assessment, myocardial perfusion imaging and myocardial metabolic imaging. PET imaging with fluorine-18 fluorodeoxyglucose (18F-FDG) and 11C-acetate, single photon emission computed tomography (SPECT) with thallium and 99mTc-sestamibi, dobutamine echocardiograpy, magnetic resonance imaging (MRI) and fast computed tomography (CT) have been used for this purpose. PET imaging, in both perfusion and glucose metabolic activity, has become a standard for myocardial viability assessment, however, similar information may be available from carefully performed studies with perfusion tracers alone.
ERBB2 amplification in breast cancer with a high rate of proliferation. (1991)

The ERBB2 proto-oncogene was studied in 539 invasive primary breast tumors and was found amplified (2- greater than 30 copies) in 19%. Amplification was correlated to most known risk factors, including; large tumor size, lymph node positivity and many tumor involved nodes, advanced stage, low patient age (less than 40 years), non-diploidy and hypertetraploidy, and most significantly (P less than 0.00001) to the absence of steroid receptors and to a high rate of proliferation (flow cytometric determined S phase fraction). ERBB2 amplification was strongly associated (P less than 0.0001) with early recurrence and death in breast cancer among node-positive patients. This connection did not, however, remain in multivariate analyses. No correlations to clinical outcome were seen among node-negative patients. Similarly, non-diploid, but not diploid, amplified tumors were particularly aggressive. Furthermore, ERBB2 amplification was associated with a high rate of proliferation and poor prognosis in steroid receptor positive, but not receptor negative tumors. In progesterone receptor positive breast cancer, amplification was an independent and with node status equally powerful (P less than 0.0001) predictor of poor survival. It is concluded that ERBB2 activity is related to an increased tumor growth rate but not directly to metastasizing ability. Its clinical relevance as a prognostic factor may be in selecting a high risk subgroup of breast cancer, in general considered as being of good prognosis.
End-to-End Multi-View Fusion for 3D Object Detection in LiDAR Point Clouds (2019)

Recent work on 3D object detection advocates point cloud voxelization in birds-eye view, where objects preserve their physical dimensions and are naturally separable. When represented in this view, however, point clouds are sparse and have highly variable point density, which may cause detectors difficulties in detecting distant or small objects (pedestrians, traffic signs, etc.). On the other hand, perspective view provides dense observations, which could allow more favorable feature encoding for such cases. In this paper, we aim to synergize the birds-eye view and the perspective view and propose a novel end-to-end multi-view fusion (MVF) algorithm, which can effectively learn to utilize the complementary information from both. Specifically, we introduce dynamic voxelization, which has four merits compared to existing voxelization methods, i) removing the need of pre-allocating a tensor with fixed size; ii) overcoming the information loss due to stochastic point/voxel dropout; iii) yielding deterministic voxel embeddings and more stable detection outcomes; iv) establishing the bi-directional relationship between points and voxels, which potentially lays a natural foundation for cross-view feature fusion. By employing dynamic voxelization, the proposed feature fusion architecture enables each point to learn to fuse context information from different views. MVF operates on points and can be naturally extended to other approaches using LiDAR point clouds. We evaluate our MVF model extensively on the newly released Waymo Open Dataset and on the KITTI dataset and demonstrate that it significantly improves detection accuracy over the comparable single-view PointPillars baseline.
Role of glucose and ketone bodies in the metabolic control of experimental brain cancer (2003)

Brain tumours lack metabolic versatility and are dependent largely on glucose for energy. This contrasts with normal brain tissue that can derive energy from both glucose and ketone bodies. We examined for the first time the potential efficacy of dietary therapies that reduce plasma glucose and elevate ketone bodies in the CT-2A syngeneic malignant mouse astrocytoma. C57BL/6J mice were fed either a standard diet unrestricted (SD-UR), a ketogenic diet unrestricted (KD-UR), the SD restricted to 40% (SD-R), or the KD restricted to 40% of the control standard diet (KD-R). Body weights, tumour weights, plasma glucose, beta-hydroxybutyrate (beta-OHB), and insulin-like growth factor 1 (IGF-1) were measured 13 days after tumour implantation. CT-2A growth was rapid in both the SD-UR and KD-UR groups, but was significantly reduced in both the SD-R and KD-R groups by about 80%. The results indicate that plasma glucose predicts CT-2A growth and that growth is dependent more on the amount than on the origin of dietary calories. Also, restriction of either diet significantly reduced the plasma levels of IGF-1, a biomarker for angiogenesis and tumour progression. Owing to a dependence on plasma glucose, IGF-1 was also predictive of CT-2A growth. Ketone bodies are proposed to reduce stromal inflammatory activities, while providing normal brain cells with a nonglycolytic high-energy substrate. Our results in a mouse astrocytoma suggest that malignant brain tumours are potentially manageable with dietary therapies that reduce glucose and elevate ketone bodies.
Hedgehog-induced phosphorylation by CK1 sustains the activity of Ci/Gli activator (2014)

Hedgehog (Hh) signaling governs many developmental processes by regulating the balance between the repressor (Ci(R)/Gli(R)) and activator (Ci(A)/Gli(A)) forms of Cubitus interruptus (Ci)/glioma-associated oncogene homolog (Gli) transcription factors. Although much is known about how Ci(R)/Gli(R) is controlled, the regulation of Ci(A)/Gli(A) remains poorly understood. Here we demonstrate that Casein kinase 1 (CK1) sustains Hh signaling downstream of Costal2 and Suppressor of fused (Sufu) by protecting Ci(A) from premature degradation. We show that Hh stimulates Ci phosphorylation by CK1 at multiple Ser/Thr-rich degrons to inhibit its recognition by the Hh-induced MATH and BTB domain containing protein (HIB), a substrate receptor for the Cullin 3 family of E3 ubiquitin ligases. In Hh-receiving cells, reduction of CK1 activity accelerated HIB-mediated degradation of Ci(A), leading to premature loss of pathway activity. We also provide evidence that Gli(A) is regulated by CK1 in a similar fashion and that CK1 acts downstream of Sufu to promote Sonic hedgehog signaling. Taken together, our study not only reveals an unanticipated and conserved mechanism by which phosphorylation of Ci/Gli positively regulates Hh signaling but also provides the first evidence, to our knowledge, that substrate recognition by the Cullin 3 family of E3 ubiquitin ligases is negatively regulated by a kinase.
Reactive oxygen species as signaling molecules in neutrophil chemotaxis (2010)

Neutrophil chemotaxis is a critical component in innate immunity. Recently, using a small-molecule functional screening, we identified NADPHoxidase- dependent Reactive Oxygen Species (ROS) as key regulators of neutrophil chemotactic migration. Neutrophils depleted of ROS form more frequent multiple pseudopodia and lost their directionality as they migrate up a chemoattractant concentration gradient. Here, we further studied the role of ROS in neutrophil chemotaxis and found that multiple pseudopodia formation induced by NADPH inhibitor diphenyleneiodonium chloride (DPI) was more prominent in relatively shallow chemoattractant gradient. It was reported that, in shallow chemoattractant gradients, new pseudopods are usually generated when existing ones bifurcate. Directional sensing is mediated by maintaining the most accurate existing pseudopod, and destroying pseudopods facing the wrong direction by actin depolymerization. We propose that NADPH-mediated ROS production may be critical for disruption of misoriented pseudopods in chemotaxing neutrophils. Thus, inhibition of ROS production will lead to formation of multiple pseudopodia.
Hic, a Novel Surface Protein of Streptococcus pneumoniae That Interferes with Complement Function (2000)

The important human pathogen Streptococcus pneumoniae was found to absorb factor H, an inhibitor of complement, from human plasma. We identified the gene encoding a novel surface protein, factor H-binding inhibitor of complement (Hic), in the pspC locus of type 3 pneumococci. Unlike PspC proteins in other serotypes, Hic is anchored to the cell wall by means of an LPXTG motif, and the overall sequence homology to various PspC proteins is low. However, the NH(2)-terminal region showed significant homology to the NH(2)-terminal region of several PspC proteins. A fragment of Hic, covering this homologous region, was expressed as a glutathione S-transferase (GST) fusion protein. GST:Hic(39-261) bound radiolabeled factor H and inhibited binding of factor H to pneumococci of different serotypes. Interaction kinetics between GST:Hic(39-261) and factor H were studied with surface plasmon resonance and showed a high affinity binding (K(A) = 5 x 10(7), K(D) = 2.3 x 10(-)(8)). Mutant pneumococci lacking Hic showed no absorption of factor H in human plasma and no binding of radiolabeled factor H, suggesting that Hic is responsible for factor H-binding in type 3 pneumococci. Factor H-dependent inhibition of the alternative pathway was not diminished by the presence of GST:Hic(39-261). In addition, an intrinsic inhibitory effect of Hic is suggested.
Method for the Quantification of Alginate in Microcapsules (1993)

Alginate is a key reagent in the preparation of microcapsules for cell transplantation. To address the question of the intracapsular alginate concentration, a sensitive assay has been developed to quantify the alginate content of microcapsules. The method is based on the metachromatic change induced by alginate binding to the dye, 1,9-dimethyl methylene blue (DMMB). The assay has a high sensitivity and precision. It covers a wide concentration range enabling the measurement of alginate in dilute supernatants as well as in microcapsules. For the latter, the membrane is initially dissolved by incubating the microcapsules in an alkaline medium. The effect of potentially interfering substances (poly-L-lysine (PLL), citrate, chloride, sodium) and of pH has been studied. Poly-L-lysine interfered with the assay at pH 6.5 but not at pH 13. Interference by sodium augmented with increasing sodium concentration and reached a plateau at 200 mM. This problem was overcome by routinely adjusting all samples to 500 mM sodium. The other substances tested had a negligible effect on the assay. The reliable measurement of alginate with this new assay will allow the optimization of the intracapsular alginate concentration.
The Role of Oxidative Stress in Alzheimer ’ s Disease (2013)

Alzheimer’s disease (AD) is a growing health care epidemic. It is the most common cause of dementia in the elderly and its incidence is rising. The disease is progressive, irreversible and debilitating. It is a great burden on both the patient and their caregivers. The two pathological hallmarks of the disease are aggregated beta-amyloid deposits and hyperphosphorylated neurofibrillary tangles. Although these lesions are found in the AD brain, their role in the pathogenesis leading to clinical dementia is largely unknown and still under debate. Age, which influences theoxidative and inflammatory states of the brain, is the most important risk factor. Recent research has highlighted the important role of oxidative stress, the role of the mitochondria in early disease and inflammation in the underlying molecular mechanism of AD. Oxidative damage predominately involves lipid peroxidation from reactive oxygen species derived from metabolism. Most patients are diagnosed after irreversible damage has been done. A better understanding of the role of these stressors could lead to early therapeutic interventions that better target the cause and have potential to modify disease course. Currently there is no disease modifying treatments available. This literature review highlights current knowledge regarding the role of oxidative stress, how it relates to the pathogenesis of AD and how further research in this field can benefit those who suffer from this debilitating disease.
Protection against electrophile and oxidant stress by induction of the phase 2 response: Fate of cysteines of the Keap1 sensor modified by inducers (2004)

Induction of a family of phase 2 genes encoding for proteins that protect against the damage of electrophiles and reactive oxygen intermediates is potentially a major strategy for reducing the risk of cancer and chronic degenerative diseases. Many phase 2 genes are regulated by upstream antioxidant response elements (ARE) that are targets of the leucine zipper transcription factor Nrf2. Under basal conditions, Nrf2 resides mainly in the cytoplasm bound to its cysteine-rich, Kelch domain-containing partner Keap1, which is itself anchored to the actin cytoskeleton and represses Nrf2 activity. Inducers disrupt the Keap1-Nrf2 complex by modifying two (C273 and C288) of the 25 cysteine residues of Keap1. The critical role of C273 and C288 was established by (i) their high reactivity when purified recombinant Keap1 was treated with dexamethasone mesylate and the dexamethasone-modified tryptic peptides were analyzed by mass spectrometry, and (ii) transfection of keap1 and nrf2 gene-deficient mouse embryonic fibroblasts with constructs expressing cysteine to alanine mutants of Keap1, and measurement of the ability of cotransfected Nrf2 to repress an ARE-luciferase reporter. Reaction of Keap1 with inducers results in formation of intermolecular disulfide bridges, probably between C273 of one Keap1 molecule and C288 of a second. Evidence for formation of such dimers was obtained by 2D PAGE of extracts of cells treated with inducers, and by the demonstration that whereas C273A and C288A mutants of Keap1 alone could not repress Nrf2 activation of the ARE-luciferase reporter, an equal mixture of these mutant constructs restored repressor activity.
The Epidemiology of Human Papillomavirus Infection and Cervical Cancer (2007)

Cervical cancer has been recognized as a rare outcome of a common Sexually Transmitted Infection (STI). The etiologic association is restricted to a limited number of viral types of the family of the Human Papillomaviruses (HPVs). The association is causal in nature and under optimal testing systems, HPV DNA can be identified in all specimens of invasive cervical cancer. As a consequence, it has been claimed that HPV infection is a necessary cause of cervical cancer. The evidence is consistent worldwide and implies both the Squamous Cell Carcinomas (SCC), the adenocarcinomas and the vast majority (i.e. > 95%) of the immediate precursors, namely High Grade Squamous Intraepithelial Lesions (HSIL)/Cervical Intraepithelial Neoplasia 3 (CIN3)/Carcinoma in situ. Co-factors that modify the risk among HPV DNA positive women include the use of oral contraceptives (OC) for five or more years, smoking, high parity (five or more full term pregnancies) and previous exposure to other sexually transmitted diseases such as Chlamydia Trachomatis (CT) and Herpes Simplex Virus type 2 (HSV-2). Women exposed to the Human Immunodeficiency Virus (HIV) are at high risk for HPV infection, HPV DNA persistency and progression of HPV lesions to cervical cancer.