gebhart/patrepeval huggingface dataset:
The Carboxyl Terminus of Interferon-γ Contains a Functional Polybasic Nuclear Localization Sequence (1999)

Cytokines such as interferon-gamma (IFN-gamma), which utilize the well studied JAK/STAT pathway for nuclear signal transduction, are themselves translocated to the nucleus. The exact mechanism for the nuclear import of IFN-gamma or the functional role of the nuclear translocation of ligand in signal transduction is unknown. We show in this study that nuclear localization of IFN-gamma is driven by a simple polybasic nuclear localization sequence (NLS) in its COOH terminus, as verified by its ability to specify nuclear import of a heterologous protein allophycocyanin (APC) in standard import assays in digitonin-permeabilized cells. Similar to other nuclear import signals, we show that a peptide representing amino acids 95-132 of IFN-gamma (IFN-gamma(95-132)) containing the polybasic sequence 126RKRKRSR132 was capable of specifying nuclear uptake of the autofluorescent protein, APC, in an energy-dependent fashion that required both ATP and GTP. Nuclear import was abolished when the above polybasic sequence was deleted. Moreover, deletions immediately NH2-terminal of this sequence did not affect the nuclear import. Thus, the sequence 126RKRKRSR132 is necessary and sufficient for nuclear localization. Furthermore, nuclear import was strongly blocked by competition with the cognate peptide IFN-gamma(95-132) but not the peptide IFN-gamma(95-125), which is deleted in the polybasic sequence, further confirming that the NLS properties were contained in this sequence. A peptide containing the prototypical polybasic NLS sequence of the SV40 large T-antigen was also able to inhibit the nuclear import mediated by IFN-gamma(95-132). This observation suggests that the NLS in IFN-gamma may function through the components of the Ran/importin pathway utilized by the SV40 T-NLS. Finally, we show that intact IFN-gamma, when coupled to APC, was also able to mediate its nuclear import. Again, nuclear import was blocked by the peptide IFN-gamma(95-132) and the SV40 T-NLS peptide, suggesting that intact IFN-gamma was also transported into the nucleus through the Ran/importin pathway. Previous studies have suggested a direct intracellular role for IFN-gamma in the induction of its biological activities. Based on our data in this study, we suggest that a key intracellular site of interaction of IFN-gamma is the one with the nuclear transport mechanism that occurs via the NLS in the COOH terminus of IFN-gamma.
PERK inhibition prevents tau-mediated neurodegeneration in a mouse model of frontotemporal dementia (2015)

The PERK-eIF2α branch of the Unfolded Protein Response (UPR) mediates the transient shutdown of translation in response to rising levels of misfolded proteins in the endoplasmic reticulum. PERK and eIF2α activation are increasingly recognised in postmortem analyses of patients with neurodegenerative disorders, including Alzheimer's disease, the tauopathies and prion disorders. These are all characterised by the accumulation of misfolded disease-specific proteins in the brain in association with specific patterns of neuronal loss, but the role of UPR activation in their pathogenesis is unclear. In prion-diseased mice, overactivation of PERK-P/eIF2α-P signalling results in the sustained reduction in global protein synthesis, leading to synaptic failure, neuronal loss and clinical disease. Critically, restoring vital neuronal protein synthesis rates by inhibiting the PERK-eIF2α pathway, both genetically and pharmacologically, prevents prion neurodegeneration downstream of misfolded prion protein accumulation. Here we show that PERK-eIF2α-mediated translational failure is a key process leading to neuronal loss in a mouse model of frontotemporal dementia, where the misfolded protein is a form of mutant tau. rTg4510 mice, which overexpress the P301L tau mutation, show dysregulated PERK signalling and sustained repression of protein synthesis by 6 months of age, associated with onset of neurodegeneration. Treatment with the PERK inhibitor, GSK2606414, from this time point in mutant tau-expressing mice restores protein synthesis rates, protecting against further neuronal loss, reducing brain atrophy and abrogating the appearance of clinical signs. Further, we show that PERK-eIF2α activation also contributes to the pathological phosphorylation of tau in rTg4510 mice, and that levels of phospho-tau are lowered by PERK inhibitor treatment, providing a second mechanism of protection. The data support UPR-mediated translational failure as a generic pathogenic mechanism in protein-misfolding disorders, including tauopathies, that can be successfully targeted for prevention of neurodegeneration.
Polymorphisms in oxidative stress‐related genes and postmenopausal breast cancer risk (2010)

Breast cancer is the most frequent cancer type among women in western countries. In addition to established risk factors like hormone replacement therapy, oxidative stress may play a role in carcinogenesis through an unbalanced generation of reactive oxygen species that leads to genetic instability. The aim of this study is to assess the influence of common single nucleotide polymorphisms (SNPs) in candidate genes related to oxidative stress on postmenopausal breast cancer risk. We genotyped 109 polymorphisms (mainly tagging SNPs) in 22 candidate genes in 1,639 postmenopausal breast cancer cases and 1,967 controls (set 1) from the German population-based case-control study "MARIE". SNPs showing association in set 1 were tested in further 863 cases and 2,863 controls from MARIE (set 2) using a joint analysis strategy. Six polymorphisms evaluated in the combined set showed significantly modified breast cancer risk per allele in the joint analysis, including SNPs in CYBA (encoding a subunit of the NADPH oxidase: rs3794624), MT2A (metallothionein 2A: rs1580833), TXN (thioredoxin: rs2301241), and in TXN2 (thioredoxin 2: rs2267337, rs2281082, rs4821494). Associations with the CYBA rs3794624 (OR per allele: 0.93, 95% CI 0.87-0.99) and TXN rs2301241 variants (OR per allele: 1.05, 95% CI 1.00-1.10) were confirmed in the summary risk estimate analysis using up to three additional studies. We found some evidence for association of polymorphisms in genes of the thioredoxin system, CYBA, and MT2A with postmenopausal breast cancer risk. Summary evidence including independent datasets indicated moderate effects in CYBA and TXN that warrant confirmation in large independent studies.
Displaying 3D radiation dose on endoscopic video for therapeutic assessment and surgical guidance (2012)

We have developed a method to register and display 3D parametric data, in particular radiation dose, on two-dimensional endoscopic images. This registration of radiation dose to endoscopic or optical imaging may be valuable in assessment of normal tissue response to radiation, and visualization of radiated tissues in patients receiving post-radiation surgery. Electromagnetic sensors embedded in a flexible endoscope were used to track the position and orientation of the endoscope allowing registration of 2D endoscopic images to CT volumetric images and radiation doses planned with respect to these images. A surface was rendered from the CT image based on the air/tissue threshold, creating a virtual endoscopic view analogous to the real endoscopic view. Radiation dose at the surface or at known depth below the surface was assigned to each segment of the virtual surface. Dose could be displayed as either a colorwash on this surface or surface isodose lines. By assigning transparency levels to each surface segment based on dose or isoline location, the virtual dose display was overlaid onto the real endoscope image. Spatial accuracy of the dose display was tested using a cylindrical phantom with a treatment plan created for the phantom that matched dose levels with grid lines on the phantom surface. The accuracy of the dose display in these phantoms was 0.8-0.99 mm. To demonstrate clinical feasibility of this approach, the dose display was also tested on clinical data of a patient with laryngeal cancer treated with radiation therapy, with estimated display accuracy of ∼2-3 mm. The utility of the dose display for registration of radiation dose information to the surgical field was further demonstrated in a mock sarcoma case using a leg phantom. With direct overlay of radiation dose on endoscopic imaging, tissue toxicities and tumor response in endoluminal organs can be directly correlated with the actual tissue dose, offering a more nuanced assessment of normal tissue toxicities following radiation therapy and accurate registration of radiation dose to the surgical field.
FPGS expression to predict overall survival in non-small cell lung cancer patients treated with pemetrexed. (2015)

e19043 Background: Pemetrexed (Pem) has been widely used in non-small cell lung cancer (NSCLC), but data of biomarkers predicting its clinical response and outcome is very limited. Thymidylate synthase (TS) and folylpolyglutamate synthase (FPGS) are key enzymes in Pem anticancer mechanism. Thyroid transcription factor-1 (TTF-1) is mainly positive in lung adenocarcinoma. TTF-1 positivity and low TS level were reported to be associated with prolonged survival in NSCLC treated with platinum doublets. We evaluated the correlation of these biomarkers with patients’ response to Pem and their clinical outcomes. Methods: A total of 100 patients with NSCLC who received treatment with pemetrexed between 2004 and 2011 were selected and retrospectively reviewed. TTF-1, TS and FPGS expression were evaluated by IHC (Mouse anti-TS antibody, Clone TS106, Invitrogen, Camarillo, CA and Rabbit polyclonal anti-human FPGS antibody, Spring Bioscience, Pleasanton, CA). TTF-1 is reported as positive or negative based on IHC staining. TS and FPGS are scored from 0 to 4 based on the percentage of cells with positive staining (0: none, 1: < 1%, 2: 1-5%, 3: 5-50%, 4: > 50%). TS and FPGS negative is defined as IHC score 0-2 and positive is defined as IHC score 3 or 4. Results: The median age of these patients was 62 years, 51% were male, majority had stage IV disease (57%). 73% were adenocarcinoma and 13% were squamous. 80% patients received Pem as second line or above. Overall response rate to Pem was 36%. 36 (46%) cases were positive for TTF-1. 40 (48%) cases had positive TS IHC staining (score 0 = 16%, 1 = 24%, 2 = 12%, 3 = 30% and 4 = 18%), and 39 (46%) had positive FPGS IHC staining (score 0 = 12%, 1 = 20%, 2 = 21%, 3 = 20% and 4 = 26%). Positive TTF-1was associated with longer Pem PFS by Kaplan Meier estimation (5.2 vs 2.4 month, p = 0.04). Positive FPGS is associated with worse OS (HR = 1.89, P = 0.01) after adjusted for age, gender and stage. Conclusions: Our study showed TTF-1 positive NSCLC has longer PFS when treated with Pem, which is consistent with better antitumor activity of Pem in non-squamous NSCLC. Interestingly we also found positive FPGS expression by IHC is associated with longer survival in patients treated with Pem, which may warrant further investigation.
Hyaluronate—Epidermal Growth Factor Conjugate for Skin Wound Healing and Regeneration (2016)

Epidermal growth factor (EGF) has been recognized as an excellent wound healing agent due to its therapeutic function stimulating skin cell growth, proliferation and differentiation. However, the transdermal delivery of EGF poses a significant challenge due to its short half-life and lack of efficient formulation. Here, to improve the transdermal delivery efficiency, EGF was conjugated to hyaluronate (HA), which was formulated into a patch-type film for skin wound healing. HA-EGF conjugate was synthesized by coupling reaction between aldehyde-modified HA and N-terminal amine group of EGF to minimize the loss of biological activities. The HA-EGF conjugates exhibited similar biological activities with native EGF as confirmed by ELISA and proliferation tests using murine and human fibroblasts. For the efficient topical delivery, HA-EGF conjugates were incorporated into a matrix film of high molecular weight HA. Two-photon microscopy clearly visualized more efficient transdermal delivery of HA-EGF conjugates to both normal skin and peripheral tissues around the wound area rather than that of EGF. Optical imaging and ELISA after in vivo transdermal delivery showed that the conjugation of EGF to HA retarded its degradation and extended its residence time in the wound area. Furthermore, in vivo transdermal delivery of HA-EGF conjugate in the patch-type HA film resulted in significantly improved regeneration of skin tissues even into hypodermis.
Future prospects of brain stimlation (2000)

Chronic high frequency (130 Hz) stimulation (HFS) of the thalamic target Vim has replaced thalamotomy as a treatment of tremor of various origins and was extended to two other targets (Subthalamic nucleus (STN) and the medial pallidus (GPi)), since 1993 based on recent experimental data in rats and monkeys. STN appears to be a target of major interest, able to control the three cardinal symptoms and to allow the decrease or suppression of levodopa treatment, which then suppresses also levodopa induced dyskinesias. The mechanisms of action of HFS are not fully understood, but are definitely related to high frequency and are probably different depending on the target. Inhibition of cellular activity or of network functions could be induced, by jamming of a retroactive loop for tremor, or by shutdown of neurotransmitter release in STN. All cardinal symptoms are alleviated from tremor to akinesia and rigidity. The effects remain stable over more than five years chronic HFS of STN, as the method of choice when a surgical procedure is indicated for the treatment of Parkinson's disease and even more when a bilateral procedure is necessary. Recent data show that STN stimulation could be useful in the treatment of dystonia as well as some forms of epilepsies. It is therefore possible that DAS in STN as well as in other targets could become a potent therapeutic tool in the future for neurological disorders. The future of brain stimulation will depend on new technologies (new circuits, electrodes, web based programmers), waveforms (alternatives to square waves, random distribution), targets (hypothalamic nuclei, locus coeruleus) and indications (dystonia, epilepsy, eating disorders.
MicroRNA 203 Modulates Glioma Cell Migration via Robo1/ERK/MMP-9 Signaling (2013)

Glioblastoma (GBM) is the most common and malignant primary adult brain cancer. Allelic deletion on chromosome 14q plays an important role in the pathogenesis of GBM, and this site was thought to harbor multiple tumor suppressor genes associated with GBM, a region that also encodes microRNA-203 (miR-203). In this study, we sought to identify the role of miR-203 as a tumor suppressor in the pathogenesis of GBM. We analyzed the miR-203 expression data of GBM patients in 10 normal and 495 tumor tissue samples derived from The Cancer Genome Atlas data set. Quantitative real-time PCR and in situ hybridization in 10 high-grade GBM and 10 low-grade anaplastic astrocytoma tumor samples showed decreased levels of miR-203 expression in anaplastic astrocytoma and GBM tissues and cell lines. Exogenous expression of miR-203 using a plasmid expressing miR-203 precursor (pmiR-203) suppressed glioma cell proliferation, migration, and invasion. We determined that one relevant target of miR-203 was Robo1, given that miR-203 expression decreased mRNA and protein levels as determined by RT-PCR and Western blot analysis. Moreover, cotransfection experiments using a luciferase-based transcription reporter assay have shown direct regulation of Robo1 by miR-203. We also show that Robo1 mediates miR-203 mediated antimigratory functions as up-regulation of Robo1 abrogates miR-203 mediated antimigratory effects. We also show that miR-203 expression suppressed ERK phosphorylation and MMP-9 expression in glioma cells. Furthermore, we demonstrate that miR-203 inhibits migration of the glioma cells by disrupting the Robo1/ERK/MMP-9 signaling axis. Taken together, these studies demonstrate that up-regulation of Robo1 in response to the decrease in miR-203 in glioma cells is responsible for glioma tumor cell migration and invasion.
Identification of the Tuberous Sclerosis Gene TSC1 on Chromosome 9q34 (1997)

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterized by the widespread development of distinctive tumors termed hamartomas. TSC-determining loci have been mapped to chromosomes 9q34 (TSC1) and 16p13 (TSC2). The TSC1 gene was identified from a 900-kilobase region containing at least 30 genes. The 8.6-kilobase TSC1 transcript is widely expressed and encodes a protein of 130 kilodaltons (hamartin) that has homology to a putative yeast protein of unknown function. Thirty-two distinct mutations were identified in TSC1, 30 of which were truncating, and a single mutation (2105delAAAG) was seen in six apparently unrelated patients. In one of these six, a somatic mutation in the wild-type allele was found in a TSC-associated renal carcinoma, which suggests that hamartin acts as a tumor suppressor.
Urinary mannose-binding lectin is a biomarker for predicting the progression of immunoglobulin (Ig)A nephropathy (2012)

Complement system activation is associated with immunoglobulin A nephropathy (IgAN) activity and progression. The aim of the present study was to investigate the importance of urinary mannose-binding lectin (MBL), at the time of renal biopsy, for evaluating disease severity and predicting the progression of IgAN. A total of 162 patients with biopsy-proven IgAN were enrolled and 50 healthy individuals were selected as normal controls. Urinary MBL was measured by sandwich enzyme-linked immunosorbent assay (ELISA) and normalized for urinary creatinine concentration. Urinary MBL was significantly higher in IgAN patients than that in normal controls, and elevated as histopathological phenotypes upgraded. Urinary MBL was correlated significantly with the well-known clinical predictors for the prognosis of IgAN; that is, renal function (represented by serum creatinine and estimated glomerular filtration rate), proteinuria and arterial hypertension. Urinary MBL was demonstrated to be correlated with the histopathological parameters which have independent value in predicting renal outcome of IgAN according to the Oxford classification; that is, mesangial hypercellularity, segmental glomerulosclerosis, endocapillary hypercellularity and tubular atrophy/interstitial fibrosis. More importantly, non-remission patients at the end of follow-up had significantly higher levels of urinary MBL compared with patients in remission. In conclusion, urinary MBL can be a reliable non-invasive biomarker for evaluating disease severity and predicting the prognosis of IgAN. This is the first report on this issue. However, our conclusions should be verified further in large-scale studies with long-term follow-up.
Ultra-low power 2.4GHz RF energy harvesting and storage system with &#x2212;25dBm sensitivity (2015)

An RF energy harvesting and storage system is described that trickle charges a battery from incident power levels as low as -25 dBm referred to the feedpoint of an 8 dBi patch antenna. The circuit is optimized for the indoor ambient power range typically observed in the 2.4 GHz ISM band so that we can harvest the energy provided by nearby Wi-Fi, Bluetooth and other devices. In this incident power regime, rectified voltages are low, so power management circuit operation in the 100mV regime is critical. We present several improvements to our prior work that significantly improve its performance, including a novel wideband multi-element antenna array, an improved boost converter, and a redesigned battery charger. At -25dBm RF input power, the new harvesting system sources 150μJ into a rechargeable battery after 1 hour. We believe that this work represents the lowest reported startup power yet achieved in battery-storage RF energy harvesting systems.
MODTRAN5: 2006 update (2006)

The MODTRAN5 radiation transport (RT) model is a major advancement over earlier versions of the MODTRAN atmospheric transmittance and radiance model. New model features include (1) finer spectral resolution via the Spectrally Enhanced Resolution MODTRAN (SERTRAN) molecular band model, (2) a fully coupled treatment of auxiliary molecular species, and (3) a rapid, high fidelity multiple scattering (MS) option. The finer spectral resolution improves model accuracy especially in the mid- and long-wave infrared atmospheric windows; the auxiliary species option permits the addition of any or all of the suite of HITRAN molecular line species, along with default and user-defined profile specification; and the MS option makes feasible the calculation of Vis-NIR databases that include high-fidelity scattered radiances. Validations of the new band model algorithms against line-by-line (LBL) codes have proven successful.
Recognizing Worsening Chronic Heart Failure as an Entity and an End Point in Clinical Trials (2014)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal