gebhart/patrepeval huggingface dataset:
In vivo genome editing at the albumin locus to treat methylmalonic acidemia (2021)

Methylmalonic acidemia (MMA) is a metabolic disorder most commonly caused by mutations in the methylmalonyl-CoA mutase (<i>MMUT</i>) gene. Although adeno-associated viral (AAV) gene therapy has been effective at correcting the disease phenotype in MMA mouse models, clinical translation may be impaired by loss of episomal transgene expression and magnified by the need to treat patients early in life. To achieve permanent correction, we developed a dual AAV strategy to express a codon-optimized <i>MMUT</i> transgene from <i>Alb</i> and tested various CRISPR-Cas9 genome-editing vectors in newly developed knockin mouse models of MMA. For one target site in intron 1 of <i>Alb</i>, we designed rescue cassettes expressing MMUT behind a 2A-peptide or an internal ribosomal entry site sequence. A second guide RNA targeted the initiator codon, and the donor cassette encompassed the proximal albumin promoter in the 5' homology arm. Although all editing approaches were therapeutic, targeting the start codon of albumin allowed the use of a donor cassette that also functioned as an episome and after homologous recombination, even without the expression of Cas9, as an integrant. Targeting the albumin locus using these strategies would be effective for other metabolic disorders where early treatment and permanent long-term correction are needed.
SS-DNA functionalized ultra-thin-film ALN Contour-mode Resonators with self-sustained oscillator for volatile organic chemical detection (2010)

This paper reports on the design and experimental verification of a new class of nanoscale gravimetric sensors based on ultra-thin-film AlN contour-mode resonant sensor (CMR-S) functionalized with ss-DNA and connected to a chip-based self-sustaining oscillator loop (fabricated in the ON semiconductor 0.5 ¿m CMOS process) for direct frequency read-out. The 220 MHz oscillator based on the ultra-thin AlN CMR-S exhibits an Allan Variance of ~20 Hz for 100 ms gate time. The sensor affinity for the adsorption of volatile organic chemicals such as 2,6 dinitroluene (DNT, a simulant for explosive vapors) is enhanced by functionalizing the top gold electrode of the device with a thiol-terminated single stranded DNA sequence (Thiol - 5' CTT CTG TCT TGA TGT TTG TCA AAC 3') enabling the detection of concentrations as low as 1.5 part per billion (ppb).
Structural Features of Clostridium botulinum Neurotoxin Subtype A2 Cell Binding Domain (2022)

Botulinum neurotoxins (BoNT) are a group of clostridial toxins that cause the potentially fatal neuroparalytic disease botulism. Although highly toxic, BoNTs are utilized as therapeutics to treat a range of neuromuscular conditions. Several serotypes (BoNT/A-/G, /X) have been identified with vastly differing toxicological profiles. Each serotype can be further sub-categorised into subtypes due to subtle variations in their protein sequence. These minor changes have been attributed to differences in both the duration of action and potency for BoNT/A subtypes. BoNTs are composed of three domains-a cell-binding domain, a translocation domain, and a catalytic domain. In this paper, we present the crystal structures of the botulinum neurotoxin A2 cell binding domain, both alone and in complex with its receptor ganglioside GD1a at 1.63 and 2.10 Å, respectively. The analysis of these structures reveals a potential redox-dependent Lys-O-Cys bridge close to the ganglioside binding site and a hinge motion between the H<sub>CN</sub> and H<sub>CC</sub> subdomains. Furthermore, we make a detailed comparison with the previously reported H<sub>C</sub>/A2:SV2C structure for a comprehensive structural analysis of H<sub>C</sub>/A2 receptor binding.
Is nonparametric learning practical in very high dimensional spaces (1997)

Many of the challenges faced by the field of Computational Intelligence in building intelligent agents, involve determining mappings between numerous and varied sensor inputs and complex and flexible action sequences. In applying nonparametric learning techniques to such problems we must therefore ask: &amp;quot;Is nonparametric learning practical in very high dimensional spaces?&amp;quot; Contemporary wisdom states that variable selection and a &amp;quot;greedy&amp;quot; choice of appropriate functional structures are essential ingredients for nonparametric learning algorithms. However, neither of these strategies is practical when learning problems have thousands of input variables, and tens of thousands of learning examples. We conclude that such nonparametric learning is practical by using a methodology which does not use either of these techniques. We propose a simple nonparametric learning algorithm to support our conclusion. The algorithm is evaluated first on 10 well known regression data sets, where it is shown ...
Demonstration of high spectral efficient OFDM-QAM long reach passive optical network (2008)

We demonstrate a high spectral-efficient LR-PON using 4 Gb/s OFDM-QAM for both up-and-downstream, achieving a high split-ratio 256, using optical components optimized for GPON.
ChemInform Abstract: Cu(I)—Pd(II)‐Catalyzed Cycloaddition—Fusion of 1‐Iodoalkynes and Azides: One‐Pot Synthesis of Fused Tricyclic Heterosystems. (2015)

Abstract The method provides pharmacologically relevant scaffolds for the construction of complex molecules.
The GPI-Linked Protein LY6A Drives AAV-PHP.B Transport across the Blood-Brain Barrier (2019)

Efficient delivery of gene therapy vectors across the blood-brain barrier (BBB) is the holy grail of neurological disease therapies. A variant of the neurotropic vector adeno-associated virus (AAV) serotype 9, called AAV-PHP.B, was shown to very efficiently deliver transgenes across the BBB in C57BL/6J mice. Based on our recent observation that this phenotype is mouse strain dependent, we used whole-exome sequencing-based genetics to map this phenotype to a specific haplotype of lymphocyte antigen 6 complex, locus A (Ly6a) (stem cell antigen-1 [Sca-1]), which encodes a glycosylphosphatidylinositol (GPI)-anchored protein whose function had been thought to be limited to the biology of hematopoiesis. Additional biochemical and genetic studies definitively linked high BBB transport to the binding of AAV-PHP.B with LY6A (SCA-1). These studies identify, for the first time, a ligand for this GPI-anchored protein and suggest a role for it in BBB transport that could be hijacked by viruses in natural infections or by gene therapy vectors to treat neurological diseases.
The neuropeptide substance P stimulates the effector functions of platelets (1990)

Sensory neuropeptides, such as substance P, appear as potent mediators of various immunological reactions, and inhibit or stimulate a wide range of functions of immune inflammatory cells. Platelets were recently shown to participate as effector cells in an IgE or lymphokine-dependent killing of parasites. Substance P and its carboxy-terminal fragment SP (4-11) induce the cytotoxic activity of platelets towards the larvae of Schistosoma mansoni, respectively, by 90% and 40%, whereas the modified C terminal SP, the SP-free acid, exhibits no effect on the platelets. The neuropeptide effects occur at low doses (10(-8) M), are specific as shown by inhibition studies with a substance P antagonist, the D-SP. Binding data obtained after flow cytofluorometry with FITC-SP lead to the conclusion that SP binds specifically to about 20% of the homogenous population of platelets. Moreover, IgE could modulate the SP-dependent functions of platelets since the pre-incubation with myeloma human IgE or with AP2 monoclonal antibodies--known to inhibit the IgE-dependent killing of these cells-leads to a dramatic decrease of the SP dependent cytotoxic activity of platelets towards the larvae. These findings identify a potent mechanism for nervous system regulation of host defence responses.
Development and Validation of A Cell Cycle Progression Signature for Decentralized Testing of Men with Prostate Cancer (2022)

<b>Aim:</b> The 46-gene Prolaris<sup>®</sup> cell cycle progression test provides information on the risk of prostate cancer progression. Here we developed and validated a 16-gene kit-based version. <b>Methods:</b> RNA was extracted from prostate cancer biopsy tissue. Amplification efficiency, minimum tumor content, repeatability, reproducibility and equivalence with the 46-gene test were evaluated. <b>Results:</b> Amplification efficiencies for all genes were within the acceptable range (90-110%), and samples with ≥50% tumor content were appropriate for the 16-gene test. Results were repeatable (standard deviation: 0.085) and reproducible (standard deviation: 0.115). Instrument, operator and kit lot had minimal impact on results. Cell cycle progression scores from the 46- and 16-gene tests were highly correlated (r = 0.969; bias = 0.217). <b>Conclusion:</b> The 16-gene test performs consistently and similarly to the 46-gene test.
Eyes free dialing for cellular telephones (2002)

The authors describe a chip set that implements voice dialing for cellular telephones using isolated-word speaker-dependent speech-recognition algorithms. High recognition rates of over 98% in noisy car cabins are achieved using noise-immune techniques for preprocessing, feature extraction, template training, and template comparison. A unique work endpoint detector is realized with a modified dynamic time warping algorithm and a noise-robust voice-activated switch. The chip set supports up to two users and a vocabulary of 32 words. It incorporates speech synthesis for guiding, prompting, and verification by vocal feedback, and allows dialing digit by digit or speed dialing of up to 10 stored numbers invoked with user-defined phrases.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">&gt;</ETX>
Burn dynamic experiment based on the field-reversed theta pinch (1982)

A D-T burn dynamic experiment using a scaled-up field-reversed theta-pinch device is proposed as a first step towards demonstration of a D-/sup 3/He burn. The feasibility of such an experiment is based on a loss-cone-like confinement scaling plus the use of combined pellet and neutral-beam injection to heat the plasma, build-up its density, and damp the m=2 instability.
Low dose oral beta-lactamase protects the gut microbiome from oral beta-lactam-mediated damage in dogs (2019)

Antibiotics, while lifesaving, damage the gut microbiome and can precipitate proliferation of pathobionts. A strategy to preserve gut microbiome integrity is to eliminate biologically active antimicrobials excreted into the gastrointestinal tract (GI) without negatively affecting antibiotic therapeutic efficacy. Clinical proof of concept was achieved with SYN-004 (ribaxamase), a beta-lactamase enzyme formulated for oral delivery with intravenous penicillins and cephalosporins. Ribaxamase inactivated intestinal ceftriaxone, protected the gut microbiome, and significantly reduced the incidence of <i>Clostridioides difficile</i> disease. For use with oral beta-lactam antibiotics, a delayed release formulation of ribaxamase, SYN-007, was engineered for dissolution in the lower small intestine distal to the site of oral antibiotic absorption. In dogs that received oral amoxicillin, SYN-007 reduced microbiome disruption without interfering with amoxicillin systemic absorption. Here, a study to determine the lowest effective dose of SYN-007 was performed. Dogs received amoxicillin (40 mg/kg, PO, TID) +/- SYN-007 (PO, TID) at three doses, 10 mg, 3 mg, or 1 mg for five days. Serum amoxicillin levels, measured after the first and last antibiotic doses, were not significantly different +/-SYN-007 at all dose levels indicating that SYN-007 did not interfere with amoxicillin systemic absorption. Microbiome analyses demonstrated that amoxicillin significantly reduced bacteria richness and microbiome diversity resulting in altered microbiome composition. However, with all doses of SYN-007, microbiome richness and diversity were not significantly different from pretreatment and changes in microbiome composition were attenuated. These data demonstrate that effective SYN-007 doses can be reduced at least 10-fold while maintaining gut microbiome preservation. The potential to employ low SYN-007 doses to protect the gut microbiota has important implications for enhancing therapeutic outcomes for patients receiving oral beta-lactam antibiotics while simultaneously reducing cost per dose and ultimately, healthcare expenses.
COVIDomic: A multi-modal cloud-based platform for identification of risk factors associated with COVID-19 severity (2021)

Coronavirus disease 2019 (COVID-19) is an acute infection of the respiratory tract that emerged in December 2019 in Wuhan, China. It was quickly established that both the symptoms and the disease severity may vary from one case to another and several strains of SARS-CoV-2 have been identified. To gain a better understanding of the wide variety of SARS-CoV-2 strains and their associated symptoms, thousands of SARS-CoV-2 genomes have been sequenced in dozens of countries. In this article, we introduce COVIDomic, a multi-omics online platform designed to facilitate the analysis and interpretation of the large amount of health data collected from patients with COVID-19. The COVIDomic platform provides a comprehensive set of bioinformatic tools for the multi-modal metatranscriptomic data analysis of COVID-19 patients to determine the origin of the coronavirus strain and the expected severity of the disease. An integrative analytical workflow, which includes microbial pathogens community analysis, COVID-19 genetic epidemiology and patient stratification, allows to analyze the presence of the most common microbial organisms, their antibiotic resistance, the severity of the infection and the set of the most probable geographical locations from which the studied strain could have originated. The online platform integrates a user friendly interface which allows easy visualization of the results. We envision this tool will not only have immediate implications for management of the ongoing COVID-19 pandemic, but will also improve our readiness to respond to other infectious outbreaks.
AwareNet (2022)

Characterizing network behavior, an essential building block for many network management tasks becomes increasingly difficult for administrators. Reasons for that are, among others, rising traffic volume and dynamicity in modern networks. To automate network behavior characterization, we present AwareNet, a system that uses Weighted Stochastic Block Models (WSBMs). By providing insight into network-inherent dynamics AwareNet supports administrators in handling the rising traffic volume and dynamicity. As an example, we show that AwareNet can detect targeted host scans in a campus network.
A Potent Apoptosis-Inducing Activity of a Sesquiterpene Lactone, Arucanolide, in HL60 Cells: a Crucial Role of Apoptosis-Inducing Factor (2005)

Six main sesquiterpene lactones (germacranolides) from Calea urticifolia were evaluated for in vitro cytotoxicity against human tumor cell lines HL60 and SW480 cells. Among them, arucanolide and parthenolide displayed marked cytotoxicity against both cell lines. Arucanolide exhibited a low IC(50) in HL60 cells. The cytotoxic activity of arucanolide was observed at lower concentrations compared to that of parthenolide, which has been reported to be a typical and simple germacranolide. The activity was found to be mainly due to apoptosis that was assessed by morphological findings, DNA ladder formation (24 - 36 h), and flow cytometric analysis in HL60 cells. Western blotting and an apoptosis inhibition assay using caspase inhibitors did not demonstrate the activation of any caspases tested. However, the mitochondrial membrane potential of HL60 cells was lost after 24-h treatment with arucanolide, and concurrently apoptosis-inducing factor (AIF) released from mitochondria was detected by Western blot analysis. The inactivation of nuclear factor-kappaB, which has been commonly shown in parthenolide-induced apoptosis, did not occur in arucanolide-induced apoptosis. Taken together, the findings presented here indicate that arucanolide induced marked apoptosis in HL60 cells mainly by dissipating mitochondrial membrane potential, which would trigger AIF-induced apoptosis.
Polymersome-mediated cytosolic delivery of cyclic dinucleotide STING agonist enhances tumor immunotherapy (2022)

Cyclic dinucleotides (CDNs) as stimulator of interferon genes (STING) agonists capable of inducing strong antitumor innate immune response are highly promising for tumor immunotherapy. The efficacy of these CDNs is, however, reduced greatly by their fast clearance, poor cell uptake and inefficient cytosolic transportation. Here, we report that reduction-responsive biodegradable chimaeric polymersomes (CPs) markedly enhance tumor retention and cytosolic delivery of a synthetic CDN, ADU-S100, and bolster STING pathway activation in the tumor microenvironment and tumor draining lymph nodes, giving significantly better tumor repression and survival of B16F10 melanoma-bearing mice compared with free CDN control. The superiority of CPs-mediated CDN delivery is further verified in combination therapy with low-dose fractionated radiation, which brings about clearly stronger and longer-term immunotherapeutic effects and protection against tumor re-challenge. The development of nano-STING agonists that are able to overcome the delivery barriers of CDNs represents an effective strategy to potentiate cancer immunotherapy.
Nonlinear wave mixing in a multilongitudinal-mode erbium-doped fiber laser (2005)

The emission spectrum of an erbium-doped fiber ring laser is shown to result from the nonlinear wave mixing taking place between the multiple oscillating longitudinal modes. The dependence of the resultant spectral broadening upon the signal power circulating in the laser cavity is investigated both theoretically and experimentally. In the case considered here, the extent of this spectral broadening is shown to be restrained only by the spectrally discriminating element inserted in the laser cavity. Predictions of the numerical simulations for the signal buildup and propagation in the laser cavity are found to be in good agreement with the experiment.
Immunopeptidomics and Peptide Expression Profiles to Develop T-Cell Receptors Against Glioma-Associated Antigens (2019)

INTRODUCTION: Diffuse infiltrating low-grade gliomas (WHO grade II and III) are slow-growing primary brain tumors, but considered malignant due to their invasive growth and inexorable malignant progression at recurrence. Highly personalized immunotherapies are currently a challenging endeavor, due to the low mutational load of gliomas, as described by various neoantigen discovery pipelines. Hence, it is important to extend our antigen search to other gene alterations such as alternative splicing or target epitopes derived from proteins that are absent in normal tissues. The purpose of this study is to address this gap and increase the available repertoire of T-cell receptors to target in gliomas. METHODS: In the current study, we start by analyzing a set of 64 peptides derived from nonmutated proteins reported by Hilf et al (Nature, 2019) as part of their actively personalized vaccination trial. These were isolated from the human leukocyte antigen (HLA)-A*02:01 and A*24:02 molecules of primary glioblastoma tissues. The initial screening for immunogenic targets was performed assessing datasets of RNA expression levels in normal brain and peripheral organs and measure the differential expression in primary gliomas paired with their corresponding recurrent tumors. RESULTS: We find 3 antigen epitopes being exclusively expressed in gliomas that increase their expression at recurrence, without significant levels in normal tissues. Furthermore, we report an epitope derived from a tumor-specific isoform, which we use to stimulate healthy-donor PBMCs and isolate reactive CD8+ T-cells to sequence their T-cell receptor and engineer patient-derived T-cells against this target. CONCLUSION: Our results suggest that cell-based immunotherapies targeting these epitopes can be highly effective and safe, reducing the likelihood of adverse events, effectively addressing tumor heterogeneity and interpatient variability. Moreover, this is the first successful attempt to target an epitope derived from a tumor-specific isoform in glioma with an engineered T-cell receptor.
COMPUTERIZED ICU ORDERS VERSUS HANDWRITTEN ICU ORDERS (1995)

OBJECTIVE: To compare computerized ICU order writing with handwritten ICU physician orders. DESIGN: Prospective study. SETTING: Medical and surgical Intensive Care Units and pharmacy of a Department of Veterans Affairs Medical Center. PATIENTS: Two hundred sixty-four individual sets of orders. INTERVENTIONS: A time study and problem analysis were performed in the pharmacy as orders were received and processed. MEASUREMENTS AND MAIN RESULTS: Two hundred sixty-four sets of orders were evaluated; MICU (handwritten; n = 133) and SICU (computerized; n = 131). Physician length of training are similar in both units. The patient age and number of major diagnoses per patient in the two ICU groups were similar. Significantly less time (min) (MICU 2.5 ± 0.3 versus SICU 1.84 ± 0.1, p < 0.05) is required to review SICU orders. The SICU had significantly fewer order problems (MICU 45 versus SICU 12, p < 0.05). Computerized SICU orders were corrected more rapidly. The majority of order problems in both groups were resolved by telephone. CONCLUSIONS: ICU orders by computer program are processed more rapidly, have fewer errors, and are corrected more rapidly than standard handwritten orders. We conclude that a dedicated ICU computerized order-writing system permits orders to be written with fewer errors and the pharmacy to process them more efficiently than handwritten orders.
Fus gene mutations in familial and sporadic amyotrophic lateral sclerosis (2010)

Mutations in the fused in sarcoma (FUS) gene have recently been found to cause familial amyotrophic lateral sclerosis (FALS). We screened FUS in a cohort of 200 ALS patients [32 FALS and 168 sporadic ALS (SALS)]. In one FALS proband, we identified a mutation (p.R521C) that was also present in her affected daughter. Their clinical phenotype was remarkably similar and atypical of classic ALS, with symmetric proximal pelvic and pectoral weakness. Distal weakness and upper motor neuron features only developed late. Neuropathological examination demonstrated FUS-immunoreactive neuronal and glial inclusions in the spinal cord and many extramotor regions, but no TDP-43 pathology. We also identified a novel mutation (p.G187S) in one SALS patient. Overall, FUS mutations accounted for 3% of our non-SOD1, non-TARDBP FALS cases and 0.6% of SALS. This study demonstrates that the phenotype with FUS mutations extends beyond classical ALS cases. Our findings suggest there are specific clinicogenetic correlations and provide the first detailed neuropathological description.
A Low-Cost Hyperspectral Scanner for Security Printing (2015)

We demonstrate a hand-held scanner that acquires two-dimensional images with up to 40 distinct wavelength channels. Light is collected through a combined slit and illumination assembly, dispersed by a diffraction grating film and analyzed using a webcam. Custom software is used to track the scanner motion and build the hyperspectral image data in real time. We tested the performance on printed fluorescent ink patterns that are of interest for security printing applications, and obtained results that are consistent with spectra acquired using a laboratory-grade spectrofluorometer.