gebhart/patrepeval huggingface dataset:
DEVELOPMENT, AND COMMERCIALIZATION OF ROUNDUP READY® CROPS (2003)

The herbicide Roundup® whose active ingredient is glyphosate (N­ [phosphonomethyl]-glycine) was introduced as a broad spectrum, post emergent herbicide in 1974. Extensive research by a number of groups showed that glyphosate's herbicidal activity resulted from inhibition of the enzyme 5-enolpyruvyl-shikimate-3-phosphate synthase (EPSPS) a key enzyme in the shikimate pathway that is responsible for the biosynthesis of aromatic amino acids in plants and microbes (reviewed, Franz et ai., 1997). Since even small amounts of Roundup® can cause severe injury to plants, it could not be applied over-the-top on crops. This changed in 1996 when the first crops tolerant to Roundup® were introduced. However, work to develop this technology began in the early 1980's. Three approaches were investigated in an effort to generate Roundup® tolerance in plants: (1) overexpression of EPSPS, (2) introduction of an EPSPS with decreased affmity for glyphosate, and (3) introduction of a glyphosate degradation gene. Two key discoveries from the latter two approaches enabled the current Roundup Ready® (RRTM) technologies. A glyphosate resistant EPSPS was identified and isolated from Agrobacterium sp. strain CP4 (CP4 EPSPS) and a glyphosate metabolizing enzyme, glyphosate oxidase (GOX) which converts glyphosate to glyoxylate and aminomethylphosphonic acid was isolated (reviewed, Padgette et ai., 1996).
Expression and functional role of formyl peptide receptor in human bone marrow‐derived mesenchymal stem cells (2007)

We investigated the expression of formyl peptide receptor (FPR) and its functional role in human bone marrow-derived mesenchymal stem cells (MSCs). We analyzed the expression of FPR by using ligand-binding assay with radio-labeled N-formyl-met-leu-phe (fMLF), and found that MSCs express FPR. FMLF stimulated intracellular calcium increase, mitogen-activated protein kinases activation, and Akt activation, which were mediated by G(i) proteins. MSCs were chemotactically migrated to fMLF. FMLF-induced MSC chemotaxis was also completely inhibited by pertussis toxin, LY294002, and PD98059, indicating the role of G(i) proteins, phosphoinositide 3-kinase, and extracellular signal regulated protein kinase. N-terminal fragment of annexin-1, Anx-1(2-26), an endogenous agonist for FPR, also induced chemotactic migration of MSCs. Thus MSCs express functional FPR, suggesting a new (patho)physiological role of FPR and its ligands in regulating MSC trafficking during induction of injured tissue repair.
Immunophenotypic evaluation of the plasma cell compartment in multiple myeloma: a tool for comparing the efficacy of different treatment strategies and predicting outcome (2002)

Multiparametric immunophenotyping can be a sensitive method for analyzing the plasma cell (PC) compartment in patients with multiple myeloma because it discriminates between myelomatous and normal PCs. Using this approach, we compared the efficacy of high-dose chemotherapy followed by autologous stem cell transplantation (ASCT) with that of conventional chemotherapy. We found that ASCT provided a significantly greater reduction in the level of residual tumor PCs and with better recovery of normal PCs. This profile of coexistence of normal PCs and myelomatous PCs resembled that observed in monoclonal gammopathy of undetermined significance. We also found that treatment-induced changes in the PC compartment correlated with disease outcome. Thus, patients in whom at least 30% of gated PCs had a normal phenotype after treatment had a significantly longer progression-free survival (60 +/- 6 months versus 34 +/- 12 months; P =.02).
AAV Gene Therapy Utilizing Glycosylation-Independent Lysosomal Targeting Tagged GAA in the Hypoglossal Motor System of Pompe Mice (2019)

Pompe disease is caused by mutations in the gene encoding the lysosomal glycogen-metabolizing enzyme, acid-alpha glucosidase (GAA). Tongue myofibers and hypoglossal motoneurons appear to be particularly susceptible in Pompe disease. Here we used intramuscular delivery of adeno-associated virus serotype 9 (AAV9) for targeted delivery of an enhanced form of GAA to tongue myofibers and motoneurons in 6-month-old Pompe (<i>Gaa</i> <sup><i>-/-</i></sup> ) mice. We hypothesized that addition of a glycosylation-independent lysosomal targeting tag to the protein would result in enhanced expression in tongue (hypoglossal) motoneurons when compared to the untagged GAA. Mice received an injection into the base of the tongue with AAV9 encoding either the tagged or untagged enzyme; tissues were harvested 4 months later. Both AAV9 constructs effectively drove GAA expression in lingual myofibers and hypoglossal motoneurons. However, mice treated with the AAV9 construct encoding the modified GAA enzyme had a >200% increase in the number of GAA-positive motoneurons as compared to the untagged GAA (p < 0.008). Our results confirm that tongue delivery of AAV9-encoding GAA can effectively target tongue myofibers and associated motoneurons in Pompe mice and indicate that the effectiveness of this approach can be improved by addition of the glycosylation-independent lysosomal targeting tag.
Splice-switching of the insulin receptor in rhabdomyosarcoma: Rescuing the IR-B isoform for better treatment options (2020)

ABSTRACT Rhabdomyosarcoma (RMS) is an aggressive pediatric tumor with poor prognosis for metastasis and recurrent disease. Large scale sequencing endeavors demonstrate that RMS tumors have limited mutations and a dearth of driver mutations that are precisely targetable. However, IGF2 signaling is known to be grossly altered in RMS. The IGF2 signalling molecule binds both its innate IGF1 receptor as well as the insulin-receptor-variant-A ( IR-A ) with high affinity. Mitogenic and proliferative signalling via the canonical IGF2 pathway is therefore augmented by IR-A . The insulin receptor ( IR ) which is a transmembrane tyrosine-kinase receptor exists in two alternatively spliced isoforms, IR-A and IR-B . In this study, we show that RMS patients express increased IR-A compared to control tissues that express predominantly the IR-B isoform. We also found that Hif1a is significantly increased in RMS tumors, portraying their hypoxic phenotype. Furthermore, the alternative-splicing of IR adapts to produce more IR-A in response to hypoxic stress. Upon examining the pre-mRNA structure of the gene, we identified a hypoxia-responsive-element, which is also the binding site for the RNA-binding protein CUG-BP1 . We designed Splice-Switching-Oligonucleotides (SSO) against this binding site to decrease the levels of IR-A in RMS cell-lines and consequently rescue the IR-B expression levels. SSO treatment resulted in significant reductions in proliferation, migration and angiogenesis. Our data show promising insight into how impeding the IGF-2 pathway by reducing IR-A expression mitigates tumor growth. Our data reveal that RMS tumors use IR alternative-splicing as yet another survival strategy which can be exploited as therapeutic intervention in conjunction with already established anti-IGF-1 receptor therapies.
Concomitant gain and loss of function pathomechanisms in C9ORF72 amyotrophic lateral sclerosis (2021)

Intronic hexanucleotide repeat expansions (HREs) in <i>C9ORF72</i> are the most frequent genetic cause of amyotrophic lateral sclerosis, a devastating, incurable motoneuron (MN) disease. The mechanism by which HREs trigger pathogenesis remains elusive. The discovery of repeat-associated non-ATG (RAN) translation of dipeptide repeat proteins (DPRs) from HREs along with reduced exonic C9ORF72 expression suggests gain of toxic functions (GOFs) through DPRs versus loss of C9ORF72 functions (LOFs). Through multiparametric high-content (HC) live profiling in spinal MNs from induced pluripotent stem cells and comparison to mutant FUS and TDP43, we show that HRE <i>C9ORF72</i> caused a distinct, later spatiotemporal appearance of mainly proximal axonal organelle motility deficits concomitant to augmented DNA double-strand breaks (DSBs), RNA foci, DPRs, and apoptosis. We show that both GOFs and LOFs were necessary to yield the overall <i>C9ORF72</i> pathology. Increased RNA foci and DPRs concurred with onset of axon trafficking defects, DSBs, and cell death, although DSB induction itself did not phenocopy C9ORF72 mutants. Interestingly, the majority of LOF-specific DEGs were shared with HRE-mediated GOF DEGs. Finally, C9ORF72 LOF was sufficient-albeit to a smaller extent-to induce premature distal axonal trafficking deficits and increased DSBs.
Expression of GP88 (Progranulin) Protein Is an Independent Prognostic Factor in Prostate Cancer Patients (2019)

Prostate cancer, the second most common cancer, is still a major cause of morbidity and mortality among men worldwide. The expression of the survival and proliferation factor progranulin (GP88) has not yet been comprehensively studied in PCa tumors. The aim of this study was to characterize GP88 protein expression in PCa by immunohistochemistry and to correlate the findings to the clinico-pathological data and prognosis. Immunohistochemical staining for GP88 was performed by TMA with samples from 442 PCa patients using an immunoreactive score (IRS). Altogether, 233 cases (52.7%) with negative GP88 staining (IRS < 2) and 209 cases (47.3%) with positive GP88 staining (IRS ≥ 2) were analyzed. A significant positive correlation was found for the GP88 IRS with the PSA value at prostatectomy and the cytoplasmic cytokeratin 20 IRS, whereas it was negatively associated with follow-up times. The association of GP88 staining with prognosis was further studied by survival analyses (Kaplan-Meier, univariate and multivariate Cox's regression analysis). Increased GP88 protein expression appeared as an independent prognostic factor for overall, disease-specific and relapse-free survival in all PCa patients. Interestingly, in the subgroup of younger PCa patients (≤65 years), GP88 positivity was associated with a 3.8-fold (<i>p</i> = 0.004), a 6.0-fold (<i>p</i> = 0.008) and a 3.7-fold (<i>p</i> = 0.003) increased risk for death, disease-specific death and occurrence of a relapse, respectively. In the PCa subgroup with negative CK20 staining, GP88 positivity was associated with a 1.8-fold (<i>p</i> = 0.018) and a 2.8-fold increased risk for death and disease-specific death (<i>p</i> = 0.028). Altogether, GP88 protein positivity appears to be an independent prognostic factor for PCa patients.
Single-pass high-harmonic generation at 208 MHz repetition rate (2011)

We report on single-pass high-harmonic generation (HHG) with amplified driving laser pulses at a repetition rate of 20.8 MHz. An Yb:YAG Innoslab amplifier system provides 35 fs pulses with 20 W average power at 1030 nm after external pulse compression. Following tight focusing into a xenon gas jet, we observe the generation of high-harmonic radiation of up to the seventeenth order. Our results show that state-of-the-art amplifier systems have become a promising alternative to cavity-assisted HHG for applications that require high repetition rates, such as frequency comb spectroscopy in the extreme UV.
Enzymatic Cyclization of 2-(Carbamoyloxy)benzoates, 2-(Sulfamoyloxy)benzoates and 2-(Carbamoyloxy)benzophenones with Yeast and Lipase (1989)

The cyclizatton of labile functionalized 2-(carbamoylaxy)-benzoates, 2-(su1famoyloxy)benzoates and 2-(carbamoyloxy)benzophsnone~ to 1,3-benzoxazine-2,4-diones, 4-oxo-3,4-dihydro-l,2,3-benzoxathiazine 2 , 2 -dioxides and 4-phenyl-L,3-benzoxazin-2-ones with yeast as well as lipase is described.This approach establishes the application of enzymes for gram seale eyclizarion of such substrates under mild conditions.Further, it is revealed that baker's yeast is most suitable for this process.
Investigating the Impact of Visual Biofeedback on Postural Control Via Informative Dynamic Balance Training in Healthy Individuals (2015)

Objective: After traumatic brain injury (TBI), postural instability often results. This can effect ambulation and, subsequently, activities of daily living. Various forms of rehabilitation have been developed, but few offer engaging activities that provide informative dynamic balance training. The goal of this pilot study was to build a goal-based system that provided visual biofeedback to create an enriched environment for dynamic postural rehabilitation. The study aimed to determine if visual biofeedback had an effect on posture and balance during training for healthy participants; as well as determine the optimal man-machine visual-biofeedback interface.
Method: A modified elliptical trainer was developed that incorporated visual-biofeedback from measured left and right lower extremity loads. Four visual displays were constructed and tested on a sample of 15 healthy participants. These displays provided targeted feedback to aid in symmetric performance. The displays differed in the amount of information provided and in the extent of algorithmic pre-processing. Data were evaluated by calculating the index of symmetry (IOS) and statistically comparing display types.
Results: Participants performed significantly better with the introduction of visual biofeedback than baseline measurements with no display based on index of symmetry values. The data suggests that the feedback display that incorporated both temporal historical data and differential pre-processing performed the best. This display was called the differential-temporal display.
Conclusion: Our results reflect that performance is enhanced with the introduction of visual biofeedback during dynamic postural training. We also established that the differential-temporal display was the optimal feedback system to reduce IOS values during elliptical trainer use. From our results, it became apparent that incorporating visual biofeedback during postural training is a sophisticated approach to improve baseline asymmetries inherent in healthy participants. It is anticipated that similar results are likely to occur in a cohort of TBI patients due to the reduction of cognitive demand.
Establishing a surrogate model for inactivation of enveloped viruses to screen viral clearance conditions during biotherapeutics process development (2021)

Viral surrogates to screen for virus inactivation (VI) can be a faster, cheaper and safer alternative to third-party testing of pathogenic BSL2 (Biosafety Level 2) model viruses. Although the bacteriophage surrogate, Ø6, has been used to assess low pH BSL2 VI, it has not been used for evaluation of detergent-mediated VI. Furthermore, Ø6 is typically assayed through host cell infectivity which introduces the risk of cross-contaminating other cell lines in the facility. To circumvent contamination, we developed an in-house RT-qPCR (reverse transcriptase quantitative polymerase chain reaction) assay for selective detection of active Ø6 from a population of live and dead phage. The RT-qPCR assay was used to evaluate Ø6 inactivation in cell culture fluid of monoclonal antibody and fusion protein. Complementary Ø6 infectivity was also conducted at a third-party testing facility. The Ø6 RT-qPCR and infectivity data was modeled against VI of three BSL2 viruses, X- MuLV, A- MuLV and HSV-1 in corresponding therapeutics. Both Ø6 methods demonstrate that any VI agent showing Ø6 clearance of ≥ 2.5 logs would demonstrate complete BSL2 VI of ≥ 4.0 logs. Compared to BSL2 virus testing, this in-house Ø6 RT-qPCR tool can screen VI agents at 5% the cost and a turnaround time of 2-3 days versus 4-7 months.
Ultra-high Power Density Server Supplies Employing GaN Power Semiconductors and PCB-Integrated Magnetics (2020)

The trend towards higher computation power per server rack has lead to an increased interest in high density server power supplies with high efficiency and low cost. This paper analyzes how the specific features of planar magnetics as transformers and inductors can be best utilized in combination with GaN power semiconductors to reach unprecedented system performance both for power supplies with 12V and with 48V output voltage. Based on the optimization results a hardware demonstrator with an ultra-high power density (350W/in3) of a 3kW DC/DC converter stage with a wide-input voltage range of 300V-430V and an output voltage of 12V is presented.
Saturation Mapping in the Interwell Reservoir Volume: A New Technology Breakthrough (2017)

Abstract A crosswell electromagnetic (EM) tomography survey was acquired between two horizontal wells, a water injector and a producer, using coil tubing conveyance. The survey was conveyed in a swept area of a naturally fractured Middle Eastern carbonate reservoir. This paper presents the work flow that was developed to integrate the EM survey results with other data to successfully map interwell hydrocarbon saturations. A slanted well was later landed in the interwell area based on the crosswell survey interpretation results. This new well targeted an oil column shown to be bypassed by the water injection in the swept area, and the well is currently on production. The survey established a number of world firsts for the EM technology, including horizontal wells deployment, well spacing &amp;gt;1.3 km, full 3D resistivity inversion and 3D apparent water saturation mapping. The field program consisted of an extensive openhole logging sequence in each well prior to the crosswell EM data collection. The crosswell EM survey measured 135 profiles, covering more than an 800 m horizontal section in each of the two wells. High quality data were acquired for almost all the data profiles, even in a 400 m cased section. The field data were interpreted with a 3D inversion code. The fracture corridors were identified as electrical conductive volumes, due to their high water saturation. The less or unswept areas were characterized by higher resistivity, due to their lower water content. A resistivity model cannot be directly used for reservoir evaluation, then the subsequent step was to convert the resistivity model into a saturation volume, based on Archie's law. An innovative workflow of petrophysical simulations was designed to define volumetric distribution of porosity and water salinity based on reservoir simulation scenarios and ad hoc laboratory analysis. Finally, the most probable scenario of apparent water saturation volume in the interwell reservoir volume was produced. This work outlines the critical need for deep characterization in cases of fractured carbonate reservoirs, and in any case where the sweep efficiency is likely to be uneven, due to heterogeneities of reservoir petrophysical properties, and particularly permeability field variations.
Toxicity of Transition Metal Complex-based Nanophotoswitches in Retina (2019)

Purpose: Nanophotoswitches (NPSs) based on transition metal complexes offer a new tool for optical stimulation of neural activity in photoreceptor degenerated retina. We previously reported robust light-elicited neural activity in degenerate retinae exposed to ruthenium bipyridine based NPSs (Rubpy-C17) and its iridium analog (Irbpy-C17). Irbpy-C17 was developed as an alternative to Rubpy-C17 for the biosafety properties of the iridium complexes. Here we present a study of the toxicity of both NPSs in rodent retinae.&#13;\nMethods: Toxicity of Rubpy-C17 was tested in wildtype C57BL/6J mice and Irbpy-C17 in wildtype Long Evans rats. Animals were intravitreally injected with the test molecules (up to 50 µM) and sacrificed at different time points post injection: 3, 7, 14 and 28 days, respectively. Retinae were obtained, fixed and sliced for histological analysis immediately after animal euthanization. H&amp;E staining was performed to examine morphological integrity of retina and TUNEL staining performed to detect apoptosis of retinal cells. For comparison, Ru(bpy)3]Cl2 injection and sham surgery were included for control.&#13;\nResults: H&amp;E staining revealed no detectable sign of morphological or structural changes in the retinae after prolonged exposure to either Rubpy-C17 or Irbpy-C17 versus the control. There was no significant reduction in the thickness of different nuclear and plexiform retinal layers or the density of retinal neurons (p&lt;0.05), nor was there evidence of significant aggregation of immune cells. TUNEL staining showed minimal occurrence of cell apoptosis in the NPS treated retinae, similar to the control (p&lt;0.05). No longitudinal changes in either the morphology or the cell apoptosis was observed with the post injection time.&#13;\nConclusions: Overall our data did not find ocular toxicity associated with either the ruthenium or the iridium based NPSs within the concentration range tested. The results obtained with both complexes are similar to that obtained with the control molecule [Ru(bpy)3]Cl2, which lacks a membrane-anchoring 17 carbon chain attached to the bipyridine group, indicating that the inclusion of the carbon chain did not enable NPSs entry into the cells, nor did it cause apoptotic response. The present study provides new evidence of biosafety of our NPSs in rodent retinae, further encouraging developing NPS-based molecular retinal prosthesis to potentially restore high-acuity prosthetic vision in the blind.
Electron Tomographic Analysis of Somatic Cell Plate Formation in Meristematic Cells of Arabidopsis Preserved by High-Pressure Freezing[W] (2004)

We have investigated the process of somatic-type cytokinesis in Arabidopsis (Arabidopsis thaliana) meristem cells with a three-dimensional resolution of approximately 7 nm by electron tomography of high-pressure frozen/freeze-substituted samples. Our data demonstrate that this process can be divided into four phases: phragmoplast initials, solid phragmoplast, transitional phragmoplast, and ring-shaped phragmoplast. Phragmoplast initials arise from clusters of polar microtubules (MTs) during late anaphase. At their equatorial planes, cell plate assembly sites are formed, consisting of a filamentous ribosome-excluding cell plate assembly matrix (CPAM) and Golgi-derived vesicles. The CPAM, which is found only around growing cell plate regions, is suggested to be responsible for regulating cell plate growth. Virtually all phragmoplast MTs terminate inside the CPAM. This association directs vesicles to the CPAM and thereby to the growing cell plate. Cell plate formation within the CPAM appears to be initiated by the tethering of vesicles by exocyst-like complexes. After vesicle fusion, hourglass-shaped vesicle intermediates are stretched to dumbbells by a mechanism that appears to involve the expansion of dynamin-like springs. This stretching process reduces vesicle volume by approximately 50%. At the same time, the lateral expansion of the phragmoplast initials and their CPAMs gives rise to the solid phragmoplast. Later arriving vesicles begin to fuse to the bulbous ends of the dumbbells, giving rise to the tubulo-vesicular membrane network (TVN). During the transitional phragmoplast stage, the CPAM and MTs disassemble and then reform in a peripheral ring phragmoplast configuration. This creates the centrifugally expanding peripheral cell plate growth zone, which leads to cell plate fusion with the cell wall. Simultaneously, the central TVN begins to mature into a tubular network, and ultimately into a planar fenestrated sheet (PFS), through the removal of membrane via clathrin-coated vesicles and by callose synthesis. Small secondary CPAMs with attached MTs arise de novo over remaining large fenestrae to focus local growth to these regions. When all of the fenestrae are closed, the new cell wall is complete. Few endoplasmic reticulum (ER) membranes are seen associated with the phragmoplast initials and with the TVN cell plate that is formed within the solid phragmoplast. ER progressively accumulates thereafter, reaching a maximum during the late PFS stage, when most cell plate growth is completed.