gebhart/patrepeval huggingface dataset:
High-power femtosecond Yb-doped fiber amplifier (2002)

We report on the generation of linearly chirped parabolic pulses with 17-W average power at 75 MHz repetition rate and diffraction-limited beam quality in a large-mode-area ytterbium-doped fiber amplifier. Highly efficient transmission gratings in fused silica are applied to recompress these pulses down to 80-fs with an efficiency of 60%, resulting in a peak power of 1.7 MW. Power scaling limitations given by the amplifier bandwidth are discussed.
Global register allocation at link time (2004)

In previous work in global register allocation, the compiler colors a conflict graph constructed from liveness dataflow information, in order to allocate the same register to many variables that are not simultaneously live. If two procedures are in separately compiled modules, however, the compiler must do this allocation separately for each procedure. As a result, the two procedures might use different registers for the same global, or the same register for different locals.We can remove these problems if we delay the register allocation until link time. Our compiler produces object modules that can be linked and run without global register allocation, but includes with each object module a body of information describing how the module uses variables and procedures. A link-time register allocator then decides which variables are used most frequently, selects registers for them, and rewrites the code to reflect the decision that these variables reside in registers rather than in memory. Construction of the call graph allows us to use the same register for locals of procedures that are not simultaneously active, giving us most of the advantages of a full-scale coloring without the expense.When we use our method for 52 registers, our benchmarks speed up by 10 to 25 percent. Even with only 8 registers, the speedup can be nearly that large if we use previously collected profile information to guide the allocation. We cannot do much better, because programs whose variables all fit in registers rarely speed up by more than 30%. Moreover, profiling shows us that we usually remove 60% to 90% of the loads and stores of scalar variables that the program performs during its execution, and often much more.
Development of a cytokine analog with enhanced stability using computational ultrahigh throughput screening (2002)

Granulocyte-colony stimulating factor (G-CSF) is used worldwide to prevent neutropenia caused by high-dose chemotherapy. It has limited stability, strict formulation and storage requirements, and because of poor oral absorption must be administered by injection (typically daily). Thus, there is significant interest in developing analogs with improved pharmacological properties. We used our ultrahigh throughput computational screening method to improve the physicochemical characteristics of G-CSF. Improving these properties can make a molecule more robust, enhance its shelf life, or make it more amenable to alternate delivery systems and formulations. It can also affect clinically important features such as pharmacokinetics. Residues in the buried core were selected for optimization to minimize changes to the surface, thereby maintaining the active site and limiting the designed protein's potential for antigenicity. Using a structure that was homology modeled from bovine G-CSF, core designs of 25-34 residues were completed, corresponding to 10(21)-10(28) sequences screened. The optimal sequence from each design was selected for biophysical characterization and experimental testing; each had 10-14 mutations. The designed proteins showed enhanced thermal stabilities of up to 13 degrees C, displayed five-to 10-fold improvements in shelf life, and were biologically active in cell proliferation assays and in a neutropenic mouse model. Pharmacokinetic studies in monkeys showed that subcutaneous injection of the designed analogs results in greater systemic exposure, probably attributable to improved absorption from the subcutaneous compartment. These results show that our computational method can be used to develop improved pharmaceuticals and illustrate its utility as a powerful protein design tool.
Experimental models of lung transplantation (2012)

Lung transplantation is a life saving treatment for end stage pulmonary diseases. The development and refinement of this therapy required the utilization of various animal models, without which this procedure would not have become a clinical reality. Canine models were critical in the initial breakthroughs in surgical technique and immunosuppressive regimens, which directly led to the first successful human lung transplantation. Orthotopic lung transplant models in the rat provided a platform for more detailed investigation of immune responses to pulmonary grafts. Investigation of chronic rejection of lungs has significantly been advanced through the use of mouse tracheal transplant experiments. And finally, the advent of orthotopic, vascularized lung transplantation in the mouse opened the door to the use of genetic and molecular tools that are necessary for the rigorous mechanistic study of alloimmune and non-alloimmune factors contributing to lung graft failure. Taken together, animal models will continue to be a cornerstone in the advancement of clinical success in lung transplantation.
The New Insulins (2007)

Diabetes is a growing problem for a large proportion of children. Insulin is the primary medication used for most cases of pediatric diabetes, though achieving adequate glycemic control with current insulin products can be extremely challenging. New insulin forms, including novel analogues and radically changed delivery systems are providing new approaches to controlling diabetes. Health care providers caring for patients with diabetes must be informed of the new insulins becoming available to patients. This CME article will provide an introduction to some of the new insulins and delivery systems.
H2B Ubiquitin Protease Ubp8 and Sgf11 Constitute a Discrete Functional Module within the Saccharomyces cerevisiae SAGA Complex (2005)

The SAGA complex is a multisubunit protein complex involved in transcriptional regulation in Saccharomyces cerevisiae. SAGA combines proteins involved in interactions with DNA-bound activators and TATA-binding protein (TBP), as well as enzymes for histone acetylation (Gcn5) and histone deubiquitylation (Ubp8). We recently showed that H2B ubiquitylation and Ubp8-mediated deubiquitylation are both required for transcriptional activation. For this study, we investigated the interaction of Ubp8 with SAGA. Using mutagenesis, we identified a putative zinc (Zn) binding domain within Ubp8 as being critical for the association with SAGA. The Zn binding domain is required for H2B deubiquitylation and for growth on media requiring Ubp8's function in gene activation. Furthermore, we identified an 11-kDa subunit of SAGA, Sgf11, and showed that it is required for the Ubp8 association with SAGA and for H2B deubiquitylation. Different approaches indicated that the functions of Ubp8 and Sgf11 are related and separable from those of other components of SAGA. In particular, the profiles of Ubp8 and Sgf11 deletions were remarkably similar in microarray analyses and synthetic genetic interactions and were distinct from those of the Spt3 and Spt8 subunits of SAGA, which are involved in TBP regulation. These data indicate that Ubp8 and Sgf11 likely represent a new functional module within SAGA that is involved in gene regulation through H2B deubiquitylation.
Microstructure of plasma-deposited a-Si : H films (1979)

Using transmission and scanning electron microscopy, it is shown that plasma deposition of amorphous silicon hydrogen films from silane or silane/argon mixtures proceeds via nucleation and growth of islands of average lateral dimensions ∼100 Å. If these islands do not coalesce into a homogeneous film, subsequent growth produces columnar morphology with low-density interstitial regions. There is a strong correlation between the columnar structure and the presence of nonradiative recombination centers.
Comparación técnico-económica del uso de zeranol más ivermectina frente a ivermectina en bovinos, en las etapas de finalización y ceba en la Orinoquia mal drenada, en Casanare, Colombia (2011)

En este estudio realizado durante el 2010 en el municipio de Paz de Ariporo (Casanare) se determinó el impacto económico y las ganancias de peso diarias (gdp), al comparar el uso de ivermectina al 3,15% frente a una mezcla de ivermectina más zeranol al 1%, en monodosis. Se seleccionaron machos Brahman comercial (n = 112), organizándolos en dos grupos. En el primer grupo (n = 56) se ubicaron los animales de finalización (&gt; 450 kg) y en el segundo (n = 56) los de ceba (&gt; 400 y &lt; de 450 kg). A la mitad de los del grupo de finalización, G1 (n = 31), y a la mitad de los machos del grupo de ceba, G3 (n = 28), se les inyectó ivermectina. A la otra mitad, G2 (n = 25), de los animales de finalización y la otra mitad de los de ceba, G4 (n = 28), se les aplicó una asociación de zeranol más ivermecina. En todos los grupos se realizaron pesajes al inicio y tres meses después del suministro de cada compuesto.Para establecer si existían diferencias estadística en los resultados de gdpse realizó un Anova (F test). No hubo diferencias significativas entre las gdpde los grupos tratados; sin embargo, la diferencia sí fue significativa al comparar los animales en etapa de finalización y los ubicados en el grupo de ceba. El grupo de finalización tuvo una gdpde 465 g/día, +138,2 mayor que la obtenida con los animales de ceba, con 400 g/día, +146. Se determinó que la utilidad después de costos directos, margen de contribución y la asociación ivermectina-zeranol fue positiva respecto a los costos del medicamento.
Docetaxel versus doxorubicin in patients with metastatic breast cancer who have failed alkylating chemotherapy: a preliminary report of the randomized phase III trial. 303 Study Group. (1998)

Three hundred twenty-six patients who had failed prior alkylating agents, given either as adjuvant therapy or therapy for advanced breast cancer or both, were randomly assigned to treatment with up to seven cycles of doxorubicin 75 mg/m2 or docetaxel (Taxotere, Rhône-Poulenc Rorer, Antony, France) 100 mg/m2 given every 3 weeks. The two arms of the study were well-matched for age, performance status, previous therapy, and the nature of the metastatic disease. Forty-seven percent of the docetaxel-treated patients and 49% of the doxorubicin-treated patients were defined as having disease that showed primary or secondary resistance. Overall, 48% of patients treated with docetaxel had an objective response. This was significantly greater than the 33% response rate seen in doxorubicin-treated patients (P = .008). Among those patients classified as having resistant disease, the difference was equally clear cut (response rate, 47% v 25%; P = .003). Overall median time to response was 12 weeks with docetaxel and 23 weeks with doxorubicin. Febrile neutropenia, grade 3/4 nausea and vomiting, and cardiotoxicity were significantly more common among the doxorubicin-treated patients, while diarrhea grade 3-4, skin toxicity, neurologic toxicity, fluid retention, and allergy of any grade were significantly more likely in the docetaxel-treated patients. This study demonstrates for the first time the superiority in terms of response rate of a taxoid over an anthracycline in the treatment of advanced breast cancer.
A block of autophagy in lysosomal storage disorders (2007)

Most lysosomal storage disorders (LSDs) are caused by deficiencies of lysosomal hydrolases. While LSDs were among the first inherited diseases for which the underlying biochemical defects were identified, the mechanisms from enzyme deficiency to cell death are poorly understood. Here we show that lysosomal storage impairs autophagic delivery of bulk cytosolic contents to lysosomes. By studying the mouse models of two LSDs associated with severe neurodegeneration, multiple sulfatase deficiency (MSD) and mucopolysaccharidosis type IIIA (MPSIIIA), we observed an accumulation of autophagosomes resulting from defective autophagosome-lysosome fusion. An impairment of the autophagic pathway was demonstrated by the inefficient degradation of exogenous aggregate-prone proteins (i.e. expanded huntingtin and mutated alpha-synuclein) in cells from LSD mice. This impairment resulted in massive accumulation of polyubiquitinated proteins and of dysfunctional mitochondria which are the putative mediators of cell death. These data identify LSDs as 'autophagy disorders' and suggest the presence of common mechanisms in the pathogenesis of these and other neurodegenerative diseases.
Protein Isoprenylation and Methylation at Carboxy-Terminal Cysteine Residues (1992)

The Hippo pathway was initially discovered in Drosophila melanogaster as a key regulator of tissue growth. It is an evolutionarily conserved signaling cascade regulating numerous biological processes, including cell growth and fate decision, organ size ...Read More
A Phase I Trial of Repeated Intrapleural Adenoviral-mediated Interferon-β Gene Transfer for Mesothelioma and Metastatic Pleural Effusions (2010)

We previously showed that a single intrapleural dose of an adenoviral vector expressing interferon-beta (Ad.IFN-beta) in patients with malignant pleural mesothelioma (MPM) or malignant pleural effusions (MPE) resulted in gene transfer, humoral antitumor immune responses, and anecdotal clinical responses manifested by modified Response Evaluation Criteria in Solid Tumors (RECIST) disease stability in 3 of 10 patients at 2 months and an additional patient with significant metabolic response on positron emission tomography (PET) imaging. This phase I trial was conducted to determine whether using two doses of Ad.IFN-beta vector would be superior. Ten patients with MPM and seven with MPE received two doses of Ad.IFN-beta through an indwelling pleural catheter. Repeated doses were generally well tolerated. High levels of IFN-beta were detected in pleural fluid after the first dose; however, only minimal levels were seen after the second dose of vector. Lack of expression correlated with the rapid induction of neutralizing Ad antibodies (Nabs). Antibody responses against tumor antigens were induced in most patients. At 2 months, modified RECIST responses were as follows: one partial response, two stable disease, nine progressive disease, and two nonmeasurable disease. One patient died after 1 month. By PET scanning, 2 patients had mixed responses and 11 had stable disease. There were seven patients with survival times longer than 18 months. This approach was safe, induced immune responses and disease stability. However, rapid development of Nabs prevented effective gene transfer after the second dose, even with a dose interval as short as 7 days.
Inclusion body myositis-like phenotype induced by transgenic overexpression of βAPP in skeletal muscle (2002)

Inclusion body myositis (IBM), the most common age-related muscle disease in the elderly population, is an incurable disorder leading to severe disability. Sporadic IBM has an unknown etiology, although affected muscle fibers are characterized by many of the pathobiochemical alterations traditionally associated with neurodegenerative brain disorders such as Alzheimer's disease. Accumulation of the amyloid-beta peptide, which is derived from proteolysis of the larger amyloid-beta precursor protein (betaAPP), seems to be an early pathological event in Alzheimer's disease and also in IBM, where in the latter, it predominantly occurs intracellularly within affected myofibers. To elucidate the possible role of betaAPP mismetabolism in the pathogenesis of IBM, transgenic mice were derived in which we selectively targeted betaAPP overexpression to skeletal muscle by using the muscle creatine kinase promoter. Here we report that older (>10 months) transgenic mice exhibit intracellular immunoreactivity to betaAPP and its proteolytic derivatives in skeletal muscle. In this transgenic model, selective overexpression of betaAPP leads to the development of a subset of other histopathological and clinical features characteristic of IBM, including centric nuclei, inflammation, and deficiencies in motor performance. These results are consistent with a pathogenic role for betaAPP mismetabolism in human IBM.
Noninvasive myocardial activation time imaging: a novel inverse algorithm applied to clinical ECG mapping data (2002)

Linear approaches like the minimum-norm least-square algorithm show insufficient performance when it comes to estimating the activation time map on the surface of the heart from electrocardiographic (ECG) mapping data. Additional regularization has to be considered leading to a nonlinear problem formulation. The Gauss-Newton approach is one of the standard mathematical tools capable of solving this kind of problem. To our experience, this algorithm has specific drawbacks which are caused by the applied regularization procedure. In particular, under clinical conditions the amount of regularization cannot be determined clearly. For this reason, we have developed an iterative algorithm solving this nonlinear problem by a sequence of regularized linear problems. At each step of iteration, an individual L-curve is computed. Subsequent iteration steps are performed with the individual optimal regularization parameter. This novel approach is compared with the standard Gauss-Newton approach. Both methods are applied to simulated ECG mapping data as well as to single beat sinus rhythm data from two patients recorded in the catheter laboratory. The proposed approach shows excellent numerical and computational performance, even under clinical conditions at which the Gauss-Newton approach begins to break down.
Potential Nationwide Improvements in Productivity and Health From Better Indoor Environments (1998)

Theoretical considerations and empirical data suggest that existing technologies and procedures can improve indoor environments in a manner that significantly increases productivity and health. Existing literature contains moderate to strong evidence that characteristics of buildings and indoor environments significantly influence rates of respiratory disease, allergy and asthma symptoms, sick building symptoms, and worker performance. While there is considerable uncertainty in our estimates of the magnitudes of productivity gains that may be obtained by providing better indoor environments, the projected gains are very large. For the U.S., we estimate potential annual savings and productivity gains of $6 to $19 billion from reduced respiratory disease, $1 to $4 billion from reduced allergies and asthma, $10 to $20 billion from reduced sick building syndrome symptoms, and $12 to $125 billion from direct improvements in worker performance that are unrelated to health. In two example calculations, the potential financial benefits of improving indoor environments exceed costs by a factor of 8 and 14. Productivity gains that are quantified and demonstrated could serve as a strong stimulus for energy efficiency measures that simultaneously improve the indoor environment.
A MRF-based approach for real-time subway monitoring (2005)

There has been an increase in the use of video surveillance and monitoring in public areas to improve safety and security. Change detection and crowding/congestion density estimation are two sub-tasks in a subway monitoring system. We propose a method that decomposes this problem into two steps. The first step consists of a change detection algorithm that distinguishes the background from the foreground. This is done using a discontinuity preserving MRF-based approach where the information from different sources (background subtraction, intensity modeling) is combined with spatial constraints to provide a smooth motion detection map. Then, the obtained change detection map is combined with a geometry module that performs a soft auto-calibration to estimate a measure of congestion of the observed area (platform). Extensive experimental results in a metro station of a metropolitan city demonstrates the performance and the potential of our method.
Noninvasive, On-Line Monitoring of the Biotransformation by Yeast of Glucose to Ethanol Using Dispersive Raman Spectroscopy and Chemometrics (1999)

We describe the first application of dispersive Raman spectroscopy using a diode laser exciting at 780 nm and a charge-coupled device (CCD) detector to the noninvasive, on-line determination of the biotransformation by yeast of glucose to ethanol. Software was developed which automatically removed the effects of cosmic rays and other noise, normalized the spectra to an invariant peak, then removed the “baseline” arising from interference by fluorescent impurities, to obtain the “true” Raman spectra. Variable selection was automatically performed on the parameters of relevant Raman peaks (height, width, position of top and center, area and skewness), and a small subset used as the input to cross-validated models based on partial least-squares (PLS) regression. The multivariate calibration models so formed were sufficiently robust to be able to predict the concentration of glucose and ethanol in a completely different fermentation with a precision better than 5%. Dispersive Raman spectroscopy, when coupled with the appropriate chemometrics, is a very useful approach to the noninvasive, on-line determination of the progress of microbial fermentations.
Structural and Functional Aspects of the Multiplicity of Neu Differentiation Factors (1994)

We used molecular cloning and functional analyses to extend the family of Neu differentiation factors (NDFs) and to explore the biochemical activity of different NDF isoforms. Exhaustive cloning revealed the existence of six distinct fibroblastic pro-NDFs, whose basic transmembrane structure includes an immunoglobulin-like motif and an epidermal growth factor (EGF)-like domain. Structural variation is confined to three domains: the C-terminal portion of the EGF-like domain (isoforms alpha and beta), the adjacent juxtamembrane stretch (isoforms 1 to 4), and the variable-length cytoplasmic domain (isoforms a, b, and c). Only certain combinations of the variable domains exist, and they display partial tissue specificity in their expression: pro-NDF-alpha 2 is the predominant form in mesenchymal cells, whereas pro-NDF-beta 1 is the major neuronal isoform. Only the transmembrane isoforms were glycosylated and secreted as biologically active 44-kDa glycoproteins, implying that the transmembrane domain functions as an internal signal peptide. Extensive glycosylation precedes proteolytic cleavage of pro-NDF but has no effect on receptor binding. By contrast, the EGF-like domain fully retains receptor binding activity when expressed separately, but its beta-type C terminus displays higher affinity than alpha-type NDFs. Likewise, structural heterogeneity of the cytoplasmic tails may determine isoform-specific rate of pro-NDF processing. Taken together, these results suggest that different NDF isoforms are generated by alternative splicing and perform distinct tissue-specific functions.