Protease inhibitors targeting coronavirus and filovirus entry.

In order to gain entry into cells, diverse viruses, including Ebola virus, SARS-coronavirus and the emerging MERS-coronavirus, depend on activation of their envelope glycoproteins by host cell proteases. The respective enzymes are thus excellent targets for antiviral intervention. In cell culture, activation of Ebola virus, as well as SARS- and MERS-coronavirus can be accomplished by the endosomal cysteine proteases, cathepsin L (CTSL) and cathepsin B (CTSB). In addition, SARS- and MERS-coronavirus can use serine proteases localized at the cell surface, for their activation. However, it is currently unclear which protease(s) facilitate viral spread in the infected host. We report here that the cysteine protease inhibitor K11777, ((2S)-N-[(1E,3S)-1-(benzenesulfonyl)-5-phenylpent-1-en-3-yl]-2-{[(E)-4-methylpiperazine-1-carbonyl]amino}-3-phenylpropanamide) and closely-related vinylsulfones act as broad-spectrum antivirals by targeting cathepsin-mediated cell entry. K11777 is already in advanced stages of development for a number of parasitic diseases, such as Chagas disease, and has proven to be safe and effective in a range of animal models. K11777 inhibition of SARS-CoV and Ebola virus entry was observed in the sub-nanomolar range. In order to assess whether cysteine or serine proteases promote viral spread in the host, we compared the antiviral activity of an optimized K11777-derivative with that of camostat, an inhibitor of TMPRSS2 and related serine proteases. Employing a pathogenic animal model of SARS-CoV infection, we demonstrated that viral spread and pathogenesis of SARS-CoV is driven by serine rather than cysteine proteases and can be effectively prevented by camostat. Camostat has been clinically used to treat chronic pancreatitis, and thus represents an exciting potential therapeutic for respiratory coronavirus infections. Our results indicate that camostat, or similar serine protease inhibitors, might be an effective option for treatment of SARS and potentially MERS, while vinyl sulfone-based inhibitors are excellent lead candidates for Ebola virus therapeutics

The growth and form of knowledge networks by kinesthetic curiosity

Throughout life, we might seek a calling, companions, skills, entertainment, truth, self-knowledge, beauty, and edification. The practice of curiosity can be viewed as an extended and open-ended search for valuable information with hidden identity and location in a complex space of interconnected information. Despite its importance, curiosity has been challenging to computationally model because the practice of curiosity often flourishes without specific goals, external reward, or immediate feedback. Here, we show how network science, statistical physics, and philosophy can be integrated into an approach that coheres with and expands the psychological taxonomies of specific-diversive and perceptual-epistemic curiosity. Using this interdisciplinary approach, we distill functional modes of curious information seeking as searching movements in information space. The kinesthetic model of curiosity offers a vibrant counterpart to the deliberative predictions of model-based reinforcement learning. In doing so, this model unearths new computational opportunities for identifying what makes curiosity curious

TEMPERA: Test-Time Prompting via Reinforcement Learning

Careful prompt design is critical to the use of large language models in zero-shot or few-shot learning. As a consequence, there is a growing interest in automated methods to design optimal prompts. In this work, we propose Test-time Prompt Editing using Reinforcement learning (TEMPERA). In contrast to prior prompt generation methods, TEMPERA can efficiently leverage prior knowledge, is adaptive to different queries and provides an interpretable prompt for every query. To achieve this, we design a novel action space that allows flexible editing of the initial prompts covering a wide set of commonly-used components like instructions, few-shot exemplars, and verbalizers. The proposed method achieves significant gains compared with recent SoTA approaches like prompt tuning, AutoPrompt, and RLPrompt, across a variety of tasks including sentiment analysis, topic classification, natural language inference, and reading comprehension. Our method achieves 5.33x on average improvement in sample efficiency when compared to the traditional fine-tuning methods

Outcome-dependent sampling design and inference for Cox’s proportional hazards Model

We propose a cost-effective outcome-dependent sampling design for the failure time data and develop an efficient inference procedure for data collected with this design. To account for the biased sampling scheme, we derive estimators from a weighted partial likelihood estimating equation. The proposed estimators for regression parameters are shown to be consistent and asymptotically normally distributed. A criteria that can be used to optimally implement the ODS design in practice is proposed and studied. The small sample performance of the proposed method is evaluated by simulation studies. The proposed design and inference procedure is shown to be statistically more powerful than existing alternative designs with the same sample sizes. We illustrate the proposed method with an existing real data from the Cancer Incidence and Mortality of Uranium Miners Study

Characterizing Ultraviolet and Infrared Observational Properties for Galaxies. I. Influences of Dust Attenuation and Stellar Population Age

The correlation between infrared-to-ultraviolet luminosity ratio and ultraviolet color, i.e. the IRX-UV relation, was regarded as a prevalent recipe for correcting extragalactic dust attenuation. Considerable dispersion in this relation discovered for normal galaxies, however, complicates its usability. In order to investigate the cause of the dispersion, in this paper, we select five nearby spiral galaxies, and perform spatially resolved studies on each of the galaxies, with a combination of ultraviolet and infrared imaging data. We measure all positions within each galaxy and divide the extracted regions into young and evolved stellar populations. By means of this approach, we attempt to discover separate effects of dust attenuation and stellar population age on the IRX-UV relation for individual galaxies. In this work, in addition to dust attenuation, stellar population age is interpreted to be another parameter in the IRX-UV function, and the diversity of star formation histories is suggested to disperse the age effects. At the same time, strong evidence shows the necessity of more parameters in the interpretation of observational data, such as variations in attenuation/extinction law. Fractional contributions of different components to the integrated luminosities of the galaxies suggest that the integrated measurements of galaxies which comprise different populations would weaken the effect of the age parameter on IRX-UV diagrams. The dependance of the IRX-UV relation on luminosity and radial distance in galaxies presents weak trends, which offers an implication of selective effects. The two-dimensional maps of the UV color and the infrared-to-ultraviolet ratio are displayed and show a disparity in the spatial distributions between the two parameters in galaxies, which offers a spatial interpretation of the scatter in the IRX-UV relation.Comment: 23 pages, 27 figures, 4 tables; accepted for publication in The Astrophysical Journal; re-typesetted in the emulateapj style; minor corrections in the figure symbols and in the tex

Recent progress in thermoelectric nanocomposites based on solution-synthesized nanoheterostructures

Thermoelectric materials, which can convert waste heat into electricity, have received increasing research interest in recent years. This paper describes the recent progress in thermoelectric nanocomposites based on solution-synthesized nanoheterostructures. We start our discussion with the strategies of improving the power factor of a given material by using nanoheterostructures. Then we discuss the methods of decreasing thermal conductivity. Finally, we highlight a way of decoupling power factor and thermal conductivity, namely, incorporating phase-transition materials into a nanowire heterostructure. We have explored the lead telluride–copper telluride thermoelectric nanowire heterostructure in this work. Future possible ways to improve the figure of merit are discussed at the end of this paper

A laboratory and pilot plant scaled continuous stirred reactor separator for the production of ethanol from sugars, corn grits/starch or biomass streams

An improved bio-reactor has been developed to allow the high speed, continues, low energy conversion of various substrates to ethanol. The Continuous Stirred Reactor Separator (CSRS) incorporates gas stripping of the ethanol using a recalculating gas stream between cascading stirred reactors in series. We have operated a 4 liter lab scale unit, and built and operated a 24,000 liter pilot scale version of the bioreactor. High rates of fermentation are maintained in the reactor stages using a highly flocculent yeast strain. Ethanol is recovered from the stripping gas using a hydrophobic solvent absorber (isothermal), after which the gas is returned to the bioreactor. Ethanol can then be removed from the solvent to recover a highly concentrated ethanol product. We have applied the lab scale CSRS to sugars (glucose/sucrose), molasses, and raw starch with simultaneous saccharification and fermentation of the starch granules (SSF). The pilot scale CSRS has been operated as a cascade reactor using dextrins as a feed. Operating data from both the lab and pilot scale CSRS are presented. Details of how the system might be applied to cellulosics, with some preliminary data are also given

(5-Bromo-2-hydroxy­phen­yl)(phen­yl)methanone

In the title compound, C13H9BrO2, the mol­ecular conformation is stabilized by an intra­molecular O—H⋯O hydrogen bond. In the crystal structure, weak inter­molecular C—H⋯O hydrogen-bonding inter­actions link the mol­ecules into chains along the c-axis direction

Stabilization of the coupled oxygen and phosphorus cycles by the evolution of bioturbation

This is the author accepted manuscript. The final version is available from Nature Research via the DOI in this record Animal burrowing and sediment-mixing (bioturbation) began during the run up to the Ediacaran/Cambrian boundary, initiating a transition between the stratified Precambrian and more well-mixed Phanerozoic sedimentary records, against the backdrop of a variable global oxygen reservoir probably smaller in size than present. Phosphorus is the long-term limiting nutrient for oxygen production via burial of organic carbon, and its retention (relative to carbon) within organic matter in marine sediments is enhanced by bioturbation. Here we explore the biogeochemical implications of a bioturbation-induced organic phosphorus sink in a simple model. We show that increased bioturbation robustly triggers a net decrease in the size of the global oxygen reservoir - the magnitude of which is contingent upon the prescribed difference in carbon to phosphorus ratios between bioturbated and laminated sediments. Bioturbation also reduces steady-state marine phosphate levels, but this effect is offset by the decline in iron-adsorbed phosphate burial that results from a decrease in oxygen concentrations. The introduction of oxygen-sensitive bioturbation to dynamical model runs is sufficient to trigger a negative feedback loop: the intensity of bioturbation is limited by the oxygen decrease it initially causes. The onset of this feedback is consistent with redox variations observed during the early Cambrian rise of bioturbation, leading us to suggest that bioturbation helped to regulate early oxygen and phosphorus cycles. © 2014 Macmillan Publishers Limited. All rights reserved.Natural Environment Research Council (NERC)Inge Lehmann ScholarshipVILLUM FoundationNational Basic Research Program of ChinaNational Natural Science Foundation of ChinaDeutsche Forschungsgemeinschaft (DFG