Theory and applications of differential scanning fluorimetry in early-stage drug discovery

Differential scanning fluorimetry (DSF) is an accessible, rapid, and economical biophysical technique that has seen many applications over the years, ranging from protein folding state detection to the identification of ligands that bind to the target protein. In this review, we discuss the theory, applications, and limitations of DSF, including the latest applications of DSF by ourselves and other researchers. We show that DSF is a powerful high-throughput tool in early drug discovery efforts. We place DSF in the context of other biophysical methods frequently used in drug discovery and highlight their benefits and downsides. We illustrate the uses of DSF in protein buffer optimization for stability, refolding, and crystallization purposes and provide several examples of each. We also show the use of DSF in a more downstream application, where it is used as an in vivo validation tool of ligand-target interaction in cell assays. Although DSF is a potent tool in buffer optimization and large chemical library screens when it comes to ligand-binding validation and optimization, orthogonal techniques are recommended as DSF is prone to false positives and negatives

Market Manipulation with Outside Incentives

Much evidence has shown that prediction markets, when used in isolation, can effectively aggregate dispersed information about uncertain future events and produce remarkably accurate forecasts. However, if the market prediction will be used for decision making, a strategic participant with a vested interest in the decision outcome may want to manipulate the market prediction in order to influence the resulting decision. The presence of such incentives outside of the market would seem to damage information aggregation because of the potential distrust among market participants. While this is true under some conditions, we find that, if the existence of such incentives is certain and common knowledge, then in many cases, there exists a separating equilibrium for the market where information is fully aggregated. This equilibrium also maximizes social welfare for convex outside payoff functions. At this equilibrium, the participant with outside incentives makes a costly move to gain the trust of other participants. When the existence of outside incentives is uncertain, however, trust cannot be established between players if the outside incentive is sufficiently large and we lose the separability in equilibrium.Engineering and Applied Science

Hierarchical multithreading: programming model and system software

This paper addresses the underlying sources of performance degradation (e.g. latency, overhead, and starvation) and the difficulties of programmer productivity (e.g. explicit locality management and scheduling, performance tuning, fragmented memory, and synchronous global barriers) to dramatically enhance the broad effectiveness of parallel processing for high end computing. We are developing a hierarchical threaded virtual machine (HTVM) that defines a dynamic, multithreaded execution model and programming model, providing an architecture abstraction for HEC system software and tools development. We are working on a prototype language, LITL-X (pronounced "little-X") for latency intrinsic-tolerant language, which provides the application programmers with a powerful set of semantic constructs to organize parallel computations in a way that hides/manages latency and limits the effects of overhead. This is quite different from locality management, although the intent of both strategies is to minimize the effect of latency on the efficiency of computation. We work on a dynamic compilation and runtime model to achieve efficient LITL-X program execution. Several adaptive optimizations were studied. A methodology of incorporating domain-specific knowledge in program optimization was studied. Finally, we plan to implement our method in an experimental testbed for a HEC architecture and perform a qualitative and quantitative evaluation on selected applications

BioCoder: A Benchmark for Bioinformatics Code Generation with Contextual Pragmatic Knowledge

Pre-trained language models like ChatGPT have significantly improved code generation. As these models scale up, there is an increasing need for the output to handle more intricate tasks. Moreover, in bioinformatics, generating functional programs poses additional notable challenges due to the amount of domain knowledge, the need for complicated data operations, and intricate functional dependencies between the operations. Here, we present BioCoder, a benchmark developed to evaluate existing pre-trained models in generating bioinformatics code. In relation to function-code generation, BioCoder covers potential package dependencies, class declarations, and global variables. It incorporates 1026 functions and 1243 methods in Python and Java from GitHub and 253 examples from the Rosalind Project. BioCoder incorporates a fuzz-testing framework for evaluation, and we have applied it to evaluate many models including InCoder, CodeGen, CodeGen2, SantaCoder, StarCoder, StarCoder+, InstructCodeT5+, and ChatGPT. Our detailed analysis of these models emphasizes the importance of domain knowledge, pragmatic code generation, and contextual understanding. Our dataset, benchmark, Docker images, and scripts required for testing are all available at https://github.com/gersteinlab/biocoder

a cross-cultural comparison between Portugal and the United States

Background: Motor competence and health-related fitness are important components for the development and maintenance of a healthy lifestyle in children. This study examined cross-cultural performances on motor competence and health-related fitness between Portuguese and U.S. children. Methods: Portuguese (n = 508; 10.14 +/- 2.13 years , mean +/- SD) and U.S. (n = 710; 9.48 +/- 1.62 years) children performed tests of cardiorespiratory fitness (Progressive Aerobic Cardiovascular Endurance Run), upper body strength (handgrip), locomotor skill performance (standing long jump), and object projection skill performance (throwing and kicking). Portuguese and U.S. children were divided into 2 age groups (6=9 and 10=13 years) for data analysis purposes. A two=factor one=way analysis of covariance (ANOVA) was conducted with the Progressive Aerobic Cardiovascular Endur ance Run, handgrip, standing long jump scores, kicking, and throwing speed (km/h) as dependent variables. Results: Results indicated that Portuguese children, irrespective of sex, presented better performances in locomotor and cardiorespiratory performance (standing long jump and Progressive Aerobic Cardiovascular Endurance Run) than U.S. children in both age bands. U.S. children outper formed Portuguese children during throwing and handgrip tests. Kicking tests presented gender differences: Portuguese boys and U.S. girls outperformed their internationally matched counterparts. Conclusion: Cultural differences in physical education curricula and sports participation may impact differences in motor competence and fitness development in these countries.4811-99FE-2ECD | Luis Paulo RodriguesN/

Regulatory role of C5a in LPS-induced IL-6 production by neutrophils during sepsis

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154469/1/fsb2fj030708fje-sup-0001.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154469/2/fsb2fj030708fje.pd

Multiferroicity in doped hexagonal LuFeO3

The hexagonal phase of LuFeO3 is a rare example of a multiferroic material possessing a weak ferromagnetic moment, which is predicted to be switchable by an electric field. We stabilize this structure in bulk form though Mn and Sc doping, and determine the complete magnetic and crystallographic structures using neutron-scattering and magnetometry techniques. The ferroelectric P6(3)cm space group is found to be stable over a wide concentration range, ordering antiferromagnetically with Neel temperatures that smoothly increase following the ratio of c to a (c/a) lattice parameters up to 172 K, the highest found in this class of materials to date. The magnetic structure for a range of temperatures and dopings is consistent with recent studies of high quality epitaxial films of pure hexagonal LuFeO3 including a ferromagnetic moment parallel to the ferroelectric axis. We propose a mechanism by which room-temperature multiferroicity could be achieved in this class of materialsopen

Correlation ECE diagnostic in Alcator C-Mod

Correlation ECE (CECE) is a diagnostic technique that allows measurement of small amplitude electron temperature, T[subscript e], fluctuations through standard cross-correlation analysis methods. In Alcator C-Mod, a new CECE diagnostic has been installed[Sung RSI 2012], and interesting phenomena have been observed in various plasma conditions. We find that local T[subscript e] fluctuations near the edge (ρ ~ 0:8) decrease across the linearto- saturated ohmic confinement transition, with fluctuations decreasing with increasing plasma density[Sung NF 2013], which occurs simultaneously with rotation reversals[Rice NF 2011]. T[subscript e] fluctuations are also reduced across core rotation reversals with an increase of plasma density in RF heated L-mode plasmas, which implies that the same physics related to the reduction of T[subscript e] fluctuations may be applied to both ohmic and RF heated L-mode plasmas. In I-mode plasmas, we observe the reduction of core T[subscript e] fluctuations, which indicates changes of turbulence occur not only in the pedestal region but also in the core across the L/I transition[White NF 2014]. The present CECE diagnostic system in C-Mod and these experimental results are described in this paper

Using sulfite chemistry for robust bioconversion of Douglas-fir forest residue to bioethanol at high titer and lignosulfonate: A pilot-scale evaluation

This study demonstrated at the pilot-scale (50 kg) use of Douglas-fir forest harvest residue, an underutilized forest biomass, for the production of high titer and high yield bioethanol using sulfite chemistry without solid–liquor separation and detoxification. Sulfite Pretreatment to Overcome the Recalcitrance of Lignocelluloses (SPORL) was directly applied to the ground forest harvest residue with no further mechanical size reduction, at a low temperature of 145°C and calcium bisulfite or total SO₂ loadings of only 6.5 or 6.6 wt% on oven dry forest residue, respectively. The low temperature pretreatment facilitated high solids fermentation of the un-detoxified pretreated whole slurry. An ethanol yield of 282 L/tonne, equivalent to 70% theoretical, with a titer of 42 g/L was achieved. SPORL solubilized approximately 45% of the wood lignin as directly marketable lignosulfonate with properties equivalent to or better than a commercial lignosulfonate, important to improve the economics of biofuel production.Keywords: High titer biofuel, Lignosulfonate, Pretreatment, Forest residues, Sulfite pulpin

Research on the Premotor Symptoms of Parkinson’s Disease: Clinical and Etiological Implications

Background: The etiology and natural history of Parkinson’s disease (PD) are not well understood. Some non-motor symptoms such as hyposmia, rapid eye movement sleep behavior disorder, and constipation may develop during the prodromal stage of PD and precede PD diagnosis by years. Objectives: We examined the promise and pitfalls of research on premotor symptoms of PD and developed priorities and strategies to understand their clinical and etiological implications. Methods: This review was based on a workshop, Parkinson’s Disease Premotor Symptom Symposium, held 7–8 June 2012 at the National Institute of Environmental Health Sciences in Research Triangle Park, North Carolina. Discussion: Research on premotor symptoms of PD may offer an excellent opportunity to characterize high-risk populations and to better understand PD etiology. Such research may lead to evaluation of novel etiological hypotheses such as the possibility that environmental toxicants or viruses may initiate PD pathogenesis in the gastrointestinal tract or olfactory bulb. At present, our understanding of premotor symptoms of PD is in its infancy and faces many obstacles. These symptoms are often not specific to PD and have low positive predictive value for early PD diagnosis. Further, the pathological bases and biological mechanisms of these premotor symptoms and their relevance to PD pathogenesis are poorly understood. Conclusion: This is an emerging research area with important data gaps to be filled. Future research is needed to understand the prevalence of multiple premotor symptoms and their etiological relevance to PD. Animal experiments and mechanistic studies will further understanding of the biology of these premotor symptoms and test novel etiological hypothesis. Citation: Chen H, Burton EA, Ross GW, Huang X, Savica R, Abbott RD, Ascherio A, Caviness JN, Gao X, Gray KA, Hong JS, Kamel F, Jennings D, Kirshner A, Lawler C, Liu R, Miller GW, Nussbaum R, Peddada SD, Comstock Rick A, Ritz B, Siderowf AD, Tanner CM, Tröster AI, Zhang J. 2013. Research on the premotor symptoms of Parkinson’s Disease: clinical and etiological implications. Environ Health Perspect 121:1245–1252; http://dx.doi.org/10.1289/ehp.130696