78 research outputs found
Effect of C-2 substitution on the stability of non-traditional cephalosporins in mouse plasma
This work is licensed under a Creative Commons Attribution 4.0 International License.A systematic study of the stability of a set of cephalosporins in mouse plasma reveals that cephalosporins lacking an acidic moiety at C-2 may be vulnerable to β-lactam cleavage in mouse plasma
DeAL: Decoding-time Alignment for Large Language Models
Large Language Models (LLMs) are nowadays expected to generate content
aligned with human preferences. Current work focuses on alignment at model
training time, through techniques such as Reinforcement Learning with Human
Feedback (RLHF). However, it is unclear if such methods are an effective choice
to teach alignment objectives to the model. First, the inability to incorporate
multiple, custom rewards and reliance on a model developer's view of universal
and static principles are key limitations. Second, the residual gaps in model
training and the reliability of such approaches are also questionable (e.g.
susceptibility to jail-breaking even after safety training). To address these,
we propose DeAL, a framework that allows the user to customize reward functions
and enables Decoding-time Alignment of LLMs (DeAL). At its core, we view
decoding as a heuristic-guided search process and facilitate the use of a wide
variety of alignment objectives. Our experiments with programmatic constraints
such as keyword and length constraints (studied widely in the pre-LLM era) and
abstract objectives such as harmlessness and helpfulness (proposed in the
post-LLM era) show that we can DeAL with fine-grained trade-offs, improve
adherence to alignment objectives, and address residual gaps in LLMs. Lastly,
while DeAL can be effectively paired with RLHF and prompting techniques, its
generality makes decoding slower, an optimization we leave for future work.Comment: The appendix contains data that is offensive / disturbing in natur
Ligand Binding Study of Human PEBP1/RKIP: Interaction with Nucleotides and Raf-1 Peptides Evidenced by NMR and Mass Spectrometry
Background
Human Phosphatidylethanolamine binding protein 1 (hPEBP1) also known as Raf kinase inhibitory protein (RKIP), affects various cellular processes, and is implicated in metastasis formation and Alzheimer's disease. Human PEBP1 has also been shown to inhibit the Raf/MEK/ERK pathway. Numerous reports concern various mammalian PEBP1 binding ligands. However, since PEBP1 proteins from many different species were investigated, drawing general conclusions regarding human PEBP1 binding properties is rather difficult. Moreover, the binding site of Raf-1 on hPEBP1 is still unknown.
Methods/Findings
In the present study, we investigated human PEBP1 by NMR to determine the binding site of four different ligands: GTP, FMN, and one Raf-1 peptide in tri-phosphorylated and non-phosphorylated forms. The study was carried out by NMR in near physiological conditions, allowing for the identification of the binding site and the determination of the affinity constants KD for different ligands. Native mass spectrometry was used as an alternative method for measuring KD values.
Conclusions/Significance
Our study demonstrates and/or confirms the binding of hPEBP1 to the four studied ligands. All of them bind to the same region centered on the conserved ligand-binding pocket of hPEBP1. Although the affinities for GTP and FMN decrease as pH, salt concentration and temperature increase from pH 6.5/NaCl 0 mM/20°C to pH 7.5/NaCl 100 mM/30°C, both ligands clearly do bind under conditions similar to what is found in cells regarding pH, salt concentration and temperature. In addition, our work confirms that residues in the vicinity of the pocket rather than those within the pocket seem to be required for interaction with Raf-1.METASU
Dark sectors 2016 Workshop: community report
This report, based on the Dark Sectors workshop at SLAC in April 2016,
summarizes the scientific importance of searches for dark sector dark matter
and forces at masses beneath the weak-scale, the status of this broad
international field, the important milestones motivating future exploration,
and promising experimental opportunities to reach these milestones over the
next 5-10 years
First measurement of the nuclear-recoil ionization yield in silicon at 100 eV
We measured the nuclear--recoil ionization yield in silicon with a cryogenic
phonon-sensitive gram-scale detector. Neutrons from a mono-energetic beam
scatter off of the silicon nuclei at angles corresponding to energy depositions
from 4\,keV down to 100\,eV, the lowest energy probed so far. The results show
no sign of an ionization production threshold above 100\,eV. These results call
for further investigation of the ionization yield theory and a comprehensive
determination of the detector response function at energies below the keV
scale
Brain energy rescue:an emerging therapeutic concept for neurodegenerative disorders of ageing
The brain requires a continuous supply of energy in the form of ATP, most of which is produced from glucose by oxidative phosphorylation in mitochondria, complemented by aerobic glycolysis in the cytoplasm. When glucose levels are limited, ketone bodies generated in the liver and lactate derived from exercising skeletal muscle can also become important energy substrates for the brain. In neurodegenerative disorders of ageing, brain glucose metabolism deteriorates in a progressive, region-specific and disease-specific manner — a problem that is best characterized in Alzheimer disease, where it begins presymptomatically. This Review discusses the status and prospects of therapeutic strategies for countering neurodegenerative disorders of ageing by improving, preserving or rescuing brain energetics. The approaches described include restoring oxidative phosphorylation and glycolysis, increasing insulin sensitivity, correcting mitochondrial dysfunction, ketone-based interventions, acting via hormones that modulate cerebral energetics, RNA therapeutics and complementary multimodal lifestyle changes
Molecular basis of USP7 inhibition by selective small-molecule inhibitors
Ubiquitination controls the stability of most cellular proteins, and its deregulation contributes to human diseases including cancer. Deubiquitinases remove ubiquitin from proteins, and their inhibition can induce the degradation of selected proteins, potentially including otherwise 'undruggable' targets. For example, the inhibition of ubiquitin-specific protease 7 (USP7) results in the degradation of the oncogenic E3 ligase MDM2, and leads to re-activation of the tumour suppressor p53 in various cancers. Here we report that two compounds, FT671 and FT827, inhibit USP7 with high affinity and specificity in vitro and within human cells. Co-crystal structures reveal that both compounds target a dynamic pocket near the catalytic centre of the auto-inhibited apo form of USP7, which differs from other USP deubiquitinases. Consistent with USP7 target engagement in cells, FT671 destabilizes USP7 substrates including MDM2, increases levels of p53, and results in the transcription of p53 target genes, induction of the tumour suppressor p21, and inhibition of tumour growth in mice
Spotlight on grazoprevir—elbasvir once-daily combination and its potential in the treatment of hepatitis C
Duminda Suraweera,1 Ashley N Weeratunga,2 Sammy Saab3 1Department of Medicine, Olive-View Medical Center, Sylmar, CA, 2Department of Medicine, Creighton University School of Medicine, Omaha, NE, 3Department of Medicine, University of California at Los Angeles, Los Angeles, CA, USA Abstract: Chronic hepatitis C virus (HCV) infection is a leading cause of health care utilization in the USA. Incidence of cirrhosis from HCV is expected to rise in the near future, further increasing this burden. There is a high medical need for effective, tolerable, safe, all-oral, short-duration therapy. To this end, several new direct-acting antiviral agents have been developed and have shown excellent sustained virologic response rates. However, patients who have previously failed treatment or who have developed cirrhosis, renal failure, or human immunodeficiency virus coinfection remain difficult-to-treat subgroups. An all-oral agent that is effective in many of these subgroups would simplify treatment of HCV greatly. Here we review currently available data on the efficacy, treatment duration, tolerability, and safety of combination of grazoprevir and elbasvir. Keywords: hepatitis C, antiviral therapy, grazoprevir, elbasvi
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