179 research outputs found
The Synthesizability of Molecules Proposed by Generative Models
The discovery of functional molecules is an expensive and time-consuming
process, exemplified by the rising costs of small molecule therapeutic
discovery. One class of techniques of growing interest for early-stage drug
discovery is de novo molecular generation and optimization, catalyzed by the
development of new deep learning approaches. These techniques can suggest novel
molecular structures intended to maximize a multi-objective function, e.g.,
suitability as a therapeutic against a particular target, without relying on
brute-force exploration of a chemical space. However, the utility of these
approaches is stymied by ignorance of synthesizability. To highlight the
severity of this issue, we use a data-driven computer-aided synthesis planning
program to quantify how often molecules proposed by state-of-the-art generative
models cannot be readily synthesized. Our analysis demonstrates that there are
several tasks for which these models generate unrealistic molecular structures
despite performing well on popular quantitative benchmarks. Synthetic
complexity heuristics can successfully bias generation toward
synthetically-tractable chemical space, although doing so necessarily detracts
from the primary objective. This analysis suggests that to improve the utility
of these models in real discovery workflows, new algorithm development is
warranted
Sample Efficiency Matters: A Benchmark for Practical Molecular Optimization
Molecular optimization is a fundamental goal in the chemical sciences and is
of central interest to drug and material design. In recent years, significant
progress has been made in solving challenging problems across various aspects
of computational molecular optimizations, emphasizing high validity, diversity,
and, most recently, synthesizability. Despite this progress, many papers report
results on trivial or self-designed tasks, bringing additional challenges to
directly assessing the performance of new methods. Moreover, the sample
efficiency of the optimization--the number of molecules evaluated by the
oracle--is rarely discussed, despite being an essential consideration for
realistic discovery applications.
To fill this gap, we have created an open-source benchmark for practical
molecular optimization, PMO, to facilitate the transparent and reproducible
evaluation of algorithmic advances in molecular optimization. This paper
thoroughly investigates the performance of 25 molecular design algorithms on 23
tasks with a particular focus on sample efficiency. Our results show that most
"state-of-the-art" methods fail to outperform their predecessors under a
limited oracle budget allowing 10K queries and that no existing algorithm can
efficiently solve certain molecular optimization problems in this setting. We
analyze the influence of the optimization algorithm choices, molecular assembly
strategies, and oracle landscapes on the optimization performance to inform
future algorithm development and benchmarking. PMO provides a standardized
experimental setup to comprehensively evaluate and compare new molecule
optimization methods with existing ones. All code can be found at
https://github.com/wenhao-gao/mol_opt
Regional variation in characteristics of patients with decompensated cirrhosis admitted to hospitals in the UK
[no abstract
Upregulation of Phosphodiesterase type 5 in the Hyperplastic Prostate
Both erectile dysfunction (ED) and lower urinary tract symptoms (LUTS)/benign prostatic hyperplasia (BPH) are common in the aging male. Numerous clinical trials have demonstrated the efficacy and safety of phosphodiesterase type 5 inhibitors (PDE5-Is) for treating LUTS/BPH with/without ED. However, the influence of BPH on prostatic PDE5 expression has never been studied. A testosterone-induced rat model of BPH was developed and human hyperplastic prostate specimens were harvested during cystoprostatectomy. PDE5, nNOS, eNOS and α1-adrenoreceptor subtypes (α1aARs, α1bARs and α1dARs) were determined with real-time RT-PCR for rat tissues whilst PDE5 and α1-adrenoreceptor subtypes were determined in human samples. PDE5 was further analyzed with Western-blot and histological examination. Serum testosterone was measured with ELISA. The rat BPH model was validated as having a significantly enlarged prostate. PDE5 localized mainly in fibromuscular stroma in prostate. Our data showed a significant and previously undocumented upregulation of PDE5 in both rat and human BPH, along with increased expression of nNOS and α1d ARs for rat tissues and α1a ARs for human BPH. The upregulation of PDE5 in the hyperplastic prostate could explain the mechanism and contribute to the high effectiveness of PDE5-Is for treating LUTS/BPH. Fibromuscular stroma could be the main target for PDE5-Is within prostate
InstructBio: A Large-scale Semi-supervised Learning Paradigm for Biochemical Problems
In the field of artificial intelligence for science, it is consistently an
essential challenge to face a limited amount of labeled data for real-world
problems. The prevailing approach is to pretrain a powerful task-agnostic model
on a large unlabeled corpus but may struggle to transfer knowledge to
downstream tasks. In this study, we propose InstructMol, a semi-supervised
learning algorithm, to take better advantage of unlabeled examples. It
introduces an instructor model to provide the confidence ratios as the
measurement of pseudo-labels' reliability. These confidence scores then guide
the target model to pay distinct attention to different data points, avoiding
the over-reliance on labeled data and the negative influence of incorrect
pseudo-annotations. Comprehensive experiments show that InstructBio
substantially improves the generalization ability of molecular models, in not
only molecular property predictions but also activity cliff estimations,
demonstrating the superiority of the proposed method. Furthermore, our evidence
indicates that InstructBio can be equipped with cutting-edge pretraining
methods and used to establish large-scale and task-specific pseudo-labeled
molecular datasets, which reduces the predictive errors and shortens the
training process. Our work provides strong evidence that semi-supervised
learning can be a promising tool to overcome the data scarcity limitation and
advance molecular representation learning
Spin glass behavior in URh_2Ge_2
URh_2Ge_2 occupies an extraordinary position among the heavy-electron
122-compounds, by exhibiting a previously unidentified form of magnetic
correlations at low temperatures, instead of the usual antiferromagnetism. Here
we present new results of ac and dc susceptibilities, specific heat and neutron
diffraction on single-crystalline as-grown URh_2Ge_2. These data clearly
indicate that crystallographic disorder on a local scale produces spin glass
behavior in the sample. We therefore conclude that URh_2Ge_2 is a 3D
Ising-like, random-bond, heavy-fermion spin glass.Comment: 10 pages, RevTeX, with 4 postscript figures, accepted by Physical
Review Letters Nov 15, 199
Tenfold Magnetoconductance in a Non-Magnetic Metal Film
We present magnetoconductance (MC) measurements of homogeneously disordered
Be films whose zero field sheet conductance (G) is described by the
Efros-Shklovskii hopping law . The low field
MC of the films is negative with G decreasing 200% below 1 T. In contrast the
MC above 1 T is strongly positive. At 8 T, G increases 1000% in perpendicular
field and 500% in parallel field. In the simpler parallel case, we observe {\em
field enhanced} variable range hopping characterized by an attenuation of
via the Zeeman interaction.Comment: 9 pages including 5 figure
Magnetic Exciton-Polariton with Strongly Coupled Atomic and Photonic Anisotropies
Anisotropy plays a key role in science and engineering. However, the
interplay between the material and engineered photonic anisotropies has hardly
been explored due to the vastly different length scales. Here we demonstrate a
matter-light hybrid system, exciton-polaritons in a 2D antiferromagnet, CrSBr,
coupled with an anisotropic photonic crystal (PC) cavity, where the spin,
atomic lattice, and photonic lattices anisotropies are strongly correlated,
giving rise to unusual properties of the hybrid system and new possibilities of
tuning. We show exceptionally strong coupling between engineered anisotropic
optical modes and anisotropic excitons in CrSBr, which is stable against
excitation densities a few orders of magnitude higher than polaritons in
isotropic materials. Moreover, the polaritons feature a highly anisotropic
polarization tunable by tens of degrees by controlling the matter-light
coupling via, for instance, spatial alignment between the material and photonic
lattices, magnetic field, temperature, cavity detuning and cavity
quality-factors. The demonstrated system provides a prototype where atomic- and
photonic-scale orders strongly couple, opening opportunities of photonic
engineering of quantum materials and novel photonic devices, such as compact,
on-chip polarized light source and polariton laser
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