TopMT-GAN: a 3D topology-driven generative model for efficient and diverse structure-based ligand design.

Recent advancements in 3D structure-based molecular generative models have shown promise in expediting the hit discovery process in drug design. Despite their potential, efficiently generating a focused library of candidate molecules that exhibit both effective interactions and structural diversity at a large scale remains a significant challenge. Moreover, current studies often lack comprehensive comparisons to high-throughput virtual screening methods, resulting in insufficient evaluation of their effectiveness.

Catalytic resonance theory: the catalytic mechanics of programmable ratchets.

Catalytic reaction networks of multiple elementary steps operating under dynamic conditions a programmed input oscillation are difficult to interpret and optimize due to reaction system complexity. To understand these dynamic systems, individual elementary catalytic reactions oscillating between catalyst states were evaluated to identify their three fundamental characteristics that define their ability to promote reactions away from equilibrium. First, elementary catalytic reactions exhibit directionality to promote reactions forward or backward from equilibrium as determined by a ratchet directionality metric comprised of the input oscillation duty cycle and the reaction rate constants.

Electronic isomerism in a heterometallic nickel-iron-sulfur cluster models substrate binding and cyanide inhibition of carbon monoxide dehydrogenase.

The nickel-iron carbon monoxide dehydrogenase (CODH) enzyme uses a heterometallic nickel-iron-sulfur ([NiFeS]) cluster to catalyze the reversible interconversion of carbon dioxide (CO) and carbon monoxide (CO). These reactions are essential for maintaining the global carbon cycle and offer a route towards sustainable greenhouse gas conversion but have not been successfully replicated in synthetic models, in part due to a poor understanding of the natural system. Though the general protein architecture of CODH is known, the electronic structure of the active site is not well-understood, and the mechanism of catalysis remains unresolved.

Recent advances in electrolyte molecular design for alkali metal batteries.

In response to societal developments and the growing demand for high-energy-density battery systems, alkali metal batteries (AMBs) have emerged as promising candidates for next-generation energy storage. Despite their high theoretical specific capacity and output voltage, AMBs face critical challenges related to high reactivity with electrolytes and unstable interphases. This review, from the perspective of electrolytes, analyzes AMB failure mechanisms, including interfacial side reactions, active materials loss, and metal dendrite growth.

Assessing Trustworthy AI in Times of COVID-19: Deep Learning for Predicting a Multiregional Score Conveying the Degree of Lung Compromise in COVID-19 Patients.

This article's main contributions are twofold: 1) to demonstrate how to apply the general European Union's High-Level Expert Group's (EU HLEG) guidelines for trustworthy AI in practice for the domain of healthcare and 2) to investigate the research question of what does "trustworthy AI" mean at the time of the COVID-19 pandemic. To this end, we present the results of a post-hoc self-assessment to evaluate the trustworthiness of an AI system for predicting a multiregional score conveying the degree of lung compromise in COVID-19 patients, developed and verified by an interdisciplinary team with members from academia, public hospitals, and industry in time of pandemic. The AI system aims to help radiologists to estimate and communicate the severity of damage in a patient's lung from Chest X-rays.

Protein quaternary structures in solution are a mixture of multiple forms.

Over half the proteins in the cytoplasm form homo or hetero-oligomeric structures. Experimentally determined structures are often considered in determining a protein's oligomeric state, but static structures miss the dynamic equilibrium between different quaternary forms. The problem is exacerbated in homo-oligomers, where the oligomeric states are challenging to characterize.

Synthesis of a fluorinated pyronin that enables blue light to rapidly depolarize mitochondria.

Fluorinated analogues of the fluorophore pyronin B were synthesized as a new class of amine-reactive drug-like small molecules. In water, 2,7-difluoropyronin B was found to reversibly react with primary amines to form covalent adducts. When this fluorinated analogue is added to proteins, these adducts undergo additional oxidation to yield fluorescent 9-aminopyronins.

Trifluoromethyl substitution enhances photoinduced activity against breast cancer cells but reduces ligand exchange in Ru(ii) complex.

A series of five ruthenium complexes containing triphenyl phosphine groups known to enhance both cellular penetration and photoinduced ligand exchange, -[Ru(bpy)(P(-R-Ph))(CHCN)], where bpy = 2,2'-bipyridine and P(-R-Ph) represent -substituted triphenylphosphine ligands with R = -OCH (), -CH () -H (), -F (), and -CF (), were synthesized and characterized. The photolysis of in water with visible light ( ≥ 395 nm) results in the substitution of the coordinated acetonitrile with a solvent molecule, generating the corresponding aqua complex as the single photoproduct. A 3-fold variation in quantum yield was measured with 400 nm irradiation, , where is the most efficient with a = 0.

Murine cancer cachexia models replicate elevated catabolic pembrolizumab clearance in humans.

Background: Monoclonal antibody (mAb) immune checkpoint inhibitor (ICI) therapies have dramatically impacted oncology this past decade. However, only about one-third of patients respond to treatment, and biomarkers to predict responders are lacking. Recent ICI clinical pharmacology data demonstrate high baseline drug clearance (CL) significantly associates with shorter overall survival, independent of ICI exposure, in patients receiving ICI mAb therapies.

A traceless linker for aliphatic amines that rapidly and quantitatively fragments after reduction.

Reduction sensitive linkers (RSLs) have the potential to transform the field of drug delivery due to their ease of use and selective cleavage in intracellular environments. However, despite their compelling attributes, developing reduction sensitive self-immolative linkers for aliphatic amines has been challenging due to their poor leaving group ability and high p values. Here a traceless self-immolative linker composed of a dithiol-ethyl carbonate connected to a benzyl carbamate (DEC) is presented, which can modify aliphatic amines and release them rapidly and quantitatively after disulfide reduction.

Dynamics and mechanism of light harvesting in UV photoreceptor UVR8.

Photosynthetic pigments form light-harvesting networks to enable nearly perfect quantum efficiency in photosynthesis excitation energy transfer. However, similar light-harvesting mechanisms have not been reported in light sensing processes in other classes of photoreceptors during light-mediated signaling. Here, based on our earlier report, we mapped out a striking energy-transfer network composed of 26 structural tryptophan residues in the plant UV-B photoreceptor UVR8.

An integrated electrocatalytic nESI-MS platform for quantification of fatty acid isomers directly from untreated biofluids.

Positional isomers of alkenes are frequently transparent to the mass spectrometer and it is difficult to provide convincing data to support their presence. This work focuses on the development of a new reactive nano-electrospray ionization (nESI) platform that utilizes non-inert metal electrodes (, Ir and Ru) for rapid detection of fatty acids by mass spectrometry (MS), with concomitant localization of the C[double bond, length as m-dash]C bond to differentiate fatty acid isomers. During the electrospray process, the electrical energy (direct current voltage) is harnessed for oxide formation on the electrode surface electro-oxidation.

Panchromatic dirhodium photocatalysts for dihydrogen generation with red light.

A series of three dirhodium complexes -[Rh(DPhB)(bncn)](BF) (, DPhB = diphenylbenzamidine; bncn = benzocinnoline), -[Rh(DPhTA)(bncn)](BF) (, DPhTA = diphenyltriazenide), and -[Rh(DPhF)(bncn)](BF) (, DPhF = ,'-diphenylformamidinate) shown to act as single-molecule photocatalysts for H production was evaluated. Complexes are able to generate H in the absence of any other catalyst in homogenous acidic solution upon irradiation with red light in the presence of the sacrificial electron donor BNAH (1-benzyl-1,4-dihydronicotinamide). The excited state of each complex is reductively quenched by BNAH, producing the corresponding one-electron reduced complex.

Foundations for Soft, Smart Matter by Active Mechanical Metamaterials.

Emerging interest to synthesize active, engineered matter suggests a future where smart material systems and structures operate autonomously around people, serving diverse roles in engineering, medical, and scientific applications. Similar to biological organisms, a realization of active, engineered matter necessitates functionality culminating from a combination of sensory and control mechanisms in a versatile material frame. Recently, metamaterial platforms with integrated sensing and control have been exploited, so that outstanding non-natural material behaviors are empowered by synergistic microstructures and controlled by smart materials and systems.

Bioinspired One Cell Culture Isolates Highly Tumorigenic and Metastatic Cancer Stem Cells Capable of Multilineage Differentiation.

Cancer stem cells (CSCs) are rare cancer cells that are postulated to be responsible for cancer relapse and metastasis. However, CSCs are difficult to isolate and poorly understood. Here, a bioinspired approach for label-free isolation and culture of CSCs, by microencapsulating one cancer cell in the nanoliter-scale hydrogel core of each prehatching embryo-like core-shell microcapsule, is reported.

Single Functionalized pRNA/Gold Nanoparticle for Ultrasensitive MicroRNA Detection Using Electrochemical Surface-Enhanced Raman Spectroscopy.

Controlling the selective one-to-one conjugation of RNA with nanoparticles is vital for future applications of RNA nanotechnology. Here, the monofunctionalization of a gold nanoparticle (AuNP) with a single copy of RNA is developed for ultrasensitive microRNA-155 quantification using electrochemical surface-enhanced Raman spectroscopy (EC-SERS). A single AuNP is conjugated with one copy of the packaging RNA (pRNA) three-way junction (RNA 3WJ).

Radical cascade synthesis of azoles tandem hydrogen atom transfer.

A radical cascade strategy for the modular synthesis of five-membered heteroarenes ( oxazoles, imidazoles) from feedstock reagents ( alcohols, amines, nitriles) has been developed. This double C-H oxidation is enabled by generated imidate and acyloxy radicals, which afford regio- and chemo-selective β C-H bis-functionalization. The broad synthetic utility of this tandem hydrogen atom transfer (HAT) approach to access azoles is included, along with experiments and computations that provide insight into the selectivity and mechanism of both HAT events.

Target identification among known drugs by deep learning from heterogeneous networks.

Without foreknowledge of the complete drug target information, development of promising and affordable approaches for effective treatment of human diseases is challenging. Here, we develop deepDTnet, a deep learning methodology for new target identification and drug repurposing in a heterogeneous drug-gene-disease network embedding 15 types of chemical, genomic, phenotypic, and cellular network profiles. Trained on 732 U.

RNA Nanotechnology to Solubilize Hydrophobic Antitumor Drug for Targeted Delivery.

Small-molecule drugs are used extensively in clinics for cancer treatment; however, many antitumor chemical drugs dissolve poorly in aqueous solution. Their poor solubility and nonselective delivery in vivo often cause severe side effects. Here, the application of RNA nanotechnology to enhance the solubility of hydrophobic drugs, using camptothecin (CPT) for proof-of-concept in targeted delivery for cancer treatment is reported.

Manipulating acoustic and plasmonic modes in gold nanostars.

In this contribution experimental evidence of plasmonic edge modes and acoustic breathing modes in gold nanostars (AuNSs) is reported. AuNSs are synthesized by a surfactant-free, one-step wet-chemistry method. Optical extinction measurements of AuNSs confirm the presence of localized surface plasmon resonances (LSPRs), while electron energy-loss spectroscopy (EELS) using a scanning transmission electron microscope (STEM) shows the spatial distribution of LSPRs and reveals the presence of acoustic breathing modes.

Gas-Shearing Fabrication of Multicompartmental Microspheres: A One-Step and Oil-Free Approach.

Multicompartmental microparticles (MCMs) have attracted considerable attention in biomedical engineering and materials sciences, as they can carry multiple materials in the separated phases of a single particle. However, the robust fabrication of monodisperse, highly compartmental MCMs at the micro- and nanoscales remains challenging. Here, a simple one-step and oil-free process, based on the gas-flow-assisted formation of microdroplets ("gas-shearing"), is established for the scalable production of monodisperse MCMs.

The Relative Influences of Government Funding and International Collaboration on Citation Impact.

A recent publication in reports that public R&D funding is only weakly correlated with the citation impact of a nation's articles as measured by the field-weighted citation index (FWCI; defined by Scopus). On the basis of the supplementary data, we up-scaled the design using Web of Science data for the decade 2003-2013 and OECD funding data for the corresponding decade assuming a 2-year delay (2001-2011). Using negative binomial regression analysis, we found very small coefficients, but the effects of international collaboration are positive and statistically significant, whereas the effects of government funding are negative, an order of magnitude smaller, and statistically nonsignificant (in two of three analyses).

Fired Bricks: CO Emission and Food Insecurity.

Fired bricks are used for construction purposes over the millennia, going back to the Indus Valley Civilization. The traditional brick-making process involves removal of agriculturally productive topsoil rich in clay and soil organic matter contents. In addition to the removal of the fertile topsoil and accelerated degradation by other processes, the traditional clay brick making process also emits CO and other gases into the atmosphere.

CO-C evolution rate in an incubation study with straw input to soil managed by different tillage systems.

A laboratory incubation experiment was conducted to assess the impact of straw input on CO-C emissions. After the winter wheat ( L.) growing season, soil samples were collected from the 0-20 cm soil layer.