Hit-to-Lead Optimization of Heterocyclic Carbonyloxycarboximidamides as Selective Antagonists at Human Adenosine A3 Receptor.

Antagonism of the human adenosine A receptor (hAR) has potential therapeutic application. Alchemical relative binding free energy calculations of and suggested that the combination of a 3-(2,6-dichlorophenyl)-isoxazolyl group with 2-pyridinyl at the ends of a carbonyloxycarboximidamide group should improve hAR affinity. Of the 25 new analogues synthesized, and showed improved hAR affinity compared to (and ).

Molecular epidemiology and genetic diversity of norovirus among hospitalized patients with acute gastroenteritis in Shandong, China, 2016-2018.

Norovirus (NoV) infection is a leading cause of acute gastroenteritis (AGE) for people of all ages. Here, we reported the molecular epidemiology and genetic diversity of NoVs among hospitalized patients with AGE between 2016 and 2018 in Shandong Province, China. Two thousand sixty-nine AGE patients from sentinel hospitals were enrolled.

Differential effects of climatic and non-climatic factors on the distribution of vegetation phenology trends on the Tibetan plateau.

The study of vegetation phenology changes is important because it is a sensitive indicator of climate change, affecting the exchange of carbon, energy and water fluxes between the land and the atmosphere. Previous studies have focused on the effects of climatic factors among environmental factors on vegetation phenology, thus the effects of non-climatic factors among environmental factors have not been well quantified. This study endeavors to scrutinize the spatiotemporal inconsistency in the start-of-season (SOS) and the end-of-season (EOS) on the Tibetan Plateau (TP) and to quantify the effects of environmental factors on phenology.

Graph MADDPG with RNN for multiagent cooperative environment.

Multiagent systems face numerous challenges due to environmental uncertainty, with scalability being a critical issue. To address this, we propose a novel multi-agent cooperative model based on a graph attention network. Our approach considers the relationship between agents and continuous action spaces, utilizing graph convolution and recurrent neural networks to define these relationships.

Discovery and Structure-Activity Relationship Studies of Novel Adenosine A Receptor-Selective Agonists.

A series of benzyloxy and phenoxy derivatives of the adenosine receptor agonists -cyclopentyl adenosine (CPA) and -cyclopentyl 5'--ethylcarboxamidoadenosine (CP-NECA) were synthesized, and their potency and selectivity were assessed. We observed that the most potent were the compounds with a halogen in the position on the aromatic ring of the benzyloxy- or phenoxycyclopentyl substituent. In general, the NECA-based compounds displayed greater AR selectivity than the adenosine-based compounds, with -2-(3-bromobenzyloxy)cyclopentyl-NECA and -2-(3-methoxyphenoxy)cyclopentyl-NECA showing ∼1500-fold improved AR selectivity compared to NECA.

Selective activation of Gαob by an adenosine A receptor agonist elicits analgesia without cardiorespiratory depression.

The development of therapeutic agonists for G protein-coupled receptors (GPCRs) is hampered by the propensity of GPCRs to couple to multiple intracellular signalling pathways. This promiscuous coupling leads to numerous downstream cellular effects, some of which are therapeutically undesirable. This is especially the case for adenosine A receptors (ARs) whose clinical potential is undermined by the sedation and cardiorespiratory depression caused by conventional agonists.

Phase separation of OCT4 controls TAD reorganization to promote cell fate transitions.

Topological-associated domains (TADs) are thought to be relatively stable across cell types, although some TAD reorganization has been observed during cellular differentiation. However, little is known about the mechanisms through which TAD reorganization affects cell fate or how master transcription factors affect TAD structures during cell fate transitions. Here, we show extensive TAD reorganization during somatic cell reprogramming, which is correlated with gene transcription and changes in cellular identity.

Hippo-YAP signaling controls lineage differentiation of mouse embryonic stem cells through modulating the formation of super-enhancers.

Hippo-YAP signaling pathway functions in early lineage differentiation of pluripotent stem cells, but the detailed mechanisms remain elusive. We found that knockout (KO) of Mst1 and Mst2, two key components of the Hippo signaling in mouse embryonic stem cells (ESCs), resulted in a disruption of differentiation into mesendoderm lineage. To further uncover the underlying regulatory mechanisms, we performed a series of ChIP-seq experiments with antibodies against YAP, ESC master transcription factors and some characterized histone modification markers as well as RNA-seq assays using wild type and Mst KO samples at ES and day 4 embryoid body stage respectively.

Removal of organic herbicides from aqueous solution by ionic liquid modified chitosan/metal-organic framework composite.

The novel ILCS/U-X powder materials were fabricated by depositing UiO-66 on ionic liquid modified chitosan, and different doping ratio materials were used to adsorb 2,4-dichlorophenoxyacetic acid in aqueous solution. The samples were characterized by X-ray powder diffraction, Fourier transform infra-red, X-ray photoelectron spectroscopy, Scanning electron microscopy, Brunauer-Emmett-Teller, Barrette-Joyner-Halenda, Thermal gravimetric analyzer, Energy dispersive spectrometer and Zeta potential. Adsorption experiments revealed that temperature and pH have a great influence on adsorption, and all adsorbents have the highest adsorption at low temperature and weak acid.

Dynamic Changes of NDVI in the Growing Season of the Tibetan Plateau During the Past 17 Years and Its Response to Climate Change.

The fragile alpine vegetation in the Tibetan Plateau (TP) is very sensitive to environmental changes, making TP one of the hotspots for studying the response of vegetation to climate change. Existing studies lack detailed description of the response of vegetation to different climatic factors using the method of multiple nested time series analysis and the method of grey correlation analysis. In this paper, based on the Normalized Difference Vegetation Index (NDVI) of TP in the growing season calculated from the MOD09A1 data product of Moderate-resolution Imaging Spectroradiometer (MODIS), the method of multiple nested time series analysis is adopted to study the variation trends of NDVI in recent 17 years, and the lag time of NDVI to climate change is analyzed using the method of Grey Relational Analysis (GRA).