Methyl 2-{[(3-methyl-5-oxo-1-phenyl-4,5-dihydro-1H-pyrazol-4-yl­idene)(thio­phen-2-yl)meth­yl]amino}-3-phenyl­propionate

In the title compound, C25H23N3O3S, an intra­molecular N—H⋯O inter­action generates an S(6) ring, which stabilizes the enamine–keto form of the compound. This S(6) ring and the pyrazole ring are essentially coplanar, making a dihedral angle of 1.49 (6)°. The bond lengths within the S(6) ring of the mol­ecule lie between classical single- and double-bond lengths, indicating extensive conjugation. The structure exhibits a thienyl-ring flip disorder, with occupancy factors in the ratio 64.7 (3):35.3 (3)

LATE ORDOVICIAN BRACHIOPOD RONGATRYPA XICHUANENSIS FROM XICHUAN, HENAN PROVINCE, CENTRAL CHINA

The atrypide brachiopod Rongatrypa Popov & Cocks, 2014 is one of the early members of the subfamily Clintonellinae. This genus was previously known only from the Kazakh terranes. Here, we reassign a species to the genus, Rongatrypa xichuanensis (Xu, 1996), from the Shiyanhe Formation (Katian, Upper Ordovician) of Xichuan, Henan Province, central China. A wide range of shell sizes was found and measured to investigate the ontogeny of the species, and several specimens were selected for serial sectioning to examine the internal morphology. The linear regression results of natural logarithms of length vs. width and depth vs. width revealed an allometric growth pattern, perhaps influenced by the development of the lophophore. Rongatrypa xichuanensis inhabited a shallow marine oxygenated environment in the South China palaeoplate near the palaeo-equator. The distribution of Rongatrypa across South China and Kazakh terranes reflects the proximity of these blocks in the Late Ordovician

Structures of human gastrin-releasing peptide receptors bound to antagonist and agonist for cancer and itch therapy

Gastrin releasing peptide receptor (GRPR), a member of the bombesin (BBN) G protein-coupled receptors, is aberrantly overexpressed in several malignant tumors, including those of the breast, prostate, pancreas, lung, and central nervous system. Additionally, it also mediates non-histaminergic itch and pathological itch conditions in mice. Thus, GRPR could be an attractive target for cancer and itch therapy. Here, we report the inactive state crystal structure of human GRPR in complex with the non-peptide antagonist PD176252, as well as two active state cryo-electron microscopy (cryo-EM) structures of GRPR bound to the endogenous peptide agonist gastrin-releasing peptide and the synthetic BBN analog [D-Ph

Local Differentially Private Heavy Hitter Detection in Data Streams with Bounded Memory

Top-$k$ frequent items detection is a fundamental task in data stream mining. Many promising solutions are proposed to improve memory efficiency while still maintaining high accuracy for detecting the Top-$k$ items. Despite the memory efficiency concern, the users could suffer from privacy loss if participating in the task without proper protection, since their contributed local data streams may continually leak sensitive individual information. However, most existing works solely focus on addressing either the memory-efficiency problem or the privacy concerns but seldom jointly, which cannot achieve a satisfactory tradeoff between memory efficiency, privacy protection, and detection accuracy. In this paper, we present a novel framework HG-LDP to achieve accurate Top-$k$ item detection at bounded memory expense, while providing rigorous local differential privacy (LDP) protection. Specifically, we identify two key challenges naturally arising in the task, which reveal that directly applying existing LDP techniques will lead to an inferior ``accuracy-privacy-memory efficiency'' tradeoff. Therefore, we instantiate three advanced schemes under the framework by designing novel LDP randomization methods, which address the hurdles caused by the large size of the item domain and by the limited space of the memory. We conduct comprehensive experiments on both synthetic and real-world datasets to show that the proposed advanced schemes achieve a superior ``accuracy-privacy-memory efficiency'' tradeoff, saving $2300\times$ memory over baseline methods when the item domain size is $41,270$. Our code is open-sourced via the link

Regulatory network of GSK3-like kinases and their role in plant stress response

Glycogen synthase kinase 3 (GSK3) family members are evolutionally conserved Ser/Thr protein kinases in mammals and plants. In plants, the GSK3s function as signaling hubs to integrate the perception and transduction of diverse signals required for plant development. Despite their role in the regulation of plant growth and development, emerging research has shed light on their multilayer function in plant stress responses. Here we review recent advances in the regulatory network of GSK3s and the involvement of GSK3s in plant adaptation to various abiotic and biotic stresses. We also discuss the molecular mechanisms underlying how plants cope with environmental stresses through GSK3s-hormones crosstalk, a pivotal biochemical pathway in plant stress responses. We believe that our overview of the versatile physiological functions of GSK3s and underlined molecular mechanism of GSK3s in plant stress response will not only opens further research on this important topic but also provide opportunities for developing stress-resilient crops through the use of genetic engineering technology

Discovery of active proteins directly from combinatorial randomized protein libraries without display, purification or sequencing:identification of novel zinc finger proteins.

We have successfully linked protein library screening directly with the identification of active proteins, without the need for individual purification, display technologies or physical linkage between the protein and its encoding sequence. By using 'MAX' randomization we have rapidly constructed 60 overlapping gene libraries that encode zinc finger proteins, randomized variously at the three principal DNA-contacting residues. Expression and screening of the libraries against five possible target DNA sequences generated data points covering a potential 40,000 individual interactions. Comparative analysis of the resulting data enabled direct identification of active proteins. Accuracy of this library analysis methodology was confirmed by both in vitro and in vivo analyses of identified proteins to yield novel zinc finger proteins that bind to their target sequences with high affinity, as indicated by low nanomolar apparent dissociation constants

Fluorescent microplate-based analysis of protein-DNA interactions II:immobilized DNA

A simple protein-DNA interaction analysis has been developed using both a high-affinity/high-specificity zinc finger protein and a low-specificity zinc finger protein with nonspecific DNA binding capability. The latter protein is designed to mimic background binding by proteins generated in randomized or shuffled gene libraries. In essence, DNA is immobilized onto the surface of microplate wells via streptavidin capture, and green fluorescent protein (GFP)-labeled protein is added in solution as part of a crude cell lysate or protein mixture. After incubation and washing, bound protein is detected in a standard microplate reader. The minimum sensitivity of the assay is approximately 0.4 nM protein. The assay format is ideally suited to investigate the interactions of DNA binding proteins from within crude cell extracts and/or mixtures of proteins that may be encountered in protein libraries generated by codon randomization or gene shuffling