Tandem Cyclization of -Hydroxyphenyl Propargyl Alcohols with Thionucleophiles: A Metal-Free and Modular Access to 3-Fluoroalkylsulfonyl/Thio Benzofurans.

Despite both fluoroalkylsulfonyl groups and benzofurans are important bioactive moieties, the construction of fluoroalkanesulfonylated benzofurans that incorporate these two fragments remains underdeveloped. Here, we report a tandem cyclization protocol to construct a wide range of 3-fluoroalkylsulfonyl benzofurans using readily accessible -hydroxyphenyl propargyl alcohols and sodium fluoroalkanesulfinates. Furthermore, this synthetic strategy can also be adapted to prepare 3-thio benzofurans by changing the S-nucleophiles to thiols or thiophenols.

Dynamic regulation of alternative polyadenylation by PQBP1 during neurogenesis.

Alternative polyadenylation (APA) is a critical post-transcriptional process that generates mRNA isoforms with distinct 3' untranslated regions (3' UTRs), thereby regulating mRNA localization, stability, and translational efficiency. Cell-type-specific APA extensively shapes the diversity of the cellular transcriptome, particularly during cell fate transition. Despite its recognized significance, the precise regulatory mechanisms governing cell-type-specific APA remain unclear.

De Novo Synthesis of 2,2'-Bipyridines and Related Bis-azines via Cascade Coupling and Double Pyridannulation of Isocyanides.

Herein, we present a new and general protocol for the assembly of 2,2'-bipyridyls from nonpyridine substrates without using any metal catalysts or organometallic reagents. The process starts from the coupling of two 1,3-dienyl isocyanides followed by a 6π-electrocyclization/aromatization cascade featuring the simultaneous formation of two pyridine rings in a single operation. Notably, this strategy is also applicable to the construction of nonsymmetrical 2-(2-pyridyl)-quinolines/-quinoxalines.

Cryo-EM of α-tubulin isotype-containing microtubules revealed a contracted structure of α4A/β2A microtubules.

Microtubules are hollow α/β-tubulin heterodimeric polymers that play critical roles in cells. In vertebrates, both α- and β-tubulins have multiple isotypes encoded by different genes, which are intrinsic factors in regulating microtubule functions. However, the structures of microtubules composed of different tubulin isotypes, especially α-tubulin isotypes, remain largely unknown.

The distinct initiation sites and processing activities of TTLL4 and TTLL7 in glutamylation of brain tubulin.

Mammalian brain tubulins undergo a reversible posttranslational modification-polyglutamylation-which attaches a secondary polyglutamate chain to the primary sequence of proteins. Loss of its erasers can disrupt polyglutamylation homeostasis and cause neurodegeneration. Tubulin tyrosine ligase like 4 (TTLL4) and TTLL7 were known to modify tubulins, both with preference for the β-isoform, but differently contribute to neurodegeneration.

A direct spino-cortical circuit bypassing the thalamus modulates nociception.

Nociceptive signals are usually transmitted to layer 4 neurons in somatosensory cortex via the spinothalamic-thalamocortical pathway. The layer 5 corticospinal neurons in sensorimotor cortex are reported to receive the output of neurons in superficial layers; and their descending axons innervate the spinal cord to regulate basic sensorimotor functions. Here, we show that a subset of layer 5 neurons receives spinal inputs through a direct spino-cortical circuit bypassing the thalamus, and thus define these neurons as spino-cortical recipient neurons (SCRNs).

Pathway and mechanism of tubulin folding mediated by TRiC/CCT along its ATPase cycle revealed using cryo-EM.

The eukaryotic chaperonin TRiC/CCT assists the folding of about 10% of cytosolic proteins through an ATP-driven conformational cycle, and the essential cytoskeleton protein tubulin is the obligate substrate of TRiC. Here, we present an ensemble of cryo-EM structures of endogenous human TRiC throughout its ATPase cycle, with three of them revealing endogenously engaged tubulin in different folding stages. The open-state TRiC-tubulin-S1 and -S2 maps show extra density corresponding to tubulin in the cis-ring chamber of TRiC.

Isocyanide Heterodimerization-Triggered Three-Component Reaction: Diversity-Oriented Synthesis of Quinoxalines.

Known isocyanide-based multicomponent reactions (IMCRs) are usually triggered by addition of the isocyano group to the strong electrophilic component. We herein report a new isocyanide-based three-component reaction, in which an unprecedented quinoxaline-based zwitterionic intermediate is generated from the chemoselective heterodimerization of weak electrophilic -diisocyanoarenes and common isocyanides. This reactive zwitterion could react with various trapping agents to furnish a range of structurally diverse quinoxalines.

Somatosensory neurons express specific sets of lincRNAs, and lincRNA CLAP promotes itch sensation in mice.

Somatosensory neurons are highly heterogeneous with distinct types of neural cells responding to specific stimuli. However, the distribution and roles of cell-type-specific long intergenic noncoding RNAs (lincRNAs) in somatosensory neurons remain largely unexplored. Here, by utilizing droplet-based single-cell RNA-seq (scRNA-seq) and full-length Smart-seq2, we show that lincRNAs, but not coding mRNAs, are enriched in specific types of mouse somatosensory neurons.

Activation of Wnt/β-catenin signaling by Zeb1 in endothelial progenitors induces vascular quiescence entry.

The establishment of a functional vasculature requires endothelial cells to enter quiescence during the completion of development, otherwise pathological overgrowth occurs. How such a transition is regulated remains unclear. Here, we uncover a role of Zeb1 in defining vascular quiescence entry.

mA-modified lincRNA Dubr is required for neuronal development by stabilizing YTHDF1/3 and facilitating mRNA translation.

Long intergenic noncoding RNAs (lincRNAs) are crucial regulators in numerous biological processes. However, the functions and mechanisms of mA-modified lincRNAs in neuronal development remain unclear. Here, we report an mA-modified lincRNA, Dppa2 upstream binding RNA (Dubr), abundantly expressed at the early developmental stage of dorsal root ganglion (DRG) and cerebral cortex.

Distinct neural networks derived from galanin-containing nociceptors and neurotensin-expressing pruriceptors.

Pain and itch are distinct sensations arousing evasion and compulsive desire for scratching, respectively. It's unclear whether they could invoke different neural networks in the brain. Here, we use the type 1 herpes simplex virus H129 strain to trace the neural networks derived from two types of dorsal root ganglia (DRG) neurons: one kind of polymodal nociceptors containing galanin () and one type of pruriceptors expressing neurotensin ().

Response characteristics of highland barley () seedlings to the stress of salinity and artemisinin under freeze–thaw environment.

In Qinghai-Tibet Plateau, crops are commonly subjected to freeze-thaw and salt stress factors simultaneously, and allelopathy is common, which affects the growth of highland barley (Hordeum vulgare L.), the largest food crop in Tibet. In order to explore the effects of artemisinin, salt and freeze-thaw (FAS) stress on physiological characteristics of highland barley seedlings, hydroponic experiment was carried out with the addition of 20mg/L artemisinin and 150mMNaCl as well as the simulation of freeze-thaw environment.

Short-term effects of combined freeze–thaw and saline–alkali stresses on the physiological response in highland barley ().

Highland barley (Hordeum vulgare L.), as the dominant crop on the Qinghai-Tibetan Plateau, is a typical representative of plants adapted to extreme environmental conditions. However, the harsh environment, severe salinisation and frequent freezing and thawing in the Qinghai-Tibetan Plateau are main limiting factor for crop growth in this region.

Fibroblastic SMOC2 Suppresses Mechanical Nociception by Inhibiting Coupled Activation of Primary Sensory Neurons.

Nociceptive information is detected and transmitted by neurons in the DRG. Recently, single-cell RNA sequencing has revealed the molecular profile of various cell types, including fibroblasts in the DRG. However, the role of molecules in fibroblasts needs to be elucidated in nociceptive regulation.

-Containing Nociceptors Are Required for Noxious Heat Sensation.

DRG neurons are classified into distinct types to mediate the somatosensation with different modalities. Recently, transcriptional profilings of DRG neurons by single-cell RNA-sequencing have provided new insights into the neuron typing and functional properties. Zinc-finger CCHC domain-containing 12 () was reported to be the representative marker for a subtype of galanin-positive () DRG neurons.

Lidocaine Ameliorates Psoriasis by Obstructing Pathogenic CGRP Signaling‒Mediated Sensory Neuron‒Dendritic Cell Communication.

Psoriasis is a chronic immune-mediated skin disorder with the nervous system contributing to its pathology. The neurogenic mediators of psoriasis are elusive, and whether the intervention of the cutaneous nervous system can treat psoriasis remains to be determined. In this study, we conducted a pilot study using an epidural injection of lidocaine to treat patients with psoriasis.

Chemoselective Trimerization of Isocyanides: De Novo Synthesis of 2-Indole-Substituted Quinolines and Pyridines.

A catalyst-free chemoselective trimerization reaction of readily available isocyanides is described. This domino reaction provides facile access to a wide range of 2-(indol-2-yl)-quinolines and 2-(indol-2-yl)-pyridines in moderate to excellent yields. A "head to head" heterodimerization of two isocyanides is proposed as the key step of this reaction.

α1A and α1C form microtubules to display distinct properties mainly mediated by their C-terminal tails.

Microtubules consisting of α/β-tubulin dimers play critical roles in cells. More than seven genes encode α-tubulin in vertebrates. However, the property of microtubules composed of different α-tubulin isotypes is largely unknown.

α-TubK40me3 is required for neuronal polarization and migration by promoting microtubule formation.

Tri-methylation on lysine 40 of α-tubulin (α-TubK40me3) is a recently identified post-translational modification involved in mitosis and cytokinesis. However, knowledge about α-TubK40me3 in microtubule function and post-mitotic cells remains largely incomplete. Here, we report that α-TubK40me3 is required for neuronal polarization and migration by promoting microtubule formation.