Carbon-nitrogen transmutation in polycyclic arenol skeletons to access N-heteroarenes.

Developing skeletal editing tools is not a trivial task, and realizing the corresponding single-atom transmutation in a ring system without altering the ring size is even more challenging. Here, we introduce a skeletal editing strategy that enables polycyclic arenols, a highly prevalent motif in bioactive molecules, to be readily converted into N-heteroarenes through carbon-nitrogen transmutation. The reaction features selective nitrogen insertion into the C-C bond of the arenol frameworks by azidative dearomatization and aryl migration, followed by ring-opening, and ring-closing (ANRORC) to achieve carbon-to-nitrogen transmutation in the aromatic framework of the arenol. Using widely available arenols as N-heteroarene precursors, this alternative approach allows the streamlined assembly of complex polycyclic heteroaromatics with broad functional group tolerance. Finally, pertinent transformations of the products, including synthesis complex biheteroarene skeletons, were conducted and exhibited significant potential in materials chemistry.

Visible-Light-Induced Alkoxypyridylation of Alkenes Using N-Alkoxypyridinium Salts as Bifunctional Reagents.

Considering the ubiquitous presence of pyridine moieties in pharmaceutical compounds, it holds immense value to develop practical and straightforward methodologies for accessing heterocyclic aromatic hydrocarbons. In recent years, N-alkoxypyridinium salts have emerged as convenient radical precursors, enabling the generation of the corresponding alkoxy radicals and pyridine through single-electron transfer. Herein, we present the first report on visible-light-mediated intermolecular alkoxypyridylation of alkenes employing N-alkoxylpyridinium salts as bifunctional reagents with an exceptionally low catalyst loading (0.5 mol %).

Stereodivergent Synthesis of All Stereoisomers of 2,3-Disubstituted δ-Lactam Derivatives via Organocatalytic Cascade Reactions and Base-Induced Epimerization.

A protocol was developed to achieve stereodivergent synthesis of stereoisomers of δ-lactam bearing vicinal chiral centers. Organocatalytic cascade reactions were employed to produce the target products as the kinetic products, which exhibited remarkable enantioselectivities. In the presence of DBU, the kinetic product underwent epimerization to form a thermodynamically more stable diastereomer without loss in enantioselectivity. By simply switching the chiral organocatalyst and its enantiomer, we can efficiently obtain four stereoisomers with high enantioselectivities.

Photocatalyzed Enantioselective Functionalization of C(sp3)-H Bonds.

Owing to its diverse activation processes including single-electron transfer (SET) and hydrogen-atom transfer (HAT), visible-light photocatalysis has emerged as a sustainable and efficient platform for organic synthesis. These processes provide a powerful avenue for the direct functionalization of C(sp3)-H bonds under mild conditions. Over the past decade, there have been remarkable advances in the enantioselective functionalization of the C(sp3)-H bond via photocatalysis combined with conventional asymmetric catalysis. Herein, we summarize the advances in asymmetric C(sp3)-H functionalization involving visible-light photocatalysis and discuss two main pathways in this emerging field: (a) SET-driven carbocation intermediates are followed by stereospecific nucleophile attacks; and (b) photodriven alkyl radical intermediates are further enantioselectively captured by (i) chiral π-SOMOphile reagents, (ii) stereoselective transition-metal complexes, and (iii) another distinct stereoscopic radical species. We aim to summarize key advances in reaction design, catalyst development, and mechanistic understanding, to provide new insights into this rapidly evolving area of research.

Crohn's disease as the intestinal manifestation of pan-lymphatic dysfunction: An exploratory proposal based on basic and clinical data.

Crohn's disease (CD) is caused by immune, environmental, and genetic factors. It can involve the entire gastrointestinal tract, and although its prevalence is rapidly increasing its etiology remains unclear. Emerging biological and small-molecule drugs have advanced the treatment of CD; however, a considerable proportion of patients are non-responsive to all known drugs. To achieve a breakthrough in this field, innovations that could guide the further development of effective therapies are of utmost urgency. In this review, we first propose the innovative concept of pan-lymphatic dysfunction for the general distribution of lymphatic dysfunction in various diseases, and suggest that CD is the intestinal manifestation of pan-lymphatic dysfunction based on basic and clinical preliminary data. The supporting evidence is fully summarized, including the existence of lymphatic system dysfunction, recognition of the inside-out model, disorders of immune cells, changes in cell plasticity, partial overlap of the underlying mechanisms, and common gut-derived fatty and bile acid metabolism. Another benefit of this novel concept is that it proposes adopting the zebrafish model for studying intestinal diseases, especially CD, as this model is good at presenting and mimicking lymphatic dysfunction. More importantly, the ensuing focus on improving lymphatic function may lead to novel and promising therapeutic strategies for CD.

YTHDF2-mediated regulations bifurcate BHPF-induced programmed cell deaths.

N6-methyladenosine (m6A) is a critical regulator in the fate of RNA, but whether and how m6A executes its functions in different tissues remains largely obscure. Here we report downregulation of a crucial m6A reader, YTHDF2, leading to tissue-specific programmed cell deaths (PCDs) upon fluorene-9-bisphenol (BHPF) exposure. Currently, Bisphenol A (BPA) substitutes are widely used in plastic manufacturing. Interrogating eight common BPA substitutes, we detected BHPF in 14% serum samples of pregnant participants. In a zebrafish model, BHPF caused tissue-specific PCDs triggering cardiac and vascular defects. Mechanistically, BHPF-mediated downregulation of YTHDF2 reduced YTHDF2-facilitated translation of m6A-gch1 for cardiomyocyte ferroptosis, and decreased YTHDF2-mediated m6A-sting1 decay for caudal vein plexus (CVP) apoptosis. The two distinct YTHDF2-mediated m6A regulations and context-dependent co-expression patterns of gch1/ythdf2 and tnfrsf1a/ythdf2 contributed to YTHDF2-mediated tissue-specific PCDs, uncovering a new layer of PCD regulation. Since BHPF/YTHDF2-medaited PCD defects were also observed in mammals, BHPF exposure represents a potential health threat.

Synthesis of benzo[f][1,2]thiazepine 1,1-dioxides based on the visible-light-mediated aza Paternò-Büchi reaction of benzo[d]isothiazole 1,1-dioxides with alkenes.

A new two-step, one-pot synthesis of benzo[f][1,2]thiazepine 1,1-dioxides was developed, which contains a visible-light mediated aza Paternò-Büchi reaction of benzo[d]isothiazole 1,1-dioxides with alkenes and a Lewis acid catalyzed ring-expansion of azetidine. In this work, the mechanism of the aza Paternò-Büchi reaction was also investigated.

Multiple miRNA Detection through a Suspended Microbead Array Encoded by Triple-Color Upconversion Luminescent Nanotags via Bi-Beam Splitter Hybrid-Multitrap Optical Tweezers.

In recent years, optical tweezers have become a novel tool for biodetection, and to improve the inefficiency of a single trap, the development of multitraps is required. Herein, we constructed a set of hybrid multitrap optical tweezers with the balance of stability and flexibility by the combination of two different beam splitters, a diffraction optical element (DOE) and galvano mirrors (GMs), to capture polystyrene (PS) microbeads in aqueous solutions to create an 18-trap suspended array. A sandwich hybridization strategy of DNA-miRNA-DNA was adopted to detect three kinds of target miRNAs associated with triple negative breast cancer (TNBC), in which different upconversion nanoparticles (UCNPs) with red, green, and blue emissions were applied as luminescent tags to encode the carrier PS microbeads to further indicate the levels of the targets. With encoded luminescent microbeads imaged by a three-channel microscopic system, the biodetection displayed high sensitivity with low limits of detection (LODs) of 0.27, 0.32, and 0.33 fM and exceptional linear ranges of 0.5 fM to 1 nM, 0.7 fM to 1 nM, and 1 fM to 1 nM for miR-343-3p, miR-155, and miR-199a-5p, respectively. In addition, this bead-based assay method was demonstrated to have the potential for being applied in patients' serum by satisfactory standard addition recovery experiment results.

The thalamic reticular nucleus-lateral habenula circuit regulates depressive-like behaviors in chronic stress and chronic pain.

Chronic stress and chronic pain are two major predisposing factors to trigger depression. Enhanced excitatory input to the lateral habenula (LHb) has been implicated in the pathophysiology of depression. However, the contribution of inhibitory transmission remains unclear. Here, we dissect an inhibitory projection from the sensory thalamic reticular nucleus (sTRN) to the LHb, which is activated by acute aversive stimuli. However, chronic restraint stress (CRS) weakens sTRN-LHb synaptic strength, and this synaptic attenuation is indispensable for CRS-induced LHb neural hyperactivity and depression onset. Moreover, artificially inhibiting the sTRN-LHb circuit induces depressive-like behaviors in healthy mice, while enhancing this circuit relieves depression induced by both chronic stress and chronic pain. Intriguingly, neither neuropathic pain nor comorbid mechanical hypersensitivity in chronic stress is affected by this pathway. Altogether, our study demonstrates an sTRN-LHb circuit in establishing and modulating depression, thus shedding light on potential therapeutic targets for preventing or managing depression.

Protocol for generation and assessment of head-like structure in zebrafish.

In vitro embryonic analogue models, such as gastruloids, trunk-like structures and embryoids, have been developed to understand principles of early development and morphogenesis. However, models that can fully mimic head formation are still missing. Here, we present a protocol for generating the head-like structure (HLS) in zebrafish embryonic explants. We describe steps for dissection and constructing cell and patterning landscapes. We then detail assessment of this structure through axis induction. For complete details on the use and execution of this protocol, please refer to Cheng et al. (2023).1.

Sc(OTf)3 catalyzed intramolecular single-electron transfer of 2-alkyl-1,4-benzoquinones: synthesis of 6-chromanols from donor-acceptor cyclopropanes.

A Sc(OTf)3 catalyzed intramolecular cyclization reaction of 2-alkyl-1,4-benzoquinone derived from D-A cyclopropane was discovered. This reaction involves single-electron transfer, proton-transfer, an aromatization driven spin center shift, and radical coupling processes, and offers an efficient method for the synthesis of 6-chromanols from D-A cyclopropanes.

A glutamatergic DRN-VTA pathway modulates neuropathic pain and comorbid anhedonia-like behavior in mice.

Chronic pain causes both physical suffering and comorbid mental symptoms such as anhedonia. However, the neural circuits and molecular mechanisms underlying these maladaptive behaviors remain elusive. Here using a mouse model, we report a pathway from vesicular glutamate transporter 3 neurons in the dorsal raphe nucleus to dopamine neurons in the ventral tegmental area (VGluT3DRN→DAVTA) wherein population-level activity in response to innocuous mechanical stimuli and sucrose consumption is inhibited by chronic neuropathic pain. Mechanistically, neuropathic pain dampens VGluT3DRN → DAVTA glutamatergic transmission and DAVTA neural excitability. VGluT3DRN → DAVTA activation alleviates neuropathic pain and comorbid anhedonia-like behavior (CAB) by releasing glutamate, which subsequently promotes DA release in the nucleus accumbens medial shell (NAcMed) and produces analgesic and anti-anhedonia effects via D2 and D1 receptors, respectively. In addition, VGluT3DRN → DAVTA inhibition produces pain-like reflexive hypersensitivity and anhedonia-like behavior in intact mice. These findings reveal a crucial role for VGluT3DRN → DAVTA → D2/D1NAcMed pathway in establishing and modulating chronic pain and CAB.

Photoredox Catalyzed [3 + 2]-Annulation Reaction of Pyridinium 1,4-Zwitterionic Thiolates with Alkenes: Synthesis of Dihydrothiophenes.

Pyridinium 1,4-zwitterionic thiolates are usually used to develop ionic annulation reactions. However, radical reactions were rare. We developed a photoredox catalyzed [3 + 2]-annulation reaction of pyridinium 1,4-zwitterionic thiolates with alkenes, disclosed the new reactivity of pyridinium 1,4-zwitterionic thiolate, and provided a new synthetic method for dihydrothiophene.

Visible-Light-Mediated Intermolecular [2 + 2]-Cycloaddition Reaction of 3-Alkylideneindolin-2-one with Alkenes via Triplet Energy Transfer for the Synthesis of 3-Spirocyclobutyl Oxindoles.

[2 + 2]-Cycloaddition is the most straightforward approach to the construction of cyclobutanes. In this paper, the intermolecular [2 + 2]-cycloaddition reaction of 3-alkylideneindolin-2-ones with alkenes was achieved. This reaction can be used in the synthesis of 3-spirocyclobutyl oxindoles, polycyclic oxindoles, and late stage modification of some drug molecules.

A spatiotemporal barrier formed by Follistatin is required for left-right patterning.

How left-right (LR) asymmetry emerges in a patterning field along the anterior-posterior axis remains an unresolved problem in developmental biology. Left-biased Nodal emanating from the LR organizer propagates from posterior to anterior (PA) and establishes the LR pattern of the whole embryo. However, little is known about the regulatory mechanism of the PA spread of Nodal and its asymmetric activation in the forebrain. Here, we identify bilaterally expressed Follistatin (Fst) as a regulator blocking the propagation of the zebrafish Nodal ortholog Southpaw (Spaw) in the right lateral plate mesoderm (LPM), and restricting Spaw transmission in the left LPM to facilitate the establishment of a robust LR asymmetric Nodal patterning. In addition, Fst inhibits the Activin-Nodal signaling pathway in the forebrain thus preventing Nodal activation prior to the arrival, at a later time, of Spaw emanating from the left LPM. This contributes to the orderly propagation of asymmetric Nodal activation along the PA axis. The LR regulation function of Fst is further confirmed in chick and frog embryos. Overall, our results suggest that a robust LR patterning emerges by counteracting a Fst barrier formed along the PA axis.

The Zinc Transporter SLC39A10 Plays an Essential Role in Embryonic Hematopoiesis.

The role of zinc in hematopoiesis is currently unclear. Here, SLC39A10 (ZIP10) is identified as a key zinc transporter in hematopoiesis. The results show that in zebrafish, Slc39a10 is a key regulator of the response to zinc deficiency. Surprisingly, both slc39a10 mutant zebrafish and hematopoietic Slc39a10-deficient mice develop a more severe form of impaired hematopoiesis than animals lacking transferrin receptor 1, a well-characterized iron gatekeeper, indicating that zinc plays a larger role than iron in hematopoiesis, at least in early hematopoietic stem cells (HSCs). Furthermore, it is shown that loss of Slc39a10 causes zinc deficiency in fetal HSCs, which in turn leads to DNA damage, apoptosis, and G1 cell cycle arrest. Notably, zinc supplementation largely restores colony formation in HSCs derived from hematopoietic Slc39a10-deficient mice. In addition, inhibiting necroptosis partially restores hematopoiesis in mouse HSCs, providing mechanistic insights into the requirement for zinc in mediating hematopoiesis. Together, these findings indicate that SLC39A10 safeguards hematopoiesis by protecting against zinc deficiency-induced necroptosis, thus providing compelling evidence that SLC39A10 and zinc homeostasis promote the development of fetal HSCs. Moreover, these results suggest that SLC39A10 may serve as a novel therapeutic target for treating anemia and zinc deficiency-related disorders.

Radiomics-based survival risk stratification of glioblastoma is associated with different genome alteration.

BACKGROUND: Glioblastoma (GBM) is a remarkable heterogeneous tumor with few non-invasive, repeatable, and cost-effective prognostic biomarkers reported. In this study, we aim to explore the association between radiomic features and prognosis and genomic alterations in GBM. METHODS: A total of 180 GBM patients (training cohort: n = 119; validation cohort 1: n = 37; validation cohort 2: n = 24) were enrolled and underwent preoperative MRI scans. From the multiparametric (T1, T1-Gd, T2, and T2-FLAIR) MR images, the radscore was developed to predict overall survival (OS) in a multistep postprocessing workflow and validated in two external validation cohorts. The prognostic accuracy of the radscore was assessed with concordance index (C-index) and Brier scores. Furthermore, we used hierarchical clustering and enrichment analysis to explore the association between image features and genomic alterations. RESULTS: The MRI-based radscore was significantly correlated with OS in the training cohort (C-index: 0.70), validation cohort 1 (C-index: 0.66), and validation cohort 2 (C-index: 0.74). Multivariate analysis revealed that the radscore was an independent prognostic factor. Cluster analysis and enrichment analysis revealed that two distinct phenotypic clusters involved in distinct biological processes and pathways, including the VEGFA-VEGFR2 signaling pathway (q-value = 0.033), JAK-STAT signaling pathway (q-value = 0.049), and regulation of MAPK cascade (q-value = 0.0015/0.025). CONCLUSIONS: Radiomic features and radiomics-derived radscores provided important phenotypic and prognostic information with great potential for risk stratification in GBM.

Nodal coordinates the anterior-posterior patterning of germ layers and induces head formation in zebrafish explants.

Much progress has been made toward generating analogs of early embryos, such as gastruloids and embryoids, in vitro. However, methods for how to fully mimic the cell movements of gastrulation and coordinate germ-layer patterning to induce head formation are still lacking. Here, we show that a regional Nodal gradient applied to zebrafish animal pole explant can generate a structure that recapitulates the key cell movements of gastrulation. Using single-cell transcriptome and in situ hybridization analysis, we assess the dynamics of the cell fates and patterning of this structure. The mesendoderm differentiates into the anterior endoderm, prechordal plate, notochord, and tailbud-like cells along an anterior-posterior axis, and an anterior-posterior-patterned head-like structure (HLS) progressively forms during late gastrulation. Among 105 immediate Nodal targets, 14 genes contain axis-induction ability, and 5 of them induce a complete or partial head structure when overexpressed in the ventral side of zebrafish embryos.

Organic photoredox catalyzed dealkylation/acylation of tertiary amines to access amides.

A mild metal-free C-N bond activation strategy for the direct conversion of inert tertiary amines with acyl chlorides into tertiary amides via organic photoredox catalysis is presented. In this protocol, a novel organic photocatalyst (Cz-NI-Ph) that showed excellent catalytic performance during C-N bond cleavage is developed. Moreover, this reaction features green and mild conditions, broad substrate scope, and readily available raw materials.

Light-Promoted Nickel-Catalyzed C-O/C-N Coupling of Aryl Halides with Carboxylic Acids and Sulfonamides.

A general strategy for the construction of dual-functional carbon-heteroatom bonds has been developed via a light-promoted nickel catalytic system. Employing a simple NiBr2 as the catalyst without any exogeneous ligands and photosensitizers, a variety of esters and sulfonamide N-arylation derivatives, including celecoxib- and glimepiride-derived sulfonamides, were readily accessed with high functional group tolerance and high efficiency. Moreover, the UV-vis absorption spectrum and free radical trapping experiments aimed at revealing the mechanism of the reaction are also presented.