Visible-Light-Driven Deoxygenative Heteroarylation of Alcohols with Heteroaryl Sulfones.

The visible-light-promoted deoxygenative radical heteroarylation of alcohols was achieved in the absence of any external photosensitizers. The processes occur through the generation of xanthate salts from alcohols, followed by SET and fragmentation, delivering alkyl radicals to react with heteroaryl sulfones. This method is amenable for a wide range of alcohols with good functional group tolerance, providing a practical strategy for the alkylation of benzo-heteroaromatics. Mechanism studies indicate that direct visible-light excitation of xanthate anions and subsequent SET initiate the reactions.

miR-22 gene therapy treats HCC by promoting anti-tumor immunity and enhancing metabolism.

MicroRNA-22 (miR-22) can be induced by beneficial metabolites that have metabolic and immune effects, including retinoic acids, bile acids, vitamin D3, and short-chain fatty acids. The tumor suppressor effects of miR-22 have been suggested, but whether miR-22 treats orthotopic hepatocellular carcinoma (HCC) is not established. The role of miR-22 in regulating tumor immunity is also poorly understood. Our data showed that miR-22 delivered by adeno-associated virus serotype 8 effectively treated HCC. Compared with FDA-approved lenvatinib, miR-22 produced better survival outcomes without noticeable toxicity. miR-22 silenced hypoxia-inducible factor 1 (HIF1α) and enhanced retinoic acid signaling in both hepatocytes and T cells. Moreover, miR-22 treatment improved metabolism and reduced inflammation. In the liver, miR-22 reduced the abundance of IL17-producing T cells and inhibited IL17 signaling by reducing the occupancy of HIF1α in the Rorc and Il17a genes. Conversely, increasing IL17 signaling ameliorated the anti-HCC effect of miR-22. Additionally, miR-22 expanded cytotoxic T cells and reduced regulatory T cells (Treg). Moreover, depleting cytotoxic T cells also abolished the anti-HCC effects of miR-22. In patients, miR-22 high HCC had upregulated metabolic pathways and reduced IL17 pro-inflammatory signaling compared with miR-22 low HCC. Together, miR-22 gene therapy can be a novel option for HCC treatment.

A Practical Method for Synthesizing Iptacopan.

Iptacopan, the first orally available small-molecule complement factor B inhibitor, was developed by Novartis AG of Switzerland. Iptacopan for the treatment of PNH was just approved by the FDA in December 2023. Other indications for treatment are still in phase III clinical trials. Iptacopan is a small-molecule inhibitor targeting complement factor B, showing positive therapeutic effects in the treatment of PNH, C3 glomerulonephritis, and other diseases. Although Iptacopan is already on the market, there has been no detailed synthesis process or specific parameter report on the intermediates during the synthesis of its compounds except for the original research patent. In this study, a practical synthesis route for Iptacopan was obtained through incremental improvement while a biosynthesis method for ketoreductase was used for the synthesis of the pivotal intermediate 12. Moreover, by screening the existing enzyme library of our research group on the basis of random as well as site-directed mutagenesis methods, an enzyme (M8) proven to be of high optical purity with a high yield for biocatalectic reduction was obtained. This enzyme was used to prepare the compound benzyl (2S,4S)-4-hydroxy-2-(4-(methoxycarbonyl)-phenyl)-piperidine-1-carboxylate) white powder (36.8 g HPLC purity: 98%, ee value: 99%). In the synthesis of intermediate 15, the reaction was improved from two-step to one-step, which indicated that the risk of chiral allosterism was reduced while the scale was expanded. Finally, Iptacopan was synthesized in a seven-step reaction with a total yield of 29%. Since three chiral intermediate impurities were synthesized directionally, this paper lays a solid foundation for the future of pharmaceutical manufacturing.

Visible-Light-Driven Multicomponent Reactions for the Versatile Synthesis of Thioamides by Radical Thiocarbamoylation.

Thioamides are widely used structures in pharmaceuticals and agrochemicals, as well as important synthons for the construction of sulfur-containing heterocycles. This report presents a series of visible-light-driven multicomponent reactions of amines, carbon disulfide, and olefins for the mild and versatile synthesis of linear thioamides and cyclic thiolactams. The use of inexpensive and readily available carbon disulfide as the thiocarbonyl source in a radical pathway enables the facile assembly of structurally diverse amine moieties with non-nucleophilic carbon-based reaction partners. Radical thiocarbamoylative cyclization provides a practical protocol that complements traditional approaches to thiolactams relying on deoxythionation. Mechanistic studies reveal that direct photoexcitation of in situ formed dithiocarbamate anions as well as versatile photoinduced electron transfer with diverse electron acceptors are key to the reactions.

Visible-Light-Driven Photocatalyst-Free Deoxygenative Radical Transformation of Alcohols to Oxime Ethers.

A visible-light-driven deoxygenative cross-coupling of alcohols with sulfonyl oxime ethers has been developed by using xanthate salts as alcohol-activating groups. Upon convenient generation and direct photoexcitation of xanthate anions, a broad range of alcohols including primary ones can efficiently undergo this transformation to afford diverse oxime ethers and derivatives. This one-pot protocol features mild conditions, broad substrate scope, and late-stage applicability, without the need for any external photocatalysts or electron donor-acceptor complex formation.

Deoxygenative coupling of alcohols with aromatic nitriles enabled by direct visible light excitation.

A general and practical protocol is presented for visible-light-driven deoxygenative coupling of alcohols with aromatic nitriles in the absence of external photocatalysts. Utilizing a hydroxyl activation strategy with carbon disulfide, this C(sp3)-C(sp2) constructing platform accommodates a broad scope of alcohols and aryl nitriles to deliver various alkyl-substituted arenes. Mechanism studies show that a single electron transfer event between a photoexcited aryl nitrile and a xanthate anion is key to the transformation.

GmYSL7 controls iron uptake, allocation, and cellular response of nodules in soybean.

Iron (Fe) is essential for DNA synthesis, photosynthesis and respiration of plants. The demand for Fe substantially increases during legumes-rhizobia symbiotic nitrogen fixation because of the synthesis of leghemoglobin in the host and Fe-containing proteins in bacteroids. However, the mechanism by which plant controls iron transport to nodules remains largely unknown. Here we demonstrate that GmYSL7 serves as a key regulator controlling Fe uptake from root to nodule and distribution in soybean nodules. GmYSL7 is Fe responsive and GmYSL7 transports iron across the membrane and into the infected cells of nodules. Alterations of GmYSL7 substantially affect iron distribution between root and nodule, resulting in defective growth of nodules and reduced nitrogenase activity. GmYSL7 knockout increases the expression of GmbHLH300, a transcription factor required for Fe response of nodules. Overexpression of GmbHLH300 decreases nodule number, nitrogenase activity and Fe content in nodules. Remarkably, GmbHLH300 directly binds to the promoters of ENOD93 and GmLbs, which regulate nodule number and nitrogenase activity, and represses their transcription. Our data reveal a new role of GmYSL7 in controlling Fe transport from host root to nodule and Fe distribution in nodule cells, and uncover a molecular mechanism by which Fe affects nodule number and nitrogenase activity.

Nuclear receptor RORγ inverse agonists/antagonists display tissue- and gene-context selectivity through distinct activities in altering chromatin accessibility and master regulator SREBP2 occupancy.

The nuclear receptor RORγ is a major driver of autoimmune diseases and certain types of cancer due to its aberrant function in T helper 17 (Th17) cell differentiation and tumor cholesterol metabolism, respectively. Compound screening using the classic receptor-coactivator interaction perturbation scheme led to identification of many small-molecule modulators of RORγ(t). We report here that inverse agonists/antagonists of RORγ such as VTP-43742 derivative VTP-23 and TAK828F, which can potently inhibit the inflammatory gene program in Th17 cells, unexpectedly lack high potency in inhibiting the growth of TNBC tumor cells. In contrast, antagonists such as XY018 and GSK805 that strongly suppress tumor cell growth and survival display only modest activities in reducing Th17-related cytokine expression. Unexpectedly, we found that VTP-23 significantly induces the cholesterol biosynthesis program in TNBC cells. Our further mechanistic analyses revealed that VTP-23 enhances the local chromatin accessibility, H3K27ac mark and the cholesterol master regulator SREBP2 recruitment at the RORγ binding sites, whereas XY018 exerts the opposite activities. Yet, they display similar inhibitory effects on circadian rhythm program. Similar distinctions and contrasting activities between TAK828F and SR2211 in their effects on local chromatin structure at Il17 genes were also observed. Together, our study shows for the first-time that structurally distinct RORγ antagonists possess different or even contrasting activities in tissue/cell-specific manner. Our findings also highlight that the activities at natural chromatin are key determinants of RORγ modulators' tissue selectivity.

Bionic orientation method based on polarization imaging in HDR scenes.

An increasing number of bio-inspired navigation approaches have been designed based on polarization cameras. However, digital cameras can sense a much narrower field of vision than the vision of insects or human beings. In this study, we propose an adaptive skylight polarized orientation method for high dynamic range (HDR) scenes. Initially, we built a model of the image acquisition pipeline that can recover HDR irradiance maps from polarization images. Subsequently, the orientation method was designed based on a combination of the irradiance maps and the least squares methods. Some preprocessing steps were utilized to eliminate occlusion interference. In addition, an autoexposure adjustment method was proposed using information entropy and heuristic segmentation. Finally, the experimental results show that the proposed method can improve the accuracy of bionic orientation and adaption to skylight with occlusions and interference in natural conditions.

A facile turn-on chemiluminescence probe for sensitive imaging on aminopeptidase N activity.

Aminopeptidase N, as a target for drug discovery, shows marked relationships with many diseases, especially liver injury and cancer. Here, we explored a chemiluminescence (CL) probe for sensing APN by tethering the APN-specific substrate group to the ortho-acrylated phenoxy-dioxetane scaffold. In this way, two CL probes (APN-CL and BAPN-CL) were designed with noncapped leucine and butoxy-carbonyl capped leucine as the protecting group to preserve the chemiexcitation energy. The uncovered leucine was demonstrated to be essential for detection of APN activity by comparing the CL intensity of two CL probes. Probe APN-CL was turned on upon APN cleavage, resulting in a high chemiluminescent emission, whereas the chemiexcitation energy of probe BAPN-CL was still restrained even with the high-level APN. The result was further elucidated by molecular docking simulations. Probe APN-CL exhibited a fast response and high sensitivity with a detection limit of 0.068 U/L, and an excellent specificity for the discrimination of APN from biological ions, small molecules, and other proteases commonly found in living system. By virtue of good stability and cell viability, probe APN-CL imaged abnormal levels of APN in tumour cells and tumour-bearing mice. Moreover, this probe APN-CL could be easily used to evaluate APN inhibitors and APN levels in plasma samples from 20 patients. Overall, as a facile and cost-effective probe, APN-CL will be a promising alternative in the early diagnosis of pathologies and for cost-effective screening of inhibitors.

Template-less Synthesis of Coded Au Nanowires.

Morphological coding of nanostructures represents a capability in rapid modulation of structural features and most importantly, the transcription of information into nanoscale. Exploiting the regioselectivity in the template-less electrochemical synthesis of ultrathin Au nanowires, we show that rapid alternation of applied potential would cause corresponding change in the width of the emerging nanowire segments. By understanding the growth kinetics, a strong correlation between the nanowire morphologies and the deposition potential is established and applied in emulating the Morse code.

Patient capability: Justice and grassroots healthcare delivery in China.

The current reform of China's healthcare system focuses mainly on two dimensions: the promotion of primary healthcare and the improvement of quality of grassroots healthcare (GH). Specifically, the reforms are aimed at meeting the needs of patients in the grassroots areas (PGAs) through the provision of universal healthcare and hierarchical diagnosis and treatment (HDT). In practice, however, disparities in health outcomes between the grassroots and upper levels persist. The gaps between increased health coverage and heightened barriers to accessing quality medical care in the grassroots areas are growing ever larger. What explains this paradox is the limited capability of PGAs to transform healthcare resources into better health-seeking behaviors and health outcomes, resulting in injustice that is built into the system, which is neither ethical nor fair. Using Amartya Sen's capability approach (CA) to explore issues of justice in relation to China's GH system and its performance, we suggest that an institutional structure, one that focuses on promoting universal coverage in the grassroots areas, although necessary, is by itself insufficient in promoting justice and equality in accessing healthcare. Institutional disparities in the healthcare system and China's household registration policy, constructed according to the rural-urban divide, have also produced injustices. We argue that greater attention should be given to meeting the medical needs of PGAs and empowering them with greater choice, permitting them a higher level of freedom and agency, and thus remedying the problems that we describe. We conclude with policy recommendations aimed at improving justice within the system.

GmbZIP1 negatively regulates ABA-induced inhibition of nodulation by targeting GmENOD40-1 in soybean.

BACKGROUND: Abscisic acid (ABA) plays an important role in plant growth and adaptation through the ABA signaling pathway. The ABA-responsive element binding (AREB/ABF) family transcriptional factors are central regulators that integrate ABA signaling with various signaling pathways. It has long been known that ABA inhibits rhizobial infection and nodule formation in legumes, but the underlying molecular mechanisms remain elusive. RESULTS: Here, we show that nodulation is very sensitive to ABA and exogenous ABA dramatically inhibits rhizobial infection and nodule formation in soybean. In addition, we proved that GmbZIP1, an AREB/ABF transcription factor, is a major regulator in both nodulation and plant response to ABA in soybean. GmbZIP1 was specifically expressed during nodule formation and development. Overexpression of GmbZIP1 resulted in reduced rhizobial infection and decreased nodule number. Furthermore, GmbZIP1 is responsive to ABA, and ectopic overexpression of GmbZIP1 increased sensitivity of Arabidopsis plants to ABA during seed germination and postgerminative growth, and conferred enhanced drought tolerance of plants. Remarkably, we found that GmbZIP1 directly binds to the promoter of GmENOD40-1, a marker gene for nodule formation, to repress its expression. CONCLUSION: Our results identified GmbZIP1 as a node regulator that integrates ABA signaling with nodulation signaling to negatively regulate nodule formation.

MicroRNA-196b promotes gastric cancer progression by targeting ECRG4.

Gastric cancer is one of the most common malignant tumors. MicroRNA-196b (miR-196b) has been demonstrated to play important roles in human cancers. However, its functions in gastric cancer progression were still largely unknown. In this study, the expression of miR-196b was determined by quantitative real-time PCR. Esophageal cancer-related gene 4 (ECRG4) level was examined by western blot assay and immunohistochemistry staining assay. Cell proliferation was evaluated by Cell Counting Kit-8 (CCK-8) assay and colony formation assay. Cell migration and invasion were analyzed by transwell assay. The association between miR-196b and ECRG4 was analyzed by dual-luciferase reporter assay. The functional role of miR-196b in vivo was analyzed by murine xenograft assay. As a result, we found the expression of miR-196b was elevated and the protein expression of ECRG4 was reduced in gastric cancer tissues and cells. MiR-196b inhibition suppressed gastric cancer cell proliferation, migration and invasion. ECRG4 was a target of miR-196b and its protein expression was negatively regulated by miR-196b. Moreover, ECRG4 overexpression showed similar effects with miR-196b inhibition on the malignant behaviors of GC cells and ECRG4 knockdown reversed the effects of miR-196b inhibition on gastric cancer cell proliferation, migration and invasion. In addition, miR-196b inhibition suppressed tumor volume and weight in vivo. In conclusion, downregulation of miR-196b inhibited gastric cancer progression by modulating ECRG4 expression, indicating that miR-196b might be a potential therapeutic target for gastric cancer.

Direct Synthesis of Ultrathin Pt Nanowire Arrays as Catalysts for Methanol Oxidation.

High-performance electrocatalysts are of critical importance for fuel cells. Morphological modulation of the catalyst materials is a rare but feasible strategy to improve their performance. In this work, Pt nanowire arrays are directly synthesized with a template-less wet chemical method. The effects of surface functionalization and the reduction kinetics are revealed to be vital to the nanowire growth. The growth mechanism of the Pt nanowires is studied. By adjusting the concentration of the organic ligands, Pt nanowire arrays with tunable surface roughness can be obtained on various substrate surfaces. Such arrays avoid the contact resistance of randomly packed particles and allow open diffusion channels for reactants and products alike, making them excellent electrocatalysts for the methanol oxidation reaction. In particular, Pt nanowire arrays with rough surface have a mass activity of 1.24 A mgPt -1 at 1.12 V (vs Ag/AgCl), 3.18-fold higher than that of the commercial Pt/C catalysts. It also shows more resistant against poisoning, as indicated by the higher If /Ib ratio (2.06), in comparison to the Pt/C catalysts (1.30).

Ferroelectric Metal-Organic Framework as a Host Material for Sulfur to Alleviate the Shuttle Effect of Lithium-Sulfur Battery.

Ferroelectricity has an excellent reversible polarization conversion behavior under an external electric field. Herein, we propose an interesting strategy to alleviate the shuttle effect of lithium-sulfur battery by utilizing ferroelectric metal-organic framework (FMOF) as a host material for the first time. Compared to other MOF with same structure but without ferroelectricity and commercial carbon black, the cathode based on FMOF exhibits a low capacity decay and high cycling stability. These results demonstrate that the polarization switching behaviors of FMOF under the discharge voltage of lithium-sulfur battery can effectively trap polysulfides by polar-polar interactions, decrease polysulfides shuttle and improve the electrochemical performance of lithium-sulfur battery.

Meta-analysis: The efficacy of metformin and other anti-hyperglycemic agents in prolonging the survival of hepatocellular carcinoma patients with type 2 diabetes.

INTRODUCTION: This study aimed to compare the therapeutic efficacy of metformin and other anti-hyperglycemic agents in hepatocellular carcinoma (HCC) patients with type 2 diabetes (T2D). MATERIALS: A systematic electronic search on keywords including HCC and different anti-hyperglycemic agents was performed through electronic databases including Medline and EMBASE. The primary outcome was the overall survival (OS). The secondary outcomes were the recurrence-free survival (RFS) and progression-free survival (PFS). RESULTS: Six retrospective cohort studies were included for analysis: Four studies with curative treatment for HCC (618 patients with metformin and 532 patients with other anti-hyperglycemic agents) and two studies with non-curative treatment for HCC (92 patients with metformin and 57 patients with other anti-hyperglycemic agents). Treatment with metformin was associated with significantly longer OS (OR1yr=2.62, 95%CI: 1.76-3.90; OR3yr=3.14, 95%CI: 2.33-4.24; OR5yr=3.31, 95%CI: 2.39-4.59, all P<0.00001) and RFS (OR1yr=2.52, 95%CI: 1.84-3.44; OR3yr=2.87, 95%CI: 2.15-3.84; all P<0.00001; and OR5yr=2.26, 95%CI: 0.94-5.45, P=0.07) rates vs. those of other anti-hyperglycemic agents after curative therapies for HCC. However, both of the two studies reported that following non-curative HCC treatment, there were no significant differences in the OS and PFS rates between the metformin and non-metformin groups (I2>50%). CONCLUSIONS: Metformin significantly prolonged the survival of HCC patients with T2D after the curative treatment of HCC. However, the efficacy of metformin needs to be further determined after non-curative therapies for HCC patients with T2D.

Transient receptor potential ankyrin 1 (TRPA1) positively regulates imiquimod-induced, psoriasiform dermal inflammation in mice.

Transient receptor potential ankyrin 1 (TRPA1), a membrane protein ion channel, is known to mediate itch and pain in skin. The function of TRPA1, however, in psoriasiform dermatitis (PsD) is uncertain. Herein, we found that expression of TRPA1 is highly up-regulated in human psoriatic lesional skin. To study the role of TRPA1 in PsD, we assessed Psoriasis Severity Index (PSI) scores, transepidermal water loss (TEWL), skin thickness and pathology, and examined dermal inflammatory infiltrates, Th17-related genes and itch-related genes in c57BL/6 as wild-type (WT) and TRPA1 gene knockout (KO) mice following daily application of topical IMQ cream for 5 days. Compared with WT mice, clinical scores, skin thickness change and TEWL scores were similar on day 3, but were significantly decreased on day 5 in IMQ-treated TRPA1 KO mice (vs WT mice), suggesting reduced inflammation and skin barrier defects. Additionally, the relative area of epidermal Munro's microabscesses and mRNA levels of neutrophil inducible chemokines (S100A8, S100A9 and CXCL1) were decreased in the treated skin of TRPA1 KO mice, suggesting that neutrophil recruitment was impaired in the KO mice. Furthermore, mast cells, CD31+ blood vascular cells, CD45+ leukocytes and CD3+ T cells were all reduced in the treated skin of TRPA1 KO mice. Lastly, mRNA expression levels of IL-1ß, IL-6, IL-23, IL-17A, IL-17F and IL-22 were decreased in TRPA1 KO mice. In summary, these results suggest a key role for TRPA1 in psoriasiform inflammation and raising its potential as a target for therapeutic intervention.

First-principle description of acoustic radiation of shear flows.

As a methodology complementary to acoustic analogy, the asymptotic approach to aeroacoustics seeks to predict aerodynamical noise on the basis of first principles by probing into the physical processes of acoustic radiation. The present paper highlights the principal ideas and recent developments of this approach, which have shed light on some of the fundamental issues in sound generation in shear flows. The theoretical work on sound wave emission by nonlinearly modulated wavepackets of supersonic and subsonic instability modes in free shear flows identifies the respective physical sources or emitters. A wavepacket of supersonic modes is itself an efficient emitter, radiating directly intensive sound in the form of a Mach wave beam, the frequencies of which are in the same band as those of the modes in the packet. By contrast, a wavepacket of subsonic modes radiates very weak sound directly. However, the nonlinear self-interaction of such a wavepacket generates a slowly modulated mean-flow distortion, which then emits sound waves with low frequencies and long wavelengths on the scale of the wavepacket envelope. In both cases, the acoustic waves emitted to the far field are explicitly expressed in terms of the amplitude function of the wavepacket. The asymptotic approach has also been applied to analyse generation of sound waves in wall-bounded shear flows on the triple-deck scale. Several subtleties have been found. The near-field approximation has to be worked out to a sufficiently higher order in order just to calculate the far-field sound at leading order. The back action of the radiated sound on the flow in the viscous sublayer and the main shear layer is accounted for by an impedance coefficient. This effect is of higher order in the subsonic regime, but becomes a leading order in the transonic and supersonic regimes. This article is part of the theme issue 'Frontiers of aeroacoustics research: theory, computation and experiment'.

Tandem Catalysis: Transforming Alcohols to Alkenes by Oxidative Dehydroxymethylation.

We report a Rh-catalyst for accessing olefins from primary alcohols by a C-C bond cleavage that results in dehomologation. This functional group interconversion proceeds by an oxidation-dehydroformylation enabled by N, N-dimethylacrylamide as a sacrificial acceptor of hydrogen gas. Alcohols with diverse functionality and structure undergo oxidative dehydroxymethylation to access the corresponding olefins. Our catalyst protocol enables a two-step semisynthesis of (+)-yohimbenone and dehomologation of feedstock olefins.