Cellular and molecular determinants of bacterial burden in leprosy granulomas revealed by single-cell multimodal omics.

BACKGROUND: Which cell populations that determine the fate of bacteria in infectious granulomas remain unclear. Leprosy, a granulomatous disease with a strong genetic predisposition, caused by Mycobacterium leprae infection, exhibits distinct sub-types with varying bacterial load and is considered an outstanding disease model for studying host-pathogen interactions. METHODS: We performed single-cell RNA and immune repertoire sequencing on 11 healthy controls and 20 patients with leprosy, and integrated single-cell data with genome-wide genetic data on leprosy. Multiplex immunohistochemistry, and in vitro and in vivo infection experiments were conducted to confirm the multimodal omics findings. FINDINGS: Lepromatous leprosy (L-LEP) granulomas with high bacterial burden were characterised by exhausted CD8+ T cells, and high RGS1 expression in CD8+ T cells was associated with L-LEP. By contrast, tuberculoid leprosy (T-LEP) granulomas with low bacterial burden displayed enrichment in resident memory IFNG+ CD8+ T cells (CD8+ Trm) with high GNLY expression. This enrichment was potentially attributable to the communication between IL1B macrophages and CD8+ Trm via CXCL10-CXCR3 signalling. Additionally, IL1B macrophages in L-LEP exhibited anti-inflammatory phenotype, with high APOE expression contributing to high bacterial burden. Conversely, IL1B macrophages in T-LEP were distinguished by interferon-γ induced GBP family genes. INTERPRETATION: The state of IL1B macrophages and functional CD8+ T cells, as well as the relationship between them, is crucial for controlling bacterial persistence within granulomas. These insights may indicate potential targets for host-directed immunotherapy in granulomatous diseases caused by mycobacteria and other intracellular bacteria. FUNDING: The Key research and development program of Shandong Province (2021LCZX07), Natural Science Foundation of Shandong Province (ZR2023MH046), Youth Science Foundation Cultivation Funding Plan of Shandong First Medical University (Shandong Academy of Medical Sciences) (202201-123), National Natural Science Foundation of China (82471800, 82230107, 82273545, 82304039), the China Postdoctoral Science Foundation (2023M742162), Shandong Province Taishan Scholar Project (tspd20230608), Joint Innovation Team for Clinical & Basic Research (202410), Central guidance for local scientific and technological development projects of Shandong Province (YDZX2023058).

The nucleus accumbens in reward and aversion processing: insights and implications.

The nucleus accumbens (NAc), a central component of the brain's reward circuitry, has been implicated in a wide range of behaviors and emotional states. Emerging evidence, primarily drawing from recent rodent studies, suggests that the function of the NAc in reward and aversion processing is multifaceted. Prolonged stress or drug use induces maladaptive neuronal function in the NAc circuitry, which results in pathological conditions. This review aims to provide comprehensive and up-to-date insights on the role of the NAc in motivated behavior regulation and highlights areas that demand further in-depth analysis. It synthesizes the latest findings on how distinct NAc neuronal populations and pathways contribute to the processing of opposite valences. The review examines how a range of neuromodulators, especially monoamines, influence the NAc's control over various motivational states. Furthermore, it delves into the complex underlying mechanisms of psychiatric disorders such as addiction and depression and evaluates prospective interventions to restore NAc functionality.

Loss-of-function mutations in Keratin 32 gene disrupt skin immune homeostasis in pityriasis rubra pilaris.

Pityriasis rubra pilaris (PRP) is an inflammatory papulosquamous dermatosis, characterized by hyperkeratotic follicular papules and erythematous desquamative plaques. The precise pathogenic mechanism underlying PRP remains incompletely understood. Herein, we conduct a case-control study involving a cohort of 102 patients with sporadic PRP and 800 healthy controls of Han Chinese population and identify significant associations (P = 1.73 × 10-6) between PRP and heterozygous mutations in the Keratin 32 gene (KRT32). KRT32 is found to be predominantly localized in basal keratinocytes and exhibits an inhibitory effect on skin inflammation by antagonizing the NF-κB pathway. Mechanistically, KRT32 binds to NEMO, promoting excessive K48-linked polyubiquitination and NEMO degradation, which hinders IKK complex formation. Conversely, loss-of-function mutations in KRT32 among PRP patients result in NF-κB hyperactivation. Importantly, Krt32 knockout mice exhibit a PRP-like dermatitis phenotype, suggesting compromised anti-inflammatory function of keratinocytes in response to external pro-inflammatory stimuli. This study proposes a role for KRT32 in regulating inflammatory immune responses, with damaging variants in KRT32 being an important driver in PRP development. These findings offer insights into the regulation of skin immune homeostasis by keratin and open up the possibility of using KRT32 as a therapeutic target for PRP.

Asymmetric Mannich Reaction of Isatin-Derived Ketimines with α-Fluoroindanones Catalyzed by a Chiral Phase-Transfer Catalyst.

A highly enantioselective Mannich reaction of α-fluoroindanones with isatin-derived N-Boc-ketimines catalyzed by a quinine-derived phase-transfer catalyst was developed. A variety of 3-substituted 3-amino-2-oxindoles bearing fluorine-containing, vicinal, tetrasubstituted stereocenters were constructed using this protocol in high yields (83-95%), with moderate to excellent enantioselectivities (66-91%) and high diastereoselectivities (up to >99:1).

Pleurotus abieticola Polysaccharide Alleviates Hyperlipidemia Symptoms via Inhibition of Nuclear Factor-κB/Signal Transducer and Activator of Transcription 3-Mediated Inflammatory Responses.

Hyperlipidemia (HLP) is a metabolic syndrome induced by obesity, which has been widely recognized as a significant threat to human health. Pleurotus abieticola, an edible lignin-degrading fungus, remains relatively understudied in terms of its bioactivity and medicinal properties. In this study, the lipid-lowering effect of Pleurotus abieticola polysaccharide (PAPS1) was systematically explored in high-fat diet (HFD)-induced HLP mice. The findings demonstrated that the administration of PAPS1 significantly inhibited bodyweight gain, ameliorated blood glucose and lipid levels, reduced fat accumulation, and mitigated hepatic injury in HLP mice. In addition, PAPS1 demonstrated the capability to increase the levels of three distinct fecal metabolites while simultaneously reducing the levels of eight other fecal metabolites in HLP mice. According to biological detection, PAPS1 reduced the hepatic level of reactive oxygen species (ROS) and pro-inflammatory factors, such as tumor necrosis factor (TNF)-α and interleukin (IL)-1ß, -6, -17A, -22, and -23, and increased the expression of anti-inflammatory factor IL-10. Combined with proteomics, Western blot and immunohistochemistry analysis showed that PAPS1 exerted suppressive effects on inflammation and oxidative damage by inhibiting the nuclear factor-κB (NF-κB)/signal transducer and activator of transcription 3 (STAT3) signaling pathway in HLP mice. These findings offer evidence supporting the effectiveness of PAPS1 as a therapeutic agent in reducing lipid levels through its targeting of chronic inflammation.

Aymmetric Aza-Friedel-Crafts Reaction of Isatin-Derived Ketimines with Indoles Catalyzed by a Chiral Phase-Transfer Catalyst.

A highly enantioselective aza-Friedel-Crafts reaction of 1H-indoles with isatin-derived N-Cbz-ketimines catalyzed by quinine-derived phase-transfer catalysts was developed. A series of chiral 3-aminobisindole compounds containing a tetrasubstituted stereocenter were constructed by this protocol in high yields (82-91%) and moderate to excellent enantioselectivities (46-94% ee).

Novel Chiral Thiourea Derived from Hydroquinine and l-Phenylglycinol: An Effective Catalyst for Enantio- and Diastereoselective Aza-Henry Reaction.

A series of chiral thiourea bearing multiple H-bond donors derived from hydroquinine has been reported. The aza-Henry reaction of isatin-derived ketimines and long-chain nitroalkanes catalyzed by these chiral thioureas can achieve high enantioselectivity (78-99% ee) and excellent diastereoselectivity (up to 99:1). This work is the first report on long-chain nitroalkanes as substrates with excellent diastereoselectivity in metal-free catalytic systems.

Enantioselective addition of thiols to trifluoromethyl ketimines: synthesis of N,S-ketals.

An efficient enantioselective addition of thiols to acyclic trifluoromethyl ketimines has been established by using a bifunctional squaramide catalyst, which was derived from quinine, and the reaction was completed in 5 to 10 min. The construction of chiral tetrasubstituted carbon centers bearing trifluoromethylated N,S-ketals has been achieved in high yields (up to 96% yield) with excellent enantioselectivities (up to 99% ee).

Monascin exhibits neuroprotective effects in rotenone model of Parkinson's disease via antioxidation and anti-neuroinflammation.

Increasing evidence verified that oxidative stress and neuroinflammatory response exacerbates motor deficits and increases neuronal loss in several rodent models of Parkinson's disease. In the present study, we explore the neuroprotective effects of monascin in a rotenone-induced Parkinson's disease model as well as the underlying mechanisms. Our results showed that monascin remarkedly attenuated behavioral impairments and the depletion of dopaminergic neurons induced by rotenone in the rats. Besides, monascin decreased the levels of pro-inflammatory factors such as interleukin-1ß, interleukin-6, tumor necrosis factor-α and oxidative stress marker malondialdehyde while promoted the expression of superoxide dismutase, glutathione peroxidase and other antioxidant factors. Further detection of the expression of related proteins showed that monascin significantly promoted the expression of proliferator-activated receptor-gamma, F-E2-related factor 2 and heme oxygenase-1, but inhibited the expression of NF-κB. What's more, levels of growth factors that are essential for neuronal and synaptic function were increased under the effects of monascin. All in all, our results revealed that monascin exerted neuroprotective effects in rotenone model of Parkinson's disease via antioxidation and anti-neuroinflammation.

Synthesis of 4-Azaindolines Using Phase-Transfer Catalysis via an Intramolecular Mannich Reaction.

A series of bifunctional asymmetric phase-transfer catalysts containing novel fluorine-containing urea groups derived from cinchona alkaloids have been synthesized and successfully applied in the asymmetric intramolecular Mannich reaction. The 4-azaindoline products bearing multiple substrates were obtained in excellent yield (90-99%), with high enantioselectivity (up to 95%) and diastereoselectivity (up to >99:1).

Andrastone A From the Deep-Sea-Derived Fungus Penicillium allii-sativi Acts as an Inducer of Caspase and RXRα-Dependent Apoptosis.

Two new (1, 2) and one known (3) meroterpenoids were isolated from the deep-sea-derived fungus Penicillium allii-sativi. The relative structures of new compounds were determined on the basis of an extensive analysis of the NMR and MS data, and the absolute configurations were established by ECD calculations. Andrastone A (1) is a rare andrastin bearing an unusual cyclopentan-1,3-dione. It shows a selectively antiproliferative effect against HepG2 tumor cells with an IC50 value of 7.8 µM. Mechanism study showed that apoptosis via Caspase and RXRα pathways are responsible for the inhibitory effect.

Visualising reactive oxygen species in live mammals and revealing of ROS-related system.

Of all the aerobic respiration by-products, cytotoxic superoxide derived from mitochondrial-leaked electrons, is the only one known to be disposed of intracellularly. Is this fate the only destiny for mitochondrial-leaked electrons? When Cynomolgus monkeys were injected intravenously with reactive oxygen species (ROS) indicators, the connective tissues of dura mater, facial fascia, pericardium, linea alba, dorsa fascia and other body parts, emitted specific and intense fluorescent signals. Moreover, the fluorescent signals along the linea alba of SD rats, did not result from the local presence of ROS but from the interaction of ROS indicators with electrons flowing through this tissue. Furthermore, the electrons travelling along the linea alba of mice were revealed to originate from mitochondria. These data suggest that mitochondrial-leaked electrons may be transported extracellularly to a hitherto undescribed system of connective tissues, which is pervasively networked, electrically conductive and metabolically related.

Highly Enantioselective Synthesis of Acyclic N,N'-Acetals by Chiral Urea Derived from Quinine Catalyzed the Addition of Aryl Amines to Isatin-Derived Ketimines.

N,N'-Acetals are sensitive compounds, and the challenging asymmetric synthesis of acyclic N,N'-acetals by the general addition of amines to ketimines has never been reported so far. In this study, highly enantioselective addition of aryl amines to isatin-derived ketimines catalyzed by chiral urea derived from quinine was developed. A series of new acyclic N,N'-acetals were constructed by this protocol in high to excellent yields (78-99%) and high to excellent enantioselectivities (76-96% ee).

LncRNA HOTAIR targets miR-126-5p to promote the progression of Parkinson's disease through RAB3IP.

Parkinson's disease (PD) is a common neurological disorder characterized by dopaminergic (DA) neuron degeneration and death in the midbrain, and the long noncoding RNA HOTAIR has been shown to affect disease progression in PD. In this study, we aimed to further illustrate the molecular mechanism of HOTAIR in PD. Bioinformatics analysis was utilized to determine the potential downstream targets of HOTAIR in PD. Luciferase assay and the RNA Binding Protein Immunoprecipitation (RIP) assay were used to validate the existence of binding sites between competing endogenous RNAs (ceRNAs). Real-time quantitative polymerase chain reaction (qRT-PCR) and Western blotting indicated that HOTAIR and RAB3IP increased while miR-126-5p decreased in PD cells and PD mice. Additionally, the CCK-8 assay and flow cytometric analysis indicated that the knockdown of HOTAIR and RAB3IP and the overexpression of miR-126-5p significantly increased cell proliferation and reduced apoptosis in PD cells. Furthermore, the results of in vivo experiments suggested that knockdown of HOTAIR expression increased the number of TH-positive cells and the number of α-synuclein-positive cells decreased while reducing the apoptosis rate among DA neurons. Our study confirmed that HOTAIR promotes PD progression by regulating miR-126-5p and RAB3IP in a ceRNA-dependent manner and further clarified how HOTAIR works in PD.

Direct enantio- and diastereoselective Mannich reactions of isatin-derived ketimines with oxo-indanecarboxylates catalyzed by chiral thiourea derived from hydroquinidine.

A highly diastereo- and enantioselective Mannich reaction of isatin-derived ketimines with oxo-indanecarboxylates catalyzed by chiral thiourea derived from hydroquinidine has been developed. A series of 3-substituted 3-amino-oxindoles containing assembled bicyclic rings linked by a C-C bond were constructed by this protocol in excellent yields (92-99%) with high enantioselectivities (85-99% ee) and diastereoselectivities (up to >99 : 1 dr).

Bifunctional Thiourea-Ammonium Salt Catalysts Derived from Cinchona Alkaloids: Cooperative Phase-Transfer Catalysts in the Enantioselective Aza-Henry Reaction of Ketimines.

An efficient enantioselective aza-Henry reaction of aryl α-ketoester-derived ketimines has been realized by using bifunctional thiourea-ammonium salt phase-transfer catalysts, which were derived from quinine. A variety of aryl α-ketoester-derived N-Ts ketimines were investigated, and the corresponding products were obtained in high to excellent yields (up to 99%) with good to high enantioselectivities (up to >99% ee).

Preparation of prolinamide with adamantane for aldol reaction catalysis in brine and separation using a poly(AN-MA-ß-CD) nanofibrous film via host-guest interaction.

Prolinamides with double-H potential were prepared and employed as organocatalysts in asymmetric aldol reactions. The catalyst with adamantane showed improved catalytic activity, which was further enhanced by using brine as the solvent. A series of aldol reactions in brine at 0 °C provided good yields (up to 98%) with high diastereoselectivities (>99 : 1) and enantioselectivities (>99%). The prepared catalyst was adsorbed by a nanofibrous film of poly(AN-MA-ß-CD) via host-guest interaction in the reaction system. The catalyst was separated from the film by applying ultrasound, with a total recovery of 96.2%. The catalyst was reused up to five times without a significant change in diastereoselectivity and enantioselectivity.

Novel α-amino acid-derived phase-transfer catalyst application to a highly enantio- and diastereoselective nitro-Mannich reaction.

New quaternary ammonium types of bifunctional asymmetric phase-transfer catalysts bearing multiple hydrogen-bonding donors derived from α-amino acids were readily prepared and found to be highly efficient in the asymmetric nitro-Mannich reactions of amidosulfones. Very broad substrate generality was observed, and the products were achieved in high enantio-/diastereoselectivities (90->99.9% ee, 90 : 10 to 92 : 8 dr). Compared with previous reports, the enantioselectivity of aliphatic amidosulfones has been improved to a high level (91-93% ee).

Enantio- and Diastereoselective Nitro-Mannich Reaction of α-Aryl Nitromethanes with Amidosulfones Catalyzed by Phase-Transfer Catalysts.

A high-yield, highly diastereo- and enantioselective nitro-Mannich reaction of α-aryl nitromethanes with amidosulfones catalyzed by a novel chiral phase-transfer catalyst, bearing multiple H-bonding donors, derived from quinine was developed. A variety of α-aryl nitromethanes and amidosulfones were investigated; and the corresponding products were obtained in excellent yields with excellent diastereo- and enantioselectivities (up to 99% yield, > 99:1 dr and >99% ee). As a demonstration of synthetic utility, the resulting ß-nitroamines could be converted to corresponding meso-symmetric and optically pure unsymmetric anti-1,2-diarylethylenediamines.