Antibiotic-induced ROS-mediated Fur allosterism contributes to Helicobacter pylori resistance by inhibiting arsR activation of mutS and mutY.

The increasing antibiotic resistance of Helicobacter pylori primarily driven by genetic mutations poses a significant clinical challenge. Although previous research has suggested that antibiotics could induce genetic mutations in H. pylori, the molecular mechanisms regulating the antibiotic induction remain unclear. In this study, we applied various techniques (e.g., fluorescence microscopy, flow cytometry, and multifunctional microplate reader) to discover that three different types of antibiotics could induce the intracellular generation of reactive oxygen species (ROS) in H. pylori. It is well known that ROS, a critical factor contributing to bacterial drug resistance, not only induces damage to bacterial genomic DNA but also inhibits the expression of genes associated with DNA damage repair, thereby increasing the mutation rate of bacterial genes and leading to drug resistance. However, further research is needed to explore the molecular mechanisms underlying the ROS inhibition of the expression of DNA damage repair-related genes in H. pylori. In this work, we validated that ROS could trigger an allosteric change in the iron uptake regulatory protein Fur, causing its transition from apo-Fur to holo-Fur, repressing the expression of the regulatory protein ArsR, ultimately causing the down-regulation of key DNA damage repair genes (e.g., mutS and mutY); this cascade increased the genomic DNA mutation rate in H. pylori. This study unveils a novel mechanism of antibiotic-induced resistance in H. pylori, providing crucial insights for the prevention and control of antibiotic resistance in H. pylori.

Sieving nanometer enantiomers using bound states in the continuum from the metasurface.

Enantioseparation of chiral molecules is an important aspect of life sciences, chemical syntheses, and physics. Yet, the prevailing chemical techniques are not effective. Recently, a few types of plasmonic apertures have been theoretically proposed to distinguish between chiral molecules that vary based on their handedness under circularly polarized illumination. Both analytic calculations and numerical simulation demonstrated that enantioselective optical sieving could be obtained at the nanoscale using a large chiral optical force based on plasmonic resonance enhanced near-field chiral gradients in the aperture. Nevertheless, scaling this scheme to chiral entities of a few nanometer size (i.e., proteins and DNA) faces formidable challenges owing to the fabrication limit of a deeply sub-nanometer aperture and the intense power levels needed for nanoscale trapping. In contrast, by extending the Friedrich-Wintgen theory of the bound states in the continuum (BIC) to photonics, one may explore another mechanism to obtain enantioselective separation of chiral nanoparticles using all-dielectric nanostructures. Here, we present a metasurface composed of an array of silicon (Si) nanodisks embedded with off-set holes, which supports a sharp high-quality (Q) magnetic dipolar (MD) resonance originating from a distortion of symmetry-protected BIC, so called quasi-BIC. We, for the very first time, show that such a quasi-BIC MD resonance can markedly improve the chiral lateral force on the paired enantiomers with linearly polarized illumination. This quasi-BIC MD resonance can enhance the chirality density gradient with alternating sign at each octant around the Si nanodisk, while exhibiting a small gradient for the electromagnetic (EM) density. This offers a chiral lateral force that is 1 order larger in magnitude compared to the non-chiral lateral forces on sub-2 nm chiral objects with a chirality parameter of ±0.01. Moreover, the quasi-BIC MD resonance can excite four pairs of diverse optical potential wells (-13k B T) that are distributed uniformly along the outer edge of the resonator, enabling a simultaneous separation of four paired enantiomers. Our proposed dielectric metasurface may move forward the techniques of enantioseparation and enantiopurification, taking a novel perspective to advanced all-optical enantiopure synthesis.

Decreased CD11c-positive dendritic cells in the tumor microenvironment predict double-hit/triple-hit genotype and survival in diffuse large B-cell lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma and is a potentially curable disease. However, it is heterogenous, and the prognosis is poor if the tumor cells harbor fusions involving MYC and BCL2 or MYC and BCL6 (double-hit [DH] lymphoma), or fusions involving all three genes (triple-hit [TH] lymphoma). Fluorescence in situ hybridization is currently the gold standard for confirming the presence of DH/TH genotypes. However, the test is laborious and not readily available in some laboratories. Germinal center B (GCB) signatures and dual expression of MYC and BCL2 are commonly used as initial screening markers (traditional model) in clinical practice. Our study proposes immunohistochemical markers for more conveniently and accessibly screening DH/TH genotypes in DLBCL. We retrospectively reviewed the clinical and pathological parameters of patients with DLBCL. We assessed the proliferative index, apoptotic index, and tumor microenvironment (TME), with regard to T cells and CD11c(+) dendritic cells, in formalin-fixed paraffin-embedded tissue. We then generated a decision tree as a screening algorithm to predict DH/TH genotypes and employed decision curve analysis to demonstrate the superiority of this new model in prediction. We also assessed the prognostic significance of related parameters. Our study revealed that GCB subtypes, a Ki67 proliferative index higher than 70%, and BCL2 expression were significantly associated with DH/TH genotypes. Decreased CD11c(+) dendritic cells in the TME indicated additional risk. Our proposed screening algorithm outperformed a traditional model in screening for the DH/TH genotypes. In addition, decreased CD11c(+) dendritic cells in the DLBCL TME were an independent unfavorable prognosticator. In conclusion, we provide a convenient, well-performing model that predicts DH/TH genotypes in DLBCL. The prognostic significance of CD11c(+) dendritic cells in the TME might influence the classification and development of immunotherapy for DLBCL in the future.

Lymphadenopathy Associated With Neutralizing Anti-interferon-gamma Autoantibodies Could Have Monoclonal T-cell Proliferation Indistinguishable From Malignant Lymphoma and Treatable by Antibiotics: A Clinicopathologic Study.

Early recognition of adult-onset immunodeficiency associated with neutralizing anti-interferon gamma autoantibodies (anti-IFNγ Abs) remains difficult, and misdiagnoses have been reported. Although febrile lymphadenopathy is among the most common initial manifestations of this disorder, no comprehensive clinicopathologic analysis of lymphadenopathy in patients with anti-IFNγ Abs has been reported. Here, we describe 26 lymph node biopsy specimens from 16 patients. All patients exhibited concurrent disseminated nontuberculous mycobacterial infections, and 31% received a tentative diagnosis of lymphoma at initial presentation. We found 3 distinct histomorphologic patterns: well-formed granuloma (46%), suppurative inflammation or loose histiocytic aggregates (31%), and lymphoproliferative disorder (LPD, 23%). The latter shared some of the features of malignant T-cell lymphoma, IgG4-related disease, and multicentric Castleman disease. Half of the specimens with LPD had monoclonal T cells, and 33.3% were indistinguishable from angioimmunoblastic T-cell lymphoma as per current diagnostic criteria. All lymphadenopathy with LPD features regressed with antibiotics without administration of cytotoxic chemotherapy or immunotherapy. The median follow-up time was 4.3 years. Our study highlights the substantial challenge of distinguishing between lymphoma and other benign lymphadenopathy in the setting of neutralizing anti-IFNγ Abs. Increased vigilance and multidisciplinary discussion among clinicians and pathologists are required to achieve the most appropriate diagnosis and management.

Experimental study on the effects of blending PODEn on performance, combustion and emission characteristics of heavy-duty diesel engines meeting China VI emission standard.

To study the influence of diesel fuel blended with polyoxymethylene dimethyl ethers (PODEn), a new alternative fuel with a high oxygen content and large cetane number, on the combustion characteristics, fuel economies, and emission characteristics of heavy-duty diesel engines that meet China VI emission standards, relevant tests were conducted on a supercharged intercooled high-pressure common-rail diesel engine. The PODEn were blended with diesel fuel at three different ratios (volume fractions of 10%, 20%, and 30%). The test results showed that the PODEn could optimize the combustion process of diesel engines that met the China VI emission standards, effectively improve the thermal efficiencies of diesel engines, and reduce the emissions of hydrocarbon (HC), carbon monoxide (CO), and soot. With an increase in the PODEn blending ratio, the peak values of the in-cylinder pressure, average in-cylinder temperature, and instantaneous heat release rate gradually decreased, and each peak progressively moved forward. As the start of combustion gradually moved forward, the combustion duration was shortened by 0.7-2.8°CA, the heat release process became more concentrated, and the effective thermal efficiency was increased by up to 2.57%. The effective fuel consumption gradually increased, yet the equivalent effective fuel consumption gradually decreased, with the largest drop being as high as 4.55%. The nitrogen oxides (NOx) emission increased slightly, and the emissions of HC, CO, and soot gradually decreased. The emissions of CO and soot declined significantly under high-speed and high-load conditions, with the highest reductions reaching 66.2% and 76.3%, respectively.

Cloning and promoter analysis of palladin 90-kDa, 140-kDa, and 200-kDa isoforms involved in skeletal muscle cell maturation.

OBJECTIVE: Palladin is a ubiquitous phosphoprotein expressed in vertebrate cells that works as a scaffolding protein. Several isoforms deriving from alternative splicing are originated from the palladin gene and involved in mesenchymal and muscle cells formation, maturation, migration, and contraction. Recent studies have linked palladin to the invasive spread of cancer and myogenesis. However, since its discovery, the promoter region of the palladin gene has never been studied. The objective of this study was to predict, identify, and measure the activity of the promoter regions of palladin gene. RESULTS: By using promoter prediction programs, we successfully identified the transcription start sites for the Palld isoforms and revealed the presence of a variety of transcriptional regulatory elements including TATA box, GATA, MyoD, myogenin, MEF, Nkx2-5, and Tcf3 upstream promoter regions. The transcriptome profiling approach confirmed the active role of predicted transcription factors in the mouse genome. This study complements the missing piece in the characterization of palladin gene and certainly contributes to understanding the complexity and enrollment of palladin regulatory factors in gene transcription.

Borneol and Luteolin from Chrysanthemum morifolium Regulate Ubiquitin Signal Degradation.

Targeting the two degradation systems, ubiquitin proteasome pathway and ubiquitin signal autophagy lysosome system, plays an important function in cancer prevention. Borneol is called an "upper guiding drug". Luteolin has demonstrated anticancer activity. The fact that borneol regulates luteolin can be sufficient to serve as an alternative strategy. Borneol activates luteolin to inhibit E1 and 20S activity (IC50 = 118.8 ± 15.7 µM) and perturb the 26S proteasome structure in vitro. Borneol regulates luteolin to inhibit 26S activity (IC50 = 157 ± 19 µM), induces apoptosis (LC50 = 134 ± 4 µM), and causes pre-G1 and G0/G1 arrest in HepG2 cells. Borneol regulates luteolin to induce ubiquitin signal autophagic degradation, resulting in induction of E1, reduction of USP47, and accumulation of p62 in HepG2 reporter cells. Interestingly, luteolin decreased Ub conjugates, while borneol increased the accumulation of Ub conjugates in HepG2 reporter cells. E1, p62, and ubiquitin levels were downregulated in borneol-treated HepG2 reporter cells at 24 h. These observations suggest a potential autophagic inhibitor of borneol that may guide luteolin in the ubiquitin proteasome pathway and the ubiquitin signal autophagic degradation.