Multi-level insights into the immuno-oncology-microbiome axis: From biotechnology to novel therapies.

The multifaceted interactions among the immune system, cancer cells and microbial components have established a novel concept of the immuno-oncology-microbiome (IOM) axis. Microbiome sequencing technologies have played a pivotal role in not only analyzing how gut microbiota affect local and distant tumors, but also providing unprecedented insights into the intratumor host-microbe interactions. Herein, we discuss the emerging trends of transiting from bulk-level to single cell- and spatial-level analyses. Moving forward with advances in biotechnology, microbial therapies, including microbiota-based therapies and bioengineering-inspired microbes, will add diversity to the current oncotherapy paradigm.

Upconversion luminescence of cubic and hexagonal structured SrTa4O11:Er3+/Yb3+ phosphors.

Cubic and hexagonal structured SrTa4O11(STO):Er3+/Yb3+ phosphors were synthesized by a solid state reaction (SSR) and molten salt synthesis (MSS). The upconversion luminescence (UCL) intensity of these samples was investigated. Hexagonal STO:Er3+/Yb3+ with much or a little ß-Ta2O5 can be synthesized by SSR in air or vacuum, respectively, and the UCL intensity of the sample synthesized by SSR in a vacuum is higher. Cubic STO:Er3+/Yb3+ can be synthesized by MSS with KCl flux, and hexagonal STO:Er3+/Yb3+ can be synthesized by MSS with B2O3 flux, which has the strongest UCL intensity among all the samples compared with samples prepared by SSR. The sample by MSS with B2O3 flux was acid pickled (AP) with HCl solution, and the green UCL intensity increased by 2.18 times, which reached 32.95% for ß-NaYF4:Er3+/Yb3+. The UCL intensity of the hexagonal STO:Er3+/Yb3+ is much higher than that of the cubic structure, which is due to the layered structure and the non-central symmetry of the Er3+/Yb3+ doped sites in hexagonal STO:Er3+/Yb3+. The temperature sensitivity of samples is evaluated by luminescence intensity ratio (LIR) technology. The maximum relative sensitivity is 0.0099 K-1 at 303 K. All the results show that hexagonal STO:Er3+/Yb3+ has excellent pure green UCL intensity and high temperature sensitivity, which can be used in UCL display and temperature sensing.

A novel white Y2(Ti0.8Hf0.2)2O7: Eu phosphors regulated by HfO2 exhibiting low color shifting for high temperature.

The development of white phosphors that can be activated in near-ultraviolet light is highly important in the field of LED lighting. In this work, a series of color-tunable Y2(Ti1-xHfx)2O7:Eu phosphors were prepared by adjusting the HfO2 and Eu3+ concentrations. In particular, white Y2(Ti0.8Hf0.2)2O7:Eu phosphors were successfully synthesized and emitted a broad band covering the entire visible light region upon excitation with 340 nm UV light. The white banded materials were composed of Eu2+ and Eu3+ emissions and HfO2 defect emission. The formation of Eu2+ ions was caused by the introduction of HfO2, which causes self-reduction of Eu3+ ions but does not require additional reducing agents. The white Y2(Ti0.8Hf0.2)2O7:Eu phosphors exhibit low color shifting at high temperature, which is very important for LED applications. The chromaticity shift of the Y2(Ti0.8Hf0.2)2O7:0.2Eu phosphor is 2.83 × 10-2 at 503 K, which is only 54.8 % that of commercial three-color white phosphors at the same temperature. The Ra value did not decrease significantly with increasing temperature and reached 90.2 at 383 K. Y2 (Ti0.8Hf0.2)2O7:0.2Eu phosphors were assembled with a 365 nm LED chip to fabricate a WLED device that showed excellent white-colored coordinates (0.345, 0.358) and a high Ra value of 90.1 under a 300 mA current.

Ursodeoxycholic acid and COVID-19 outcomes: a cohort study and data synthesis of state-of-art evidence.

BACKGROUND: The potential of ursodeoxycholic acid (UDCA) in inhibiting angiotensin-converting enzyme 2 was demonstrated. However, conflicting evidence emerged regarding the association between UDCA and COVID-19 outcomes, prompting the need for a comprehensive investigation. RESEARCH DESIGN AND METHODS: Patients diagnosed with COVID-19 infection were retrospectively analyzed and divided into two groups: the UDCA-treated group and the control group. Kaplan-Meier recovery analysis and Cox proportional hazards models were used to evaluate the recovery time and hazard ratios. Additionally, study-level pooled analyses for multiple clinical outcomes were performed. RESULTS: In the 115-patient cohort, UDCA treatment was significantly associated with a reduced recovery time. The subgroup analysis suggests that the 300 mg subgroup had a significant (adjusted hazard ratio: 1.63 [95% CI, 1.01 to 2.60]) benefit with a shorter duration of fever. The results of pooled analyses also show that UDCA treatment can significantly reduce the incidence of severe/critical diseases in COVID-19 (adjusted odds ratio: 0.68 [95% CI, 0.50 to 0.94]). CONCLUSIONS: UDCA treatment notably improves the recovery time following an Omicron strain infection without observed safety concerns. These promising results advocate for UDCA as a viable treatment for COVID-19, paving the way for further large-scale and prospective research to explore the full potential of UDCA.

Cooling Condition Effect on Spectral Properties and Smartphone-Based Anticounterfeiting Application of Zn3Ga2Ge2O10/Cr3+ Phosphors.

The influence of cooling history for the Zn3Ga2Ge2O10/Cr3+ phosphors prepared by solid state reaction on the spectral properties was discovered, and an anticounterfeiting scheme based on the identification with smartphone was proposed and experimentally demonstrated using the studied phosphors. A combination of color-tunable visible fluorescence emission and near-infrared (NIR) afterglow emission in Zn3Ga2Ge2O10/x mol % Cr3+(x = 0, 0.05, 1, 2, 3, and 4) phosphors to achieve multimode anticounterfeiting was reported. It is found that with the increasing Cr3+ concentrations, the visible emission can be tuned from green, light pink, and light red to deep red under 254 nm ultraviolet (UV) excitation. This phenomenon is related to the formation of oxygen vacancies in the host during the process of natural cooling and the characteristic emission of Cr3+. In addition, the persistent time of the Cr3+ emission centered at 700 nm can be also tuned by various Cr3+ concentrations. A possible mechanism was deduced to explain the afterglow phenomenon. Lastly, a flower pattern applied in anticounterfeiting was fabricated using the Zn3Ga2Ge2O10/x mol % Cr3+ (x = 0, 0.05, 1, 2, 3, and 4) phosphors to present tunable color and NIR afterglow signals at different excitation modes, and the camera of smartphone was chosen as a detection tool to take the NIR images. The results obtained above suggest that the prepared phosphors at natural cooling condition have great potential in affording advanced optical anticounterfeiting.

Highly Reactive Group I Introns Ubiquitous in Pathogenic Fungi.

Systemic fungal infections are a growing public health threat, and yet viable antifungal drug targets are limited as fungi share a similar proteome with humans. However, features of RNA metabolism and the noncoding transcriptomes in fungi are distinctive. For example, fungi harbor highly structured RNA elements that humans lack, such as self-splicing introns within key housekeeping genes in the mitochondria. However, the location and function of these mitochondrial riboregulatory elements has largely eluded characterization. Here we used an RNA-structure-based bioinformatics pipeline to identify the group I introns interrupting key mitochondrial genes in medically relevant fungi, revealing their fixation within a handful of genetic hotspots and their ubiquitous presence across divergent phylogenies of fungi, including all highest priority pathogens such as Candida albicans, Candida auris, Aspergillus fumigatus and Cryptococcus neoformans. We then biochemically characterized two representative introns from C. albicans and C. auris, demonstrating their exceptionally efficient splicing catalysis relative to previously-characterized group I introns. Indeed, the C. albicans mitochondrial intron displays extremely rapid catalytic turnover, even at ambient temperatures and physiological magnesium ion concentrations. Our results unmask a significant new set of players in the RNA metabolism of pathogenic fungi, suggesting a promising new type of antifungal drug target.

Molten Salt Synthesized CaTa4O11:Er3+/Yb3+ with Superior Upconversion Luminescence.

Low phonon tantalate-based phosphors with a layer structure are considered to have excellent upconversion luminescence (UCL) intensity, which could be reduced due to the existence of impure phase defects and inappropriate doped rare earth ions. To improve their UCL performance, we have prepared single-phase CaTa4O11:Er3+/Yb3+ samples by a molten salt synthesis (MSS) using KCl as the reaction medium and compared its UCL properties with counterparts made by a conventional solid-state reaction (SSR) in this study. We have demonstrated that the MSS samples have a much higher UCL intensity under 980 nm laser excitation than the SSR ones due to accurate replacement of Ca2+ sites by Er3+/Yb3+ in high-purity single-phase MSS samples. We have further enhanced the green UCL intensity of the MSS samples by 1.57 times via acid picking (AP). Under 980 nm laser excitation at a high powder density of 61.3 W/cm2, the green UCL intensity of the MSS-AP samples can reach 3.72 times that of the SSR-AP samples. For potential luminescence thermometry applications, the maximum absolute sensitivity (SA) of the MSS-AP samples reaches 0.01316 K-1 at 501 K based on the luminescence intensity ratio. This study shows that CaTa4O11:Er3+/Yb3+ phosphors prepared by the MSS method are single-phase samples with excellent pure green UCL as a suitable temperature sensing material.

Multicolor-emitting Er3+ and Er3+/Yb3+ doped Zn2GeO4 phosphors combining static and dynamic identifications for advanced anti-counterfeiting application.

Anti-counterfeiting labels based on luminescence materials are a newly emerging technique for protecting legal goods and intellectual property. In the anti-counterfeiting field to prevent forgery and cloning, luminescence materials with properties different from the commercialized and traditional ones are in urgent need. In this work, multicolor-emitting Er3+ single-doped and Er3+/Yb3+ co-doped Zn2GeO4 phosphors combining static and dynamic identifications were developed in order to achieve advanced anti-counterfeiting application. The variation of trap content with increasing the doping content of rare earth ions was analyzed through X - ray photoelectron spectroscopy, thermoluminescence analysis. It was found that there are two types of traps with different depth in Zn2GeO4 phosphors. The depths of the traps were experimentally confirmed to be 0.68 and 0.79 eV, respectively. The transient photocurrent response measurement confirmed the existence of charge carriers, and the mechanism for long persistent luminescence was deduced. The multicolor upconversion mechanisms under 980 and 1550 nm excitation were also discovered. Based on the multicolor steady and transient emission features, an anti-counterfeiting pattern was designed using the phosphors. Static and dynamic identification was demonstrated and presented in detail. Finally, it is indicated that the studied phosphors are excellent candidates for potential applications in luminescence anti-counterfeiting labels.

Making RNA: Using T7 RNA polymerase to produce high yields of RNA from DNA templates.

RNA is playing an ever-growing role in molecular biology and biomedicine due to the many ways it influences gene expression and its increasing use in modern therapeutics. Hence, production of RNA molecules in large quantity and high purity has become essential for advancing basic scientific research and for developing next-generation therapeutics. T7 RNA polymerase (RNAP) is a DNA-dependent RNA polymerase of bacteriophage origin and it is the most widely-utilized tool enzyme for producing RNA. Here we describe a set of robust methods for in vitro transcribing RNA molecules from DNA templates using T7 RNAP, along with a set of subsequent RNA purification schemes. In the first part of this chapter, we provide the general method for T7 RNAP-based in vitro transcription and technical notes for troubleshooting failed or inefficient transcription. We also provide modified protocols for preparing specialized RNA transcripts. In the second part, we provide two purification methods using either gel-based denaturing purification or size exclusion column-based non-denaturing purification for isolating high-purity RNA products from transcription reaction mixtures and preparing them for downstream applications. This chapter is designed to provide researchers with versatile ways to efficiently generate RNA molecules of interest and a troubleshooting guide should they encounter problems while working with in vitro transcription using T7 RNAP.

Structural insights into intron catalysis and dynamics during splicing.

The group II intron ribonucleoprotein is an archetypal splicing system with numerous mechanistic parallels to the spliceosome, including excision of lariat introns1,2. Despite the importance of branching in RNA metabolism, structural understanding of this process has remained elusive. Here we present a comprehensive analysis of three single-particle cryogenic electron microscopy structures captured along the splicing pathway. They reveal the network of molecular interactions that specifies the branchpoint adenosine and positions key functional groups to catalyse lariat formation and coordinate exon ligation. The structures also reveal conformational rearrangements of the branch helix and the mechanism of splice site exchange that facilitate the transition from branching to ligation. These findings shed light on the evolution of splicing and highlight the conservation of structural components, catalytic mechanism and dynamical strategies retained through time in premessenger RNA splicing machines.

A molecular beacon assay for monitoring RNA splicing.

Small molecule targeting of self-splicing RNAs like group I and II introns has been limited in part by the lack of a universal high-throughput screening platform for studies of splicing inhibition and kinetics. Here, we present the development of a molecular beacon assay for monitoring the accumulation of spliced exons during RNA splicing reactions. In this case, we applied it to the autocatalyzed reaction of the H.c.LSU group II intron found in the mitochondria of the pathogenic dimorphic fungus Histoplasma capsulatum. We find that a molecular beacon with the loop length of 18 nucleotides selectively recognizes ligated exons formed during self-splicing and exhibits high fluorescent signal upon binding of its target. We demonstrate that the fluorescent assay using molecular beacons can be successfully applied to kinetic characterization of the splicing reaction and determination of inhibition constants for small molecules. The results presented herein offer support for a molecular beacon approach to identifying small molecule inhibitors of intron splicing.

Discovery of highly reactive self-splicing group II introns within the mitochondrial genomes of human pathogenic fungi.

Fungal pathogens represent an expanding global health threat for which treatment options are limited. Self-splicing group II introns have emerged as promising drug targets, but their development has been limited by a lack of information on their distribution and architecture in pathogenic fungi. To meet this challenge, we developed a bioinformatic workflow for scanning sequence data to identify unique RNA structural signatures within group II introns. Using this approach, we discovered a set of ubiquitous introns within thermally dimorphic fungi (genera of Blastomyces, Coccidioides and Histoplasma). These introns are the most biochemically reactive group II introns ever reported, and they self-splice rapidly under near-physiological conditions without protein cofactors. Moreover, we demonstrated the small molecule targetability of these introns by showing that they can be inhibited by the FDA-approved drug mitoxantrone in vitro. Taken together, our results highlight the utility of structure-based informatic searches for identifying riboregulatory elements in pathogens, revealing a striking diversity of reactive self-splicing introns with great promise as antifungal drug targets.

Synthesis of ß-Keto Sulfones by a Catalyst-Free Reaction of Aryldiazonium Tetrafluoroborates, Sulfur Dioxide, and Silyl Enol Ethers.

A green approach for the generation of ß-keto sulfones through a reaction of aryldiazonium tetrafluoroborates and sulfur dioxide with silyl enol ether under catalyst- and additive-free conditions has been realized. This reaction proceeds efficiently at room temperature and goes to completion in half an hour. During the reaction process, aryldiazonium tetrafluoroborate is treated with DABCO⋅(SO2 )2 (DABCO=1,4-diazabicyclo[2.2.2]octane) to provide a sulfonyl radical as the key intermediate, which then initiates the transformation. Oxidants or metal catalysts are avoided, and the presence of DABCO also plays an important role in the reaction.