Vitamin A Metabolism by Dendritic Cells Triggers an Antimicrobial Response against Mycobacterium tuberculosis.

Epidemiological evidence correlates low serum vitamin A (retinol) levels with increased susceptibility to active tuberculosis (TB); however, retinol is biologically inactive and must be converted into its bioactive form, all-trans retinoic acid (ATRA). Given that ATRA triggers a Niemann-Pick type C2 (NPC2)-dependent antimicrobial response against Mycobacterium tuberculosis, we investigated the mechanism by which the immune system converts retinol into ATRA at the site of infection. We demonstrate that granulocyte-macrophage colony-stimulating factor (GM-CSF)-derived dendritic cells (DCs), but not macrophages, express enzymes in the vitamin A metabolic pathway, including aldehyde dehydrogenase 1 family, member a2 (ALDH1A2) and short-chain dehydrogenase/reductase family, member 9 (DHRS9), enzymes capable of the two-step conversion of retinol into ATRA, which is subsequently released from the cell. Additionally, mRNA and protein expression levels of ALDH1A2 and DC marker CD1B were lower in tuberculosis lung tissues than in normal lung. The conditioned medium from DCs cultured with retinol stimulated antimicrobial activity from M. tuberculosis-infected macrophages, as well as the expression of NPC2 in monocytes, which was blocked by specific inhibitors, including retinoic acid receptor inhibitor (RARi) or N,N-diethylaminobenzaldehyde (DEAB), an ALDH1A2 inhibitor. These results indicate that metabolism of vitamin A by DCs transactivates macrophage antimicrobial responses.IMPORTANCE Tuberculosis (TB) is the leading cause of death by a single infectious agent worldwide. One factor that contributes to the success of the microbe is the deficiency in immunomodulatory nutrients, such as vitamin A (retinol), which are prevalent in areas where TB is endemic. Clinical trials show that restoration of systemic retinol levels in active TB patients is ineffective in mitigating the disease; however, laboratory studies demonstrate that activation of the vitamin A pathway in Mycobacterium tuberculosis-infected macrophages triggers an antimicrobial response. Therefore, the goal of this study was to determine the link between host retinol levels and retinoic acid-mediated antimicrobial responses against M. tuberculosis By combining established in vitro models with in situ studies of lung tissue from TB patients, this study demonstrates that the innate immune system utilizes transcellular metabolism leading to activation between dendritic cells and macrophages as a means to combat the pathogen

New OH Zeeman measurements of magnetic field strengths in molecular clouds

We present the results of a new survey of 23 molecular clouds for the Zeeman effect in OH undertaken with the ATNF Parkes 64-m radio telescope and the NRAO Green Bank 43-m radio telescope. The Zeeman effect was clearly detected in the cloud associated with the HII region RCW 38, with a field strength of 38+/-3 micro-Gauss, and possibly detected in a cloud associated with the HII region RCW 57, with a field strength of -203+/-24 micro-Gauss. The remaining 21 measurements give formal upper limits to the magnetic field strength, with typical 1-sigma sensitivities <20 micro-Gauss. For 22 of the molecular clouds we are also able to determine thecolumn density of the gas in which we have made a sensitive search for the Zeeman effect. We combine these results with previous Zeeman studies of 29 molecular clouds, most of which were compiled by Crutcher (1999), for a comparsion of theoretical models with the data. This comparison implies that if the clouds can be modeled as initially spherical with uniform magnetic fields and densities that evolve to their final equilibrium state assuming flux-freezing then the typical cloud is magnetically supercritical, as was found by Crutcher (1999). If the clouds can be modeled as highly flattened sheets threaded by uniform perpendicular fields, then the typical cloud is approximately magnetically critical, in agreement with Shu et al. (1999), but only if the true values of the field for the non-detections are close to the 3-sigma upper limits. If instead these values are significantly lower (for example, similar to the 1-sigma limits), then the typical cloud is generally magnetically supercritical.Comment: 39 pages, 7 figures. Accepted for publication in Ap

Effect of real-time computer-aided polyp detection system (ENDO-AID) on adenoma detection in endoscopists-in-training: a randomized trial

Background The effect of computer-aided polyp detection (CADe) on adenoma detection rate (ADR) among endoscopists-in-training remains unknown. Methods We performed a single-blind, parallel-group, randomized controlled trial in Hong Kong between April 2021 and July 2022 (NCT04838951). Eligible subjects undergoing screening/surveillance/diagnostic colonoscopies were randomized 1:1 to receive colonoscopies with CADe (ENDO-AID(OIP-1), Olympus Co., Japan) or not (control) during withdrawal. Procedures were performed by endoscopists-in-training with <500 procedures and <3 years’ experience. Randomization was stratified by patient age, sex, and endoscopist experience (beginner vs intermediate-level, <200 vs 200-500 procedures). Image enhancement and distal attachment devices were disallowed. Subjects with incomplete colonoscopies or inadequate bowel preparation were excluded. Treatment allocation was blinded to outcome assessors. The primary outcome was ADR. Secondary outcomes were ADR for different adenoma sizes and locations, mean number of adenomas, and non-neoplastic resection rate. Results 386 and 380 subjects were randomized to CADe and control groups, respectively. The overall ADR was significantly higher in CADe than control group (57.5% vs 44.5%, adjusted relative risk 1.41, 95%CI 1.17-1.72, p<0.001). The ADRs for <5mm (40.4% vs 25.0%) and 5-10mm adenomas (36.8% vs 29.2%) were higher in CADe group. The ADRs were higher in CADe group in both right (42.0% vs 30.8%) and left colon (34.5% vs 27.6%), but there was no significant difference in advanced ADR. The ADRs were higher in CADe group among beginners (60.0% vs 41.9%) and intermediate-level endoscopists (56.5% vs 45.5%). Mean number of adenomas (1.48 vs 0.86) and non-neoplastic resection rate were higher in CADe group (52.1% vs 35.0%). Conclusions Among endoscopists-in-training, the use of CADe during colonoscopies was associated with increased overall ADR. (ClinicalTrials.gov: NCT04838951

Segregation and ordering at the (1×2) reconstructed Pt80Fe20(110) surface determined by low-energy electron diffraction

The surface of an ordered Pt80Fe20(110) crystal exhibits (1×2) and (1×3) reconstructions depending on the annealing treatment after ion bombardment. The (1×3) structure occurs after annealing in the range 750 to 900 K. Annealing above 1000 K leads to the (1×2) structure, which is, from the present result, unambiguously attributed to the same geometrical reconstruction as Pt(110) but with smaller relaxation amplitudes: a detailed low-energy electron-diffraction analysis concludes to a missing-row structure with row pairing in layers 2 and 4 accompanied by a buckling in layers 3 and 5. The top layer spacing is contracted by 13%, and further relaxations are detectable down to the fifth layer. The specific diffraction spots associated with the bulk chemical ordering along the dense [1¯10] rows are very weak: The I(V) analysis shows that this chemical ordering is absent in the outermost ‘‘visible’’ rows but gradually recovers over five to six layers deep. General Pt enrichment is found in the surface ‘‘visible’’ rows (in layers 1–3), but segregation and order yield a subtle redistribution of Pt and Fe atoms in deeper rows: For example, in layer 2, the visible row is Pt rich, whereas the other row (buried under layer 1) is enriched with Fe. Because of the many parameters considered, a fit procedure was applied to a large data basis to solve the structure; the results were confirmed and illustrated subsequently by a standard I(V) analysis for the most relevant parameters. The final r factors are RDE=0.36, RP=0.34, and RZJ=0.14 for two beam sets at normal and oblique incidence consisting of 26 and 21 beams, respectively

Hydrostatic pressure-induced modifications of structural transitions lead to large enhancements of magnetocaloric effects in MnNiSi-based systems

A remarkable decrease of the structural transition temperature of MnNiSi from 1200 to transitions, leading to a large magnetocaloric effect near room temperature. Application of relatively low hydrostatic pressures (∼2.4 kbar) lead to an extraordinary enhancement of the isothermal entropy change from -ΔS=44 to 89 J/kgK at ambient and 2.4 kbar applied pressures, respectively, for a field change of ΔB=5T, and is associated with a large relative volume change of about 7% with P=2.4 kbar

LAB/NTAL Facilitates Fungal/PAMP-induced IL-12 and IFN-γ Production by Repressing β-Catenin Activation in Dendritic Cells.

Fungal pathogens elicit cytokine responses downstream of immunoreceptor tyrosine-based activation motif (ITAM)-coupled or hemiITAM-containing receptors and TLRs. The Linker for Activation of B cells/Non-T cell Activating Linker (LAB/NTAL) encoded by Lat2, is a known regulator of ITAM-coupled receptors and TLR-associated cytokine responses. Here we demonstrate that LAB is involved in anti-fungal immunity. We show that Lat2−/− mice are more susceptible to C. albicans infection than wild type (WT) mice. Dendritic cells (DCs) express LAB and we show that it is basally phosphorylated by the growth factor M-CSF or following engagement of Dectin-2, but not Dectin-1. Our data revealed a unique mechanism whereby LAB controls basal and fungal/pathogen-associated molecular patterns (PAMP)-induced nuclear β-catenin levels. This in turn is important for controlling fungal/PAMP-induced cytokine production in DCs. C. albicans- and LPS-induced IL-12 and IL-23 production was blunted inLat2−/− DCs. Accordingly, Lat2−/− DCs directed reduced Th1 polarization in vitro and Lat2−/−mice displayed reduced Natural Killer (NK) and T cell-mediated IFN-γ production in vivo/ex vivo. Thus our data define a novel link between LAB and β-catenin nuclear accumulation in DCs that facilitates IFN-γ responses during anti-fungal immunity. In addition, these findings are likely to be relevant to other infectious diseases that require IL-12 family cytokines and an IFN-γ response for pathogen clearance

Smc5/6 coordinates formation and resolution of joint molecules with chromosome morphology to ensure meiotic divisions

During meiosis, Structural Maintenance of Chromosome (SMC) complexes underpin two fundamental features of meiosis: homologous recombination and chromosome segregation. While meiotic functions of the cohesin and condensin complexes have been delineated, the role of the third SMC complex, Smc5/6, remains enigmatic. Here we identify specific, essential meiotic functions for the Smc5/6 complex in homologous recombination and the regulation of cohesin. We show that Smc5/6 is enriched at centromeres and cohesin-association sites where it regulates sister-chromatid cohesion and the timely removal of cohesin from chromosomal arms, respectively. Smc5/6 also localizes to recombination hotspots, where it promotes normal formation and resolution of a subset of joint-molecule intermediates. In this regard, Smc5/6 functions independently of the major crossover pathway defined by the MutLγ complex. Furthermore, we show that Smc5/6 is required for stable chromosomal localization of the XPF-family endonuclease, Mus81-Mms4Eme1. Our data suggest that the Smc5/6 complex is required for specific recombination and chromosomal processes throughout meiosis and that in its absence, attempts at cell division with unresolved joint molecules and residual cohesin lead to severe recombination-induced meiotic catastroph

Singing the same tune? International continuities and discontinuities in how police talk about using force

This article focuses on a research project conducted in six jurisdictions: England, The Netherlands, Germany, Australia, Venezuela, and Brazil. These societies are very different ethnically, socially, politically, economically, historically and have wildly different levels of crime. Their policing arrangements also differ significantly: how they are organised; how their officers are equipped and trained; what routine operating procedures they employ; whether they are armed; and much else besides. Most relevant for this research, they represent policing systems with wildly different levels of police shootings, Police in the two Latin American countries represented here have a justified reputation for the frequency with which they shoot people, whereas at the other extreme the police in England do not routinely carry firearms and rarely shoot anyone. To probe whether these differences are reflected in the way that officers talk about the use of force, police officers in these different jurisdictions were invited to discuss in focus groups a scenario in which police are thwarted in their attempt to arrest two youths (one of whom is a known local criminal) by the youths driving off with the police in pursuit, and concludes with the youths crashing their car and escaping in apparent possession of a gun, It might be expected that focus groups would prove starkly different, and indeed they were, but not in the way that might be expected. There was little difference in affirmation of normative and legal standards regarding the use of force. It was in how officers in different jurisdictions envisaged the circumstances in which the scenario took place that led Latin American officers to anticipate that they would shoot the suspects, whereas officers in the other jurisdictions had little expectation that they would open fire in the conditions as they imagined them to be