Viral DNA Binding to NLRC3, an Inhibitory Nucleic Acid Sensor, Unleashes STING, a Cyclic Dinucleotide Receptor that Activates Type I Interferon.

Immune suppression is a crucial component of immunoregulation and a subgroup of nucleotide-binding domain (NBD), leucine-rich repeat (LRR)-containing proteins (NLRs) attenuate innate immunity. How this inhibitory function is controlled is unknown. A key question is whether microbial ligands can regulate this inhibition. NLRC3 is a negative regulator that attenuates type I interferon (IFN-I) response by sequestering and attenuating stimulator of interferon genes (STING) activation. Here, we report that NLRC3 binds viral DNA and other nucleic acids through its LRR domain. DNA binding to NLRC3 increases its ATPase activity, and ATP-binding by NLRC3 diminishes its interaction with STING, thus licensing an IFN-I response. This work uncovers a mechanism wherein viral nucleic acid binding releases an inhibitory innate receptor from its target.

The Innate Immune Sensor NLRC3 Acts as a Rheostat that Fine-Tunes T Cell Responses in Infection and Autoimmunity.

Appropriate immune responses require a fine balance between immune activation and attenuation. NLRC3, a non-inflammasome-forming member of the NLR innate immune receptor family, attenuates inflammation in myeloid cells and proliferation in epithelial cells. T lymphocytes express the highest amounts of Nlrc3 transcript where its physiologic relevance is unknown. We show that NLRC3 attenuated interferon-γ and TNF expression by CD4+ T cells and reduced T helper 1 (Th1) and Th17 cell proliferation. Nlrc3-/- mice exhibited increased and prolonged CD4+ T cell responses to lymphocytic choriomeningitis virus infection and worsened experimental autoimmune encephalomyelitis (EAE). These functions of NLRC3 were executed in a T-cell-intrinsic fashion: NLRC3 reduced K63-linked ubiquitination of TNF-receptor-associated factor 6 (TRAF6) to limit NF-κB activation, lowered phosphorylation of eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1), and diminished glycolysis and oxidative phosphorylation. This study reveals an unappreciated role for NLRC3 in attenuating CD4+ T cell signaling and metabolism.

Protective and aggressive bacterial subsets and metabolites modify hepatobiliary inflammation and fibrosis in a murine model of PSC.

OBJECTIVE: Conflicting microbiota data exist for primary sclerosing cholangitis (PSC) and experimental models. GOAL: define the function of complex resident microbes and their association relevant to PSC patients by studying germ-free (GF) and antibiotic-treated specific pathogen-free (SPF) multidrug-resistant 2 deficient (mdr2-/- ) mice and microbial profiles in PSC patient cohorts. DESIGN: We measured weights, liver enzymes, RNA expression, histological, immunohistochemical and fibrotic biochemical parameters, faecal 16S rRNA gene profiling and metabolomic endpoints in gnotobiotic and antibiotic-treated SPF mdr2-/- mice and targeted metagenomic analysis in PSC patients. RESULTS: GF mdr2-/- mice had 100% mortality by 8 weeks with increasing hepatic bile acid (BA) accumulation and cholestasis. Early SPF autologous stool transplantation rescued liver-related mortality. Inhibition of ileal BA transport attenuated antibiotic-accelerated liver disease and decreased total serum and hepatic BAs. Depletion of vancomycin-sensitive microbiota exaggerated hepatobiliary disease. Vancomycin selectively decreased Lachnospiraceae and short-chain fatty acids (SCFAs) but expanded Enterococcus and Enterobacteriaceae. Antibiotics increased Enterococcus faecalis and Escherichia coli liver translocation. Colonisation of GF mdr2-/- mice with translocated E. faecalis and E. coli strains accelerated hepatobiliary inflammation and mortality. Lachnospiraceae colonisation of antibiotic pretreated mdr2-/- mice reduced liver fibrosis, inflammation and translocation of pathobionts, and SCFA-producing Lachnospiraceae and purified SCFA decreased fibrosis. Faecal Lachnospiraceae negatively associated, and E. faecalis/ Enterobacteriaceae positively associated, with PSC patients' clinical severity by Mayo risk scores. CONCLUSIONS: We identified novel functionally protective and detrimental resident bacterial species in mdr2-/- mice and PSC patients with associated clinical risk score. These insights may guide personalised targeted therapeutic interventions in PSC patients.

STING Agonist Mitigates Experimental Autoimmune Encephalomyelitis by Stimulating Type I IFN-Dependent and -Independent Immune-Regulatory Pathways.

The cGAS-cyclic GMP-AMP (cGAMP)-stimulator of IFN genes (STING) pathway induces a powerful type I IFN (IFN-I) response and is a prime candidate for augmenting immunity in cancer immunotherapy and vaccines. IFN-I also has immune-regulatory functions manifested in several autoimmune diseases and is a first-line therapy for relapsing-remitting multiple sclerosis. However, it is only moderately effective and can induce adverse effects and neutralizing Abs in recipients. Targeting cGAMP in autoimmunity is unexplored and represents a challenge because of the intracellular location of its receptor, STING. We used microparticle (MP)-encapsulated cGAMP to increase cellular delivery, achieve dose sparing, and reduce potential toxicity. In the C57BL/6 experimental allergic encephalomyelitis (EAE) model, cGAMP encapsulated in MPs (cGAMP MPs) administered therapeutically protected mice from EAE in a STING-dependent fashion, whereas soluble cGAMP was ineffective. Protection was also observed in a relapsing-remitting model. Importantly, cGAMP MPs protected against EAE at the peak of disease and were more effective than rIFN-ß. Mechanistically, cGAMP MPs showed both IFN-I-dependent and -independent immunosuppressive effects. Furthermore, it induced the immunosuppressive cytokine IL-27 without requiring IFN-I. This augmented IL-10 expression through activated ERK and CREB. IL-27 and subsequent IL-10 were the most important cytokines to mitigate autoreactivity. Critically, cGAMP MPs promoted IFN-I as well as the immunoregulatory cytokines IL-27 and IL-10 in PBMCs from relapsing-remitting multiple sclerosis patients. Collectively, this study reveals a previously unappreciated immune-regulatory effect of cGAMP that can be harnessed to restrain T cell autoreactivity.

Inflammatory Monocytes Promote Granuloma-Mediated Control of Persistent Salmonella Infection.

Persistent infections generally involve a complex balance between protective immunity and immunopathology. We used a murine model to investigate the role of inflammatory monocytes in immunity and host defense against persistent salmonellosis. Mice exhibit increased susceptibility to persistent infection when inflammatory monocytes cannot be recruited into tissues or when they are depleted at specific stages of persistent infection. Inflammatory monocytes contribute to the pathology of persistent salmonellosis and cluster with other cells in pathogen-containing granulomas. Depletion of inflammatory monocytes during the chronic phase of persistent salmonellosis causes regression of already established granulomas with resultant pathogen growth and spread in tissues. Thus, inflammatory monocytes promote granuloma-mediated control of persistent salmonellosis and may be key to uncovering new therapies for granulomatous diseases.

Editing the immune system in vivo in mice using CRISPR/Cas9 ribonucleoprotein (RNP)-mediated gene editing of transplanted hematopoietic stem cells.

CRISPR/Cas9-based genome editing has been widely used to evaluate target gene function in biomedical research. The CRISPR/Cas9 system can introduce gene knockout, knock-in and mutations with more ease than earlier generations of genome editing tools. Using CRISPR/Cas9-based genome editing, researchers have successfully modified the DNA of different immune components, including primary T cells, B cells, macrophages, and immune system progenitors, i.e. hematopoietic stem cells (HSCs), which are also known as Lin-Sca1 + Kit + cells (LSKs) in mice. We previously reported that the transplantation of HSCs with lentivirus-mediated CRISPR/Cas9-based genetic modifications into lethally irradiated congenic mice repopulated the ablated recipient immune system with the donor immune system. In this report, we efficiently manipulated CD40 expression in LSK cells using Cas9 RNP and demonstrated the functional impact in a colitis model. Compared to a virus-based strategy, the RNP approach has the potential to enable investigation of target gene biology in any mouse strain and eliminates the time and effort associated with virus production and infection. Therefore, in vivo RNP-based CRISPR/Cas9 gene editing of transplanted HSCs represents a promising new strategy for exploring gene function in the immune system of mice.

Fracture and Fatigue of Al2O3-Graphene Nanolayers.

Al2O3-graphene nanolayers are widely used within integrated micro/nanoelectronic systems; however, their lifetimes are largely limited by fracture both statically and dynamically. Here, we present a static and fatigue study of thin (1-11 nm) free-standing Al2O3-graphene nanolayers. A remarkable fatigue life of greater than one billion cycles was obtained for films <2.2 nm thick under large mean stress levels, which was up to 3 orders of magnitude longer than that of its thicker (11 nm) counterpart. A similar thickness dependency was also identified for the elastic and static fracture behavior, where the enhancement effect of graphene is prominent only within a thickness of ∼3.3 nm. Moreover, plastic deformation, manifested by viscous creep, was observed and appeared to be more substantial for thicker films. This study provides mechanistic insights on both the static and dynamic reliability of Al2O3-graphene nanolayers and can potentially guide the design of graphene-based devices.

Fatigue of graphene.

Materials can suffer mechanical fatigue when subjected to cyclic loading at stress levels much lower than the ultimate tensile strength, and understanding this behaviour is critical to evaluating long-term dynamic reliability. The fatigue life and damage mechanisms of two-dimensional (2D) materials, of interest for mechanical and electronic applications, are currently unknown. Here, we present a fatigue study of freestanding 2D materials, specifically graphene and graphene oxide (GO). Using atomic force microscopy, monolayer and few-layer graphene were found to exhibit a fatigue life of more than 109 cycles at a mean stress of 71 GPa and a stress range of 5.6 GPa, higher than any material reported so far. Fatigue failure in monolayer graphene is global and catastrophic without progressive damage, while molecular dynamics simulations reveal this is preceded by stress-mediated bond reconfigurations near defective sites. Conversely, functional groups in GO impart a local and progressive fatigue damage mechanism. This study not only provides fundamental insights into the fatigue enhancement behaviour of graphene-embedded nanocomposites, but also serves as a starting point for the dynamic reliability evaluation of other 2D materials.

Inflammatory monocytes provide a niche for Salmonella expansion in the lumen of the inflamed intestine.

Salmonella exploit host-derived nitrate for growth in the lumen of the inflamed intestine. The generation of host-derived nitrate is dependent on Nos2, which encodes inducible nitric oxide synthase (iNOS), an enzyme that catalyzes nitric oxide (NO) production. However, the cellular sources of iNOS and, therefore, NO-derived nitrate used by Salmonella for growth in the lumen of the inflamed intestine remain unidentified. Here, we show that iNOS-producing inflammatory monocytes infiltrate ceca of mice infected with Salmonella. In addition, we show that inactivation of type-three secretion system (T3SS)-1 and T3SS-2 renders Salmonella unable to induce CC- chemokine receptor-2- and CC-chemokine ligand-2-dependent inflammatory monocyte recruitment. Furthermore, we show that the severity of the pathology of Salmonella- induced colitis as well as the nitrate-dependent growth of Salmonella in the lumen of the inflamed intestine are reduced in mice that lack Ccr2 and, therefore, inflammatory monocytes in the tissues. Thus, inflammatory monocytes provide a niche for Salmonella expansion in the lumen of the inflamed intestine.

Influence of the Sodium Precursor on the Cubic-to-Hexagonal Phase Transformation and Controlled Preparation of Uniform NaNdF4 Nanoparticles.

NaLnF4 nanoparticles (NPs) with lighter lanthanides (where Ln = La, Ce, Nd, or Pr) are more difficult to prepare than those with heavier lanthanides [Naduviledathu et al. Chem Mater., 2014, 26, 5689]. Our knowledge is weakest for NaLnF4 NPs with the lowest atomic mass lanthanides (Yan's group 1: La to Nd) and more advanced for group 2 (Sm to Tb) NaLnF4 NPs [Mai et al., J. Am. Chem. Soc., 2006, 128, 6426]. Here we focus on the synthesis of NaNdF4 NPs. We employed the high-temperature chemical coprecipitation method and explored the influence of a wide range of synthesis parameters (e.g., reaction time and temperature, precursor ratios (Na+/Nd3+ and F-/Nd3+), choice of a sodium precursor (Na-oleate or NaOH), and the amount of oleic acid) on the size and uniformity of the NPs obtained. We tried to identify "sweet spots" in the reaction space that led to uniform NaNdF4 NPs with sizes appropriate for mass tag applications in mass cytometry. We were able to obtain NPs with a variety of sizes in the range of 5-38 nm with several different shapes (e.g., polyhedra, spheres, and rods). XRD patterns recorded for aliquots collected at different reaction time intervals revealed that NaNdF4 nucleated in the cubic phase (α) and then transformed to the hexagonal phase (ß) as the reaction progressed up to 2 h. A very striking observation was that the NPs synthesized using NaOH as a reactant preferred to remain in the α-phase, and for a lower reaction temperature (285 °C), did not undergo a phase transformation to the ß-phase over 2 h of reaction time. Under similar experimental conditions, NPs prepared using Na-oleate exhibited an α → ß phase transformation. Nevertheless, NaNdF4 NPs prepared at a higher temperature (315 °C) using either of the Na+ precursors exhibited the α → ß phase transformation over time. This transition, however, appeared to be faster in the case of the NPs synthesized using Na-oleate. We found that, in many instances, syntheses carried out using Na-oleate produced more uniform NPs compared to those synthesized using NaOH. Under the conditions we employed for the Na-oleate precursor, the NPs initially formed were polydisperse spheres that evolved into irregular polyhedra and eventually formed more uniform rod-shaped NPs. The aspect ratio of the final NPs depended on the Na+/Nd3+ precursor ratio. High-resolution transmission electron micrographs and corresponding fast Fourier transform of the data provided information about the preferred growth direction of the NaNdF4 nanorods.

Spherulite-Like Micelles.

One-dimensional (1D) and 2D structures by crystallization-driven self-assembly of block copolymers (BCPs) can form fascinating hierarchical structures through secondary self-assembly. But examples of 3D structures formed via hierarchical self-assembly are rare. Here we report seeded growth experiments in decane of a poly(ferrocenyldimethylsilane) BCP with an amphiphilic corona forming block in which lenticular platelets grow into classic spherulite-like uniform colloidally stable structures. These 3D objects are spherically symmetric on the exterior, but asymmetric near the core, where there is a more open structure consisting of sheaf-like leaves. The most remarkable aspect of these experiments is that growth stops at different stages of growth process, depending upon how much unimer is added in the seeded growth step. The system provides a model for studying spherulitic growth where real-time observations on their growth at different stages remains challenging.

ZSM-5 decrystallization and dealumination in hot liquid water.

Zeolites have recently attracted attention for upgrading renewable resources in the presence of liquid water phases; however, the stability of zeolites in the presence of liquid-phase water is not completely understood. Accordingly, the stability of the ZSM-5 framework and its acid sites was studied in the presence of water at temperatures ranging from 250 to 450 °C and at pressures sufficient to maintain a liquid or liquid-like state (25 MPa). Treated samples were analyzed for framework degradation and Al content and coordination using a variety of complementary techniques, including X-ray diffraction, electron microscopy, N2 sorption, 27Al and 29Si NMR spectroscopy, and several different types of infrared spectroscopy. These analyses indicate that the ZSM-5 framework retains >80% crystallinity at all conditions, and that 300-400 °C are the most aggressive. Decrystallization appears to initiate primarily at crystal surfaces and share many characteristics in common with alkali promoted desilication. Liquid water treatment promotes ZSM-5 dealumination, following a mechanism analogous to that observed under steaming conditions: initiation by Al-O hydrolysis, Al migration to the surface, and finally deposition as extra framework Al or possibly complete dissolution under some conditions. As with the framework, dealumination is most aggressive at 300-400 °C. Several models were evaluated to capture the non-Arrhenius effect of temperature on decrystallization and dealumination, the most successful of which included temperature dependent values of the water auto-ionization constant. These results can help interpretation of previous studies on ZSM-5 catalysis in hot liquid water and suggest future approaches to extend catalyst lifetime.

Professional advancement, performance, and injury characteristics of baseball players entering the Major League Baseball draft after treatment for shoulder injuries.

BACKGROUND: How shoulder injuries treated before the Major League Baseball (MLB) draft affect the player's performance over their career is unclear. The purpose of this study was to determine whether prior shoulder injuries were associated with a difference in the level of performance and advancement of MLB draftees. METHODS: Before entering the draft, 119 professional baseball players from 2004 to 2010 were treated for a shoulder injury (73% treated surgically) as an amateur. A 3:1 matched case-control was performed to players without prior shoulder injuries by age, position, round selected, and signing bonus. Follow-up data were collected in 2016, and professional advancement, disabled list time, and in-game performance statistics for pitchers were analyzed and compared. RESULTS: Players with a prior shoulder injury had a statistically higher chance to be assigned to the disabled list then controls (P = .03), but there was no difference in disabled list time or professional advancement. Pitchers with a prior shoulder injury pitched a statistically lower number of innings per game than controls (P = .04). All other in-game performance statistics were not statistically different. The type of treatment did not have any effect on future performance or advancement. CONCLUSIONS: Professional baseball players treated for prior shoulder injuries at the amateur level were more likely to sustain future disability than their matched controls, but it did not affect professional advancement.

CCR2+ Inflammatory Dendritic Cells and Translocation of Antigen by Type III Secretion Are Required for the Exceptionally Large CD8+ T Cell Response to the Protective YopE69-77 Epitope during Yersinia Infection.

During Yersinia pseudotuberculosis infection of C57BL/6 mice, an exceptionally large CD8+ T cell response to a protective epitope in the type III secretion system effector YopE is produced. At the peak of the response, up to 50% of splenic CD8+ T cells recognize the epitope YopE69-77. The features of the interaction between pathogen and host that result in this large CD8+ T cell response are unknown. Here, we used Y. pseudotuberculosis strains defective for production, secretion and/or translocation of YopE to infect wild-type or mutant mice deficient in specific dendritic cells (DCs). Bacterial colonization of organs and translocation of YopE into spleen cells was measured, and flow cytometry and tetramer staining were used to characterize the cellular immune response. We show that the splenic YopE69-77-specific CD8+ T cells generated during the large response are polyclonal and are produced by a "translocation-dependent" pathway that requires injection of YopE into host cell cytosol. Additionally, a smaller YopE69-77-specific CD8+ T cell response (~10% of the large expansion) can be generated in a "translocation-independent" pathway in which CD8α+ DCs cross present secreted YopE. CCR2-expressing inflammatory DCs were required for the large YopE69-77-specific CD8+ T cell expansion because this response was significantly reduced in Ccr2-/- mice, YopE was translocated into inflammatory DCs in vivo, inflammatory DCs purified from infected spleens activated YopE69-77-specific CD8+ T cells ex vivo and promoted the expansion of YopE69-77-specific CD8+ T cells in infected Ccr2-/- mice after adoptive transfer. A requirement for inflammatory DCs in producing a protective CD8+ T cell response to a bacterial antigen has not previously been demonstrated. Therefore, the production of YopE69-77-specific CD8+ T cells by inflammatory DCs that are injected with YopE during Y. pseudotuberculosis infection represents a novel mechanism for generating a massive and protective adaptive immune response.

Quantifying the Relationship Between the Transverse Acetabular Ligament and the Radiographic Teardrop.

BACKGROUND: The transverse acetabular ligament (TAL) has been described as an anatomic landmark to guide in the positioning of the acetabular component during total hip arthroplasty. On plain films, the radiographic teardrop (RT) has similarly been used as a measure of appropriate cup positioning. The goal of this study is to quantify the distance and location between the anatomic TAL and RT landmarks to aid in the positioning of acetabular component. METHODS: Sixteen randomly selected cadaveric pelvises (eight males, eight females) underwent dissection. Radiographic markers were placed bilaterally at the anteromedial insertions of the TAL, and true anteroposterior pelvic radiographs of the cadavers were obtained. Distances between the markers and the lateral borders of the RT were measured. RESULTS: The mean distance between the anteromedial insertion of the TAL and the lateral border of the RT in the male specimens was 11.8 (99% confidence interval, 11.4-12.2) mm. In the female specimens, the TAL to RT distance was shorter, with a mean of 8.4 (99% CI, 7.2-9.6) mm. There was a statistically significant difference between male and female cadavers (P < .01). CONCLUSION: The distance between the RT and TAL differs between males and females. Understanding the distance between these anatomic and radiographic landmarks should aid surgeons in obtaining a more accurate degree of acetabular component medialization and can serve as a guide to minimize overmedialization in order to achieve more accurate and reproducible placement of acetabular components during a total hip arthroplasty.

CD11b+ Ly6Chi Ly6G- immature myeloid cells recruited in response to Salmonella enterica serovar Typhimurium infection exhibit protective and immunosuppressive properties.

Immature myeloid cells in bone marrow are a heterogeneous population of cells that, under normal conditions, provide tissues with protective cell types such as granulocytes and macrophages. Under certain pathological conditions, myeloid cell homeostasis is altered and immature forms of these cells appear in tissues. Murine immature myeloid cells that express CD11b and Ly6C or Ly6G (two isoforms of Gr-1) have been associated with immunosuppression in cancer (in the form of myeloid-derived suppressor cells) and, more recently, infection. Here, we found that CD11b(+) Ly6C(hi) Ly6G(-) and CD11b(+) Ly6C(int) Ly6G(+) cells accumulated and persisted in tissues of mice infected with Salmonella enterica serovar Typhimurium (S. Typhimurium). Recruitment of CD11b(+) Ly6C(hi) Ly6G(-) but not CD11b(+) Ly6C(int) Ly6G(+) cells from bone marrow into infected tissues depended on chemokine receptor CCR2. The CD11b(+) Ly6C(hi) Ly6G(-) cells exhibited a mononuclear morphology, whereas the CD11b(+) Ly6C(int) Ly6G(+) cells exhibited a polymorphonuclear or band-shaped nuclear morphology. The CD11b(+) Ly6C(hi) Ly6G(-) cells differentiated into macrophage-like cells following ex vivo culture and could present antigen to T cells in vitro. However, significant proliferation of T cells was observed only when the ability of the CD11b(+) Ly6C(hi) Ly6G(-) cells to produce nitric oxide was blocked. CD11b(+) Ly6C(hi) Ly6G(-) cells recruited in response to S. Typhimurium infection could also present antigen to T cells in vivo, but increasing their numbers by adoptive transfer did not cause a corresponding increase in T cell response. Thus, CD11b(+) Ly6C(hi) Ly6G(-) immature myeloid cells recruited in response to S. Typhimurium infection exhibit protective and immunosuppressive properties that may influence the outcome of infection.

Superhydrophobicity mechanism of refoliated quaking aspen leaves after complete defoliation by LDD (gypsy, spongy) moth caterpillars.

Complete defoliation of trees due to periodic LDD (Lymantria dispar dispar) moth outbreaks in many parts of the world is a significant stress factor for the survival of individual trees and entire forests over vast areas. This study addresses such a mid-summer defoliation event in Ontario, Canada for quaking aspen trees during 2021. It is shown that complete refoliation in the same year is possible for these trees, albeit with significantly smaller leaf size. Regrown leaves showed the well-known non-wetting behaviour typically observed for the quaking aspen tree without a defoliation event. These leaves have the same hierarchical dual-scale surface structure consisting of nanometre-size epicuticular wax (ECW) crystals superimposed on micrometre-sized papillae. This structure provides for the Cassie-Baxter non-wetting state with a very high water contact angle on the adaxial surface of the leaves. Subtle differences in the leaf surface morphology of the refoliation leaves compared with the regular growth leaves are likely due to environmental factors such as seasonal temperature during the leaf growth period after budbreak.

Molecular-Additive-Assisted Tellurium Homogenization in ZnSeTe Quantum Dots.

Addition of aqueous hydrohalic acids during the synthesis of colloidal quantum dots (QDs) is widely employed to achieve high-quality QDs. However, this reliance on the use of aqueous solutions is incompatible with oxygen- and water-sensitive precursors such as those used in the synthesis of Te-alloyed ZnSe QDs. Herein, it is shown that this incompatibility leads to phase segregation into Te-rich and Te-poor regions, causing spectral broadening and luminescence peak shifting under high laser irradiation and applied electrical bias. Here, a synthetic strategy to produce anhydrous-HF in situ by using benzenecarbonyl fluoride (BF) as a chemical additive is reported. Through in situ 19 F NMR spectroscopy, it is found that BF reacts with surfactants in tandem, ultimately producing intermediary F···H···trioctylamine adducts. These act as a pseudo-HF source that releases anhydrous HF. The controlled release of HF during nucleation and growth steps homogenizes Te distribution in ZnSeTe lattice, leading to spectrally stable blue-emitting QDs under increasing laser flux from ≈3 µW to ≈12 mW and applied bias from 2.6 to 10 V. Single-dot photoluminescence (PL) spectroscopy and analyses of the absorption, PL and transient absorption spectra together with density functional theory point to the role of anhydrous HF as a Te homogenizer.

Phenotypic, morphological, and functional heterogeneity of splenic immature myeloid cells in the host response to tularemia.

Recent studies have linked accumulation of the Gr-1⁺ CD11b⁺ cell phenotype with functional immunosuppression in diverse pathological conditions, including bacterial and parasitic infections and cancer. Gr-1⁺ CD11b⁺ cells were the largest population of cells present in the spleens of mice infected with sublethal doses of the Francisella tularensis live vaccine strain (LVS). In contrast, the number of T cells present in the spleens of these mice did not increase during early infection. There was a significant delay in the kinetics of accumulation of Gr-1⁺ CD11b⁺ cells in the spleens of B-cell-deficient mice, indicating that B cells play a role in recruitment and maintenance of this population in the spleens of mice infected with F. tularensis. The splenic Gr-1⁺ CD11b⁺ cells in tularemia were a heterogeneous population that could be further subdivided into monocytic (mononuclear) and granulocytic (polymorphonuclear) cells using the Ly6C and Ly6G markers and differentiated into antigen-presenting cells following ex vivo culture. Monocytic, CD11b⁺ Ly6C(hi) Ly6G⁻ cells but not granulocytic, CD11b⁺ Ly6C(int) Ly6G⁺ cells purified from the spleens of mice infected with F. tularensis suppressed polyclonal T-cell proliferation via a nitric oxide-dependent pathway. Although the monocytic, CD11b⁺ Ly6C(hi) Ly6G⁻ cells were able to suppress the proliferation of T cells, the large presence of Gr-1⁺ CD11b⁺ cells in mice that survived F. tularensis infection also suggests a potential role for these cells in the protective host response to tularemia.

A combined proteomics and metabolomics profiling of gastric cardia cancer reveals characteristic dysregulations in glucose metabolism.

Gastric cardia cancer (GCC), which occurs at the gastric-esophageal boundary, is one of the most malignant tumors. Despite its high mortality and morbidity, the molecular mechanism of initiation and progression of this disease is largely unknown. In this study, using proteomics and metabolomics approaches, we found that the level of several enzymes and their related metabolic intermediates involved in glucose metabolism were deregulated in GCC. Among these enzymes, two subunits controlling pyruvic acid efflux, lactate dehydrogenase A (LDHA) and pyruvate dehydrogenase B (PDHB), were further analyzed in vitro. Either down-regulation of LDH subunit LDHA or overexpression of PDH subunit PDHB could force pyruvic acid into the Krebs cycle rather than the glycolysis process in AGS gastric cancer cells, which inhibited cell growth and cell migration. Our results reflect an important glucose metabolic signature, especially the dysregulation of pyruvic acid efflux in the development of GCC. Forced transition from glycolysis to the Krebs cycle had an inhibitory effect on GCC progression, providing potential therapeutic targets for this disease.