Succinate produced by the commensal protist
(
) stimulates chemosensory tuft cells, resulting in intestinal type 2 immunity. Tuft cells express the succinate receptor SUCNR1, yet this receptor does ...not mediate antihelminth immunity nor alter protist colonization. Here, we report that microbial-derived succinate increases Paneth cell numbers and profoundly alters the antimicrobial peptide (AMP) landscape in the small intestine. Succinate was sufficient to drive this epithelial remodeling, but not in mice lacking tuft cell chemosensory components required to detect this metabolite. Tuft cells respond to succinate by stimulating type 2 immunity, leading to interleukin-13-mediated epithelial and AMP expression changes. Moreover, type 2 immunity decreases the total number of mucosa-associated bacteria and alters the small intestinal microbiota composition. Finally, tuft cells can detect short-term bacterial dysbiosis that leads to a spike in luminal succinate levels and modulate AMP production in response. These findings demonstrate that a single metabolite produced by commensals can markedly shift the intestinal AMP profile and suggest that tuft cells utilize SUCNR1 and succinate sensing to modulate bacterial homeostasis.
Airway instillation of bleomycin (BLM) in mice is a widely used, yet challenging, model for acute lung injury (ALI) with high variability in treatment scheme and animal outcomes among investigators. ...Whether the gut microbiota plays any role in the outcome of BLM-induced lung injury is currently unknown.
Intratracheal instillation of BLM into C57BL/6 mice was performed. Fecal microbiomes were analyzed by 16s rRNA amplicon and metagenomic sequencing. Germ-free mice conventionalization and fecal microbiota transfer between SPF mice were performed to determine dominant commensal species that are associated with more severe BLM response. Further, lungs and gut draining lymph nodes of the mice were analyzed by flow cytometry to define immunophenotypes associated with the BLM-sensitive microbiome.
Mice from two SPF barrier facilities at the University of Chicago exhibited significantly different mortality and weight loss during BLM-induced lung injury. Conventionalizing germ-free mice with SPF microbiota from two different housing facilities recapitulated the respective donors' response to BLM. Fecal microbiota transfer from the facility where the mice had worse mortality into the mice in the facility with more survival rendered recipient mice more susceptible to BLM-induced weight loss in a dominant negative manner. BLM-sensitive phenotype was associated with the presence of Helicobacter and Desulfovibrio in the gut, decreased Th17-neutrophil axis during steady state, and augmented lung neutrophil accumulation during the acute phase of the injury response.
The composition of gut microbiota has significant impact on BLM-induced wasting and death suggesting a role of the lung-gut axis in lung injury.
The persistent murine norovirus strain MNV
is a model for human norovirus and enteric viral persistence. MNV
causes chronic infection by directly infecting intestinal tuft cells, rare chemosensory ...epithelial cells. Although MNV
induces functional MNV-specific CD8
T cells, these lymphocytes fail to clear infection. To examine how tuft cells promote immune escape, we interrogated tuft cell interactions with CD8
T cells by adoptively transferring JEDI (just EGFP death inducing) CD8
T cells into Gfi1b-GFP tuft cell reporter mice. Unexpectedly, some intestinal tuft cells partially resisted JEDI CD8
T cell-mediated killing-unlike Lgr5
intestinal stem cells and extraintestinal tuft cells-despite seemingly normal antigen presentation. When targeting intestinal tuft cells, JEDI CD8
T cells predominantly adopted a T resident memory phenotype with decreased effector and cytotoxic capacity, enabling tuft cell survival. JEDI CD8
T cells neither cleared nor prevented MNV
infection in the colon, the site of viral persistence, despite targeting a virus-independent antigen. Ultimately, we show that intestinal tuft cells are relatively resistant to CD8
T cells independent of norovirus infection, representing an immune-privileged niche that can be leveraged by enteric microbes.
Objectives: To examine the clinical characteristics and outcomes of cancer patients with venous thromboembolism (VTE) in order to identify factors that place these patients at an increased risk for ...fatal pulmonary embolism (PE) or fatal bleeding. Patients and methods: Registro Informatizado de la Enfermedad Trombo Embólica (RIETE) is a prospective registry of consecutive patients with symptomatic, objectively confirmed, acute VTE. Results: Up to January 2006, a total of 14 391 patients with symptomatic acute VTE were enrolled in RIETE, of whom 2945 (20%) had cancer. During the 3‐month follow‐up period the frequency of fatal PE in cancer patients was 2.6%, and that of fatal bleeding 1.0%. These frequencies were significantly higher than in VTE patients without cancer (1.4% and 0.3%, respectively). In patients with cancer, abnormal renal function, metastatic disease, recent major bleeding and recent immobility for ≥ 4 days (42% of the 108 patients who died from PE or bleeding had recent immobility) were factors independently associated with an increased risk for both fatal PE and fatal bleeding. In addition, PE diagnosis on admission was an independent risk factor for fatal PE, while body weight < 60 kg was an independent risk factor for fatal bleeding. Conclusions: Both fatal PE and fatal bleeding are more common in cancer patients with VTE than in those patients without cancer. In cancer patients, abnormal renal function, metastatic disease, recent major bleeding and recent immobility for ≥ 4 days are associated with an increased risk for both fatal PE and fatal bleeding.
Background: While the primary therapy for most patients with a pulmonary embolism (PE) consists of anticoagulation, the efficacy of thrombolysis relative to standard therapy remains unclear.
...Methods: In this retrospective cohort study of 15 944 patients with an objectively confirmed symptomatic acute PE, identified from the multicenter, international, prospective, Registro Informatizado de la Enfermedad TromboEmbólica (RIETE registry), we aimed to assess the association between thrombolytic therapy and all‐cause mortality during the first 3 months after the diagnosis of a PE. After creating two subgroups, stratified by systolic blood pressure (SBP) (< 100 mm Hg vs. other), we used propensity score‐matching for a comparison of patients who received thrombolysis to those who did not in each subgroup.
Results: Patients who received thrombolysis were younger, had fewer comorbid diseases and more signs of clinical severity compared with those who did not receive it. In the subgroup with systolic hypotension, analysis of propensity score‐matched pairs (n = 94 pairs) showed a non‐statistically significant but clinically relevant lower risk of death for thrombolysis compared with no thrombolysis (odds ratio OR 0.72; 95% confidence interval CI, 0.36–1.46; P = 0.37). In the normotensive subgroup, analysis of propensity score‐matched pairs (n = 217 pairs) showed a statistically significant and clinically meaningful increased risk of death for thrombolysis compared with no thrombolysis (OR 2.32; 95% CI, 1.15–4.68; P = 0.018). When we imputed data for missing values for echocardiography and troponin tests in the group of normotensive patients, we no longer detected the increased risk of death associated with thrombolytic therapy.
Conclusions: In normotensive patients with acute symptomatic PE, thrombolytic therapy is associated with a higher risk of death than no thrombolytic therapy. In hemodynamically unstable patients, thrombolytic therapy is possibly associated with a lower risk of death than no thrombolytic therapy. However, study design limitations do not imply a causal relationship between thrombolytics and outcome.
We report on thermally resilient planar waveguides fabricated on nc-YSZ by direct fs-laser inscription in transparent nc-yttria stabilized zirconia (nc-YSZ) polycrystalline ceramic. The waveguides ...consisted of rectangular sections (4.5 × 2 mm
2
) on the surface of the sample. Optical characterization at 633 and 810 nm was performed. We estimate a laser-induced refractive index contrast of 10
–4
. Post-waveguide-fabrication thermal annealing treatments at 750°C for 24 h were carried out to test the resilience of the waveguides and to further reduce the waveguide losses. Both micro-Raman spectroscopy and XPS characterization revealed unmodified lattice and steady chemical features, which are consistent with the waveguide thermal resilience. Our results suggest a promising potential use of nc-YSZ in harsh and high temperature demanding photonic environments.
We describe a modular apparatus for use in parity-violation measurements in epithermal neutron–nucleus resonances with high instantaneous neutron fluxes at the Manuel Lujan Jr. Neutron Scattering ...Center at Los Alamos National Laboratory. This apparatus is designed to conduct high-precision measurements of the parity-odd transmission asymmetry of longitudinally polarized neutrons through targets containing nuclei with p-wave neutron–nucleus resonances in the 0.1–10 eV energy regime and to accommodate a future search for time reversal violation in polarized neutron transmission through polarized nuclear targets. The apparatus consists of an adjustable neutron and gamma collimation system, a 3He-4He ion chamber neutron flux monitor, two identical cryostats for target cooling, an adiabatic eV-neutron spin flipper, a near-unit efficiency 6Li-7Li scintillation detector operated in current mode, a flexible CAEN data acquisition system, and a neutron spin filter based on spin-exchange optical pumping of 3He gas. We describe the features of the apparatus design devoted to the suppression of systematic errors in parity-odd asymmetry measurements. We describe the configuration of the apparatus used to conduct a precision measurement of parity violation at the 0.7 eV p-wave resonance in 139La which employs two identical 139La targets, one to polarize the beam on the p-wave resonance using the weak interaction and one to analyze the polarization.
Surfactant addition during support synthesis resulted in materials with defined porosity, smaller particle size, and the absence of segregated ZrO
2
and TiO
2
crystalline phases at least to the XRD ...detection limit. The data obtained by N
2
physisorption showed improved textural properties compared with the individual pure oxides. The Ultraviolet–visible (UV–Vis) diffuse spectroscopy revealed broadband assigned to the mixed-phase. Meanwhile, the micrographs obtained by transmission electron microscopy showed nanometric domains of crystallinity and a worm-like morphology in all the samples. Raman spectroscopy showed the possible formation of the TiZrO
4
forming the mixed oxides support. The chemical analysis performed by ICP-OES corroborates the expected equimolar relation Zr/Ti and the atomic ratio Ni/(Ni + W) approximately equal to 0.31. The support properties intrinsically influenced the WS
2
nano slabs, as observed by TEM micrographs for the NiW/ZT-x sulfided series. The XPS analysis revealed that sulfidation degree increases and the highest amount of NiWS phase among all the materials are observed when the NiW system is deposited on the mixed oxides prepared with pluronic. The latter was also related to the reaction rates, where the sulfided NiW/ZT-x catalysts presented higher values than the NiW/ZT reference material. NiW/ZT-P sulfided sample showed the maximum reaction rate among the series studied.
E coli isolates (108) from Mexican women, clinically diagnosed with urinary tract infection, were screened to identify virulence genes, phylogenetic groups, and antibiotic resistance. Isolates were ...identified by MicroScan4 system; additionally, the minimum inhibitory concentration (MIC) was assessed. The phylogenetic groups and 16 virulence genes encoding adhesins, toxins, siderophores, lipopolysaccharide (LPS), and invasins were identified by PCR. Phylogenetic groups distribution was as follows: B1 9.3%, A 30.6%, B2 55.6%, and D 4.6%. Virulence genes prevalence was ecp 98.1%, fimH 86.1%, traT 77.8%, sfa/focDE 74.1%, papC 62%, iutA 48.1%, fyuA 44.4%, focG 2.8%, sfaS 1.9%, hlyA 7.4%, cnf-1 6.5%, cdt-B 0.9%, cvaC 2.8%, ibeA 2.8%, and rfc 0.9%. Regarding antimicrobial resistance it was above 50% to ampicillin/sulbactam, ampicillin, piperacillin, trimethoprim/sulfamethoxazole, ciprofloxacin, and levofloxacin. Uropathogenic E. coli clustered mainly in the pathogenic phylogenetic group B2. The isolates showed a high presence of siderophores and adhesion genes and a low presence of genes encoding toxins. The high frequency of papC gene suggests that these isolates have the ability to colonize the kidneys. High resistance to drugs considered as first choice treatment such as trimethoprim/sulfamethoxazole and fluoroquinolones was consistently observed.
PDF
