Interactions between platelets, leukocytes and the vessel wall provide alternative pathological routes of thrombo-inflammatory leukocyte recruitment. We found that when platelets were activated by a ...range of agonists in whole blood, they shed platelet-derived extracellular vesicles which rapidly and preferentially bound to blood monocytes compared to other leukocytes. Platelet-derived extracellular vesicle binding to monocytes was initiated by P-selectin-dependent adhesion and was stabilised by binding of phosphatidylserine. These interactions resulted in the progressive transfer of the platelet adhesion receptor GPIbα to monocytes. GPIbα
monocytes tethered and rolled on immobilised von Willebrand Factor or were recruited and activated on endothelial cells treated with TGF-β1 to induce the expression of von Willebrand Factor. In both models monocyte adhesion was ablated by a function-blocking antibody against GPIbα. Monocytes could also bind platelet-derived extracellular vesicle in mouse blood
and
Intratracheal instillations of diesel nanoparticles, to model chronic pulmonary inflammation, induced accumulation of GPIbα on circulating monocytes. In intravital experiments, GPIbα
-monocytes adhered to the microcirculation of the TGF-β1-stimulated cremaster muscle, while in the
model of atherosclerosis, GPIbα
-monocytes adhered to the carotid arteries. In trauma patients, monocytes bore platelet markers within 1 hour of injury, the levels of which correlated with severity of trauma and resulted in monocyte clearance from the circulation. Thus, we have defined a novel thrombo-inflammatory pathway in which platelet-derived extracellular vesicles transfer a platelet adhesion receptor to monocytes, allowing their recruitment in large and small blood vessels, and which is likely to be pathogenic.
IMPORTANCE: In most patients, a prodromal period precedes the onset of schizophrenia. Although clinical criteria for identifying the psychosis risk syndrome (PRS) show promising predictive validity, ...assessment of neurophysiologic abnormalities in at-risk individuals may improve clinical prediction and clarify the pathogenesis of schizophrenia. OBJECTIVE: To determine whether P300 event-related potential amplitude, which is deficient in schizophrenia, is reduced in the PRS and associated with clinical outcomes. DESIGN, SETTING, AND PARTICIPANTS: Auditory P300 data were collected as part of the multisite, case-control North American Prodrome Longitudinal Study (NAPLS-2) at 8 university-based outpatient programs. Participants included 552 individuals meeting PRS criteria and 236 healthy controls with P300 data. Auditory P300 data of participants at risk who converted to psychosis (n = 73) were compared with those of nonconverters who were followed up for 24 months and continued to be symptomatic (n = 135) or remitted from the PRS (n = 90). Data were collected from May 27, 2009, to September 17, 2014, and were analyzed from December 3, 2015, to May 1, 2019. MAIN OUTCOMES AND MEASURES: Baseline electroencephalography was recorded during an auditory oddball task. Two P300 subcomponents were measured: P3b, elicited by infrequent target stimuli, and P3a, elicited by infrequent nontarget novel stimuli. RESULTS: This study included 788 participants. The PRS group (n = 552) included 236 females (42.8%) (mean SD age, 19.21 4.38 years), and the healthy control group (n = 236) included 111 females (47.0%) (mean SD age, 20.44 4.73 years). Target P3b and novelty P3a amplitudes were reduced in at-risk individuals vs healthy controls (d = 0.37). Target P3b, but not novelty P3a, was significantly reduced in psychosis converters vs nonconverters (d = 0.26), and smaller target P3b amplitude was associated with a shorter time to psychosis onset in at-risk individuals (hazard ratio, 1.45; 95% CI, 1.04-2.00; P = .03). Participants with the PRS who remitted had baseline target P3b amplitudes that were similar to those of healthy controls and greater than those of converters (d = 0.51) and at-risk individuals who remained symptomatic (d = 0.41). CONCLUSIONS AND RELEVANCE: In this study, deficits in P300 amplitude appeared to precede psychosis onset. Target P3b amplitudes, in particular, may be sensitive to clinical outcomes in the PRS, including both conversion to psychosis and clinical remission. Auditory target P3b amplitude shows promise as a putative prognostic biomarker of clinical outcome in the PRS.
Regulatory T cells (Tregs) have been shown to enhance immune reconstitution and prevent graft-versus-host disease (GVHD) after hematopoietic stem cell transplantation; however, it is unclear how ...Tregs mediate these effects. Here, we developed a model to examine the mechanism of Treg-dependent regulation of immune reconstitution. Lymphopenic mice were selectively reconstituted with Tregs prior to transfer of conventional CD4+ T cells. Full Treg reconstitution prevented the rapid oligoclonal proliferation that gives rise to pathogenic CD4 effector T cells, while preserving the slow homeostatic form of lymphopenia-induced peripheral expansion that repopulates a diverse peripheral T cell pool. Treg-mediated CTLA-4-dependent downregulation of CD80/CD86 on DCs was critical for inhibition of rapid proliferation and was a function of the Treg/DC ratio achieved by reconstitution. In an allogeneic BM transplant model, selective Treg reconstitution before T cell transfer also normalized DC costimulation and provided complete protection against GVHD. In contrast, cotransfer of Tregs was not protective. Our results indicate that achieving optimal recovery from lymphopenia should aim to improve early Treg reconstitution in order to increase the relative number of Tregs to DCs and thereby inhibit spontaneous oligoclonal T cell proliferation.
Objective The purpose of this study was to characterize the urinary microbiota in women who are planning treatment for urgency urinary incontinence and to describe clinical associations with urinary ...symptoms, urinary tract infection, and treatment outcomes. Study Design Catheterized urine samples were collected from multisite randomized trial participants who had no clinical evidence of urinary tract infection; 16S ribosomal RNA gene sequencing was used to dichotomize participants as either DNA sequence-positive or sequence-negative. Associations with demographics, urinary symptoms, urinary tract infection risk, and treatment outcomes were determined. In sequence-positive samples, microbiotas were characterized on the basis of their dominant microorganisms. Results More than one-half (51.1%; 93/182) of the participants’ urine samples were sequence-positive. Sequence-positive participants were younger (55.8 vs 61.3 years old; P = .0007), had a higher body mass index (33.7 vs 30.1 kg/m2 ; P = .0009), had a higher mean baseline daily urgency urinary incontinence episodes (5.7 vs 4.2 episodes; P < .0001), responded better to treatment (decrease in urgency urinary incontinence episodes, –4.4 vs –3.3; P = .0013), and were less likely to experience urinary tract infection (9% vs 27%; P = .0011). In sequence-positive samples, 8 major bacterial clusters were identified; 7 clusters were dominated not only by a single genus, most commonly Lactobacillus (45%) or Gardnerella (17%), but also by other taxa (25%). The remaining cluster had no dominant genus (13%). Conclusion DNA sequencing confirmed urinary bacterial DNA in many women with urgency urinary incontinence who had no signs of infection. Sequence status was associated with baseline urgency urinary incontinence episodes, treatment response, and posttreatment urinary tract infection risk.
To update the ASCO adjuvant endocrine therapy guideline based on emerging data concerning the benefits and risks of ovarian suppression in addition to standard adjuvant therapy in premenopausal women ...with estrogen receptor-positive breast cancer.
ASCO convened an Update Panel and conducted a systematic review of randomized clinical trials investigating ovarian suppression.
Two trials investigating the addition of ovarian suppression to tamoxifen did not show an overall clinical benefit for ovarian suppression. Nonetheless, the addition of ovarian suppression to standard adjuvant therapy with tamoxifen or with an aromatase inhibitor improved disease-free survival and improved freedom from breast cancer and distant recurrence compared with tamoxifen alone among the subset of patients who were at sufficient risk for recurrence such that adjuvant chemotherapy was warranted. Compared with tamoxifen alone, ovarian suppression was associated with a substantial increase in menopausal symptoms, sexual dysfunction, and diminished quality of life.
The Panel recommends that higher-risk patients should receive ovarian suppression in addition to adjuvant endocrine therapy, whereas lower-risk patients should not. Women with stage II or III breast cancers who would ordinarily be advised to receive adjuvant chemotherapy should receive ovarian suppression with endocrine therapy. The panel recommends that some women with stage I or II breast cancers at higher risk of recurrence who might consider chemotherapy may also be offered ovarian suppression with endocrine therapy. Women with stage I breast cancers not warranting chemotherapy should not receive ovarian suppression, nor should women with node-negative cancers 1 cm or less. Ovarian suppression may be administered with either tamoxifen or an aromatase inhibitor. Additional information is available at www.asco.org/guidelines/endocrinebreast and www.asco.org/guidelineswiki.
The tumour stroma regulates nearly all stages of carcinogenesis. Stromal heterogeneity in human triple‐negative breast cancers (TNBCs) remains poorly understood, limiting the development of ...stromal‐targeted therapies. Single‐cell RNA sequencing of five TNBCs revealed two cancer‐associated fibroblast (CAF) and two perivascular‐like (PVL) subpopulations. CAFs clustered into two states: the first with features of myofibroblasts and the second characterised by high expression of growth factors and immunomodulatory molecules. PVL cells clustered into two states consistent with a differentiated and immature phenotype. We showed that these stromal states have distinct morphologies, spatial relationships and functional properties in regulating the extracellular matrix. Using cell signalling predictions, we provide evidence that stromal‐immune crosstalk acts via a diverse array of immunoregulatory molecules. Importantly, the investigation of gene signatures from inflammatory‐CAFs and differentiated‐PVL cells in independent TNBC patient cohorts revealed strong associations with cytotoxic T‐cell dysfunction and exclusion, respectively. Such insights present promising candidates to further investigate for new therapeutic strategies in the treatment of TNBCs.
Synopsis
This single‐cell gene expression resource deciphers the composition of triple‐negative breast cancer (TNBC) stroma, revealing distinct subclasses of cancer‐associated fibroblasts (CAFs) and perivascular‐like (PVL) cells. These signatures are informative on tumour aetiology and potential strategies for development of targeted therapies.
Single‐cell analysis of primary TNBC highlights clusters of stromal and immune cell types.
TNBC stroma is comprised of myofibroblast‐like CAFs, inflammatory‐like CAFs, differentiated PVL and immature PVL cells.
Stromal subclasses differ in surface markers, spatial localisation in tissue, ECM functions, and predicted cellular crosstalk with immune cells.
Inflammatory‐like CAF and differentiated PVL cells are associated with cytotoxic T‐cell dysfunction and exclusion in independent TNBC‐patient cohorts.
Single‐cell profiling of primary breast cancer provides unprecedented insights into cell‐type heterogeneity within the tumor microenvironment.
Needle deformation in longleaf pines Harris, Thomas B; Munro, Holly L
Frontiers in ecology and the environment,
February 2021, 2021-02-00, 20210201, Letnik:
19, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Longleaf pine (Pinus palustris) is a fire-dependent conifer endemic to the southeastern US. Historically extending across 37 million hectares, the species' current range has declined by 97% since ...1930. This contraction was largely due to extensive logging and urban development, as well as fire suppression, which further prevented natural regeneration. In the past few decades, federal agencies have subsidized landowner restoration of longleaf pine forests to promote biodiversity and conservation values. Longleaf pine ecosystems provide habitat to numerous endangered species and, as compared to ecosystems dominated by other southern pines, are more resilient to pests, pathogens, and extreme weather events.
► Cognitive attentional syndrome (CAS) is a core construct of metacognitive theory. ► Assessed relations between CAS and symptoms of psychopathology. ► Examined whether attentional control (AC) ...moderated such relations. ► CAS was related to increased symptoms of psychopathology at low levels of AC.
Wells’s (2009) metacognitive theory suggests that inflexible and recurrent styles of thinking in response to negative thoughts, feelings, and beliefs exacerbate symptoms of psychopathology. Such styles of thinking underlie the cognitive attentional syndrome (CAS). Using a large nonclinical sample (N=456), the present study examined whether attentional control moderates the relationship between activation of the CAS and symptoms of psychopathology (i.e., depression, anxiety, and stress symptoms). Consistent with predictions, relationships between activation of the CAS and assessed symptoms became increasingly stronger as attentional control decreased. Thus, for individuals who have a relative inability to disengage and shift attention from threat information (i.e., low attentional control), use of CAS-relevant coping strategies (e.g., rumination, worry) appears to be associated with especially deleterious psychological effects. Conceptual and therapeutic implications are discussed.
To describe snacking characteristics and patterns in children and examine associations with diet quality and BMI.
Children's weight and height were measured. Participants/adult proxies completed ...multiple 24 h dietary recalls. Snack occasions were self-identified. Snack patterns were derived for each sample using exploratory factor analysis. Associations of snacking characteristics and patterns with Healthy Eating Index-2010 (HEI-2010) score and BMI were examined using multivariable linear regression models.
Childhood Obesity Prevention and Treatment Research (COPTR) Consortium, USA: NET-Works, GROW, GOALS and IMPACT studies.
Predominantly low-income, racial/ethnic minorities: NET-Works (n 534, 2-4-year-olds); GROW (n 610, 3-5-year-olds); GOALS (n 241, 7-11-year-olds); IMPACT (n 360, 10-13-year-olds).
Two snack patterns were derived for three studies: a meal-like pattern and a beverage pattern. The IMPACT study had a similar meal-like pattern and a dairy/grains pattern. A positive association was observed between meal-like pattern adherence and HEI-2010 score (P for trend < 0⋅01) and snack occasion frequency and HEI-2010 score (β coefficient (95 % CI): NET-Works, 0⋅14 (0⋅04, 0⋅23); GROW, 0⋅12 (0⋅02, 0⋅21)) among younger children. A preference for snacking while using a screen was inversely associated with HEI-2010 score in all studies except IMPACT (β coefficient (95 % CI): NET-Works, -3⋅15 (-5⋅37, -0⋅92); GROW, -2⋅44 (-4⋅27, -0⋅61); GOALS, -5⋅80 (-8⋅74, -2⋅86)). Associations with BMI were almost all null.
Meal-like and beverage patterns described most children's snack intake, although patterns for non-Hispanic Blacks or adolescents may differ. Diets of 2-5-year-olds may benefit from frequent meal-like pattern snack consumption and diets of all children may benefit from decreasing screen use during eating occasions.
Nematodes represent the most abundant benthic metazoa in one of the largest habitats on earth, the deep sea. Characterizing major patterns of biodiversity within this dominant group is a critical ...step towards understanding evolutionary patterns across this vast ecosystem. The present study has aimed to place deep-sea nematode species into a phylogenetic framework, investigate relationships between shallow water and deep-sea taxa, and elucidate phylogeographic patterns amongst the deep-sea fauna.
Molecular data (18 S and 28 S rRNA) confirms a high diversity amongst deep-sea Enoplids. There is no evidence for endemic deep-sea lineages in Maximum Likelihood or Bayesian phylogenies, and Enoplids do not cluster according to depth or geographic location. Tree topologies suggest frequent interchanges between deep-sea and shallow water habitats, as well as a mixture of early radiations and more recently derived lineages amongst deep-sea taxa. This study also provides convincing evidence of cosmopolitan marine species, recovering a subset of Oncholaimid nematodes with identical gene sequences (18 S, 28 S and cox1) at trans-Atlantic sample sites.
The complex clade structures recovered within the Enoplida support a high global species richness for marine nematodes, with phylogeographic patterns suggesting the existence of closely related, globally distributed species complexes in the deep sea. True cosmopolitan species may additionally exist within this group, potentially driven by specific life history traits of Enoplids. Although this investigation aimed to intensively sample nematodes from the order Enoplida, specimens were only identified down to genus (at best) and our sampling regime focused on an infinitesimal small fraction of the deep-sea floor. Future nematode studies should incorporate an extended sample set covering a wide depth range (shelf, bathyal, and abyssal sites), utilize additional genetic loci (e.g. mtDNA) that are informative at the species level, and apply high-throughput sequencing methods to fully assay community diversity. Finally, further molecular studies are needed to determine whether phylogeographic patterns observed in Enoplids are common across other ubiquitous marine groups (e.g. Chromadorida, Monhysterida).
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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