Squamous cell carcinomas (SCCs) are one of the most frequent forms of human malignancy, but, other than TP53 mutations, few causative somatic aberrations have been identified. We identified NOTCH1 or ...NOTCH2 mutations in ∼75% of cutaneous SCCs and in a lesser fraction of lung SCCs, defining a spectrum for the most prevalent tumor suppressor specific to these epithelial malignancies. Notch receptors normally transduce signals in response to ligands on neighboring cells, regulating metazoan lineage selection and developmental patterning. Our findings therefore illustrate a central role for disruption of microenvironmental communication in cancer progression. NOTCH aberrations include frameshift and nonsense mutations leading to receptor truncations as well as point substitutions in key functional domains that abrogate signaling in cell-based assays. Oncogenic gain-of-function mutations in NOTCH1 commonly occur in human T-cell lymphoblastic leukemia/lymphoma and B-cell chronic lymphocytic leukemia. The bifunctional role of Notch in human cancer thus emphasizes the context dependency of signaling outcomes and suggests that targeted inhibition of the Notch pathway may induce squamous epithelial malignancies.
The evolution of seed size may be influenced by intrinsic attributes of populations, such as mating system and extrinsic factors, such as climate. Several hypotheses propose that the evolution of ...self‐fertilization from an outcrossing progenitor will be accompanied by a reduction in seed size, but this prediction has not been rigorously tested. Many studies report that the mean seed size of populations or taxa is associated with long‐term climate conditions. Here, we examined the effects on seed size of both mating system and climate within a single genus.
In the California wildflower genus, Clarkia (Onagraceae), we sampled seeds from 58 populations representing three pairs of sister taxa; each pair included a predominantly outcrossing and a facultatively selfing taxon. We then examined the independent effects on population mean seed size of mating system, elevation, long‐term (30‐year) climate conditions, and climate anomalies (the deviation between conditions in the year of collection and the long‐term mean), focusing on maximum monthly temperature (Tmax), cumulative moisture deficit and cumulative precipitation (PPT) during Clarkia's growing season (fall, winter and spring).
In each taxon pair, the selfing taxon had smaller seeds than the outcrosser. Local, long‐term (1921–1980 and 1981–2000) mean Tmax, PPT and elevation were independently and negatively associated with seed size. Long‐term means for Tmax and PPT explain geographical variation in seed size better than climate anomalies in the year of collection.
Synthesis. We corroborated two key hypotheses concerning the drivers of geographical variation in mean seed size. Small seeds in Clarkia co‐evolve with selfing (although the mechanism remains elusive) and in response to chronically warm and wet conditions. The effect of long‐term mean precipitation on seed size differs qualitatively from the effect of precipitation anomalies; relatively large seeds are produced in populations experiencing wetter‐than‐normal years. Ongoing climate change may therefore generate conflicting selection on seed size in Clarkia: intensifying drought is likely to lead to an evolutionary increase in seed size due to its effects on seedling survivorship, while climate‐driven declines in pollinators or selection favouring more rapid reproduction may promote the evolution of self‐pollination, facilitating the evolution of smaller seeds.
We corroborated two key hypotheses concerning the drivers of geographical variation in mean seed size. Small seeds in Clarkia co‐evolve with selfing (although the mechanism remains elusive) and in response to chronically warm and wet conditions. The effect of long‐term mean precipitation on seed size differs qualitatively from the effect of precipitation anomalies; relatively large seeds are produced in populations experiencing wetter‐than‐normal years. Ongoing climate change may therefore generate conflicting selection on seed size in Clarkia: intensifying drought is likely to lead to an evolutionary increase in seed size due to its effects on seedling survivorship, while climate‐driven declines in pollinators or selection favouring more rapid reproduction may promote the evolution of self‐pollination, facilitating the evolution of smaller seeds. Image credit: Heather Schneider merits credit for the photo of Clarkia unguiculata, and Leah Dudley took the photo of Clarkia xantiana.
Localized shimming in single-voxel MRS often results in large B
inhomogeneity outside the volume-of-interest. This causes unacceptable degradation in motion navigator images. Switching back and forth ...between whole-brain shim and localized shim is possible for linear shims, but not for higher-order shims. Here we propose motion navigators largely insensitive to B
inhomogeneity for prospective motion-corrected MRS with localized higher-order shimming.
A recent fast high-resolution motion navigator based on spiral-in/out k-space trajectories and multislice-to-volume registration was modified by splitting the readout into multiple shot interleaves which shortened the echo time and reduced the effect of B
inhomogeneity. The performance of motion correction was assessed in healthy subjects in the prefrontal cortex using a sLASER sequence at 3T (N = 5) and 7T (N = 5).
With multiple spatial interleaves, excellent quality navigator images were acquired in the whole brain in spite of large B
inhomogeneity outside the MRS voxel. The total duration of the navigator in sLASER remained relatively short even with multiple shots (3T: 10 spatial interleaves 94 ms per slice; 7T: 15 spatial interleaves 103 ms per slice). Prospective motion correction using the multi-shot navigators yielded comparable spectral quality (water linewidth and metabolite SNR) with and without subject motion.
B
-insensitive motion navigators enable prospective motion correction for MRS with all first- and second-order shims adjusted in the MRS voxel, providing optimal spectral linewidth.
Purpose
Localized shimming in single‐voxel MRS often results in large B0 inhomogeneity outside the volume‐of‐interest. This causes unacceptable degradation in motion navigator images. Switching back ...and forth between whole‐brain shim and localized shim is possible for linear shims, but not for higher‐order shims. Here we propose motion navigators largely insensitive to B0 inhomogeneity for prospective motion‐corrected MRS with localized higher‐order shimming.
Methods
A recent fast high‐resolution motion navigator based on spiral‐in/out k‐space trajectories and multislice‐to‐volume registration was modified by splitting the readout into multiple shot interleaves which shortened the echo time and reduced the effect of B0 inhomogeneity. The performance of motion correction was assessed in healthy subjects in the prefrontal cortex using a sLASER sequence at 3T (N = 5) and 7T (N = 5).
Results
With multiple spatial interleaves, excellent quality navigator images were acquired in the whole brain in spite of large B0 inhomogeneity outside the MRS voxel. The total duration of the navigator in sLASER remained relatively short even with multiple shots (3T: 10 spatial interleaves 94 ms per slice; 7T: 15 spatial interleaves 103 ms per slice). Prospective motion correction using the multi‐shot navigators yielded comparable spectral quality (water linewidth and metabolite SNR) with and without subject motion.
Conclusion
B0‐insensitive motion navigators enable prospective motion correction for MRS with all first‐ and second‐order shims adjusted in the MRS voxel, providing optimal spectral linewidth.
Timely intervention for cancer requires knowledge of its earliest genetic aberrations. Sequencing of tumors and their metastases reveals numerous abnormalities occurring late in progression. A means ...to temporally order aberrations in a single cancer, rather than inferring them from serially acquired samples, would define changes preceding even clinically evident disease. We integrate DNA sequence and copy number information to reconstruct the order of abnormalities as individual tumors evolve for 2 separate cancer types. We detect vast, unreported expansion of simple mutations sharply demarcated by recombinative loss of the second copy of TP53 in cutaneous squamous cell carcinomas (cSCC) and serous ovarian adenocarcinomas, in the former surpassing 50 mutations per megabase. In cSCCs, we also report diverse secondary mutations in known and novel oncogenic pathways, illustrating how such expanded mutagenesis directly promotes malignant progression. These results reframe paradigms in which TP53 mutation is required later, to bypass senescence induced by driver oncogenes.
Bacterial products are able to act on nociceptive neurons during pathogenic infection. Neurogenic inflammation is an active part of pain signaling and has recently been shown to impact host-pathogen ...defense.
Edema Toxin (ET) produces striking edema in peripheral tissues, but the cellular mechanisms involved in tissue swelling are not completely understood. Here, we find that nociceptive neurons play a role in ET-induced edema and inflammation in mice. Subcutaneous footpad infection of
Sterne caused ET-dependent local mechanical allodynia, paw swelling and body weight gain. Subcutaneous administration of ET induced paw swelling and vascular leakage, the early phases of which were attenuated in the absence of Trp
1
or Na
1.8
nociceptive neurons. Nociceptive neurons express the anthrax toxin receptor ANTXR2, but this did not mediate ET-induced edema. ET induced local cytokine expression and neutrophil recruitment, which were dependent in part on Trp
1
nociceptive neurons. Ablation of Trp
1
or Na
1.8
nociceptive neurons also attenuated early increases in paw swelling and body weight gain during live
infection. Our findings indicate that nociceptive neurons play an active role in inflammation caused by
and Edema Toxin to potentially influence bacterial pathogenesis.
Development of imaging biomarkers for rare neurodegenerative diseases such as spinocerebellar ataxia (SCA) is important to non-invasively track progression of disease pathology and monitor response ...to interventions. Diffusion MRI (dMRI) has been shown to identify cross-sectional degeneration of white matter (WM) microstructure and connectivity between healthy controls and patients with SCAs, using various analysis methods. In this paper, we present dMRI data in SCAs type 1, 2, 3, and 6 and matched controls, including longitudinal acquisitions at 12–24-month intervals in a subset of the cohort, with up to 5 visits. The SCA1 cohort also contained 3 premanifest patients at baseline, with 2 showing ataxia symptoms at the time of the follow-up scans. We focused on two aspects: first, multimodal evaluation of the dMRI data in a cross-sectional approach, and second, longitudinal trends in dMRI data in SCAs. Three different pipelines were used to perform cross-sectional analyses in WM: region of interest (ROI), tract-based spatial statistics (TBSS), and fixel-based analysis (FBA). We further analyzed longitudinal changes in dMRI metrics throughout the brain using ROI-based analysis. Both ROI and TBSS analyses identified higher mean (MD), axial (AD), and radial (RD) diffusivity and lower fractional anisotropy (FA) in the cerebellum for all SCAs compared to controls, as well as some cerebral alterations in SCA1, 2, and 3. FBA showed lower fiber density (FD) and fiber crossing (FC) regions similar to those identified by ROI and TBSS analyses. FBA also highlighted corticospinal tract (CST) abnormalities, which was not detected by the other two pipelines. Longitudinal ROI-based analysis showed significant increase in AD in the middle cerebellar peduncle (MCP) for patients with SCA1, suggesting that the MCP may be a good candidate region to monitor disease progression. The patient who remained symptom-free throughout the study displayed no microstructural abnormalities. On the other hand, the two patients who were at the premanifest stage at baseline, and showed ataxia symptoms in their follow-up visits, displayed AD values in the MCP that were already in the range of symptomatic patients with SCA1 at their baseline visit, demonstrating that microstructural abnormalities are detectable prior to the onset of ataxia.
Wiskott-Aldrich syndrome protein (WASp) is an actin nucleation promoting factor that is required for macrophages to directionally migrate towards various chemoattractants. The chemotaxis defect of ...WASp-deficient cells and its activation by Cdc42 in vivo suggest that WASp plays a role in directional sensing, however, its precise role in macrophage chemotaxis is still unclear. Using shRNA-mediated downregulation of WASp in the murine monocyte/macrophage cell line RAW/LR5 (shWASp), we found that WASp was responsible for the initial wave of actin polymerization in response to global stimulation with CSF-1, which in Dictyostelium discoideum amoebae and carcinoma cells has been correlated with the ability to migrate towards chemoattractants. Real-time monitoring of shWASp cells, as well as WASp⁻/⁻ bone marrow-derived macrophages (BMMs), in response to a CSF-1 gradient revealed that the protrusions from WASp-deficient cells were directional, showing intact directional sensing. However, the protrusions from WASp-deficient cells demonstrated reduced persistence compared to their respective control shRNA and wild-type cells. Further examination showed that tyrosine phosphorylation of WASp was required for both the first wave of actin polymerization following global CSF-1 stimulation and proper directional responses towards CSF-1. Importantly, the PI3K, Rac1 and WAVE2 proteins were incorporated normally in CSF-1 - elicited protrusions in the absence of WASp, suggesting that membrane protrusion driven by the WAVE2 complex signaling is intact. Collectively, these results suggest that WASp and its phosphorylation play critical roles in coordinating the actin cytoskeleton rearrangements necessary for the persistence of protrusions required for directional migration of macrophages towards CSF-1.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Chronic innate immune activation is a key hallmark of many neurological diseases and is known to result in the upregulation of GPR84 in myeloid cells (macrophages, microglia, and monocytes). As such, ...GPR84 can potentially serve as a sensor of proinflammatory innate immune responses. To assess the utility of GPR84 as an imaging biomarker, we synthesized 11 C-MGX-10S and 11 C-MGX-11S via carbon-11 alkylation for use as positron emission tomography (PET) tracers targeting this receptor. In vitro experiments demonstrated significantly higher binding of both radiotracers to hGPR84-HEK293 cells than that of parental control HEK293 cells. Co-incubation with the GPR84 antagonist GLPG1205 reduced the binding of both radiotracers by >90%, demonstrating their high specificity for GPR84 in vitro. In vivo assessment of each radiotracer via PET imaging of healthy mice illustrated the superior brain uptake and pharmacokinetics of 11 C-MGX-10S compared to 11 C-MGX-11S. Subsequent use of 11 C-MGX-10S to image a well-established mouse model of systemic and neuro-inflammation revealed a high PET signal in affected tissues, including the brain, liver, lung, and spleen. In vivo specificity of 11 C-MGX-10S for GPR84 was confirmed by the administration of GLPG1205 followed by radiotracer injection. When compared with 11C-DPA-713an existing radiotracer used to image innate immune activation in clinical research studies 11 C-MGX-10S has multiple advantages, including its higher binding signal in inflamed tissues in the CNS and periphery and low background signal in healthy saline-treated subjects. The pronounced uptake of 11 C-MGX-10S during inflammation, its high specificity for GPR84, and suitable pharmacokinetics strongly support further investigation of 11 C-MGX-10S for imaging GPR84-positive myeloid cells associated with innate immune activation in animal models of inflammatory diseases and human neuropathology.
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