Activation of class I phosphatidylinositol 3-kinase (PI3K) leads to formation of phosphatidylinositol-3,4,5-trisphophate (PIP3) and phosphatidylinositol-3,4-bisphophate (PI34P2), which ...spatiotemporally coordinate and regulate a myriad of cellular processes. By simultaneous quantitative imaging of PIP3 and PI34P2 in live cells, we here show that they have a distinctively different spatiotemporal distribution and history in response to growth factor stimulation, which allows them to selectively induce the membrane recruitment and activation of Akt isoforms. PI34P2 selectively activates Akt2 at both the plasma membrane and early endosomes, whereas PIP3 selectively stimulates Akt1 and Akt3 exclusively at the plasma membrane. These spatiotemporally distinct activation patterns of Akt isoforms provide a mechanism for their differential regulation of downstream signaling molecules. Collectively, our studies show that different spatiotemporal dynamics of PIP3 and PI34P2 and their ability to selectively activate key signaling proteins allow them to mediate class I PI3K signaling pathways in a spatiotemporally specific manner.
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•PIP3 and PI34P2 after PI3K activation are quantitatively determined in live cells•PIP3 and PI34P2 have distinctively different spatiotemporal history and dynamics•PIP3 and PI34P2 induce site- and isoform-specific activation of Akt proteins
PI3K signaling is mediated by two lipids, PIP3 and PI34P2. By means of quantitative lipid imaging, we determined the spatiotemporal dynamics of PIP3 and PI34P2 in live cells and elucidated how they specifically control the cellular activities of different Akt isoforms and their downstream signaling proteins.
Neuronal types in the central nervous system differ dramatically in their resilience to injury or other insults. Here we studied the selective resilience of mouse retinal ganglion cells (RGCs) ...following optic nerve crush (ONC), which severs their axons and leads to death of ∼80% of RGCs within 2 weeks. To identify expression programs associated with differential resilience, we first used single-cell RNA-seq (scRNA-seq) to generate a comprehensive molecular atlas of 46 RGC types in adult retina. We then tracked their survival after ONC; characterized transcriptomic, physiological, and morphological changes that preceded degeneration; and identified genes selectively expressed by each type. Finally, using loss- and gain-of-function assays in vivo, we showed that manipulating some of these genes improved neuronal survival and axon regeneration following ONC. This study provides a systematic framework for parsing type-specific responses to injury and demonstrates that differential gene expression can be used to reveal molecular targets for intervention.
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•46 transcriptionally distinct type of retinal ganglion cells (RGCs) in mice•RGC types differ dramatically in survival following axonal transection•Different genes expressed by resilient and vulnerable RGC types•Manipulation of differentially expressed genes promotes RGC survival and regeneration
High-throughput single-cell RNA-seq characterizes 46 types of adult mouse retinal ganglion cells and documents dramatic differences among them in their ability to survive axotomy. Manipulation of genes differentially expressed between resilient and vulnerable types enhances survival and axon regeneration.
Although the identification of the hemodynamic significance of coronary lesions becomes important for revascularization strategy, the potential role of 3-dimensional high-resolution intracoronary ...optical coherence tomography (OCT) for predicting functional significance of coronary lesions remains unclear. We assessed the diagnostic performance of 2 computational approaches for deriving fractional flow reserve (FFR) from intravascular OCT images. We developed 2 methods to derive FFR-OCT by AFD (FFR-OCTAFD) and FFR-OCT by CFD (FFR-OCTCFD). Among 217 eligible patients between 2011 and 2014, 104 were included for data analysis (9 for derivation, 95 for validation). Luminal geometries from 3-dimensional OCT were used for both FFR-OCTAFD and FFR-OCTCFD calculations. The analytical fluid dynamics method calculated FFR from the blood flow resistance estimated using Poiseuille's law. For computational fluid dynamics, we numerically solved the Navier–Stokes equation in a steady-state flow with the distal porous media model for the capillary vessels. We examined the diagnostic performance of FFR-OCTAFD and FFR-OCTCFD compared with the pressure-wire measured FFR. The accuracy, sensitivity, specificity, PPV, and NPV were 86%, 65%, 94%, 81%, and 88% for FFR-OCTAFD and 86%, 73%, 91%, 76%, and 90% for FFR-OCTCFD. The area under the curve of the receiver-operating characteristic curve was 0.88 for FFR-OCTAFD and 0.86 for FFR-OCTCFD. FFR-OCTAFD and FFR-OCTCFD showed a strong linear correlation with the measured FFR (r = 0.631; p <0.001, r = 0.655; p <0.001, respectively). FFR derived from high-resolution volumetric OCT images showed high diagnostic performance for the detection of coronary ischemia. In conclusion, OCT-derived FFR may be useful for guiding the management of coronary artery disease.
Cutaneous squamous-cell carcinomas and keratoacanthomas are common findings in patients treated with BRAF inhibitors.
We performed a molecular analysis to identify oncogenic mutations (HRAS, KRAS, ...NRAS, CDKN2A, and TP53) in the lesions from patients treated with the BRAF inhibitor vemurafenib. An analysis of an independent validation set and functional studies with BRAF inhibitors in the presence of the prevalent RAS mutation was also performed.
Among 21 tumor samples, 13 had RAS mutations (12 in HRAS). In a validation set of 14 samples, 8 had RAS mutations (4 in HRAS). Thus, 60% (21 of 35) of the specimens harbored RAS mutations, the most prevalent being HRAS Q61L. Increased proliferation of HRAS Q61L-mutant cell lines exposed to vemurafenib was associated with mitogen-activated protein kinase (MAPK)-pathway signaling and activation of ERK-mediated transcription. In a mouse model of HRAS Q61L-mediated skin carcinogenesis, the vemurafenib analogue PLX4720 was not an initiator or a promoter of carcinogenesis but accelerated growth of the lesions harboring HRAS mutations, and this growth was blocked by concomitant treatment with a MEK inhibitor.
Mutations in RAS, particularly HRAS, are frequent in cutaneous squamous-cell carcinomas and keratoacanthomas that develop in patients treated with vemurafenib. The molecular mechanism is consistent with the paradoxical activation of MAPK signaling and leads to accelerated growth of these lesions. (Funded by Hoffmann-La Roche and others; ClinicalTrials.gov numbers, NCT00405587, NCT00949702, NCT01001299, and NCT01006980.).
To increase awareness, outline strategies, and offer guidance on the recommended management of immune-related adverse events (irAEs) in patients treated with immune checkpoint inhibitor (ICPi) ...therapy.
A multidisciplinary panel of medical oncology, dermatology, gastroenterology, rheumatology, pulmonology, endocrinology, neurology, hematology, emergency medicine, nursing, trialists, and advocacy experts was convened to update the guideline. Guideline development involved a systematic literature review and an informal consensus process. The systematic review focused on evidence published from 2017 through 2021.
A total of 175 studies met the eligibility criteria of the systematic review and were pertinent to the development of the recommendations. Because of the paucity of high-quality evidence, recommendations are based on expert consensus.
Recommendations for specific organ system-based toxicity diagnosis and management are presented. While management varies according to the organ system affected, in general, ICPi therapy should be continued with close monitoring for grade 1 toxicities, except for some neurologic, hematologic, and cardiac toxicities. ICPi therapy may be suspended for most grade 2 toxicities, with consideration of resuming when symptoms revert ≤ grade 1. Corticosteroids may be administered. Grade 3 toxicities generally warrant suspension of ICPis and the initiation of high-dose corticosteroids. Corticosteroids should be tapered over the course of at least 4-6 weeks. Some refractory cases may require other immunosuppressive therapy. In general, permanent discontinuation of ICPis is recommended with grade 4 toxicities, except for endocrinopathies that have been controlled by hormone replacement. Additional information is available at www.asco.org/supportive-care-guidelines.
Abstract
We have recently reported that some cancers induce accumulation of bone marrow (BM) B-cell precursors in the spleen to convert them into metastasis-promoting, immunosuppressive B cells. ...Here, using various murine tumor models and samples from humans with breast and ovarian cancers, we provide evidence that cancers also co-opt differentiation of these B-cell precursors to generate macrophage-like cells (termed B-MF). We link the transdifferentiation to a small subset of CSF1R
+
Pax5
Low
cells within BM pre-B and immature B cells responding to cancer-secreted M-CSF with downregulation of the transcription factor Pax5 via CSF1R signaling. Although the primary source of tumor-associated macrophages is monocytes, B-MFs are phenotypically and functionally distinguishable. Compared to monocyte-derived macrophages, B-MFs more efficiently phagocytize apoptotic cells, suppress proliferation of T cells and induce FoxP3
+
regulatory T cells. In mouse tumor models, B-MFs promote shrinkage of the tumor-infiltrating IFNγ
+
CD4 T cell pool and increase cancer progression and metastasis, suggesting that this cancer-induced transdifferentiation pathway is functionally relevant and hence could serve as an immunotherapeutic target.
To assess changes in the prevalence rates of probable common mental disorders (CMDs) and in rates of disability support pensions (DSPs) for people with psychiatric disorders in Australia between 2001 ...and 2014.
Secondary analysis of data from five successive Australian national health surveys of representative samples of the working age population (18-65 years of age) and national data on DSP recipients.
Prevalence of probable CMDs with very high symptom level (defined by a Kessler Psychological Distress Scale K10 score of 30 or more) or with high symptom level (K10 score of 22 or more); the proportion of working age Australians receiving DSPs for psychiatric conditions.
There was no change in the prevalence rate of probable CMDs with very high symptom levels between 2001 and 2014, but a slight decrease in the prevalence of probable CMDs with high symptoms levels, particularly among those under 45 years of age. Over the same period, the proportion of working age individuals receiving DSPs for psychiatric conditions increased by 51% (for trend, P < 0.001), equivalent to one additional DSP for every 182 working age Australians.
Contrary to popular belief, the prevalence of probable CMDs in Australia was stable between 2001 and 2014. However, the proportion of the working age population receiving DSPs for psychiatric conditions increased dramatically over the same period. This conundrum is a major public health problem that should be further examined.
Animal and human studies have documented the existence of developmental windows (or sensitive periods) when experience can have lasting effects on brain structure or function, behavior, and disease. ...Although sensitive periods for depression likely arise through a complex interplay of genes and experience, this possibility has not yet been explored in humans. We examined the effect of genetic pathways regulating sensitive periods, alone and in interaction with common childhood adversities, on depression risk. Guided by a translational approach, we: (1) performed association analyses of three gene sets (60 genes) shown in animal studies to regulate sensitive periods using summary data from a genome-wide association study of depression (n = 807,553); (2) evaluated the developmental expression patterns of these genes using data from BrainSpan (n = 31), a transcriptional atlas of postmortem brain samples; and (3) tested gene-by-development interplay (dGxE) by analyzing the combined effect of common variants in sensitive period genes and time-varying exposure to two types of childhood adversity within a population-based birth cohort (n = 6254). The gene set regulating sensitive period opening associated with increased depression risk. Notably, 6 of the 15 genes in this set showed developmentally regulated gene-level expression. We also identified a statistical interaction between caregiver physical or emotional abuse during ages 1-5 years and genetic risk for depression conferred by the opening genes. Genes involved in regulating sensitive periods are differentially expressed across the life course and may be implicated in depression vulnerability. Our findings about gene-by-development interplay motivate further research in large, more diverse samples to further unravel the complexity of depression etiology through a sensitive period lens.
The exploration of new physical properties for various THz-based applications, such as THz-wave sensing, modulation, and imaging devices, is a key challenge in the research on organic–inorganic ...hybrid perovskite materials. These THz-based applications require satisfactory, sensitive, and stable absorption properties with values between 0.5 and 3 THz. To achieve these properties, candidate materials should possess a purified structure that induces regular and fixed phonon modes without any defects or impurities. CH3NH3PbBr3, an organic–inorganic hybrid perovskite thin film produced by a sequential vacuum evaporation method on a flexible PET substrate, was investigated in this study. Although the thin film contains only molecular defects related to CH3NH2 incorporated into the perovskite structure, our THz-wave absorption measurement and first-principles simulation confirmed that these molecular defects do not influence the three phonon modes originating from the transverse vibration (0.8 THz), the longitudinal optical vibrations (1.4 THz) of the Pb–Br–Pb bonds, and the optical Br vibration (2.0 THz). After spin-casting an ultrathin PTAA polymer protective layer (5 nm) on the hybrid perovskite thin film, it was additionally observed that there was no significant effect on the phonon modes. Thus, this novel flexible organic–inorganic hybrid perovskite material is a potential candidate for THz-based applications.NPG Asia MaterialsOptical materials: a new choice for security imagingA material useful for security imaging has been identified by an international team of scientists. Radiation between the infrared and microwave parts of the electromagnetic spectrum can pass through clothing. This so-called terahertz radiation is valuable for security screening technology as it can identify a wider range of materials than metal detectors and is much quicker than a manual pat-down. A team led by Young-Kyun Kwon from Kyung Hee University, Seoul, South Korea, and Min-Cherl Jung from the University of Tsukuba, Ibaraki, Japan, demonstrated that a material already used with great success in optoelectronic and solar cell applications, known as an organic–inorganic hybrid perovskite, also has useful terahertz properties. The team created thin films of this material on a flexible substrate and showed that it absorbed radiation at fixed terahertz frequencies.
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