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ASEAN 50 : regional security cooperation through selected documents
\"The book ASEAN 50: A Security Community curates key official documents from its foundation in 1967 to 2016. With an emphasis on ASEAN as a political-security community, this book puts together selected documents that trace the development of the Association through periods of its formation, the Cold War in Asia, the post-Cold War security environment, its expansion and adaption to the shifting geopolitical dynamics. Through the documents and their accompanying commentaries, 50 Years of ASEAN: A Security Community aims to provide an important resource for researchers of ASEAN and Southeast Asia\"-- Provided by publisher.
Book
Long noncoding RNAs in cancer metastasis
Metastasis is a major contributor to cancer-associated deaths. It is characterized by a multistep process that occurs through the acquisition of molecular and phenotypic changes enabling cancer cells from a primary tumour to disseminate and colonize at distant organ sites. Over the past decade, the discovery and characterization of long noncoding RNAs (lncRNAs) have revealed the diversity of their regulatory roles, including key contributions throughout the metastatic cascade. Here, we review how lncRNAs promote metastasis by functioning in discrete pro-metastatic steps including the epithelial–mesenchymal transition, invasion and migration and organotrophic colonization, and by influencing the metastatic tumour microenvironment, often by interacting within ribonucleoprotein complexes or directly with other nucleic acid entities. We discuss well-characterized lncRNAs with in vivo phenotypes and highlight mechanistic commonalities such as convergence with the TGFβ–ZEB1/ZEB2 axis or the nuclear factor-κB pathway, in addition to lncRNAs with controversial mechanisms and the influence of methodologies on mechanistic interpretation. Furthermore, some lncRNAs can help identify tumours with increased metastatic risk and spur novel therapeutic strategies, with several lncRNAs having shown potential as novel targets for antisense oligonucleotide therapy in animal models. In addition to well-characterized examples of lncRNAs functioning in metastasis, we discuss controversies and ongoing challenges in lncRNA biology. Finally, we present areas for future study for this rapidly evolving field.This Review discusses how long noncoding RNAs influence metastasis by functioning in discrete pro-metastatic steps including the epithelial–mesenchymal transition, invasion and migration and organotrophic colonization, and by influencing the tumour microenvironment. Diagnostic and therapeutic potential as well as controversies and ongoing technical challenges are discussed.
Journal Article
Forging our understanding of lncRNAs in the brain
During both development and adulthood, the human brain expresses many thousands of long noncoding RNAs (lncRNAs), and aberrant lncRNA expression has been associated with a wide range of neurological diseases. Although the biological significance of most lncRNAs remains to be discovered, it is now clear that certain lncRNAs carry out important functions in neurodevelopment, neural cell function, and perhaps even diseases of the human brain. Given the relatively inclusive definition of lncRNAs—transcripts longer than 200 nucleotides with essentially no protein coding potential—this class of noncoding transcript is both large and very diverse. Furthermore, emerging data indicate that lncRNA genes can act via multiple, non-mutually exclusive molecular mechanisms, and specific functions are difficult to predict from lncRNA expression or sequence alone. Thus, the different experimental approaches used to explore the role of a lncRNA might each shed light upon distinct facets of its overall molecular mechanism, and combining multiple approaches may be necessary to fully illuminate the function of any particular lncRNA. To understand how lncRNAs affect brain development and neurological disease, in vivo studies of lncRNA function are required. Thus, in this review, we focus our discussion upon a small set of neural lncRNAs that have been experimentally manipulated in mice. Together, these examples illustrate how studies of individual lncRNAs using multiple experimental approaches can help reveal the richness and complexity of lncRNA function in both neurodevelopment and diseases of the brain.
Journal Article
Mindfulness and compassion: an examination of mechanism and scalability
Emerging evidence suggests that meditation engenders prosocial behaviors meant to benefit others. However, the robustness, underlying mechanisms, and potential scalability of such effects remain open to question. The current experiment employed an ecologically valid situation that exposed participants to a person in visible pain. Following three-week, mobile-app based training courses in mindfulness meditation or cognitive skills (i.e., an active control condition), participants arrived at a lab individually to complete purported measures of cognitive ability. Upon entering a public waiting area outside the lab that contained three chairs, participants seated themselves in the last remaining unoccupied chair; confederates occupied the other two. As the participant sat and waited, a third confederate using crutches and a large walking boot entered the waiting area while displaying discomfort. Compassionate responding was assessed by whether participants gave up their seat to allow the uncomfortable confederate to sit, thereby relieving her pain. Participants' levels of empathic accuracy was also assessed. As predicted, participants assigned to the mindfulness meditation condition gave up their seats more frequently than did those assigned to the active control group. In addition, empathic accuracy was not increased by mindfulness practice, suggesting that mindfulness-enhanced compassionate behavior does not stem from associated increases in the ability to decode the emotional experiences of others.
Journal Article
Limited Intervention and Moral Kindergartens
Recently, William Hasker and Cheryl Chen have argued that James Sterba’s argument for the non-existence of God based on the existence of horrendous evil consequences fails. Hasker, among other things, contends that eliminating horrendous evil consequences will result in a moral kindergarten. It is unclear, however, whether the elimination of horrendous evil consequences will result in a moral kindergarten. Moreover, if Hasker is right, then it may be that most people in the actual world live in a moral kindergarten. Chen argues that eliminating horrendous evil consequences may lead to a morally worse world. While Chen is ultimately right about this, it is not fatal to the basic intuition at the heart of Sterba’s argument.
Journal Article
Single-cell profiling of human gliomas reveals macrophage ontogeny as a basis for regional differences in macrophage activation in the tumor microenvironment
Background
Tumor-associated macrophages (TAMs) are abundant in gliomas and immunosuppressive TAMs are a barrier to emerging immunotherapies. It is unknown to what extent macrophages derived from peripheral blood adopt the phenotype of brain-resident microglia in pre-treatment gliomas. The relative proportions of blood-derived macrophages and microglia have been poorly quantified in clinical samples due to a paucity of markers that distinguish these cell types in malignant tissue.
Results
We perform single-cell RNA-sequencing of human gliomas and identify phenotypic differences in TAMs of distinct lineages. We isolate TAMs from patient biopsies and compare them with macrophages from non-malignant human tissue, glioma atlases, and murine glioma models. We present a novel signature that distinguishes TAMs by ontogeny in human gliomas. Blood-derived TAMs upregulate immunosuppressive cytokines and show an altered metabolism compared to microglial TAMs. They are also enriched in perivascular and necrotic regions. The gene signature of blood-derived TAMs, but not microglial TAMs, correlates with significantly inferior survival in low-grade glioma. Surprisingly, TAMs frequently co-express canonical pro-inflammatory (M1) and alternatively activated (M2) genes in individual cells.
Conclusions
We conclude that blood-derived TAMs significantly infiltrate pre-treatment gliomas, to a degree that varies by glioma subtype and tumor compartment. Blood-derived TAMs do not universally conform to the phenotype of microglia, but preferentially express immunosuppressive cytokines and show an altered metabolism. Our results argue against status quo therapeutic strategies that target TAMs indiscriminately and in favor of strategies that specifically target immunosuppressive blood-derived TAMs.
Journal Article
CRISPRi-based genome-scale identification of functional long noncoding RNA loci in human cells
The human genome generates many thousands of long noncoding RNAs (lncRNAs). A very small number of lncRNAs have been shown to be functional. Liu et al. carried out a large-scale CRISPR-based screen to assess the function of ∼17,000 lncRNAs in seven different human cell lines. A considerable number (∼500) of the tested lncRNAs influenced cell growth, suggesting biological function. In almost all cases, though, the function was highly cell type—specific, often limited to just one cell type. Science , this issue p. 10.1126/science.aah7111 A considerable fraction of long noncoding RNAs have highly cell type–specific biological functions. The human genome produces thousands of long noncoding RNAs (lncRNAs)—transcripts >200 nucleotides long that do not encode proteins. Although critical roles in normal biology and disease have been revealed for a subset of lncRNAs, the function of the vast majority remains untested. We developed a CRISPR interference (CRISPRi) platform targeting 16,401 lncRNA loci in seven diverse cell lines, including six transformed cell lines and human induced pluripotent stem cells (iPSCs). Large-scale screening identified 499 lncRNA loci required for robust cellular growth, of which 89% showed growth-modifying function exclusively in one cell type. We further found that lncRNA knockdown can perturb complex transcriptional networks in a cell type–specific manner. These data underscore the functional importance and cell type specificity of many lncRNAs.
Journal Article
Spatiotemporal gene expression trajectories reveal developmental hierarchies of the human cortex
Systematic analyses of spatiotemporal gene expression trajectories during organogenesis have been challenging because diverse cell types at different stages of maturation and differentiation coexist in the emerging tissues. We identified discrete cell types as well as temporally and spatially restricted trajectories of radial glia maturation and neurogenesis in developing human telencephalon. These lineage-specific trajectories reveal the expression of neurogenic transcription factors in early radial glia and enriched activation of mammalian target of rapamycin signaling in outer radial glia. Across cortical areas, modest transcriptional differences among radial glia cascade into robust typological distinctions among maturing neurons. Together, our results support a mixed model of topographical, typological, and temporal hierarchies governing cell-type diversity in the developing human telencephalon, including distinct excitatory lineages emerging in rostral and caudal cerebral cortex.
Journal Article
Single-cell analysis of long non-coding RNAs in the developing human neocortex
Background
Long non-coding RNAs (lncRNAs) comprise a diverse class of transcripts that can regulate molecular and cellular processes in brain development and disease. LncRNAs exhibit cell type- and tissue-specific expression, but little is known about the expression and function of lncRNAs in the developing human brain. Furthermore, it has been unclear whether lncRNAs are highly expressed in subsets of cells within tissues, despite appearing lowly expressed in bulk populations.
Results
We use strand-specific RNA-seq to deeply profile lncRNAs from polyadenylated and total RNA obtained from human neocortex at different stages of development, and we apply this reference to analyze the transcriptomes of single cells. While lncRNAs are generally detected at low levels in bulk tissues, single-cell transcriptomics of hundreds of neocortex cells reveal that many lncRNAs are abundantly expressed in individual cells and are cell type-specific. Notably,
LOC646329
is a lncRNA enriched in single radial glia cells but is detected at low abundance in tissues. CRISPRi knockdown of
LOC646329
indicates that this lncRNA regulates cell proliferation.
Conclusion
The discrete and abundant expression of lncRNAs among individual cells has important implications for both their biological function and utility for distinguishing neural cell types.
Journal Article
ChatGPT performance in assessing musculoskeletal MRI scan appropriateness based on ACR appropriateness criteria
Large Language Models (LLMs) hold potential as clinical decision support tools, particularly when integrated with domain-specific knowledge. In radiology, there is limited research on LLMs for assessing imaging appropriateness. This study evaluates a contextualized GPT-4-based LLM’s performance in assessing the appropriateness of musculoskeletal MRI scan requests with standard models and different versions of optimization. The LLMs’ performances was also compared against human clinicians with varying experience (two radiology residents, two subspecialist attendings, an orthopaedic surgeon). Using a retrieval-augmented generation framework, the LLM was provided with a domain-specific knowledge base from 33 American College of Radiology Appropriateness Criteria guidelines. A test dataset of 70 fictional case scenarios was created, including cases with insufficient clinical information. Quantitative analysis using the McNemar mid-P test revealed that the optimized LLM achieved 92.86% accuracy, significantly outperforming the baseline model (61.43%,
P
< .001) and the standard GPT-4 model (51.29%,
P
< .001). The optimized model also excelled in identifying cases with insufficient clinical information. In comparison to human clinicians, the optimized LLM performed better than all but one radiologist. This study demonstrates that with contextualization and optimization, GPT-4-based LLMs can improve performance in assessing imaging appropriateness and show promise as clinical decision support tools in radiology.
Journal Article