Abstract
RNA N6-methyladenosine (m6A) modification occurs in approximately 25% of mRNAs at the transcriptome-wide level. RNA m6A is regulated by the RNA m6A methyltransferases methyltransferase-like ...3 (METTL3), METTL14, and METTL16 (writers), demethylases FTO and ALKBH5 (erasers), and binding proteins YTHDC1–2, YTHDF1–3, IGF2BP1–3, and SND1 (readers). These RNA m6A modification proteins are frequently upregulated or downregulated in human cancer tissues and are often associated with poor patient prognosis. By modulating pre-mRNA splicing, mRNA nuclear export, decay, stability, and translation of oncogenic and tumor suppressive transcripts, RNA m6A modification proteins regulate cancer cell proliferation, survival, migration, invasion, tumor initiation, progression, metastasis, and sensitivity to anticancer therapies. Importantly, small-molecule activators of METTL3, as well as inhibitors of METTL3, FTO, ALKBH5, and IGF2BP1 have recently been identified and have shown considerable anticancer effects when administered alone or in combination with other anticancer agents, both in vitro and in mouse models of human cancers. Future compound screening and design of more potent and selective RNA m6A modification protein inhibitors and activators are expected to provide novel anticancer agents, appropriate for clinical trials in patients with cancer tissues harboring aberrant RNA m6A modification protein expression or RNA m6A modification protein–induced resistance to cancer therapy.
Experimentally manipulating Approximate Number System (ANS) precision has been found to influence children’s subsequent symbolic math performance. Here in three experiments (N = 160; 81 girls; ...3–5 year old) we replicated this effect and examined its duration and developmental trajectory. We found that modulation of 5‐year‐olds’ ANS precision continued to affect their symbolic math performance after a 30‐min delay. Furthermore, our cross‐sectional investigation revealed that children 4.5 years and older experienced a significant transfer effect of ANS manipulation on math performance, whereas younger children showed no such transfer, despite experiencing significant changes in ANS precision. These findings support the existence of a causal link between nonverbal numerical approximation and symbolic math performance that first emerges during the preschool years.
Decades of research has revealed that humans can concurrently represent small quantities of three‐dimensional objects as those objects move through space or into occlusion. For infants (but not older ...children or adults), this ability apparently comes with a significant limitation: when the number of occluded objects exceeds three, infants experience what has been characterized as a “catastrophic” set size limit, failing to represent even the approximate quantity of the hidden array. Infants’ apparent catastrophic representational failures suggest a significant information processing limitation in the first years of life, and the evidence has been used as support for prominent theories of the development of object and numerical cognition. However, the evidence for catastrophic failure consists of individual small‐n experiments that use null hypothesis significance testing to obtain null results (i.e., p > 0.05). Whether catastrophic representational failures are robust or reliable across studies, methods, and labs is not known. Here we report a systematic review and Bayesian meta‐analysis to examine the strength of the evidence in favor of catastrophic representational failures in infancy. Our analysis of 22 experiments across 12 reports, with a combined total of n = 367 infants aged 10–20 months, revealed strong support for the evidence for catastrophic set size limits. A complementary analysis found moderate support for infants’ success when representing fewer than four objects. We discuss the implications of our findings for theories of object and numerical cognitive development.
Research Highlights
Previous work has suggested that infants are unable to concurrently represent four or more objects—a “catastrophic” set size limit.
We reviewed this work and conducted a Bayesian meta‐analysis to examine the robustness of this limit across individual small‐n experiments.
We found strong support for the evidence for catastrophic set size limits, and moderate support for infants’ success when representing fewer than four objects.
Children do not understand the meanings of count words like “two” and “three” until the preschool years. But even before knowing the meanings of these individual words, might they recognize that ...counting is “about” the dimension of number? Here in five experiments, we asked whether infants already associate counting with quantities. We measured 14‐ and 18‐month olds’ ability to remember different numbers of hidden objects that either were or were not counted by an experimenter before hiding. As in previous research, we found that infants failed to differentiate four hidden objects from two when the objects were not counted—suggesting an upper limit on the number of individual objects they could represent in working memory. However, infants succeeded when the objects were simply counted aloud before hiding. We found that counting also helped infants differentiate four hidden objects from six (a 2:3 ratio), but not three hidden objects from four (a 3:4 ratio), suggesting that counting helped infants represent the arrays’ approximate cardinalities. Hence counting directs infants’ attention to numerical aspects of the world, showing that they recognize counting as numerically relevant years before acquiring the meanings of number words.
Fourteen‐ and 18‐month‐old infants remembered more hidden objects when objects were counted before hiding than when they were not. Counting directs infants’ attention to the dimension of numerosity long before children understand the meanings of individual count words.
G protein-coupled receptors (GPCRs) are a large superfamily of cell-surface signaling proteins that bind extracellular ligands and transduce signals into cells via heterotrimeric G proteins. GPCRs ...are highly tractable drug targets. Aberrant expression of GPCRs and G proteins has been observed in various cancers and their importance in cancer stem cells has begun to be appreciated. We have recently reported essential roles for G protein-coupled receptor 84 (GPR84) and G protein subunit Gαq in the maintenance of cancer stem cells in acute myeloid leukemia. This review will discuss how GPCRs and G proteins regulate stem cells with a focus on cancer stem cells, as well as their implications for the development of novel targeted cancer therapies.
Lateral flow devices (LFDs) are viral antigen tests for the detection of SARS-CoV-2 that produce a rapid result, are inexpensive and easy to operate. They have been advocated for use by the World ...Health Organisation to help control outbreaks and break the chain of transmission of COVID-19 infections. There are now several studies assessing their accuracy but as yet no systematic review. Our aims were to assess the sensitivity and specificity of LFDs in a systematic review and summarise the sensitivity and specificity of these tests. A targeted search of Pubmed and Medxriv, using PRISMA principles, was conducted identifying clinical studies assessing the sensitivity and specificity of LFDs as their primary outcome compared to reverse transcriptase polymerase chain reaction (RT-PCR) for the detection of SARS-CoV-2. Based on extracted data sensitivity and specificity was calculated for each study. Data was pooled based on manufacturer of LFD and split based on operator (self-swab or by trained professional) and sensitivity and specificity data were calculated. Twenty-four papers were identified involving over 26,000 test results. Sensitivity from individual studies ranged from 37.7% (95% CI 30.6-45.5) to 99.2% (95% CI 95.5-99.9) and specificity from 92.4% (95% CI 87.5-95.5) to 100.0% (95% CI 99.7-100.0). Operation of the test by a trained professional or by the test subject with self-swabbing produced comparable results. This systematic review identified that the performance of lateral flow devices is heterogeneous and dependent on the manufacturer. Some perform with high specificity but a great range of sensitivities were shown (38.32-99.19%). Test performance does not appear dependent on the operator. Potentially, LFDs could support the scaling up of mass testing to aid track and trace methodology and break the chain of transmission of COVID-19 with the additional benefit of providing individuals with the results in a much shorter time frame.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Recent work shows that 18‐month old infants understand that counting is numerically relevant—infants who see objects counted are more likely to represent the approximate number of objects in the ...array than infants who see the objects labeled but not counted. Which aspects of counting signal infants to attend to numerosity in this way? Here we asked whether infants rely on familiarity with the count words in their native language, or on procedures instantiated by the counting routine, independent of specific tokens. In three experiments (N = 48), we found that 18‐month old infants from English‐speaking households successfully distinguished four hidden objects from two when the objects were counted correctly, regardless of their familiarity with the count words (i.e., when objects were counted in familiar English and in unfamiliar German). However, when the objects were counted using familiar English count words in ways that violated basic counting principles, infants no longer represented the arrays, failing to distinguish four hidden objects from two. Together with previous findings, these results suggest that children may link the procedure of counting with numerosity years before they learn the meanings of the count words.
The paper investigates how unrestricted global capitalism and a Confucian culture of hierarchy and obedience combine to create a form of modern slavery in China. The cases cited involve ...semi‐structured interviews with 11 managers and 19 workers working in the hospitality and manufacturing sectors. The interviews are analysed to determine how managers use controls to exploit power/distance, high levels of insecurity, and unenforced labour rights to impose harsh working conditions. Prior research has examined what mechanisms are imposed in a society that retains a Confucian legacy of obedience but not ‘how’ they are imposed in a way that constitutes a form of modern slavery.
Laser powder bed fusion additive manufacturing is an emerging 3D printing technique for the fabrication of advanced metal components. Widespread adoption of it and similar additive technologies is ...hampered by poor understanding of laser-metal interactions under such extreme thermal regimes. Here, we elucidate the mechanism of pore formation and liquid-solid interface dynamics during typical laser powder bed fusion conditions using in situ X-ray imaging and multi-physics simulations. Pores are revealed to form during changes in laser scan velocity due to the rapid formation then collapse of deep keyhole depressions in the surface which traps inert shielding gas in the solidifying metal. We develop a universal mitigation strategy which eliminates this pore formation process and improves the geometric quality of melt tracks. Our results provide insight into the physics of laser-metal interaction and demonstrate the potential for science-based approaches to improve confidence in components produced by laser powder bed fusion.
Abstract
Genomic amplification of the distal portion of chromosome 3q, which encodes a number of oncogenic proteins, is one of the most frequent chromosomal abnormalities in malignancy. Here we ...functionally characterise a non-protein product of the 3q region, the long noncoding RNA (lncRNA) PLANE, which is upregulated in diverse cancer types through copy number gain as well as E2F1-mediated transcriptional activation. PLANE forms an RNA-RNA duplex with the nuclear receptor co-repressor 2 (NCOR2) pre-mRNA at intron 45, binds to heterogeneous ribonucleoprotein M (hnRNPM) and facilitates the association of hnRNPM with the intron, thus leading to repression of the alternative splicing (AS) event generating NCOR2-202, a major protein-coding NCOR2 AS variant. This is, at least in part, responsible for PLANE-mediated promotion of cancer cell proliferation and tumorigenicity. These results uncover the function and regulation of PLANE and suggest that PLANE may constitute a therapeutic target in the pan-cancer context.
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