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Our study explores whether lifelong learning is associated with the subjective wellbeing among the elderly in Singapore. Through a primary survey of 300 individuals aged 65 and above, we develop a novel index to capture three different aspects of subjective wellbeing, which we term “Quality of Life”, “Satisfaction with Life” and “Psychological Wellbeing”. Utilizing both supervised and unsupervised machine learning techniques, our findings reveal that attitudes towards lifelong learning are positively associated with quality of life, while participation in class activities is positively associated with all three measures of wellbeing. Although the study does not establish causality, it highlights a connection between lifelong learning and the perceived wellbeing of the elderly, offering support for policies that encourage lifelong learning among this population.

Utilizing language measures from a paper by Melitz and Toubal, we estimate a gravity model to examine how various aspects of language may influence bilateral FDI. Our paper shows that while common language can help to foster bilateral FDI between countries, some aspects of language are more important than others. We find that bilateral FDI tends to be higher between countries that share a common official language, have common native languages, or languages that are linguistically proximate. However, it does not appear to be influenced merely by countries speaking a common language. We also observe that common native language, which indicates ethnic ties and trust, is the strongest predictor of FDI. This association is driven mainly by countries sharing English as the native language, but not by countries sharing the same non-English European native languages.

Triple Negative Breast Cancer (TNBC) is the most aggressive breast cancer subtype suffering from limited targeted treatment options. Following recent reports correlating Fibroblast growth factor-inducible 14 (Fn14) receptor overexpression in Estrogen Receptor (ER)-negative breast cancers with metastatic events, we show that Fn14 is specifically overexpressed in TNBC patients and associated with poor survival. We demonstrate that constitutive Fn14 signalling rewires the transcriptomic and epigenomic landscape of TNBC, leading to enhanced tumour growth and metastasis. We further illustrate that such mechanisms activate TNBC-specific super enhancers (SE) to drive the transcriptional activation of cancer dependency genes via chromatin looping. In particular, we uncover the SE-driven upregulation of Nicotinamide phosphoribosyltransferase (NAMPT), which promotes NAD+ and ATP metabolic reprogramming critical for filopodia formation and metastasis. Collectively, our study details the complex mechanistic link between TWEAK/Fn14 signalling and TNBC metastasis, which reveals several vulnerabilities which could be pursued for the targeted treatment of TNBC patients. Triple Negative Breast Cancer (TNBC) is the most aggressive breast cancer subtype. Here, the authors show that TWEAK/Fn14 signalling promotes TNBC metastasis through extensive transcriptomic and epigenetic remodelling, highlighting it as a promising therapeutic target.

Gliomas are highly invasive and chemoresistant cancers, making them challenging to treat. Chronic inflammation is a key driver of glioma progression as it promotes aberrant activation of inflammatory pathways such as NF-κB signalling, which drives cancer cell invasion and angiogenesis. NF-κB factors typically dimerise with its own family members, but emerging evidence of their promiscuous interactions with other oncogenic factors has been reported to promote transcription of new target genes and function. Here, we show that non-canonical NF-κB activation directly regulates p52 at the ETS1 promoter, activating its expression. This impacts the genomic and transcriptional landscape of ETS1 in a glioma-specific manner. We further show that enhanced non-canonical NF-κB signalling promotes the co-localisation of p52 and ETS1, resulting in transcriptional activation of non-κB and/or non-ETS glioma-promoting genes. We conclude that p52-induced ETS1 overexpression in glioma cells remodels the genome-wide regulatory network of p52 and ETS1 to transcriptionally drive cancer progression. p52-induced ETS1 overexpression in glioma cells remodels the genome-wide regulatory network of p52 and ETS1 to transcriptionally drive cancer progression.

Multiple myeloma (MM) is the second most common hematological malignancy that displays diverse genetic heterogeneity leading to treatment resistance. Recurrent mutations causing hyperactivation of the non-canonical NF-ĸB pathway are highly prevalent in relapsed, refractory MM patients, but the precise mechanisms driving chemoresistance are poorly understood. Here, we identify a long non-coding RNA termed PLUM , that is overexpressed in NF-ĸB mutant high-risk MM subtypes and patients who are refractory to VRd treatment regimen. Mechanistically, PLUM interacts with Polycomb Repressive Complex 2 to regulate its stability and histone methyltransferase activity, modulating the expression of tumor suppressor genes, FOXO3 and ZFP36 , to activate the unfolded protein response (UPR). Importantly, disruption of PLUM -EZH2 interaction using steric antisense oligonucleotides re-sensitizes myeloma cells to drug treatment in vivo, correlating with the loss of PRC2 stability and H3K27 trimethylation activity. These findings indicate that PLUM facilitates formation of PRC2 complex and enhances EZH2 activity, modulating the myeloma epigenome to mediate chemoresistance. Hence, targeting PLUM -EZH2 interactions may represent a clinically potent strategy for the treatment of relapsed, refractory MM. Understanding the mechanisms of chemoresistance in multiple myeloma (MM) remains elusive. Here, the authors identify a long non-coding RNA termed as PLUM that is overexpressed in NF-ĸB mutant high-risk MM and interacts with EZH2 to mediate PRC2 complex formation promoting chemoresistance via the activation of the UPR pathway.

DNA replication is tightly regulated to occur once per cell cycle, with the MCM2-7 helicase loaded onto replication origins only during G1-phase. In higher eukaryotes, geminin negatively regulates this process during S-, G2- and M-phases by binding the essential licensing factor CDT1. Although geminin’s function is crucial for genomic stability, its inhibitory mechanism remains elusive. Here, we utilise a fully reconstituted human DNA replication licensing assay to dissect geminin’s role. AlphaFold modelling provides structural insights into an N-terminal CDT1-binding helix of geminin, which proves essential for inhibition. Structural docking of the CDT1-geminin complex into the ORC-CDC6-CDT1-MCM2-7 (OCCM) assembly shows that geminin’s long coiled-coil domain sterically clashes with the MCM2 C-terminus, rather than directly blocking CDT1 binding to ORC-CDC6-MCM2-7. Shortening the coiled-coil preserves geminin dimerisation and CDT1 binding but abolishes inhibition, confirming its mechanistic role. Surprisingly, geminin is not able to fully inhibit DNA licensing. However, CDK1/2-cyclin A can partially inhibit DNA licensing and, in conjunction with geminin, result in a complete block. These findings uncover geminin’s steric inhibitory mechanism and suggest that a dual CDK-geminin axis controls human DNA replication. Geminin regulates DNA replication by binding CDT1 and preventing MCM helicase loading. Using a reconstituted system and structural modelling, the authors find geminin inhibits via steric clash with MCM, not by blocking the CDT1–MCM interface. Combined with CDK activity, it fully halts licensing.

Rapid population expansions in urban areas have significant implications for housing costs, creating challenges for housing affordability. However, estimating the causal effect of population on housing costs is challenging due to various confounding issues, such as unobserved location-specific attributes, measurement error, and the potential bi-directional relationship between population and housing costs. To address them, we adopt a city-level analysis and introduce a novel instrumental variable (IV) that enables us to employ fixed effects IV estimation. Our findings indicate that housing costs tend to increase at a faster rate than population growth. As individuals and households with lower incomes tend to allocate a larger proportion of their earnings to housing expenses, an upward trajectory of housing costs may dramatically widen the inequality in income after housing expenditure.

It is becoming increasingly evident that the non-coding genome and transcriptome exert great influence over their coding counterparts through complex molecular interactions. Among non-coding RNAs (ncRNA), long non-coding RNAs (lncRNAs) in particular present increased potential to participate in dysregulation of post-transcriptional processes through both RNA and protein interactions. Since such processes can play key roles in contributing to cancer progression, it is desirable to continue expanding the search for lncRNAs impacting cancer through post-transcriptional mechanisms. The sheer diversity of mechanisms requires diverse resources and methods that have been developed and refined over the past decade. We provide an overview of computational resources as well as proven low-to-high throughput techniques to enable identification and characterisation of lncRNAs in their complex interactive contexts. As more cancer research strategies evolve to explore the non-coding genome and transcriptome, we anticipate this will provide a valuable primer and perspective of how these technologies have matured and will continue to evolve to assist researchers in elucidating post-transcriptional roles of lncRNAs in cancer.

We report a case of changing semiology of intractable right temporal lobe epilepsy. The patient’s semiology of ictal spitting, altered awareness, automatisms and occasional secondary generalization remained stable for many years. 3T MRI head was normal, and subsequent advanced imaging and neu- rophysiology localised the seizure focus to the right temporal lobe and surrounding regions. He received a right temporal lobectomy, with subsequent redo surgery due to incomplete margins. These did not confer seizure freedom. Subsequently his seizure semiology changed to episodic fluent dysphasia with preserved awareness. This was correlated with scalp EEG changes now showing lateralisation to the bilateral temporal lobes.This case demonstrates that seemingly unilateral temporal lobe epilepsy may arise from bilateral networks, which can manifest for years from one hemisphere. It is also possible that extra-temporal origin seizures (for example from perisylvian, fronto-basal or parietal locations) can manifest with temporal-like semiology and can spread to either temporal lobe, and thus can be a cause of epilepsy surgery failure.nchlasim@doctors.org.uk35

Having robust estimates of how global warming affects agriculture is important to policymakers, but the existing econometric-based studies have been at odds on what this effect might be. This article conducts a meta-analysis based on 130 primary econometric-based studies to better understand the conflict among the existing estimates on the effect of warming on agriculture. We find that differences in the latitude of the study sample, the temperature measure that was used, and the econometric approach that was applied can explain why the primary studies disagree We also have evidence of publication bias where negative effects of warming are more likely to be published than positive effects are. Finally, we find that the disagreement could be reduced if the studies account for adaptation by using a yearly temperature measure and the hedonic approach.