Poly-ADP-ribosylation dynamics, signaling, and analysis.

ADP-ribosylation is a reversible post-translational modification that plays a role as a signaling mechanism in various cellular processes. This modification is characterized by its structural diversity, highly dynamic nature, and short half-life. Hence, it is tightly regulated at many levels by cellular factors that fine-tune its formation, downstream signaling, and degradation that together impacts cellular outcomes. Poly-ADP-ribosylation is an essential signaling mechanism in the DNA damage response that mediates the recruitment of DNA repair factors to sites of DNA damage via their poly-ADP-ribose (PAR)-binding domains (PBDs). PAR readers, encoding PBDs, convey the PAR signal to mediate cellular outcomes that in some cases can be dictated by PAR structural diversity. Several PBD families have been identified, each with variable PAR-binding affinity and specificity, that also recognize and bind to distinct parts of the PAR chain. PARylation signaling has emerged as an attractive target for the treatment of specific cancer types, as the inhibition of PAR formation or degradation can selectively eliminate cancer cells with specific DNA repair defects and can enhance radiation or chemotherapy response. In this review, we summarize the key players of poly-ADP-ribosylation and its regulation and highlight PBDs as tools for studying PARylation dynamics and the expanding potential to target PARylation signaling in cancer treatment.

An abbreviated Chinese dyslexia screening behavior checklist for primary school students using a machine learning approach.

To increase early identification and intervention of dyslexia, a prescreening instrument is critical to identifying children at risk. The present work sought to shorten and validate the 30-item Mandarin Dyslexia Screening Behavior Checklist for Primary School Students (the full checklist; Fan et al., , 19, 521-527, 2021). Our participants were 15,522 Mandarin-Chinese-speaking students and their parents, sampled from classrooms in grades 2-6 across regions in mainland China. A machine learning approach (lasso regression) was applied to shorten the full checklist (Fan et al., , 19, 521-527, 2021), constructing grade-specific brief checklists first, followed by a compilation of the common brief checklist based on the similarity across grade-specific checklists. All checklists (the full, grade-specific brief, and common brief versions) were validated and compared with data in our sample and an external sample (N = 114; Fan et al., , 19, 521-527, 2021). The results indicated that the six-item common brief checklist showed consistently high reliability (αs > .82) and reasonable classification performance (about 60% prediction accuracy and 70% sensitivity), comparable to that of the full checklist and all grade-specific brief checklists across our current sample and the external sample from Fan et al., , 19, 521-527, (2021). Our analysis showed that 2.42 (out of 5) was the cutoff score that helped classify children's reading status (children who scored higher than 2.42 might be considered at risk for dyslexia). Our final product is a valid, accessible, common brief checklist for prescreening primary school children at risk for Chinese dyslexia, which can be used across grades and regions in mainland China.

Readers of RNA Modification in Cancer and Their Anticancer Inhibitors.

Cancer treatment has always been a challenge for humanity. The inadequacies of current technologies underscore the limitations of our efforts against this disease. Nevertheless, the advent of targeted therapy has introduced a promising avenue, furnishing us with more efficacious tools. Consequently, researchers have turned their attention toward epigenetics, offering a novel perspective in this realm. The investigation of epigenetics has brought RNA readers to the forefront, as they play pivotal roles in recognizing and regulating RNA functions. Recently, the development of inhibitors targeting these RNA readers has emerged as a focal point in research and holds promise for further strides in targeted therapy. In this review, we comprehensively summarize various types of inhibitors targeting RNA readers, including non-coding RNA (ncRNA) inhibitors, small-molecule inhibitors, and other potential inhibitors. We systematically elucidate their mechanisms in suppressing cancer progression by inhibiting readers, aiming to present inhibitors of readers at the current stage and provide more insights into the development of anticancer drugs.

Fragment-based discovery of small molecule inhibitors of the HDGFRP2 PWWP domain.

The PWWP domain of hepatoma-derived growth factor-related protein 2 (HDGFRP2) recognizes methylated histones to initiate the recruitment of homologous recombination repair proteins to damaged silent genes. The combined depletion of HDGFRP2 and its paralog PSIP1 effectively impedes the onset and progression of diffuse intrinsic pontine glioma (DIPG). Here, we discovered varenicline and 4-(4-bromo-1H-pyrazol-3-yl) pyridine (BPP) as inhibitors of the HDGFRP2 PWWP domain through a fragment-based screening method. The complex crystal structures reveal that both Varenicline and BPP engage with the aromatic cage of the HDGFRP2 PWWP domain, albeit via unique binding mechanisms. Notably, BPP represents the first single-digit micromolar inhibitor of the HDGFRP2 PWWP domain with a high ligand efficiency. As a dual inhibitor targeting both HDGFRP2 and PSIP1 PWWP domains, BPP offers an exceptional foundation for further optimization into a chemical tool to dissect the synergetic function of HDGFRP2 and PSIP1 in DIPG pathogenesis.

Regulations of m6A and other RNA modifications and their roles in cancer.

RNA modification is an essential component of the epitranscriptome, regulating RNA metabolism and cellular functions. Several types of RNA modifications have been identified to date; they include N6-methyladenosine (m6A), N1-methyladenosine (m1A), 5-methylcytosine (m5C), N7-methylguanosine (m7G), N6,2'-O-dimethyladenosine (m6Am), N4-acetylcytidine (ac4C), etc. RNA modifications, mediated by regulators including writers, erasers, and readers, are associated with carcinogenesis, tumor microenvironment, metabolic reprogramming, immunosuppression, immunotherapy, chemotherapy, etc. A novel perspective indicates that regulatory subunits and post-translational modifications (PTMs) are involved in the regulation of writer, eraser, and reader functions in mediating RNA modifications, tumorigenesis, and anticancer therapy. In this review, we summarize the advances made in the knowledge of different RNA modifications (especially m6A) and focus on RNA modification regulators with functions modulated by a series of factors in cancer, including regulatory subunits (proteins, noncoding RNA or peptides encoded by long noncoding RNA) and PTMs (acetylation, SUMOylation, lactylation, phosphorylation, etc.). We also delineate the relationship between RNA modification regulator functions and carcinogenesis or cancer progression. Additionally, inhibitors that target RNA modification regulators for anticancer therapy and their synergistic effect combined with immunotherapy or chemotherapy are discussed.

The climate battles of ideas: Minority discourses in readers' comments to climate change articles in the Portuguese press.

Today, the dominant climate change discourses affirm its anthropogenic nature and the urgency for policies. However, minority discourses remain active in the worldwide debate, refining arguments beyond simple denial-as shown regarding formal/official discourses of the United States and European far-right parties. This makes it necessary to examine the public understanding of climate change in everyday, informal minority discourses, looking at how they work for broadening societal space for "quarantining" the transformative potential of climate change meanings/policies. For this, we analyze readers' comments on climate change articles from two Portuguese newspapers, drawing from the frameworks of neutralization techniques and meaning barriers. Findings show that although denial of anthropogenic climate change remains, discursive efforts concentrate on person-stigmatizing depictions of climate change actors, delegitimized as "elites" in populist vocabularies, reflecting a consistent alignment between everyday discourses and those of the United States and European official far-right. We discuss the functions this pattern may have for the growth of climate change minority positions.

Electrophysiological markers of orthographic pattern learning in school-aged children with reading challenges: An ERP investigation.

BACKGROUND: Previous studies suggested that children with reading difficulty have impaired statistical learning ability in extracting distributional orthographic regularities. However, the neural mechanisms underlying have not been fully investigated. AIMS: The current study aimed to identify the electrophysiological markers and to examine the neural underpinnings of statistical learning of orthographic regularities in children with reading difficulties. METHODS AND PROCEDURES: Using the event-related potentials (ERPs) and the orthographic learning task, 157 children were exposed to a sequence of artificial pseudocharacters with varying levels of positional and semantic consistency (low at 60 %, moderate at 80 %, and high at 100 %). OUTCOMES AND RESULTS: Poor readers elicited an increased N170 response in the low consistency and a lack of left-lateralized P300 effect when learning positional regularities of radicals. Similarly, larger N170 effects were observed in poor readers, while similar N400 effects were found in both poor and average readers when learning semantic regularities of radicals. CONCLUSIONS AND IMPLICATIONS: Our findings indicate that poor readers may have trouble using statistical information for early-stage orthographic pattern extraction, yet they can identify semantic inconsistencies after sufficient exposure. These results deepen our understanding of the neural mechanisms involved in statistical learning for poor readers and aid in improving criteria for differentiating between typically developing children and those with reading challenges.

Cortical Structure in Pre-Readers at Cognitive Risk for Dyslexia: Baseline Differences and Response to Intervention.

Early childhood is a critical period for structural brain development as well as an important window for the identification and remediation of reading difficulties. Recent research supports the implementation of interventions in at-risk populations as early as kindergarten or first grade, yet the neurocognitive mechanisms following such interventions remain understudied. To address this, we investigated cortical structure by means of anatomical MRI before and after a 12-week tablet-based intervention in: (1) at-risk children receiving phonics-based training (n = 29; n = 16 complete pre-post datasets), (2) at-risk children engaging with AC training (n = 24; n = 15 complete pre-post datasets) and (3) typically developing children (n = 25; n = 14 complete pre-post datasets) receiving no intervention. At baseline, we found higher surface area of the right supramarginal gyrus in at-risk children compared to typically developing peers, extending previous evidence that early anatomical differences exist in children who may later develop dyslexia. Our longitudinal analysis revealed significant post-intervention thickening of the left supramarginal gyrus, present exclusively in the intervention group but not the active control or typical control groups. Altogether, this study contributes new knowledge to our understanding of the brain morphology associated with cognitive risk for dyslexia and response to early intervention, which in turn raises new questions on how early anatomy and plasticity may shape the trajectories of long-term literacy development.

Why choose BJPsych Bulletin?

BJPsych Bulletin was first established as the Bulletin of the Royal College of Psychiatrists in 1977. Since then, it has extended its influence within the field, and it is now the go-to journal for practical clinical considerations in psychiatry, and mental health more widely. It stands together with the wider family of RCPsych journals - BJPsych, BJPsych Advances, BJPsych Open and BJPsych International - and offers a number of distinct advantages for readers and authors. I commend it to you.

Assessment of Reader Technologies for Over-the-Counter Diagnostic Testing.

Background: Over-the-counter (OTC) diagnostic testing is on the rise with many in vitro diagnostic tests being lateral flow assays (LFAs). A growing number of these are adopting reader technologies, which provides an alternative to visual readouts for results interpretation, allowing for improved accessibility of OTC diagnostics. As the reader technology market develops, there are many technologies entering the market, but no clear, single solution has yet been identified. The purpose of this research is to identify and discuss important parameters for the assessment of LFA reader technologies for consideration by manufacturers or researchers. Methods: As part of The National Institute of Biomedical Imaging and Bioengineering's Rapid Acceleration of Diagnostics (RADx) Tech program, reader manufacturers were interviewed to investigate the current state of reader technology development through several parameters identified as important industry standards. Readers were categorized by technology type and parameters including cost, detection method, multiplex capabilities, assay type, maturity, and use case were all assessed. Results: Fifteen reader manufacturers were identified and interviewed, and information on a total of 19 technologies was assessed. Reader technology type was found to be predictive of other attributes, whether the reader is smart technology only, a standalone reader, a reader with smart technology required, or a reader with smart technology optional. Conclusions: Pairing reader technology with OTC diagnostic tests is important for improving existing COVID-19 tests and can be utilized in other diagnostics as the OTC use case grows in popularity. Reader technology type, which is predictive of core reader attributes, should be considered when selecting a reader technology for a specific LFA test within the context of regulatory guidance. As diagnostics increase in complexity, readers provide solutions to accessibility challenges, facilitate public health reporting, and ease the transition to multiplex testing, therefore increasing market availability.

Cultivating efficiency: high-throughput growth analysis of anaerobic bacteria in compact microplate readers.

Anaerobic microbes play crucial roles in environmental processes, industry, and human health. Traditional methods for monitoring the growth of anaerobes, including plate counts or subsampling broth cultures for optical density measurements, are time and resource-intensive. The advent of microplate readers revolutionized bacterial growth studies by enabling high-throughput and real-time monitoring of microbial growth kinetics. Yet, their use in anaerobic microbiology has remained limited. Here, we present a workflow for using small-footprint microplate readers and the Growthcurver R package to analyze the kinetic growth metrics of anaerobic bacteria. We benchmarked the small-footprint Cerillo Stratus microplate reader against a BioTek Synergy HTX microplate reader in aerobic conditions using Escherichia coli DSM 28618 cultures. The growth rates and carrying capacities obtained from the two readers were statistically indistinguishable. However, the area under the logistic curve was significantly higher in cultures monitored by the Stratus reader. We used the Stratus to quantify the growth responses of anaerobically grown E. coli and Clostridium bolteae DSM 29485 to different doses of the toxin sodium arsenite. The growth of E. coli and C. bolteae was sensitive to arsenite doses of 1.3 µM and 0.4 µM, respectively. Complete inhibition of growth was achieved at 38 µM arsenite for C. bolteae and 338 µM in E. coli. These results show that the Stratus performs similarly to a leading brand of microplate reader and can be reliably used in anaerobic conditions. We discuss the advantages of the small format microplate readers and our experiences with the Stratus. IMPORTANCE: We present a workflow that facilitates the production and analysis of growth curves for anaerobic microbes using small-footprint microplate readers and an R script. This workflow is a cost and space-effective solution to most high-throughput solutions for collecting growth data from anaerobic microbes. This technology can be used for applications where high throughput would advance discovery, including microbial isolation, bioprospecting, co-culturing, host-microbe interactions, and drug/toxin-microbial interactions.

Dataset of controversial news posts in Spanish from the reader's perspective.

This paper presents a corpus of Spanish news posts obtained from X with the annotation of controversy made via crowdsourcing. A total of 60 tweets were obtained from 8 different newspapers. For the annotation task, a survey was developed and sent to 31 different participants to answer it with the controversy level they perceived from the news post summary and headline presented on the post. The most frequent selected option was assigned as the initial controversy level of the post. The final annotation of the corpus was made via an analysis of the raw data by computing the Inter Annotator Agreement (IAA). The analysis showed that the binarization of the data was the most convenient way to annotate it. A potential use for this dataset is detailed in further sections.

Chemical inhibitors targeting histone methylation readers.

Histone methylation reader domains are protein modules that recognize specific histone methylation marks, such as methylated or unmethylated lysine or arginine residues on histones. These reader proteins play crucial roles in the epigenetic regulation of gene expression, chromatin structure, and DNA damage repair. Dysregulation of these proteins has been linked to various diseases, including cancer, neurodegenerative diseases, and developmental disorders. Therefore, targeting these proteins with chemical inhibitors has emerged as an attractive approach for therapeutic intervention, and significant progress has been made in this area. In this review, we will summarize the development of inhibitors targeting histone methylation readers, including MBT domains, chromodomains, Tudor domains, PWWP domains, PHD fingers, and WD40 repeat domains. For each domain, we will briefly discuss its identification and biological/biochemical functions, and then focus on the discovery of inhibitors tailored to target this domain, summarizing the property and potential application of most inhibitors. We will also discuss the structural basis for the potency and selectivity of these inhibitors, which will aid in further lead generation and optimization. Finally, we will also address the challenges and strategies involved in the development of these inhibitors. It should facilitate the rational design and development of novel chemical scaffolds and new targeting strategies for histone methylation reader domains with the help of this body of data.

Orthographic and Phonological Code Activation in Deaf and Hearing Readers.

Grainger et al. (2006) were the first to use ERP masked priming to explore the differing contributions of phonological and orthographic representations to visual word processing. Here we adapted their paradigm to examine word processing in deaf readers. We investigated whether reading-matched deaf and hearing readers (n = 36) exhibit different ERP effects associated with the activation of orthographic and phonological codes during word processing. In a visual masked priming paradigm, participants performed a go/no-go categorization task (detect an occasional animal word). Critical target words were preceded by orthographically-related (transposed letter - TL) or phonologically-related (pseudohomophone - PH) masked non-word primes were contrasted with the same target words preceded by letter substitution (control) non-words primes. Hearing readers exhibited typical N250 and N400 priming effects (greater negativity for control compared to TL or PH primed targets), and the TL and PH priming effects did not differ. For deaf readers, the N250 PH priming effect was later (250-350 ms), and they showed a reversed N250 priming effect for TL primes in this time window. The N400 TL and PH priming effects did not differ between groups. For hearing readers, those with better phonological and spelling skills showed larger early N250 PH and TL priming effects (150-250 ms). For deaf readers, those with better phonological skills showed a larger reversed TL priming effect in the late N250 window. We speculate that phonological knowledge modulates how strongly deaf readers rely on whole-word orthographic representations and/or the mapping from sublexical to lexical representations.

Deaf readers use leftward information to read more efficiently: Evidence from eye tracking.

Little is known about how information to the left of fixation impacts reading and how it may help to integrate what has been read into the context of the sentence. To better understand the role of this leftward information and how it may be beneficial during reading, we compared the sizes of the leftward span for reading-matched deaf signers (n = 32) and hearing adults (n = 40) using a gaze-contingent moving window paradigm with windows of 1, 4, 7, 10, and 13 characters to the left, as well as a no-window condition. All deaf participants were prelingually and profoundly deaf, used American Sign Language (ASL) as a primary means of communication, and were exposed to ASL before age eight. Analysis of reading rates indicated that deaf readers had a leftward span of 10 characters, compared to four characters for hearing readers, and the size of the span was positively related to reading comprehension ability for deaf but not hearing readers. These findings suggest that deaf readers may engage in continued word processing of information obtained to the left of fixation, making reading more efficient, and showing a qualitatively different reading process than hearing readers.

Research progress of N1-methyladenosine RNA modification in cancer.

N1-methyladenosine (m1A) is a post-transcriptionally modified RNA molecule that plays a pivotal role in the regulation of various biological functions and activities. Especially in cancer cell invasion, proliferation and cell cycle regulation. Over recent years, there has been a burgeoning interest in investigating the m1A modification of RNA. Most studies have focused on the regulation of m1A in cancer enrichment areas and different regions. This review provides a comprehensive overview of the methodologies employed for the detection of m1A modification. Furthermore, this review delves into the key players in m1A modification, known as the "writers," "erasers," and "readers." m1A modification is modified by the m1A methyltransferases, or writers, such as TRMT6, TRMT61A, TRMT61B, TRMT10C, NML, and, removed by the demethylases, or erasers, including FTO and ALKBH1, ALKBH3. It is recognized by m1A-binding proteins YTHDF1, TYHDF2, TYHDF3, and TYHDC1, also known as "readers". Additionally, we explore the intricate relationship between m1A modification and its regulators and their implications for the development and progression of specific types of cancer, we discuss how m1A modification can potentially facilitate the discovery of novel approaches for cancer diagnosis, treatment, and prognosis. Our summary of m1A methylated adenosine modification detection methods and regulatory mechanisms in various cancers provides useful insights for cancer diagnosis, treatment, and prognosis. Video Abstract.

Progress in elementary school reading linked to growth of cortical responses to familiar letter combinations within visual word forms.

Learning to read depends on the ability to extract precise details of letter combinations, which convey critical information that distinguishes tens of thousands of visual word forms. To support fluent reading skill, one crucial neural developmental process is one's brain sensitivity to statistical constraints inherent in combining letters into visual word forms. To test this idea in early readers, we tracked the impact of two years of schooling on within-subject longitudinal changes in cortical responses to three different properties of words: coarse tuning for print, and fine tuning to either familiar letter combinations within visual word forms or whole word representations. We then examined how each related to growth in reading skill. Three stimulus contrasts-words versus pseudofonts, words versus pseudowords, pseudowords versus nonwords-were presented while high-density EEG Steady-State Visual Evoked Potentials (SSVEPs, n = 31) were recorded. Internalization of abstract visual word form structures over two years of reading experience resulted in a near doubling of SSVEP amplitude, with increasing left lateralization. Longitudinal changes (decreases) in brain responses to such word form structural information were linked to the growth in reading skills, especially in rapid automatic naming of letters. No such changes were observed for whole word representation processing and coarse tuning for print. Collectively, these findings indicate that sensitivity to visual word form structure develops rapidly through exposure to print and is linked to growth in reading skill. RESEARCH HIGHLIGHTS: Longitudinal changes in cognitive responses to coarse print tuning, visual word from structure, and whole word representation were examined in early readers. Visual word form structure processing demonstrated striking patterns of growth with nearly doubled in EEG amplitude and increased left lateralization. Longitudinal changes (decreases) in brain responses to visual word form structural information were linked to the growth in rapid automatic naming for letters. No longitudinal changes were observed for whole word representation processing and coarse tuning for print.

Adults at low reading level are sluggish in disengaging spatial attention.

An increasing number of studies show that attentional shifting is a primary contributor during the process of learning to read. However, it remains unclear what is the relationship between attentional shifting and word-reading ability in adult readers whose reading skills have matured. More fundamentally, how attentional shifting affects individuals' reading ability remains poorly understood. To address these issues, we grouped adult readers by the level of Chinese character reading and examined the time course of attentional shifting by setting up multiple stimulus-onset asynchronies (SOAs) in the Posner cue-target paradigm. Based on the phonological mediation hypothesis, we also measured multiple abilities involving phonological processing (i.e., rapid automatic naming and phonological awareness). Results showed that compared with adults at the high reading level, adults at the low reading level showed a selective impairment of attentional disengagement. Rapid automatic naming of Chinese characters played a partially mediating role in the association between attentional shifting and word reading. These results provided evidence for the phonological mediation hypothesis, and suggest that attentional shifting affects word reading by influencing phonological processing in adult Chinese readers.

m6A modification of plant virus enables host recognition by NMD factors in plants.

N6-methyladenosine (m6A) is the most abundant eukaryotic mRNA modification and is involved in various biological processes. Increasing evidence has implicated that m6A modification is an important anti-viral defense mechanism in mammals and plants, but it is largely unknown how m6A regulates viral infection in plants. Here we report the dynamic changes and functional anatomy of m6A in Nicotiana benthamiana and Solanum lycopersicum during Pepino mosaic virus (PepMV) infection. m6A modification in the PepMV RNA genome is conserved in these two species. Overexpression of the m6A writers, mRNA adenosine methylase A (MTA), and HAKAI inhibit the PepMV RNA accumulation accompanied by increased viral m6A modifications, whereas deficiency of these writers decreases the viral RNA m6A levels but enhances virus infection. Further study reveals that the cytoplasmic YTH-domain family protein NbECT2A/2B/2C as m6A readers are involved in anti-viral immunity. Protein-protein interactions indicate that NbECT2A/2B/2C interact with nonsense-mediated mRNA decay (NMD)-related proteins, including NbUPF3 and NbSMG7, but not with NbUPF1. m6A modification-mediated restriction to PepMV infection is dependent on NMD-related factors. These findings provide new insights into the functionality of m6A anti-viral activity and reveal a distinct immune response that NMD factors recognize the m6A readers-viral m6A RNA complex for viral RNA degradation to limit virus infection in plants.

Detecting Deceptive Dark-Pattern Web Advertisements for Blind Screen-Reader Users.

Advertisements have become commonplace on modern websites. While ads are typically designed for visual consumption, it is unclear how they affect blind users who interact with the ads using a screen reader. Existing research studies on non-visual web interaction predominantly focus on general web browsing; the specific impact of extraneous ad content on blind users' experience remains largely unexplored. To fill this gap, we conducted an interview study with 18 blind participants; we found that blind users are often deceived by ads that contextually blend in with the surrounding web page content. While ad blockers can address this problem via a blanket filtering operation, many websites are increasingly denying access if an ad blocker is active. Moreover, ad blockers often do not filter out internal ads injected by the websites themselves. Therefore, we devised an algorithm to automatically identify contextually deceptive ads on a web page. Specifically, we built a detection model that leverages a multi-modal combination of handcrafted and automatically extracted features to determine if a particular ad is contextually deceptive. Evaluations of the model on a representative test dataset and 'in-the-wild' random websites yielded F1 scores of 0.86 and 0.88, respectively.