bluuebunny/crossref_metadata_2025_split huggingface dataset:
METTL3 inhibition-activated cGAS/STING axis enhances immunotherapy and PARP inhibitor sensitivity of lung carcinoma
Authors: Zhou Jiawang , He Jiaxin , Lu Yunqing , Yi Cheng , Chang Xing , Tao Lijun , Zhong Ke , Zhang Haisheng , Li Jiexin , Chen Zhuojia , Wang Hongsheng 
Published: September 2024

AbstractThe cGAS/STING-mediated type I interferon response can augment antitumor activity, while the regulatory factors within this innate immune response remain elusive. Herein we found that the RNA m6A methyltransferase METTL3 was upregulated in lung carcinoma tissues. Elevated METTL3 level was correlated with diminished CD8+T cell infiltration and cancer progression in lung carcinoma patients. METTL3 deficiency exacerbated nuclear DNA leakage into the cytoplasm, activating the cGAS pathway and thereby enhancing anti-tumor immunity. Mechanistically, METTL3 deficiency reduced the homologous recombination repair efficacy via downregulation of MSH5, a mutS family protein involved in DNA mismatch repair, leading to increased cytosolic DNA levels. m6A methylation of A2521 ofMSH5stabilized its mRNA via binding with IGF2BP2. On the other hand, m6A methylation of A1545 at the CDS of cGAS decreased mRNA stability and regulates its protein expression. Functionally, knockdown of METTL3 sensitized lung carcinoma cells to the PARP inhibitors.In vivoand clinical data confirmed the positive roles of METTL3 inhibition-activated cGAS/STING axis in tumor growth and lung adenocarcinoma progression. Collectively, METTL3 inhibition activates the cGAS/STING-mediated anti-tumor immunity via induction of cytosolic DNA and cGAS expression, which in turn regulate PARP inhibitor response and cancer progression in lung carcinoma.
Proteome-wide non-cleavable crosslink identification with MS Annika 3.0 reveals the structure of theC. elegansBox C/D complex
Authors: Birklbauer Micha J. , Müller Fränze , Geetha Sowmya Sivakumar , Matzinger Manuel , Mechtler Karl , Dorfer Viktoria 
Published: September 2024

AbstractThe field of crosslinking mass spectrometry has seen substantial advancements over the past decades, enabling the structural analysis of proteins and protein-complexes and serving as a powerful tool in protein-protein interaction studies. However, data analysis of large non-cleavable crosslink studies is still a mostly unsolved problem due to itsn-squared complexity. We here introduce a novel algorithm for the identification of non-cleavable crosslinks implemented in our crosslinking search engine MS Annika that is based on sparse matrix multiplication and allows for proteome-wide searches on commodity hardware. Application of this new algorithm enabled us to employ a proteome-wide search ofC. elegansnuclei samples, where we were able to uncover previously unknown protein interactions and conclude a comprehensive structural analysis that provides a detailed view of the Box C/D complex, enhancing our understanding of its assembly and functional dynamics. Our findings provide valuable insights into the intricate regulation of cellular homeostasis and immune responses, which are conserved across species, including humans. Moreover, our algorithm will enable researchers to conduct similar studies that were previously unfeasible.
VHL synthetic lethality screens uncover CBF-β as a negative regulator of STING
Authors: Bertlin James A C , Pauzaite Tekle , Liang Qian , Wit Niek , Williamson James C , Sia Jia Jhing , Matheson Nicholas J , Ortmann Brian M , Mitchell Thomas J , Speak Anneliese O , Zhang Qing , Nathan James A 
Published: September 2024

SummaryClear cell renal cell carcinoma (ccRCC) represents the most common form of kidney cancer and is typified by biallelic inactivation of the von Hippel-Lindau (VHL) tumour suppressor gene. Here, we undertake genome-wide CRISPR/Cas9 screening to reveal synthetic lethal interactors ofVHL, and uncover that loss of Core Binding Factor β (CBF-β) causes cell death inVHL-null ccRCC cell lines and impairs tumour establishment and growthin vivo. This synthetic relationship is independent of the elevated activity of hypoxia inducible factors (HIFs) inVHL-null cells, but does involve the RUNX transcription factors that are known binding partners of CBF-β. Mechanistically, CBF-β loss leads to upregulation of type I interferon signalling, and we uncover a direct inhibitory role for CBF-β at theSTINGlocus controlling Interferon Stimulated Gene expression. Targeting CBF-β in kidney cancer both selectively induces tumour cell lethality and promotes activation of type I interferon signalling.
CODE - XAI: Construing and Deciphering Treatment Effects via Explainable AI using Real-world Clinical Data
Authors: Lu Mingyu , Covert Ian , White Nathan J. , Lee Su-In 
Published: September 2024

AbstractUnderstanding which features drive the treatment effect has long been a complex and critical question in clinical decision-making. Significant advances have been made in estimating treatment effects, particularly with Conditional Average Treatment Effect (CATE) models. These models account for confounding variables, e.g. age, and gender, thereby capturing heterogeneity in treatment effects. However, identifying the specific features driving these effects remains largely unexplored. To bridge these gaps, we propose CODE-XAI, a framework that interprets CATE models using Explainable AI (XAI) to perform feature discovery. CODE-XAI provides feature attribution at individual and cohort levels, enhancing our understanding of treatment responses. We benchmark these XAI methods using real-world clinical data, demonstrating their effectiveness in uncovering feature contributions and enabling cross-cohort analysis, advancing precision medicine and scientific discovery.
Functional Roles of Sensorimotor Alpha and Beta Oscillations in Overt Speech Production
Authors: Huang Lydia Z. , Cao Yang , Janse Esther , Piai Vitória 
Published: September 2024

AbstractPower decreases, or desynchronization, of sensorimotor alpha and beta oscillations (i.e., alpha and beta ERD) have long been considered as indices of sensorimotor control in overt speech production. However, their specific functional roles are not well understood. Hence, we first conducted a systematic review to investigate how these two oscillations are modulated by speech motor tasks in typically fluent speakers (TFS) and in persons who stutter (PWS). Eleven EEG/MEG papers with source localization were included in our systematic review. The results revealed consistent alpha and beta ERD in the sensorimotor cortex of TFS and PWS. Furthermore, the results suggested that sensorimotor alpha and beta ERD may be functionally dissociable, with alpha related to (somato-)sensory feedback processing during articulation and beta related to motor processes throughout planning and articulation. To (partly) test this hypothesis of a potential functional dissociation between alpha and beta ERD, we then analyzed existing intracranial electroencephalography (iEEG) data from the primary somatosensory cortex (S1) of picture naming. We found moderate evidence for alpha, but not beta, ERD’s sensitivity to speech movements in S1, lending supporting evidence for the functional dissociation hypothesis identified by the systematic review.
The Rapid Online Cognitive Assessment
Authors: Howard Calvin W. , Johnson Amy , Peedicail Joseph , Ng Marcus 
Published: September 2024

AbstractINTRODUCTIONPaper-based screening examinations are well-validated but minimally scalable. If a DCA replicate paper-based screening, it would improve scalability while benefiting from their extensive validation.METHODSWe developed and evaluated the Rapid Online Cognitive Assessment (RoCA) against gold-standard paper-based tests in patients with a range of cognitive integrity (n = 46). Patient perception of the RoCA was also evaluated with post-examination survey.RESULTSThe RoCA classifies patients similarly to gold standard paper-based tests, with a receiver operating characteristic area under the curve of 0.81 (95%CI 0.67-0.91, p < 0.001). It achieves a sensitivity of 0.94 (95%CI 0.80-1.0, p < 0.001). This was robust to multiple control analyses. 83% of patient respondents reported the RoCA as highly intuitive, with 95% perceiving it as adding value to their care.DISCUSSIONThe RoCA may act as a simple and highly scalable cognitive screen.
Dissociable dynamic effects of expectation during statistical learning
Authors: McDermott Hannah H. , De Martino Federico , Schwiedrzik Caspar M. , Auksztulewicz Ryszard 
Published: September 2024

AbstractThe brain is thought to generate internal predictions, based on previous statistical regularities in the environment, to optimise behaviour. Predictive processing has been repeatedly demonstrated and seemingly explains expectation suppression (ES), or the attenuation of neural activity in response to expected stimuli. However, the mechanisms behind ES are unclear and various models of the mechanisms supporting ES have been suggested with conflicting evidence. Sharpening models propose that expectations suppress neurons that are not tuned to the expected stimulus, increasing the signal-to-noise ratio for expected stimuli. In contrast, dampening models posit that expectations suppress neurons that are tuned to the expected stimuli, increasing the relative response amplitude for unexpected stimuli. Previous studies have used decoding analyses to examine these effects, with increases in decoding accuracy interpreted in terms of sharpening and decreases related to dampening. The opposing process theory (OPT) has suggested that both processes may occur at different time points, namely that initial sharpening is followed by later dampening of the neural representations of the expected stimulus as learning progresses. In this study we aim to test this theory and shed light on the dynamics of expectation effects, both at single trial level and over time. Thirty-one participants completed a statistical learning task consisting of paired scene categories whereby a “leading” image from one category is quickly followed by a “trailing” image from a different category. Multivariate EEG analyses focussed on decoding stimulus information related to the trailing image category. Within-trial, decoding analyses showed that stimulus expectation increased decoding accuracy at early latencies and decreased decoding accuracy at later latencies, in line with OPT. However, across trials, stimulus expectation decreased decoding accuracy in initial trials and increased decoding accuracy in later trials. We theorise that these dissociable dynamics of expectation effects within and across trials can be explained in the context of hierarchical learning mechanisms. Our single trial results provide evidence for the OPT, while our results over time suggest that sharpening and dampening effects emerge at different stages of learning.
A Distinct Alternative mRNA Splicing Profile Identifies the Oncogenic CD44 Transcript Variant 3 in KMT2A-Rearranged Pediatric T-cell Acute Lymphoblastic Leukemia Cells
Authors: Amor Amanda Ramilo , Enlund Sabina , Sinha Indranil , Jiang Qingfei , Hermanson Ola , Nilsson Anna , Shirazi Fard Shahrzad , Holm Frida 
Published: September 2024

ABSTRACTT-cell acute lymphoblastic leukemia (T-ALL), which constitutes of 10-15% of all pediatric ALL cases, is known for its complex pathology due to pervasive genetic and chromosomal abnormalities. Although most children are successfully cured, chromosomal rearrangements involving the KMT2A (KMT2A) gene is considered a poor prognostic factor. In a cohort of 171 pediatric T-ALL samples we have studied differences in gene and splice variant patterns in KMT2A rearranged (KMT2A-r) T-ALL compared to KMT2A negative (KMT2A-wt) T-ALL samples. Our results have identified a distinct gene expression and splice variant expression pattern in pediatric KMT2A-r patient samples including significant expression of splicing regulatory markers ESRP1 and MBNL3. Additionally, the pro-survival long transcript variant of BCL2 were upregulated in KMT2A-r compared to KMT2A-wt T-ALL samples. Lastly, increased levels of activating methylation in the promoter region of CD44 were identified followed by an upregulation of the oncogenic transcript variant CD44v3 in KMT2A-r T-ALL. Together this suggests that CD44v3 could play a potential role as gene expression-based risk stratification of KMT2A-r rearranged T-ALL and could possibly serve as a therapeutic target using splicing modulators.
TheShigella flexnerieffector IpaH1.4 facilitates RNF213 degradation and protects cytosolic bacteria against interferon-induced ubiquitylation
Authors: Saavedra-Sanchez Luz , Dickinson Mary S. , Apte Shruti , Zhang Yifeng , de Jong Maarten , Skavicus Samantha , Heaton Nicholas S. , Alto Neal M. , Coers Jörn 
Published: September 2024

ABSTRACTA central signal that marshals host defense against many infections is the lymphocyte-derived cytokine interferon-gamma (IFNγ). The IFNγ receptor is expressed on most human cells and its activation leads to the expression of antimicrobial proteins that execute diverse cell-autonomous immune programs. One such immune program consists of the sequential detection, ubiquitylation, and destruction of intracellular pathogens. Recently, the IFNγ-inducible ubiquitin E3 ligase RNF213 was identified as a pivotal mediator of such a defense axis. RNF213 provides host protection against viral, bacterial, and protozoan pathogens. To establish infections, potentially susceptible intracellular pathogens must have evolved mechanisms that subdue RNF213-controlled cell-autonomous immunity. In support of this hypothesis, we demonstrate here that a causative agent of bacillary dysentery,Shigella flexneri,uses the type III secretion system (T3SS) effector IpaH1.4 to induce the degradation of RNF213.S. flexnerimutants lacking IpaH1.4 expression are bound and ubiquitylated by RNF213 in the cytosol of IFNγ-primed host cells. Linear (M1-) and lysine-linked ubiquitin is conjugated to bacteria by RNF213 independent of the linear ubiquitin chain assembly complex (LUBAC). We find that ubiquitylation ofS. flexneriis insufficient to kill intracellular bacteria, suggesting thatS. flexneriemploys additional virulence factors to escape from host defenses that operate downstream from RNF213-driven ubiquitylation. In brief, this study identified the bacterial IpaH1.4 protein as a direct inhibitor of mammalian RNF213 and highlights evasion of RNF213-driven immunity as a characteristic of the human-tropic pathogenShigella.
Image-Based Quantitative Single-Cell Method Showed Increase of Global Chromatin Accessibility in Tumor Compared to Normal Cells
Authors: Commane Mairead , Jadhav Vidula , Leonova Katerina , Buckley Brian , Withers Henry , Gurova Katerina 
Published: September 2024

AbstractThe phenotypic plasticity of cancer cells has recently emerged as an important factor of treatment failure. The mechanisms of phenotypic plasticity are not fully understood. One of the hypotheses is that the degree of chromatin accessibility defines the easiness of cell transitions between different phenotypes. To test this, a method to compare overall chromatin accessibility between cells in a population or between cell populations is needed. We propose to measure chromatin accessibility by fluorescence signal from nuclei of cells stained with DNA binding fluorescent molecules. This method is based on the observations that small molecules bind nucleosome-free DNA more easily than nucleosomal DNA. Thus, nuclear fluorescence is proportional to the amount of nucleosome-free DNA, serving as a measure of chromatin accessibility. We optimized the method using several DNA intercalators and minor groove binders and known chromatin-modulating agents and demonstrated that chromatin accessibility is increased upon oncogene-induced transformation and further in tumor cells.
Assessing the Antimicrobial potentials of selected Plant Extracts against Post Harvest White Yam Rot
Authors: Ibuot Aniefon A , James Iniobong I 
Published: September 2024

AbstractAntimicrobial potentials of selected aqueous and ethanolic plant extracts against post-harvest white yam rot was studied. Different concentrations (0.05%, 0.1%, 0.5%, 1.0%, 5.0% and 10%) of the selected plant extractAzadirachta indica, Chromolaena odorata, Cymbopogan citratus, Ocimum gratissimum, Zingiber officinaleandAllium sativumwere prepared. Fungi associated with post-harvest yam rot isolated and their percentage occurrence were;F oxysporum (23.7%),Penicillium oxalicum(27.55%),Botryodiploidia theobromae(10.98%),Aspergillus niger(17.89%),Sclerotium rolfsii(19.82%). The effect of selected plant extract on the growth of fungal isolates revealed ethanolic extract ofAllium sativumhaving a very high growth inhibitory effect on all the fungal isolates which ranged from 71.8±0.98% to 100±0.00% at between 1.0% and 10% concentration of the plants extract. The aqueous plant extract ofAllium sativumshowed high inhibitory effect on all the fungal isolates but slightly lower than the ethanolic extract. Other plants extracts varied in their fungal inhibitory effect depending on the fungi. The phytochemical analysis of selected plants extracts showed the presence of most phytochemicals except for very few exceptions.
CryptKeeper: a negative design tool for reducing unintentional gene expression in bacteria
Authors: Roots Cameron T. , Barrick Jeffrey E. 
Published: September 2024

AbstractFoundational techniques in molecular biology—such as cloning genes, tagging biomolecules for purification or identification, and overexpressing recombinant proteins—rely on introducing non-native or synthetic DNA sequences into organisms. These sequences may be recognized by the transcription and translation machinery in their new context in unintended ways. The cryptic gene expression that sometimes results has been shown to produce genetic instability and mask experimental signals. Computational tools have been developed to predict individual types of gene expression elements, but it can be difficult for researchers to contextualize their collective output. Here, we introduce CryptKeeper, a software pipeline that visualizes predictions of bacterial gene expression signals and estimates the translational burden possible from a DNA sequence. We investigate several published examples where cryptic gene expression inE. coliinterfered with experiments. CryptKeeper accurately postdicts unwanted gene expression from both eukaryotic virus infectious clones and individual proteins that led to genetic instability. It also identifies off-target gene expression elements that resulted in truncations that confounded protein purification. Incorporating negative design using CryptKeeper into reverse genetics and synthetic biology workflows can help to mitigate cloning challenges and avoid unexplained failures and complications that arise from unintentional gene expression.
Targeting Specific Kinase Substrates Rescues Increased Colitis Severity Induced by the Crohn’s Disease-Linked LRRK2-N2081D Variant
Authors: Heaton George R. , Li Xianting , Zhou Xiaoting , Zhang Yuanxi , Vu Duc Tung , Oeller Marc , Karayel Ozge , Hoang Quyen Q. , Kars Meltem Ece , Wang Minghui , Tarassishin Leonid , Mann Matthias , Peter Inga , Yue Zhenyu 
Published: September 2024

AbstractLRRK2 contains a kinase domain where both the N2081D Crohn’s disease (CD) risk and the G2019S Parkinson’s disease (PD)-pathogenic variants are located. The mechanisms by which the N2081D variant increase CD risk, and how these adjacent mutations result in distinct diseases, remain unclear. To investigate the pathophysiology of the CD-linked LRRK2 N2081D variant, we generated a knock-in (KI) mouse model and compared its effects to those of the LRRK2-G2019S mutation. We find thatLrrk2N2081DKI mice demonstrate heightened sensitivity to induced colitis, resulting in more severe inflammation and intestinal damage thanLrrk2G2019SKI and wild-type mice. Analysis of Colon tissue revealed distinct mutation-dependent LRRK2 RAB substrate phosphorylation, with significantly elevated phosphorylated RAB10 levels inLrrk2N2081Dmice. In cells, we demonstrate that the N2081D mutation activates LRRK2 through a mechanism distinct from that of LRRK2-G2019S. We further find that proinflammatory stimulation enhances LRRK2 kinase activity, leading to mutation-dependent differences in RAB phosphorylation and inflammatory responses in dendritic cells. Finally, we show that genetic knockout ofRab12, but not pharmacological LRRK2 kinase inhibition, significantly reduced colitis severity inLrrk2N2081Dmice. Our study characterizes the pathogenic mechanisms of LRRK2-linked CD, highlights important structural and functional differences between disease-associated LRRK2 variants, and suggests RAB proteins as promising therapeutic targets for modulating LRRK2 activity in CD treatment.
Spectral wall in collisions of excited Abelian Higgs vortices
Authors: Alonso Izquierdo A. , Mateos Guilarte J. , Rees M. , Wereszczyński A. 
Published: September 2024

We find a spectral wall in collisions of two vortices in the Abelian Higgs model at the critical coupling. It occurs if the out-of-phase mode of initially separated vortices is excited.

Published by the American Physical Society
2024
The impact of CEO overconfidence on digital transformation in specialized, refined, distinctive and innovative enterprises: evidence from China
Authors: Cui Wen Jing , Meng Sheng Fan 
Published: September 2024

PurposeThis study aims to reveal the mechanism of CEO overconfidence in the digital transformation of specialized, refined, distinctive and innovative (SRDI) enterprises, thereby enriching research related to upper echelons theory and corporate digital transformation.Design/methodology/approachThis study uses listed SRDI companies in China from 2017 to 2022 as a sample and adopts a fixed-effects regression model to analyze the direct, mediating, and moderating effects of CEO overconfidence on corporate digital transformation.FindingsFirst, CEO overconfidence significantly promotes SRDI enterprises' digital transformation. Second, according to the “cognition-behavior-outcome” model, we found that entrepreneurial orientation plays a mediating role. Third, based on the principle of procedural rationality and the interaction perspective between the CEO and the executive team, we introduce the heterogeneity of the executive team as a moderating variable. Our findings indicate that age heterogeneity within the executive team has a negative moderating effect, whereas educational and occupational heterogeneities have positive moderating effects.Originality/valueThis study expands on earlier research that focuses primarily on CEO demographic characteristics. It enriches the analytical perspective of upper echelons theory on corporate digital transformation by analyzing the psychological characteristics of CEOs, that is, overconfidence and its mediating pathways. Moreover, this study goes beyond the previous literature that does not differentiate between CEOs and executive teams by introducing the concept of CEOs' interactions with the executive team and including the heterogeneity of the executive team as a moderating variable in the literature. Thus, continuing to deepen the application of upper echelons theory to corporate digital transformation. Additionally, this study contributes to the literature on the positive consequences of overconfidence.