bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B025: A genome-wide CRISPR screen identifies synthetic lethality of double-stranded RNA with BRCA1 loss
Authors: Mazzarella Luca , Trastulli Deborah , Galavotti Sara , Vozza Gianluca , Pinamonti Veronica , Zagaria Nunzia 
Published: June 2024

Abstract
Double-stranded RNAs (dsRNAs) are potent immunostimulatory nucleic acids of viral origin but also physiologically produced by mammalian cells. Recent studies demonstrated that elevating dsRNA levels, either exogenously through dsRNA mimetics like Polyinosinic-polycytidylic acid (pI:C) or endogenously through epigenetic modulation of retroviral elements, can elicit anticancer effects. In response to dsRNA, cells elicit a dual response consisting in Interferon (IFN) production and translational shutdown associated, in some cells, with cell death. These two responses are linked in a feed-forward loop in which induced cytokines themselves enhance dsRNA sensing by the death-inducing pathway, complicating our understanding of the cell-intrinsic mechanisms at play. The 2',5'-oligoadenylate synthetase (OAS)-RNASEL system is widely thought to be the main responsible for dsRNA-induced cell death, but it remains unclear how its activity leads to cell death. To elucidate these mechanisms, we decided to minimize the impact of interferon modulation by studying dsRNA-induced death in interferon-saturated conditions. We performed a genome-wide CRISPR screen for factors involved in dsRNA-induced death in our interferon-saturated conditions in HT29 cells. Pathway enrichment analysis of screen hits revealed that RNA surveillance, RNA Polymerase II Transcription Initiation, Mitochondrial translation and respiratory chain and DNA Repair genes have a protective role against dsRNA increase. In particular, we identifiedBRCA1 but not BRCA2 as a candidate hit. The differential sensitivity of BRCA1-KO cells was subsequently validated in cloncal populations. Ongoing research is aimed at validating this interaction in vivo models. Our work shed light on potential new mechanisms involved in dsRNA dependent cell death, revealing a connection with DNA damage and BRCA1. If confirmed, these findings may pave the way for the use of dsRNA mimetics, possibly in conjunction with immune checkpoint inhibitors, in the treatment of BRCA1-mutated tumors.
Citation Format: Luca Mazzarella, Deborah Trastulli, Sara Galavotti, Gianluca Vozza, Veronica Pinamonti, Nunzia Zagaria. A genome-wide CRISPR screen identifies synthetic lethality of double-stranded RNA with BRCA1 loss [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Expanding and Translating Cancer Synthetic Vulnerabilities; 2024 Jun 10-13; Montreal, Quebec, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(6 Suppl):Abstract nr B025.
Abstract IA006: Synthetic lethalities for SWI/SNF mutant cancers
Authors: Roberts Charles W.M. 
Published: June 2024

Abstract
Genes that encode subunits of SWI/SNF (BAF) chromatin remodeling complexes are mutated in over 20% of cancers. These include recurrent mutations of ARID1A (BAF250a) in ovarian, endometrioid, bladder, stomach, colorectal and pancreatic cancers and neuroblastoma; of the SMARCA4 (BRG1) subunit in medulloblastomas and non-small cell lung cancers; of the PBRM1 subunit in renal carcinomas; of the ARID2 subunit in hepatocellular, lung, and pancreas carcinomas as well as melanomas; of the BRD7 subunit in breast cancers. The SWI/SNF complex includes both core and lineage-specific subunits and utilizes the energy of ATP to modulate chromatin structure and regulate transcription. My laboratory began studying the SWI/SNF complex when SMARCB1 (INI1/SNF5/BAF47) became the first SWI/SNF subunit linked to tumor suppression when it was found to be biallelically inactivated in nearly all cases of a highly aggressive type of pediatric cancer called malignant rhabdoid tumor (MRT). Despite the extremely aggressive and lethal nature of MRT we have shown that these cancers are diploid and have remarkably simple genomes. We leverage this model tumor to identify how SWI/SNF complexes function, to determine how mutation of SWI/SNF subunits drive cancer and other diseases, and to identify therapeutic vulnerabilities that result from SWI/SNF mutations. We have leverage the Cancer Dependency Map, and the Pediatric Cancer Dependencies Accelerator, to systematically identify robust and impactful synthethic lethalities resulting from SWI/SNF mutations. These mechanisms and insights will be presented.
Citation Format: Charles W.M. Roberts. Synthetic lethalities for SWI/SNF mutant cancers [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Expanding and Translating Cancer Synthetic Vulnerabilities; 2024 Jun 10-13; Montreal, Quebec, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(6 Suppl):Abstract nr IA006.
Abstract IA017: Synthetic dependencies arising during tumor evolution
Authors: Wood Kris C. 
Published: June 2024

Abstract
Our research focuses on defining tumor-selective survival dependencies and understanding how these dependencies change during tumor evolution. In this talk, I will provide an overview of our lab’s work, highlighting recent and ongoing studies uncovering mechanism-based synthetic lethalities arising in residual and fully drug resistant tumors whose therapeutic exploitation has the potential to select against the most aggressive forms of disease.
Citation Format: Kris C. Wood. Synthetic dependencies arising during tumor evolution [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Expanding and Translating Cancer Synthetic Vulnerabilities; 2024 Jun 10-13; Montreal, Quebec, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(6 Suppl):Abstract nr IA017.
Abstract IA021: Environmental challenge rewires functional connections among human genes
Authors: Gilbert Luke , Herken Ben 
Published: June 2024

Abstract
A fundamental question in biology is how a limited number of genes combinatorially govern cellular responses to environmental changes. While the prevailing hypothesis is that relationships between genes, processes, and ontologies could be plastic to achieve this adaptability, quantitatively comparing human gene functional connections between specific environmental conditions at scale is very challenging. Therefore, it remains unclear whether and how human genetic interaction networks are rewired in response to changing environmental conditions. Here, we developed a framework for mapping context-specific genetic interactions, enabling us to measure the plasticity of human genetic architecture upon environmental challenge for ∼250,000 interactions, using cell cycle interruption, genotoxic perturbation, and nutrient deprivation as archetypes. We discover large-scale rewiring of human gene relationships across conditions, highlighted by dramatic shifts in the functional connections of epigenetic regulators (TIP60), cell cycle regulators (PP2A), and glycolysis metabolism. Our study demonstrates that upon environmental perturbation, intra-complex genetic rewiring is rare while inter-complex rewiring is common, suggesting a modular and flexible evolutionary genetic strategy that allows a limited number of human genes to enable adaptation to a large number of environmental conditions.
Citation Format: Luke Gilbert, Ben Herken. Environmental challenge rewires functional connections among human genes [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Expanding and Translating Cancer Synthetic Vulnerabilities; 2024 Jun 10-13; Montreal, Quebec, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(6 Suppl):Abstract nr IA021.
Abstract PR002: Nimbolide targets RNF114 to induce the trapping of PARP1 and synthetic lethality in BRCA-mutated cancer
Authors: Li Peng , Zhen Yuanli , Kim Chiho , Liu Zhengshuai , Hao Jianwei , Deng Heping , Deng Hejun , Zhou Min , Wang Xu-Dong , Qin Tian , Yu Yonghao 
Published: June 2024

Abstract
Despite the tremendous success of PARP1 inhibitors (PARPi) for the treatment of BRCA mut tumors, intrinsic and acquired resistance to PARPi remains a critical challenge in the clinic. This is, at least in part, due to the incomplete understanding of the mechanism of action (MoA) of PARPi. Recent studies from both our lab and others have pointed to PARP1 trapping as a key determinant of the anticancer effects of PARP1 inhibitors (PARPi). However, the molecular underpinnings of PARP1 trapping are poorly understood. Here we performed a proteomics-based chromatin relocalization screen, and identified RNF114, as a PARylation-dependent, E3 ubiquitin ligase involved in DNA damage response. Upon sensing genotoxicity, RNF114 was recruited, in a PAR-dependent manner, to DNA lesions, where it targeted PARP1 for degradation. The blockade of this pathway interfered with the removal of PARP1 from DNA lesions, leading to profound PARP1 trapping. A unique feature of this pathway is its druggability. We showed that a natural product, nimbolide, inhibited the E3 ligase activity of RNF114 and thus caused PARP1 trapping. However, unlike conventional PARPi, nimbolide treatment induced the trapping of both PARP1 and PARylation-dependent DNA repair factors. The unique mechaism of action of nimbolide translated into its superior cytotoxicity against BRCA mut cancer cells, compared to regular PARPi. It is also able to potentially overcome intrinsic and acquired resistance to PARPi, both in vitro and in vivo. In collaboration with Dr. Tian Qin, we recently performed the first total synthesis of nimbolide via a pharmacophore-directed, late-stage coupling strategy. Using this method, we have obtained a large panel of novel nimbolide analogs with improved activity and drug-like properties. We have further garnered key SAR (structure-activity relationship) insights into nimbolide. These results point to the exciting possibility of translating nimbolide analogs into novel PARP1-targeting agents for the treatment of BRCA mut cancers.
Citation Format: Peng Li, Yuanli Zhen, Chiho Kim, Zhengshuai Liu, Jianwei Hao, Heping Deng, Hejun Deng, Min Zhou, Xu-Dong Wang, Tian Qin, Yonghao Yu. Nimbolide targets RNF114 to induce the trapping of PARP1 and synthetic lethality in BRCA-mutated cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Expanding and Translating Cancer Synthetic Vulnerabilities; 2024 Jun 10-13; Montreal, Quebec, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(6 Suppl):Abstract nr PR002.
Abstract PR013: Detecting pairwise and higher-order antagonistic epistatic effects among somatic cancer genotypes to discover synthetic lethality
Authors: Alfaro-Murillo Jorge A. , Dasari Krishna , Townsend Jeffrey P. 
Published: June 2024

Abstract
The mutual exclusivity of somatic variants in cancer suggests that current somatic variants can exert antagonistic epistatic effects on the selection of new mutations, contributing to a complex landscape of evolutionary trajectories. However, quantifying pairwise and higher-order epistatic effects—which are essential to estimation of the trajectory of likely cancer genotypes—has been a challenge. We have developed a continuous-time Markov chain model that enables the estimation of mutation origination and fixation, dependent on somatic cancer genotype. We coupled the continuous-time Markov chain model with an approach that deconvolutes the underlying mutation rates and selection intensities across trajectories of oncogenesis. By elucidating the routes of variant evolution and the strengths of selective forces at play, our approach lays the groundwork for quantifying antagonistic epistatic effects of specific somatic genotypes. We applied our approach to report the variant mutation rates, selection intensities, and consequent substitution rates for lung adenocarcinoma, comparing smoker and nonsmoker tumor cohorts. We describe the distinct influences of smoking on underlying mutation rates and on physiology affecting the selective regime of lung tissue. Inference of the most likely routes of site-specific variant evolution, as well as estimation of the selection strength operating on each step along the route represents a key component for prioritization, development, and implementation of personalized cancer therapies that target synthetic lethality.
Citation Format: Jorge A. Alfaro-Murillo, Krishna Dasari, Jeffrey P. Townsend. Detecting pairwise and higher-order antagonistic epistatic effects among somatic cancer genotypes to discover synthetic lethality [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Expanding and Translating Cancer Synthetic Vulnerabilities; 2024 Jun 10-13; Montreal, Quebec, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(6 Suppl):Abstract nr PR013.
The position of visual word forms in the anatomical and
representational space of visual categories in occipitotemporal
cortex
Authors: Pillet Ineke , Cerrahoğlu Begüm , Philips Roxane Victoria , Dumoulin Serge , de Beeck Hans Op 
Published: June 2024

Abstract
Recent reviews emphasized the need for investigating the complexity of multiple subareas of word selectivity and how this relates to selectivity for other visual categories, at the individual level at a high spatial resolution (without normalization or smoothing). To investigate this, both on the brain surface and in the representational space of the occipitotemporal cortex, we presented 19 participants with images of 20 different categories during 7T fMRI. These categories included several word-like conditions, and in addition cover many of the dimensions that have been suggested to define object space, such as animacy and real-world size. In the left hemisphere, we found three subareas of the visual word form area (VWFA) and one extra subarea around the pFus face-selective area. We also observed several areas of selectivity to hands that could consistently guide the localization of word and face areas. No clear predictive anatomical landmarks were found. Results of the right hemisphere were less clear, in part due to weaker word selectivity. In the representational space, word selectivity stood out from other categories. It had multiple neighboring categories at a similar distance (e.g., faces, bodies, hands, cars), so no special relationship was found with, for example, faces. These results enable a consistent and reliable way to locate subareas of word selectivity and may inspire future research into words in the representational space of the occipitotemporal cortex.
Scheler on the Concept of Productive Imagination in His Phenomenology and Metaphysics
Authors: Kelly Eugene 
Published: June 2024

Abstract
The paper is a critical analysis of Max Scheler’s concept of productive phantasy as it functions in two ways that the author finds philosophically interesting. First, it examines critically Scheler’s attempt to overturn the basis for the claims of David Hume that there is no genuine productive phantasy, and that all phantasy is reproductive where it is at all legitimate. Scheler responds with a theory of perception through which he attempts to demonstrate that productive phantasy is an essential component of all perceptual acts. Second, it examines Scheler’s development of the theory of productive phantasy in his late efforts in metaphysics and aesthetics. Here he claims that productive phantasy functions in the Ground of Being in the process of world-creation, with humankind as its helpmate. The result is a genetic phenomenology exhibiting the ways in which the mind comes to constitute a coherent world. The author agrees with Scheler that productive phantasy is indeed essential for the constitution of the everyday world and for the works of art that illuminate that world, but contrary to Scheler, the author argues that Scheler’s claims about the function of the term are incoherent, and it therefore cannot serve as one of the foundations of his “possibly true” metaphysical system.
Using Constitutional Imaginaries in Constitutional Comparison – yes, but how?
Authors: Teutsch Alexander 
Published: June 2024

Abstract
This article1 explores how constitutional imaginaries could be used in comparative constitutional research. It claims that, while western imaginaries are partly responsible for a western-oriented focus in constitutional comparison, constitutional imaginaries could, if conceptualised differently, fruitfully contribute to inquiries concerning different parts of the globe. Given this Janus-faced feature of constitutional imaginaries, the analysis highlights the variety of these imaginaries and their non-reducibility to a single overarching Imaginary. Building on Paul Blokker’s “Imaginary components”, making up two distinct ideal type Imaginaries, modernist and democratic, the article introduces a framework entailing three different normative stances in conceptualising imaginaries, being homogeneity, tension and disengaged coexistence. These stances range from a western-centred to a global-pluralistic take on Imaginaries. The benefits comparative constitutional research may obtain using this framework are twofold: first, it allows a more nuanced description of specific Imaginaries; second, it creates an adequate methodological setting to be applied also to non-western settings.
Genomic analysis based on chromosome-level genome assembly reveals Myrtaceae evolution and terpene biosynthesis of rose myrtle
Authors: Yang Ling , Jin Jingjing , Lyu Shanwu , Zhang Fangqiu , Cao Peijian , Qin Qiaomei , Zhang Guanghui , Feng Chen , Lu Peng , Li Huiguang , Deng Shulin 
Published: June 2024

Abstract
Background
Rose myrtle (Rhodomyrtus tomentosa (Ait.) Hassk), is an evergreen shrub species belonging to the family Myrtaceae, which is enriched with bioactive volatiles (α-pinene and β-caryophyllene) with medicinal and industrial applications. However, the mechanism underlying the volatile accumulation in the rose myrtle is still unclear.

Results
Here, we present a chromosome-level genomic assembly of rose myrtle (genome size = 466 Mb, scaffold N50 = 43.7 Mb) with 35,554 protein-coding genes predicted. Through comparative genomic analysis, we found that gene expansion and duplication had a potential contribution to the accumulation of volatile substances. We proposed that the action of positive selection was significantly involved in volatile accumulation. We identified 43 TPS genes in R. tomentosa. Further transcriptomic and TPS gene family analyses demonstrated that the distinct gene subgroups of TPS may contribute greatly to the biosynthesis and accumulation of different volatiles in the Myrtle family of shrubs and trees. The results suggested that the diversity of TPS-a subgroups led to the accumulation of special sesquiterpenes in different plants of the Myrtaceae family.

Conclusions
The high quality chromosome-level rose myrtle genome and the comparative analysis of TPS gene family open new avenues for obtaining a higher commercial value of essential oils in medical plants.
Allelopathic effect of the methanol extract of the weed species-red sorrel (Rumex acetosella L.) on the growth, phytohormone content and antioxidant activity of the cover crop - white clover (Trifolium repens L.)
Authors: Gam Ho-Jun , Injamum-Ul-Hoque Md. , Kang Yosep , Ahsan S. M. , Hasan Md. Mahadi , Shaffique Shifa , Kang Sang-Mo , Lee In-Jung 
Published: June 2024

AbstractAllelopathy is a biological process in which one organism releases biochemicals that affect the growth and development of other organisms. The current investigation sought to determine the allelopathic effect of Rumex acetosella on white clover (Trifolium repens) growth and development by using its shoot extract (lower IC50 value) as a foliar treatment. Here, different concentrations (25, 50, 100, and 200 g/L) of shoot extract from Rumex acetosella were used as treatments. With increasing concentrations of shoot extract, the plant growth parameters, chlorophyll and total protein content of Trifolium repens decreased. On the other hand, ROS, such as O2.− and H2O2, and antioxidant enzymes, including SOD, CAT, and POD, increased with increasing shoot extract concentration. A phytohormonal study indicated that increased treatment concentrations increased ABA and SA levels while JA levels were reduced. For the identification of allelochemicals, liquid‒liquid extraction, thin-layer chromatography, and open-column chromatography were conducted using R. acetosella shoot extracts, followed by a seed bioassay on the separated layer. A lower IC50 value was obtained through GC/MS analysis. gammaSitosterol was identified as the most abundant component. The shoot extract of Rumex acetosella has strong allelochemical properties that may significantly impede the growth and development of Trifolium repens. This approach could help to understand the competitive abilities of this weed species and in further research provide an alternate weed management strategy.
Maternal serum biomarkers of placental insufficiency at 24–28 weeks of pregnancy in relation to the risk of delivering small-for-gestational-age infant in Sylhet, Bangladesh: a prospective cohort study
Authors: Rahman Sayedur , Islam Md. Shafiqul , Roy Anjan Kumar , Hasan Tarik , Chowdhury Nabidul Haque , Ahmed Salahuddin , Raqib Rubhana , Baqui Abdullah H. , Khanam Rasheda 
Published: June 2024

Abstract
Background
Small-for-gestational-age (SGA), commonly caused by poor placentation, is a major contributor to global perinatal mortality and morbidity. Maternal serum levels of placental protein and angiogenic factors are changed in SGA. Using data from a population-based pregnancy cohort, we estimated the relationships between levels of second-trimester pregnancy-associated plasma protein-A (PAPP-A), placental growth factor (PlGF), and serum soluble fms-like tyrosine kinase-1 (sFlt-1) with SGA.

Methods
Three thousand pregnant women were enrolled. Trained health workers prospectively collected data at home visits. Maternal blood samples were collected, serum aliquots were prepared and stored at -80℃. Included in the analysis were 1,718 women who delivered a singleton live birth baby and provided a blood sample at 24–28 weeks of gestation. We used Mann-Whitney U test to examine differences of the median biomarker concentrations between SGA (< 10th centile birthweight for gestational age) and appropriate-for-gestational-age (AGA). We created biomarker concentration quartiles and estimated the risk ratios (RRs) and 95% confidence intervals (CIs) for SGA by quartiles separately for each biomarker. A modified Poisson regression was used to determine the association of the placental biomarkers with SGA, adjusting for potential confounders.

Results
The median PlGF level was lower in SGA pregnancies (934 pg/mL, IQR 613–1411 pg/mL) than in the AGA (1050 pg/mL, IQR 679–1642 pg/mL; p < 0.001). The median sFlt-1/PlGF ratio was higher in SGA pregnancies (2.00, IQR 1.18–3.24) compared to AGA pregnancies (1.77, IQR 1.06–2.90; p = 0.006). In multivariate regression analysis, women in the lowest quartile of PAPP-A showed 25% higher risk of SGA (95% CI 1.09–1.44; p = 0.002). For PlGF, SGA risk was higher in women in the lowest (aRR 1.40, 95% CI 1.21–1.62; p < 0.001) and 2nd quartiles (aRR 1.30, 95% CI 1.12–1.51; p = 0.001). Women in the highest and 3rd quartiles of sFlt-1 were at reduced risk of SGA delivery (aRR 0.80, 95% CI 0.70–0.92; p = 0.002, and aRR 0.86, 95% CI 0.75–0.98; p = 0.028, respectively). Women in the highest quartile of sFlt-1/PlGF ratio showed 18% higher risk of SGA delivery (95% CI 1.02–1.36; p = 0.025).

Conclusions
This study provides evidence that PAPP-A, PlGF, and sFlt-1/PlGF ratio measurements may be useful second-trimester biomarkers for SGA.