bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of treatment interruptions on overall survival in patients with triple-negative breast cancer
Authors: Chow Ronald , Hasan Shaakir , Choi J Isabelle , Fox Jana , Chhabra Arpit M , Marshall Deborah C , Bakst Richard L , Simone Charles B 
Published: July 2023

Abstract

Introduction
Currently, there are no data regarding the impact of treatment interruptions during radiotherapy for breast cancer. In this study, we examine the correlation between treatment interruptions during radiotherapy and outcomes in triple-negative breast cancer patients.

Methods
A total of 35 845 patients with triple-negative breast cancer treated between 2010 and 2014 were identified and analyzed from the National Cancer Database. The number of interrupted radiotherapy treatment days was calculated as the difference between the total elapsed days from the start to end of radiation treatment (both initial treatment and boost treatment, when boost was administered) and the total number of expected treatment days, defined as the number of expected treatment days with an addition of 2 weekend days for every multiple of 5 treatment days. Binomial multivariate regression analysis was used to detect correlates of treatment interruptions, and propensity-score matched multivariable Cox proportional hazard models were used to evaluate the association between treatment interruption and overall survival (OS).

Results
When modeled as a continuous variable, longer treatment duration was associated with poorer OS (hazard ratio [HR] = 1.023, 95% confidence interval [CI] = 1.015 to 1.031). In reference to 0-1 days of interruption, patients with 2-5 interrupted days (HR = 1.069, 95% CI = 1.002 to 1.140 interrupted days), 6-10 interrupted days (HR = 1.239, 95% CI = 1.140 to 1.348 interrupted days), and 11-15 interrupted days (HR = 1.265, 95% CI = 1.126 to 1.431 interrupted days) experienced increasing likelihood of mortality.

Conclusion
In the first study of its kind, we report a correlation between treatment interruptions during adjuvant radiotherapy in triple-negative breast cancer and OS.
Hierarchical confusion matrix for classification performance evaluation
Authors: Riehl Kevin , Neunteufel Michael , Hemberg Martin 
Published: July 2023

Abstract
This study proposes the novel concept of hierarchical confusion matrix, opening the door for popular confusion-matrix-based (flat) evaluation measures from binary classification problems, while considering the peculiarities of hierarchical classification problems. The concept is developed to a generalised form and proven its applicability to all types of hierarchical classification problems including directed acyclic graphs, multi-path labelling, and non-mandatory leaf-node prediction. Finally, measures based on the novel confusion matrix are used for three real-world hierarchical classification applications and compared to established evaluation measures. The results, the conformity with important attributes of hierarchical classification schemes and its broad applicability justify its recommendation.
Evolutionary Shortcuts via Multinucleotide Substitutions and Their Impact on Natural Selection Analyses
Authors: Lucaci Alexander G , Zehr Jordan D , Enard David , Thornton Joseph W , Kosakovsky Pond Sergei L 
Published: July 2023

Abstract
Inference and interpretation of evolutionary processes, in particular of the types and targets of natural selection affecting coding sequences, are critically influenced by the assumptions built into statistical models and tests. If certain aspects of the substitution process (even when they are not of direct interest) are presumed absent or are modeled with too crude of a simplification, estimates of key model parameters can become biased, often systematically, and lead to poor statistical performance. Previous work established that failing to accommodate multinucleotide (or multihit, MH) substitutions strongly biases dN/dS-based inference towards false-positive inferences of diversifying episodic selection, as does failing to model variation in the rate of synonymous substitution (SRV) among sites. Here, we develop an integrated analytical framework and software tools to simultaneously incorporate these sources of evolutionary complexity into selection analyses. We found that both MH and SRV are ubiquitous in empirical alignments, and incorporating them has a strong effect on whether or not positive selection is detected (1.4-fold reduction) and on the distributions of inferred evolutionary rates. With simulation studies, we show that this effect is not attributable to reduced statistical power caused by using a more complex model. After a detailed examination of 21 benchmark alignments and a new high-resolution analysis showing which parts of the alignment provide support for positive selection, we show that MH substitutions occurring along shorter branches in the tree explain a significant fraction of discrepant results in selection detection. Our results add to the growing body of literature which examines decades-old modeling assumptions (including MH) and finds them to be problematic for comparative genomic data analysis. Because multinucleotide substitutions have a significant impact on natural selection detection even at the level of an entire gene, we recommend that selection analyses of this type consider their inclusion as a matter of routine. To facilitate this procedure, we developed, implemented, and benchmarked a simple and well-performing model testing selection detection framework able to screen an alignment for positive selection with two biologically important confounding processes: site-to-site synonymous rate variation, and multinucleotide instantaneous substitutions.
Stepwise Evolution of E. coli C and ΦX174 Reveals Unexpected Lipopolysaccharide (LPS) Diversity
Authors: Romeyer Dherbey Jordan , Parab Lavisha , Gallie Jenna , Bertels Frederic 
Published: July 2023

Abstract
Phage therapy is a promising method for the treatment of multidrug-resistant bacterial infections. However, its long-term efficacy depends on understanding the evolutionary effects of the treatment. Current knowledge of such evolutionary effects is lacking, even in well-studied systems. We used the bacterium Escherichia coli C and its bacteriophage ΦX174, which infects cells using host lipopolysaccharide (LPS) molecules. We first generated 31 bacterial mutants resistant to ΦX174 infection. Based on the genes disrupted by these mutations, we predicted that these E. coli C mutants collectively produce eight unique LPS structures. We then developed a series of evolution experiments to select for ΦX174 mutants capable of infecting the resistant strains. During phage adaptation, we distinguished two types of phage resistance: one that was easily overcome by ΦX174 with few mutational steps (“easy” resistance) and one that was more difficult to overcome (“hard” resistance). We found that increasing the diversity of the host and phage populations could accelerate the adaptation of phage ΦX174 to overcome the hard resistance phenotype. From these experiments, we isolated 16 ΦX174 mutants that, together, can infect all 31 initially resistant E. coli C mutants. Upon determining the infectivity profiles of these 16 evolved phages, we uncovered 14 distinct profiles. Given that only eight profiles are anticipated if the LPS predictions are correct, our findings highlight that the current understanding of LPS biology is insufficient to accurately forecast the evolutionary outcomes of bacterial populations infected by phage.
ZMYM2 is essential for methylation of germline genes and active transposons in embryonic development
Authors: Graham-Paquin Adda-Lee , Saini Deepak , Sirois Jacinthe , Hossain Ishtiaque , Katz Megan S , Zhuang Qinwei Kim-Wee , Kwon Sin Young , Yamanaka Yojiro , Bourque Guillaume , Bouchard Maxime , Pastor William A 
Published: July 2023

AbstractZMYM2 is a transcriptional repressor whose role in development is largely unexplored. We found that Zmym2−/− mice show embryonic lethality by E10.5. Molecular characterization of Zmym2−/− embryos revealed two distinct defects. First, they fail to undergo DNA methylation and silencing of germline gene promoters, resulting in widespread upregulation of germline genes. Second, they fail to methylate and silence the evolutionarily youngest and most active LINE element subclasses in mice. Zmym2−/− embryos show ubiquitous overexpression of LINE-1 protein as well as aberrant expression of transposon-gene fusion transcripts. ZMYM2 homes to sites of PRC1.6 and TRIM28 complex binding, mediating repression of germline genes and transposons respectively. In the absence of ZMYM2, hypermethylation of histone 3 lysine 4 occurs at target sites, creating a chromatin landscape unfavourable for establishment of DNA methylation. ZMYM2−/− human embryonic stem cells also show aberrant upregulation and demethylation of young LINE elements, indicating a conserved role in repression of active transposons. ZMYM2 is thus an important new factor in DNA methylation patterning in early embryonic development.
Simultaneous multifunctional transcriptome engineering by CRISPR RNA scaffold
Authors: Liu Zukai , Jillette Nathaniel , Robson Paul , Cheng Albert Wu 
Published: July 2023

Abstract
RNA processing and metabolism are subjected to precise regulation in the cell to ensure integrity and functions of RNA. Though targeted RNA engineering has become feasible with the discovery and engineering of the CRISPR-Cas13 system, simultaneous modulation of different RNA processing steps remains unavailable. In addition, off-target events resulting from effectors fused with dCas13 limit its application. Here we developed a novel platform, Combinatorial RNA Engineering via Scaffold Tagged gRNA (CREST), which can simultaneously execute multiple RNA modulation functions on different RNA targets. In CREST, RNA scaffolds are appended to the 3’ end of Cas13 gRNA and their cognate RNA binding proteins are fused with enzymatic domains for manipulation. Taking RNA alternative splicing, A-to-G and C-to-U base editing as examples, we developed bifunctional and tri-functional CREST systems for simultaneously RNA manipulation. Furthermore, by fusing two split fragments of the deaminase domain of ADAR2 to dCas13 and/or PUFc respectively, we reconstituted its enzyme activity at target sites. This split design can reduce nearly 99% of off-target events otherwise induced by a full-length effector. The flexibility of the CREST framework will enrich the transcriptome engineering toolbox for the study of RNA biology.
PEPseq quantifies transcriptome-wide changes in protein occupancy and reveals selective translational repression after translational stress
Authors: Trendel Jakob , Boileau Etienne , Jochem Marco , Dieterich Christoph , Krijgsveld Jeroen 
Published: July 2023

Abstract
Post-transcriptional gene regulation is accomplished by the interplay of the transcriptome with RNA-binding proteins, which occurs in a dynamic manner in response to altered cellular conditions. Recording the combined occupancy of all proteins binding to the transcriptome offers the opportunity to interrogate if a particular treatment leads to any interaction changes, pointing to sites in RNA that undergo post-transcriptional regulation. Here, we establish a method to monitor protein occupancy in a transcriptome-wide fashion by RNA sequencing. To this end, peptide-enhanced pull-down for RNA sequencing (or PEPseq) uses metabolic RNA labelling with 4-thiouridine (4SU) for light-induced protein–RNA crosslinking, and N-hydroxysuccinimide (NHS) chemistry to isolate protein-crosslinked RNA fragments across all long RNA biotypes. We use PEPseq to investigate changes in protein occupancy during the onset of arsenite-induced translational stress in human cells and reveal an increase of protein interactions in the coding region of a distinct set of mRNAs, including mRNAs coding for the majority of cytosolic ribosomal proteins. We use quantitative proteomics to demonstrate that translation of these mRNAs remains repressed during the initial hours of recovery after arsenite stress. Thus, we present PEPseq as a discovery platform for the unbiased investigation of post-transcriptional regulation.
Establishing artificial gene connections through RNA displacement–assembly-controlled CRISPR/Cas9 function
Authors: Wang Wei-Jia , Lin Jiao , Wu Chao-Qun , Luo Ai-Ling , Xing Xiwen , Xu Liang 
Published: July 2023

Abstract
Construction of synthetic circuits that can reprogram genetic networks and signal pathways is a long-term goal for manipulation of biosystems. However, it is still highly challenging to build artificial genetic communications among endogenous RNA species due to their sequence independence and structural diversities. Here we report an RNA-based synthetic circuit that can establish regulatory linkages between expression of endogenous genes in both Escherichiacoli and mammalian cells. This design employs a displacement–assembly approach to modulate the activity of guide RNA for function control of CRISPR/Cas9. Our experiments demonstrate the great effectiveness of this RNA circuit for building artificial connections between expression of originally unrelated genes. Both exogenous and naturally occurring RNAs, including small/microRNAs and long mRNAs, are capable of controlling expression of another endogenous gene through this approach. Moreover, an artificial signal pathway inside mammalian cells is also successfully established to control cell apoptosis through our designed synthetic circuit. This study provides a general strategy for constructing synthetic RNA circuits, which can introduce artificial connections into the genetic networks of mammalian cells and alter the cellular phenotypes.
A clickable melphalan for monitoring DNA interstrand crosslink accumulation and detecting ICL repair defects in Fanconi anemia patient cells
Authors: Berrada Sara , Martínez-Balsalobre Elena , Larcher Lise , Azzoni Violette , Vasquez Nadia , Da Costa Mélanie , Abel Sébastien , Audoly Gilles , Lee Lara , Montersino Camille , Castellano Rémy , Combes Sébastien , Gelot Camille , Ceccaldi Raphaël , Guervilly Jean-Hugues , Soulier Jean , Lachaud Christophe 
Published: July 2023

AbstractFanconi anemia (FA) is a genetic disorder associated with developmental defects, bone marrow failure and cancer. The FA pathway is crucial for the repair of DNA interstrand crosslinks (ICLs). In this study, we have developed and characterized a new tool to investigate ICL repair: a clickable version of the crosslinking agent melphalan which we name click-melphalan. Our results demonstrate that click-melphalan is as effective as its unmodified counterpart in generating ICLs and associated toxicity. The lesions induced by click-melphalan can be detected in cells by post-labelling with a fluorescent reporter and quantified using flow cytometry. Since click-melphalan induces both ICLs and monoadducts, we generated click-mono-melphalan, which only induces monoadducts, in order to distinguish between the two types of DNA repair. By using both molecules, we show that FANCD2 knock-out cells are deficient in removing click-melphalan-induced lesions. We also found that these cells display a delay in repairing click-mono-melphalan-induced monoadducts. Our data further revealed that the presence of unrepaired ICLs inhibits monoadduct repair. Finally, our study demonstrates that these clickable molecules can differentiate intrinsic DNA repair deficiencies in primary FA patient cells from those in primary xeroderma pigmentosum patient cells. As such, these molecules may have potential for developing diagnostic tests.
Ribosomal proteins can hold a more accurate record of bacterial thermal adaptation compared to rRNA
Authors: van den Elzen Antonia , Helena-Bueno Karla , Brown Charlotte R , Chan Lewis I , Melnikov Sergey V 
Published: July 2023

AbstractRibosomal genes are widely used as ‘molecular clocks’ to infer evolutionary relationships between species. However, their utility as ‘molecular thermometers’ for estimating optimal growth temperature of microorganisms remains uncertain. Previously, some estimations were made using the nucleotide composition of ribosomal RNA (rRNA), but the universal application of this approach was hindered by numerous outliers. In this study, we aimed to address this problem by identifying additional indicators of thermal adaptation within the sequences of ribosomal proteins. By comparing sequences from 2021 bacteria with known optimal growth temperature, we identified novel indicators among the metal-binding residues of ribosomal proteins. We found that these residues serve as conserved adaptive features for bacteria thriving above 40°C, but not at lower temperatures. Furthermore, the presence of these metal-binding residues exhibited a stronger correlation with the optimal growth temperature of bacteria compared to the commonly used correlation with the 16S rRNA GC content. And an even more accurate correlation was observed between the optimal growth temperature and the YVIWREL amino acid content within ribosomal proteins. Overall, our work suggests that ribosomal proteins contain a more accurate record of bacterial thermal adaptation compared to rRNA. This finding may simplify the analysis of unculturable and extinct species.
Duty-related trauma and PTSD symptoms in US urban firefighters
Authors: Pao C , Arbona C , Fan W , Tran J 
Published: July 2023

Abstract

Background
Little is known about the multi-dimensional nature of traumatic duty-related events encountered by firefighters in relation to their post-traumatic stress disorder (PTSD) risk.

Aims
To describe the types of duty-related events encountered by career firefighters and explore if years in the fire service or total event load moderated the association of trauma exposure to PTSD symptoms.

Methods
Participants included 755 career, male firefighters (19% of the department’s firefighters and 76% of those who accessed the electronic anonymous survey). The Duty-Related Incident Stressors scale was used to assess exposure to 25 potentially traumatic events (event load) and self-appraisal of the stress associated with these events, grouped by type of event (indirect, direct and colleague-related). The Post-Traumatic Stress Disorder Checklist was used to assess PTSD symptoms.

Results
Firefighters rated colleague-related events as the most stressful, followed by indirect and direct events. Event load (r = 0.25) and indirect, direct and colleague-related events stress (r = 0.32–0.35) were positively associated with PTSD symptoms. Results of moderation analyses indicated that event load served as a risk factor in the relation of indirect events stress to PTSD symptoms, and as a buffer in the relation of direct events stress to PTSD symptoms. Years in the fire service were not associated with PTSD symptoms nor moderated the relation of event stress to PTSD symptoms.

Conclusions
Findings underscored the importance of considering the differential effects that types of duty-related traumatic events and cumulative exposure to trauma may have on firefighters’ PTSD symptoms.
Thermosensitive SUMOylation of TaHsfA1 defines a dynamic ON/OFF molecular switch for the heat stress response in wheat
Authors: Wang Haoran , Feng Man , Jiang Yujie , Du Dejie , Dong Chaoqun , Zhang Zhaoheng , Wang Wenxi , Liu Jing , Liu Xiangqing , Li Sufang , Chen Yongming , Guo Weilong , Xin Mingming , Yao Yingyin , Ni Zhongfu , Sun Qixin , Peng Huiru , Liu Jie 
Published: July 2023

Abstract
Dissecting genetic components in crop plants associated with heat stress (HS) sensing and adaptation will facilitate the design of modern crop varieties with improved thermotolerance. However, the molecular mechanisms underlying the ON/OFF switch controlling HS responses (HSRs) in wheat (Triticum aestivum) remain largely unknown. In this study, we focused on the molecular action of TaHsfA1, a class A heat shock transcription factor, in sensing dynamically changing HS signals and regulating HSRs. We show that the TaHsfA1 protein is modified by small ubiquitin–related modifier (SUMO) and that this modification is essential for the full transcriptional activation activity of TaHsfA1 in triggering downstream gene expression. During sustained heat exposure, the SUMOylation of TaHsfA1 is suppressed, which partially reduces TaHsfA1 protein activity, thereby reducing the intensity of downstream HSRs. In addition, we demonstrate that TaHsfA1 interacts with the histone acetyltransferase TaHAG1 in a thermosensitive manner. Together, our findings emphasize the importance of TaHsfA1 in thermotolerance in wheat. In addition, they define a highly dynamic SUMOylation-dependent “ON/OFF” molecular switch that senses temperature signals and contributes to thermotolerance in crops.
Molecular bases of strawberry fruit quality traits: Advances, challenges, and opportunities
Authors: Liu Zhongchi , Liang Tong , Kang Chunying 
Published: July 2023

AbstractThe strawberry is one of the world's most popular fruits, providing humans with vitamins, fibers, and antioxidants. Cultivated strawberry (Fragaria × ananassa) is an allo-octoploid and highly heterozygous, making it a challenge for breeding, quantitative trait locus (QTL) mapping, and gene discovery. Some wild strawberry relatives, such as Fragaria vesca, have diploid genomes and are becoming laboratory models for the cultivated strawberry. Recent advances in genome sequencing and CRISPR-mediated genome editing have greatly improved the understanding of various aspects of strawberry growth and development in both cultivated and wild strawberries. This review focuses on fruit quality traits that are most relevant to the consumers, including fruit aroma, sweetness, color, firmness, and shape. Recently available phased-haplotype genomes, single nucleotide polymorphism (SNP) arrays, extensive fruit transcriptomes, and other big data have made it possible to locate key genomic regions or pinpoint specific genes that underlie volatile synthesis, anthocyanin accumulation for fruit color, and sweetness intensity or perception. These new advances will greatly facilitate marker-assisted breeding, the introgression of missing genes into modern varieties, and precise genome editing of selected genes and pathways. Strawberries are poised to benefit from these recent advances, providing consumers with fruit that is tastier, longer-lasting, healthier, and more beautiful.
Rice transformation treatments leave specific epigenome changes beyond tissue culture
Authors: Hsieh Jo-Wei Allison , Chang Pearl , Kuang Lin-Yun , Hsing Yue-Ie C , Chen Pao-Yang 
Published: July 2023

Abstract
During transgenic plant production, tissue culture often carries epigenetic, and genetic changes that underlie somaclonal variations, leading to unpredictable phenotypes. Additionally, specific treatments for rice (Oryza sativa) transformation processes may individually or jointly contribute to somaclonal variations, but their specific impacts on rice epigenomes toward transcriptional variations remain unknown. Here, the impact of individual transformation treatments on genome-wide DNA methylation and the transcriptome were examined. In addition to activating stress-responsive genes, individual transformation components targeted different gene expression modules that were enriched in specific functional categories. The transformation treatments strongly impacted DNA methylation and expression; 75% were independent of tissue culture. Furthermore, our genome-wide analysis showed that the transformation treatments consistently resulted in global hypo-CHH methylation enriched at promoters highly associated with downregulation, particularly when the promoters were colocalized with miniature inverted-repeat transposable elements. Our results clearly highlight the specificity of impacts triggered by individual transformation treatments during rice transformation with the potential association between DNA methylation and gene expression. These changes in gene expression and DNA methylation resulting from rice transformation treatments explain a significant portion of somaclonal variations, that is, way beyond the tissue culture effect.