bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comprehensive molecular characterization of lung tumors implicates AKT and MYC signaling in adenocarcinoma to squamous cell transdifferentiation
Authors: Quintanal-Villalonga Alvaro , Taniguchi Hirokazu , Zhan Yingqian A. , Hasan Maysun M. , Chavan Shweta S. , Meng Fanli , Uddin Fathema , Allaj Viola , Manoj Parvathy , Shah Nisargbhai S. , Chan Joseph M. , Ciampricotti Metamia , Chow Andrew , Offin Michael , Ray-Kirton Jordana , Egger Jacklynn D. , Bhanot Umesh K. , Linkov Irina , Asher Marina , Roehrl Michael H. , Ventura Katia , Qiu Juan , de Stanchina Elisa , Chang Jason C. , Rekhtman Natasha , Houck-Loomis Brian , Koche Richard P. , Yu Helena A. , Sen Triparna , Rudin Charles M. 
Published: October 2021

AbstractBackgroundLineage plasticity, the ability to transdifferentiate among distinct phenotypic identities, facilitates therapeutic resistance in cancer. In lung adenocarcinomas (LUADs), this phenomenon includes small cell and squamous cell (LUSC) histologic transformation in the context of acquired resistance to targeted inhibition of driver mutations. LUAD-to-LUSC transdifferentiation, occurring in up to 9% ofEGFR-mutant patients relapsed on osimertinib, is associated with notably poor prognosis. We hypothesized that multi-parameter profiling of the components of mixed histology (LUAD/LUSC) tumors could provide insight into factors licensing lineage plasticity between these histologies.MethodsWe performed genomic, epigenomics, transcriptomics and protein analyses of microdissected LUAD and LUSC components from mixed histology tumors, pre-/post-transformation tumors and reference non-transformed LUAD and LUSC samples. We validated our findings through genetic manipulation of preclinical models in vitro and in vivo and performed patient-derived xenograft (PDX) treatments to validate potential therapeutic targets in a LUAD PDX model acquiring LUSC features after osimertinib treatment.ResultsOur data suggest that LUSC transdifferentiation is primarily driven by transcriptional reprogramming rather than mutational events. We observed consistent relative upregulation of PI3K/AKT, MYC and PRC2 pathway genes. Concurrent activation of PI3K/AKT and MYC induced squamous features inEGFR-mutant LUAD preclinical models. Pharmacologic inhibition of EZH1/2 in combination with osimertinib prevented relapse with squamous-features in an EGFR-mutant patient-derived xenograft model, and inhibition of EZH1/2 or PI3K/AKT signaling re-sensitized resistant squamous-like tumors to osimertinib.ConclusionsOur findings provide the first comprehensive molecular characterization of LUSC transdifferentiation, suggesting putative drivers and potential therapeutic targets to constrain or prevent lineage plasticity.
Replication catastrophe is responsible for intrinsic PAR glycohydrolase inhibitor-sensitivity in patient-derived ovarian cancer models
Authors: Coulson-Gilmer Camilla , Morgan Robert D. , Nelson Louisa , Barnes Bethany M. , Tighe Anthony , Wardenaar René , Spierings Diana C. J. , Schlecht Helene , Burghel George J. , Foijer Floris , Desai Sudha , McGrail Joanne C. , Taylor Stephen S. 
Published: October 2021

Abstract
Background
Patients with ovarian cancer often present at advanced stage and, following initial treatment success, develop recurrent drug-resistant disease. PARP inhibitors (PARPi) are yielding unprecedented survival benefits for women with BRCA-deficient disease. However, options remain limited for disease that is platinum-resistant and/or has inherent or acquired PARPi-resistance. PARG, the PAR glycohydrolase that counterbalances PARP activity, is an emerging target with potential to selectively kill tumour cells harbouring oncogene-induced DNA replication and metabolic vulnerabilities. Clinical development of PARG inhibitors (PARGi) will however require predictive biomarkers, in turn requiring an understanding of their mode of action. Furthermore, differential sensitivity to PARPi is key for expanding treatment options available for patients.

Methods
A panel of 10 ovarian cancer cell lines and a living biobank of patient-derived ovarian cancer models (OCMs) were screened for PARGi-sensitivity using short- and long-term growth assays. PARGi-sensitivity was characterized using established markers for DNA replication stress, namely replication fibre asymmetry, RPA foci, KAP1 and Chk1 phosphorylation, and pan-nuclear γH2AX, indicating DNA replication catastrophe. Finally, gene expression in sensitive and resistant cells was also examined using NanoString or RNAseq.

Results
PARGi sensitivity was identified in both ovarian cancer cell lines and patient-derived OCMs, with sensitivity accompanied by markers of persistent replication stress, and a pre-mitotic cell cycle block. Moreover, DNA replication genes are down-regulated in PARGi-sensitive cell lines consistent with an inherent DNA replication vulnerability. However, DNA replication gene expression did not predict PARGi-sensitivity in OCMs. The subset of patient-derived OCMs that are sensitive to single-agent PARG inhibition, includes models that are PARPi- and/or platinum-resistant, indicating that PARG inhibitors may represent an alternative treatment strategy for women with otherwise limited therapeutic options.

Conclusions
We discover that a subset of ovarian cancers are intrinsically sensitive to pharmacological PARG blockade, including drug-resistant disease, underpinned by a common mechanism of replication catastrophe. We explore the use of a transcript-based biomarker, and provide insight into the design of future clinical trials of PARGi in patients with ovarian cancer. However, our results highlight the complexity of developing a predictive biomarker for PARGi sensitivity.
M6A associated TSUC7 inhibition contributed to Erlotinib resistance in lung adenocarcinoma through a notch signaling activation dependent way
Authors: Li Kai , Peng Zi-Yang , Gao Shan , Wang Qing-Shi , Wang Rui , Li Xiang , Xiao Guo-Dong , Zhang Jing , Ren Hong , Tang Shou-Ching , Sun Xin 
Published: October 2021

Abstract
Background
The small tyrosine kinase inhibitors (TKIs) subversively altered the lung cancer treatments, but patients will inevitably face the therapy resistance and disease recurrence. We aim to explore the potential roles of non-coding RNAs in sensitizing the TKIs effects. Methods: Multiple cellular and molecular detections were applied to confirm the mechanistic regulations and intracellular connections.

Results
We explored the specific gene features of candidates in association with resistance, and found that m6A controlled the stemness of EMT features through METTL3 and YTHDF2. The miR-146a/Notch signaling was sustained highly activated in a m6A dependent manner, and the m6A regulator of YTHDF2 suppressed TUSC7, both of which contributed to the resistant features. Functionally, the sponge type of TUSC7 regulation of miR-146a inhibited Notch signaling functions, and affected the cancer progression and stem cells’ renewal in Erlotinib resistant PC9 cells (PC9ER) and Erlotinib resistant HCC827 cells (HCC827ER) cells. The Notch signaling functions manipulated the cMYC and DICER inner cytoplasm, and the absence of either cMYC or DICER1 lead to TUSC7 and miR-146a decreasing respectively, formed the closed circle to maintain the balance.

Conclusion
PC9ER and HCC827ER cells harbored much more stem-like cells, and the resistance could be reversed by Notch signaling inactivation. The intrinsic miR-146 and TUSC7 levels are monitored by m6A effectors, the alternation of either miR-146 or TUSC7 expression could lead to the circling loop to sustain the new homeostasis. Further in clinics, the combined delivery of TKIs and Notch specific inhibitory non-coding RNAs will pave the way for yielding the susceptibility to targeted therapy in lung cancer.
Confidence interval of risk difference by different statistical methods and its impact on the study conclusion in antibiotic non-inferiority trials
Authors: Bai Anthony D. , Komorowski Adam S. , Lo Carson K. L. , Tandon Pranav , Li Xena X. , Mokashi Vaibhav , Cvetkovic Anna , Findlater Aidan , Liang Laurel , Tomlinson George , Loeb Mark , Mertz Dominik ,   the McMaster Infectious Diseases Fellow Research Group
Published: October 2021

AbstractBackgroundNumerous statistical methods can be used to calculate the confidence interval (CI) of risk differences. There is consensus in previous literature that the Wald method should be discouraged. We compared five statistical methods for estimating the CI of risk difference in terms of CI width and study conclusion in antibiotic non-inferiority trials.MethodsIn a secondary analysis of a systematic review, we included non-inferiority trials that compared different antibiotic regimens, reported risk differences for the primary outcome, and described the number of successes and/or failures as well as patients in each arm. For each study, we re-calculated the risk difference CI using the Wald, Agresti-Caffo, Newcombe, Miettinen-Nurminen, and skewness-corrected asymptotic score (SCAS) methods. The CIs by different statistical methods were compared in terms of CI width and conclusion on non-inferiority. A wider CI was considered to be more conservative.ResultsThe analysis included 224 comparisons from 213 studies. The statistical method used to calculate CI was not reported in 134 (59.8%) cases. The median (interquartile range IQR) for CI width by Wald, Agresti-Caffo, Newcombe, Miettinen-Nurminen, and SCAS methods was 13.0% (10.8%, 17.4%), 13.3% (10.9%, 18.5%), 13.6% (11.1%, 18.9%), 13.6% (11.1% and 19.0%), and 13.4% (11.1%, 18.9%), respectively. In 216 comparisons that reported a non-inferiority margin, the conclusion on non-inferiority was the same across the five statistical methods in 211 (97.7%) cases. The differences in CI width were more in trials with a sample size of 100 or less in each group and treatment success rate above 90%. Of the 18 trials in this subgroup with a specified non-inferiority margin, non-inferiority was shown in 17 (94.4%), 16 (88.9%), 14 (77.8%), 14 (77.8%), and 15 (83.3%) cases based on CI by Wald, Agresti-Caffo, Newcombe, Miettinen-Nurminen, and SCAS methods, respectively.ConclusionsThe statistical method used to calculate CI was not reported in the majority of antibiotic non-inferiority trials. Different statistical methods for CI resulted in different conclusions on non-inferiority in 2.3% cases. The differences in CI widths were highest in trials with a sample size of 100 or less in each group and a treatment success rate above 90%.Trial registrationPROSPEROCRD42020165040. April 28, 2020.
Characterization of an APP/tau rat model of Alzheimer’s disease by positron emission tomography and immunofluorescent labeling
Authors: Filip Thomas , Mairinger Severin , Neddens Joerg , Sauberer Michael , Flunkert Stefanie , Stanek Johann , Wanek Thomas , Okamura Nobuyuki , Langer Oliver , Hutter-Paier Birgit , Kuntner Claudia 
Published: October 2021

Abstract
Background
To better understand the etiology and pathomechanisms of Alzheimer’s disease, several transgenic animal models that overexpress human tau or human amyloid-beta (Aβ) have been developed. In the present study, we generated a novel transgenic rat model by cross-breeding amyloid precursor protein (APP) rats with tau rats. We characterized this model by performing positron emission tomography scans combined with immunofluorescent labeling and cerebrospinal fluid analyses.

Methods
APP/Tau rats were generated by cross-breeding male McGill-R-Thy1-APP transgenic rats with female hTau-40/P301L transgenic rats. APP/Tau double transgenic rats and non-transgenic (ntg) littermates aged 7, 13, and 21 months were subjected to dynamic [11C] PiB scan and dynamic [18F]THK-5317 scans. For regional brain analysis, a template was generated from anatomical MR images of selected animals, which was co-registered with the PET images. Regional analysis was performed by application of the simplified reference tissue model ([11C]PiB data), whereas [18F]THK-5317 data were analyzed using a 2-tissue compartment model and Logan graphical analysis. In addition, immunofluorescent labeling (tau, amyloid) and cerebrospinal fluid analyses were performed.

Results
[11C]PiB binding potential (BPND) and [18F]THK-5317 volume of distribution (VT) showed an increase with age in several brain regions in the APP/Tau group but not in the ntg control group. Immunohistochemical analysis of brain slices of PET-scanned animals revealed a positive correlation between Aβ labeling and [11C]PiB regional BPND. Tau staining yielded a trend towards higher levels in the cortex and hippocampus of APP/Tau rats compared with ntg littermates, but without reaching statistical significance. No correlation was found between tau immunofluorescence labeling results and the respective [18F]THK-5317 VT values.

Conclusions
We thoroughly characterized a novel APP/Tau rat model using combined PET imaging and immunofluorescence analysis. We observed an age-related increase in [11C]PiB and [18F]THK-5317 binding in several brain regions in the APP/Tau group but not in the ntg group. Although we were able to reveal a positive correlation between amyloid labeling and [11C]PiB regional brain uptake, we observed relatively low human tau and amyloid fibril expression levels and a somewhat unstable brain pathology which questions the utility of this animal model for further studies.
Results on exact controllability of second-order semilinear control system in Hilbert spaces
Authors: Arora Urvashi , Vijayakumar V. , Shukla Anurag , Nisar Kottakkaran Sooppy , Rezapour Shahram , Jamshed Wasim 
Published: October 2021

AbstractIn our manuscript, we extend the controllability outcomes given by Bashirov (Math. Methods Appl. Sci. 44(9):7455–7462, 2021) for a family of second-order semilinear control system by formulating a sequence of piecewise controls. This approach does not involve large estimations which are required to apply fixed point theorems. Therefore, we avoid the use of fixed point theory and the contraction mapping principle. We establish that a second-order semilinear system drives any starting position to the required final position from the domain of the system. To achieve the required results, we suppose that the linear system is exactly controllable at every non-initial time period, the norm of the inverse of the controllability Grammian operator increases as the time approaches zero with the slower rate in comparison to the reciprocal of the square function, and the nonlinear term is bounded. Finally, an example has been presented to validate the results.
Biogeographic traits of dimethyl sulfide and dimethylsulfoniopropionate cycling in polar oceans
Authors: Teng Zhao-Jie , Qin Qi-Long , Zhang Weipeng , Li Jian , Fu Hui-Hui , Wang Peng , Lan Musheng , Luo Guangfu , He Jianfeng , McMinn Andrew , Wang Min , Chen Xiu-Lan , Zhang Yu-Zhong , Chen Yin , Li Chun-Yang 
Published: October 2021

Abstract
Background
Dimethyl sulfide (DMS) is the dominant volatile organic sulfur in global oceans. The predominant source of oceanic DMS is the cleavage of dimethylsulfoniopropionate (DMSP), which can be produced by marine bacteria and phytoplankton. Polar oceans, which represent about one fifth of Earth’s surface, contribute significantly to the global oceanic DMS sea-air flux. However, a global overview of DMS and DMSP cycling in polar oceans is still lacking and the key genes and the microbial assemblages involved in DMSP/DMS transformation remain to be fully unveiled.

Results
Here, we systematically investigated the biogeographic traits of 16 key microbial enzymes involved in DMS/DMSP cycling in 60 metagenomic samples from polar waters, together with 174 metagenome and 151 metatranscriptomes from non-polar Tara Ocean dataset. Our analyses suggest that intense DMS/DMSP cycling occurs in the polar oceans. DMSP demethylase (DmdA), DMSP lyases (DddD, DddP, and DddK), and trimethylamine monooxygenase (Tmm, which oxidizes DMS to dimethylsulfoxide) were the most prevalent bacterial genes involved in global DMS/DMSP cycling. Alphaproteobacteria (Pelagibacterales) and Gammaproteobacteria appear to play prominent roles in DMS/DMSP cycling in polar oceans. The phenomenon that multiple DMS/DMSP cycling genes co-occurred in the same bacterial genome was also observed in metagenome assembled genomes (MAGs) from polar oceans. The microbial assemblages from the polar oceans were significantly correlated with water depth rather than geographic distance, suggesting the differences of habitats between surface and deep waters rather than dispersal limitation are the key factors shaping microbial assemblages involved in DMS/DMSP cycling in polar oceans.

Conclusions
Overall, this study provides a global overview of the biogeographic traits of known bacterial genes involved in DMS/DMSP cycling from the Arctic and Antarctic oceans, laying a solid foundation for further studies of DMS/DMSP cycling in polar ocean microbiome at the enzymatic, metabolic, and processual levels.
Advances in the DNA methylation hydroxylase TET1
Authors: Liu Wenzheng , Wu Guanhua , Xiong Fei , Chen Yongjun 
Published: October 2021

Abstract
Background
The ten-eleven translocation 1 (TET1) protein is a 5-methylcytosine hydroxylase that belongs to the TET protein family of human α-ketoglutarate oxygenases. TET1 recognizes and binds to regions of high genomic 5′-CpG-3′ dinucleotide density, such as CpG islands, initiates the DNA demethylation program, and maintains DNA methylation and demethylation balance to maintain genomic methylation homeostasis and achieve epigenetic regulation. This article reviews the recent research progress of TET1 in the mechanism of demethylation, stem cells and immunity, various malignant tumours and other clinical diseases.

Conclusion
TET1 acts as a key factor mediating demethylation, the mechanism of which still remains to be investigated in detail. TET1 is also critical in maintaining the differentiation pluripotency of embryonic stem cells and plays anti- or oncogenic roles in combination with different signalling pathways in different tumours. In certain tumours, its role is still controversial. In addition, the noncatalytic activity of TET1 has gradually attracted attention and has become a new direction of research in recent years.
Separable convolutional neural networks for facial expressions recognition
Authors: Chowanda Andry 
Published: October 2021

AbstractSocial interactions are important for us, humans, as social creatures. Emotions play an important part in social interactions. They usually express meanings along with the spoken utterances to the interlocutors. Automatic facial expressions recognition is one technique to automatically capture, recognise, and understand emotions from the interlocutor. Many techniques proposed to increase the accuracy of emotions recognition from facial cues. Architecture such as convolutional neural networks demonstrates promising results for emotions recognition. However, most of the current models of convolutional neural networks require an enormous computational power to train and process emotional recognition. This research aims to build compact networks with depthwise separable layers while also maintaining performance. Three datasets and three other similar architectures were used to be compared with the proposed architecture. The results show that the proposed architecture performed the best among the other architectures. It achieved up to 13% better accuracy and 6–71% smaller and more compact than the other architectures. The best testing accuracy achieved by the architecture was 99.4%.
The colours of the Higgs boson: a study in creativity and science motivation among high-school students in Italy
Authors: Alexopoulos Angelos N. , Paolucci Pierluigi , Sotiriou Sofoklis A. , Bogner Franz X. , Dorigo Tommaso , Fedi Mariaelena , Menasce Dario , Michelotto Michele , Paoletti Simone , Scianitti Francesca 
Published: October 2021

AbstractWith the increasing shift from STEM to STEAM education, arts-based approaches to science teaching and learning are considered promising for aligning school science curricula with the development of twenty-first century skills, including creativity. Yet the impact of STEAM practices on student creativity and specifically on how the latter is associated with science learning outcomes have thus far received scarce empirical support. This paper contributes to this line of research by reporting on a two-wave quantitative study that examines the effect of a long-term STEAM intervention on two cognitive processes associated with creativity (act, flow) and their interrelationships with intrinsic and extrinsic components of science motivation. Using pre- and post-survey data from 175 high-school students in Italy, results show an overall positive effect of the intervention both on the act subscale of creativity and science career motivation, whereas a negative effect is found on self-efficacy. Gender differences in the above effects are also observed. Further, results provide support for the mediating role of self-efficacy in the relationship between creativity and science career motivation. Implications for the design of STEAM learning environments are discussed.
Shifts in learning assistants’ self-determination due to COVID-19 disruptions in Calculus II course delivery
Authors: Hite R. L. , Childers G. , Gottlieb J. , Velasco R. , Johnson L. , Williams G. B. , Griffith K. , Dwyer J. 
Published: October 2021

AbstractBackgroundThe Learning Assistant (LA) model with its subsequent support and training has evidenced significant gains for undergraduate STEM learning and persistence, especially in high-stakes courses like Calculus. Yet, when a swift and unexpected transition occurs from face-to-face to online, remote learning of the LA environment, it is unknown how LAs are able to maintain their motivation (competence, autonomy, and relatedness), adapt to these new challenges, and sustain their student-centered efforts. This study used Self-Determination Theory (SDT) to model theoretical aspects of LAs’ motivations (persistence and performance) both before and after changes were made in delivery of a Calculus II course at Texas Tech University due to COVID-19 interruptions.ResultsAnalysis of weekly written reflections, a focus group session, and a post-course questionnaire of 13 Calculus II LAs throughout Spring semester of 2020 showed that LAs’ reports of competence proportionally decreased when they transitioned online, which was followed by a moderate proportional increase in reports of autonomy (actions they took to adapt to distance instruction) and a dramatic proportional increase in reports of relatedness (to build structures for maintaining communication and building community with undergraduate students).ConclusionsRelatedness emerged as the most salient factor from SDT to maintain LA self-determination due to the COVID-19 facilitated interruption to course delivery in a high-stakes undergraduate STEM course. Given that online learning continues during the pandemic and is likely to continue after, this research provides an understanding to how LAs responded to this event and the mounting importance of relatedness when LAs are working with undergraduate STEM learners. Programmatic recommendations are given for enhancing LA preparation including selecting LAs for autonomy and relatedness factors (in addition to competence), modeling mentoring for remote learners, and coaching in best practices for online instruction.