bluuebunny/crossref_metadata_2025_split huggingface dataset:
L-Galaxies 2020: the formation and chemical evolution of stellar haloes in Milky Way analogues and galaxy clusters
Authors: Murphy Geoff G , Yates Robert M , Mohamed Shazrene S 
Published: December 2021

ABSTRACT
We present an analysis of the formation and chemical evolution of stellar haloes around (a) Milky Way analogue (MWA) galaxies and (b) galaxy clusters in the L-Galaxies 2020 semi-analytic model of galaxy evolution. Observed stellar halo properties are better reproduced when assuming a gradual stripping model for the removal of cold gas and stars from satellites, compared to an instantaneous stripping model. The slope of the stellar mass–metallicity relation for MWA stellar haloes is in good agreement with that observed in the local Universe . This extends the good agreement between L-Galaxies 2020 and metallicity observations from the gas and stars inside galaxies to those outside. Halo stars contribute on average only ∼0.1 per cent of the total circumgalactic medium enrichment by z = 0 in MWAs, ejecting predominantly carbon produced by asymptotic giant branch stars. Around a quarter of MWAs have a single ‘significant progenitor’ with a mean mass of ∼$2.3\times {}10^{9}\, \rm {M}_{\odot }$, similar to that measured for Gaia Enceladus. For galaxy clusters, L-Galaxies 2020 shows good correspondence with observations of stellar halo mass fractions, but slightly overpredicts stellar masses. Assuming a Navarro–Frenk–White profile for the stellar halo mass distribution provides the best agreement. On average, the intracluster stellar component is responsible for 5.4 per cent of the total intracluster medium iron enrichment, exceeding the contribution from the brightest cluster galaxy by z = 0. We find that considering gradual stripping of satellites and realistic radial profiles is crucial for accurately modelling stellar halo formation on all scales in semi-analytic models.
Ancient Human Genomes and Environmental DNA from the Cement Attaching 2,000-Year-Old Head Lice Nits
Authors: Pedersen Mikkel W , Antunes Catia , De Cahsan Binia , Moreno-Mayar J Víctor , Sikora Martin , Vinner Lasse , Mann Darren , Klimov Pavel B , Black Stuart , Michieli Catalina Teresa , Braig Henk R , Perotti M Alejandra 
Published: December 2021

Abstract
Over the past few decades, there has been a growing demand for genome analysis of ancient human remains. Destructive sampling is increasingly difficult to obtain for ethical reasons, and standard methods of breaking the skull to access the petrous bone or sampling remaining teeth are often forbidden for curatorial reasons. However, most ancient humans carried head lice and their eggs abound in historical hair specimens. Here we show that host DNA is protected by the cement that glues head lice nits to the hair of ancient Argentinian mummies, 1,500–2,000 years old. The genetic affinities deciphered from genome-wide analyses of this DNA inform that this population migrated from north-west Amazonia to the Andes of central-west Argentina; a result confirmed using the mitochondria of the host lice. The cement preserves ancient environmental DNA of the skin, including the earliest recorded case of Merkel cell polyomavirus. We found that the percentage of human DNA obtained from nit cement equals human DNA obtained from the tooth, yield 2-fold compared with a petrous bone, and 4-fold to a bloodmeal of adult lice a millennium younger. In metric studies of sheaths, the length of the cement negatively correlates with the age of the specimens, whereas hair linear distance between nit and scalp informs about the environmental conditions at the time before death. Ectoparasitic lice sheaths can offer an alternative, nondestructive source of high-quality ancient DNA from a variety of host taxa where bones and teeth are not available and reveal complementary details of their history.
Tissue-specific regulation of translational readthrough tunes functions of the traffic jam transcription factor
Authors: Karki Prajwal , Carney Travis D , Maracci Cristina , Yatsenko Andriy S , Shcherbata Halyna R , Rodnina Marina V 
Published: December 2021

Abstract
Translational readthrough (TR) occurs when the ribosome decodes a stop codon as a sense codon, resulting in two protein isoforms synthesized from the same mRNA. TR has been identified in several eukaryotic organisms; however, its biological significance and mechanism remain unclear. Here, we quantify TR of several candidate genes in Drosophila melanogaster and characterize the regulation of TR in the large Maf transcription factor Traffic jam (Tj). Using CRISPR/Cas9-generated mutant flies, we show that the TR-generated Tj isoform is expressed in a subset of neural cells of the central nervous system and is excluded from the somatic cells of gonads. Control of TR in Tj is critical for preservation of neuronal integrity and maintenance of reproductive health. The tissue-specific distribution of a release factor splice variant, eRF1H, plays a critical role in modulating differential TR of leaky stop codon contexts. Fine-tuning of gene regulatory functions of transcription factors by TR provides a potential mechanism for cell-specific regulation of gene expression.
Computational investigation of the impact of core sequence on immobile DNA four-way junction structure and dynamics
Authors: Adendorff Matthew R , Tang Guo Qing , Millar David P , Bathe Mark , Bricker William P 
Published: December 2021

Abstract
Immobile four-way junctions (4WJs) are core structural motifs employed in the design of programmed DNA assemblies. Understanding the impact of sequence on their equilibrium structure and flexibility is important to informing the design of complex DNA architectures. While core junction sequence is known to impact the preferences for the two possible isomeric states that junctions reside in, previous investigations have not quantified these preferences based on molecular-level interactions. Here, we use all-atom molecular dynamics simulations to investigate base-pair level structure and dynamics of four-way junctions, using the canonical Seeman J1 junction as a reference. Comparison of J1 with equivalent single-crossover topologies and isolated nicked duplexes reveal conformational impact of the double-crossover motif. We additionally contrast J1 with a second junction core sequence termed J24, with equal thermodynamic preference for each isomeric configuration. Analyses of the base-pair degrees of freedom for each system, free energy calculations, and reduced-coordinate sampling of the 4WJ isomers reveal the significant impact base sequence has on local structure, isomer bias, and global junction dynamics.
Reexamining assumptions about miRNA-guided gene silencing
Authors: Kilikevicius Audrius , Meister Gunter , Corey David R 
Published: December 2021

Abstract
MicroRNAs (miRNAs) are short endogenously expressed RNAs that have the potential to regulate the expression of any RNA. This potential has led to the publication of several thousand papers each year connecting miRNAs to many different genes and human diseases. By contrast, relatively few papers appear that investigate the molecular mechanism used by miRNAs. There is a disconnect between rigorous understanding of mechanism and the extraordinary diversity of reported roles for miRNAs. Consequences of this disconnect include confusion about the assumptions underlying the basic science of human miRNAs and slow development of therapeutics that target miRNAs. Here, we present an overview of investigations into miRNAs and their impact on gene expression. Progress in our understanding of miRNAs would be aided by a greater focus on the mechanism of miRNAs and a higher burden of evidence on researchers who seek to link expression of a particular miRNA to a biological phenotype.
Stimulation of adaptive gene amplification by origin firing under replication fork constraint
Authors: Whale Alex J , King Michelle , Hull Ryan M , Krueger Felix , Houseley Jonathan 
Published: December 2021

Abstract
Adaptive mutations can cause drug resistance in cancers and pathogens, and increase the tolerance of agricultural pests and diseases to chemical treatment. When and how adaptive mutations form is often hard to discern, but we have shown that adaptive copy number amplification of the copper resistance gene CUP1 occurs in response to environmental copper due to CUP1 transcriptional activation. Here we dissect the mechanism by which CUP1 transcription in budding yeast stimulates copy number variation (CNV). We show that transcriptionally stimulated CNV requires TREX-2 and Mediator, such that cells lacking TREX-2 or Mediator respond normally to copper but cannot acquire increased resistance. Mediator and TREX-2 can cause replication stress by tethering transcribed loci to nuclear pores, a process known as gene gating, and transcription at the CUP1 locus causes a TREX-2-dependent accumulation of replication forks indicative of replication fork stalling. TREX-2-dependent CUP1 gene amplification occurs by a Rad52 and Rad51-mediated homologous recombination mechanism that is enhanced by histone H3K56 acetylation and repressed by Pol32 and Pif1. CUP1 amplification is also critically dependent on late-firing replication origins present in the CUP1 repeats, and mutations that remove or inactivate these origins strongly suppress the acquisition of copper resistance. We propose that replicative stress imposed by nuclear pore association causes replication bubbles from these origins to collapse soon after activation, leaving a tract of H3K56-acetylated chromatin that promotes secondary recombination events during elongation after replication fork re-start events. The capacity for inefficient replication origins to promote copy number variation renders certain genomic regions more fragile than others, and therefore more likely to undergo adaptive evolution through de novo gene amplification.
Clinical utility of targeted next-generation sequencing assay in IDH-wildtype glioblastoma for therapy decision-making
Authors: Lim-Fat Mary Jane , Youssef Gilbert C , Touat Mehdi , Iorgulescu J Bryan , Whorral Sydney , Allen Marie , Rahman Rifaquat , Chukwueke Ugonma , McFaline-Figueroa J Ricardo , Nayak Lakshmi , Lee Eudocia Q , Batchelor Tracy T , Arnaout Omar , Peruzzi Pier Paolo , Chiocca E Antonio , Reardon David A , Meredith David , Santagata Sandro , Beroukhim Rameen , Bi Wenya Linda , Ligon Keith L , Wen Patrick Y 
Published: December 2021

AbstractBackgroundTargeted gene NGS testing is available through many academic institutions and commercial entities and is increasingly incorporated in practice guidelines for glioblastoma (GBM). This single-center retrospective study aimed to evaluate the clinical utility of incorporating NGS results in the management of GBM patients at a clinical trials-focused academic center.MethodsWe identified 1011 consecutive adult patients with pathologically confirmed GBM (IDHwt or IDHmut) who had somatic tumor sequencing (Oncopanel, ~500 cancer gene panel) at DFCI from 2013–2019. Clinical records of all IDHwt GBM patients were reviewed to capture clinical trial enrollment and off-label targeted therapy use based on NGS results.ResultsOf the 557 IDHwt GBM patients with sequencing, 182 entered clinical trials at diagnosis (32.7%) and 213 (38.2%) entered after recurrence. Sequencing results for 130 patients (23.3%) were utilized for clinical trial enrollment for either targeted therapy indications (6.9 % upfront and 27.7% at recurrent clinical trials and 3.1% for off-label targeted therapy) or exploratory studies (55.4% upfront and 6.9% recurrent clinical trials). Median overall survival was 20.1 months with no survival difference seen between patients enrolled in clinical trials compared to those who were not, in a posthoc analysis.ConclusionsWhile NGS testing has become essential for improved molecular diagnostics, our study illustrates that targeted gene panels remain underutilized for selecting therapy in GBM-IDHwt. Targeted therapy and clinical trial design remain to be improved to help leverage the potential of NGS in clinical care.
SPDR-1 HSP90 inhibition overcomes resistant to molecular targeted therapy in BRAFV600E mutant glioblastoma
Authors: Sasame Jo , Ikegaya Naoki , Miyake Yohei , Hayashi Takahiro , Oshima Akito , Homma Hirokuni , Isoda Masataka , Takabayashi Katsuhiro , Yamamoto Tetsuya , Tateishi Kensuke 
Published: December 2021

Abstract
The BRAFV600E mutation results in the constitutive activation of downstream mitogen activated protein kinase (MAPK) pathway that promotes tumor growth. Recently, molecular targeted therapy using BRAF/MEK inhibitor has been reported for BRAFV600E mutant high-grade glioma, but the therapeutic effect is limited by the emergence of drug resistance. Herein, we established paired BRAFV600E mutant glioblastoma (GBM) patient-derived xenograft (PDX) models, which were derived from tumors at prior to and recurrence after molecular targeted therapy. These PDX models were found to extensively recapitulate the histology, genetic abnormalities, and even the clinical course of the patients. Furthermore, BRAF/MEK inhibitor gradually caused resistance in cell lines derived from specimens that initially responded to molecular targeted therapy. In this study, genomic and epigenomic changes had little effect on the resistance mechanism. On the other hand, we found that hyperactivation of the MAPK pathway through c-Raf and the AKT/mTOR pathway primarily caused resistance to molecular targeted therapy in BRAFV600E mutant GBM. Through a high throughput drug screening, we find that HSP90 inhibitor with BRAF/MEK inhibitor coordinately deactivates MAPK pathway and AKT/mTOR pathway, and mediates potent toxicity in vitro and in vivo in refractory and acquired resistant models. These findings support that this therapeutic approach can overcome the limitation of current molecular targeted therapy in BRAFV600E mutant GBM.
STMO-5 Utilization of intraoperative multimodal technologies [PET and 5-ALA] for treating glioblastoma
Authors: Miyake Keisuke , Ogawa Daisuke , Hatakeyama Tetsuhiro 
Published: December 2021

Abstract
Background: We can improve prognosis of glioblastoma by using positron emission tomography (PET) scans to guide them in removing tumors, and intraoperative magnetic resonance imaging (IoMRI) and 5-aminolevulinic acid (5-ALA) for identifying residual tumors. Tau proteins are reported to accumulate in glioblastomas, so we compared the efficacy of their PET tracer, THK5351, against that of 11C-MET, 18F-FLT, and 18F-FMISO. Methods: Patients (n = 11) underwent scans between February 2020 and July 2021 for glioblastoma resection. Tumor-to-normal tissue accumulation ratio (TNR) and accumulation volumes of 4 PET tracers were evaluated. Following excisions, 5-ALA fluorescent evaluation was classified as strong, vague, or none. Residual tumor volumes and removal rates were determined using T1Gd assessments and PET tracers. IoMRI confirmed presence of residual tumors.Results: THK5351 had a TNR of 5.20, and its accumulated volume was greater than that of other tracers: 1.80 for 11C-MET, 1.72 for 18F-FLT, and 2.82 for 18F-FMISO. 5-ALA fluorescent evaluation was vague (n = 7) or none (n = 4); respective residual tumor volumes (mL) were 2.3 and 0.2 (T1Gd), 5.7 and 0.9 (11C-MET), 5.6 and 0.6 (18F-FLT), 1.3 and 0.4 (18F-FMISO), and 7 and 1.4 (THK5351); respective tumor removal rates (%) were 90.4 and 99.6 (T1Gd), 79.2 and 86.4 (11C-MET), 84.4 and 89.2 (18F-FLT), 94.3 and 94.4 (18F-FMISO), and 72.3 and 83.4 (THK5351). The excised tumor tissue was found in the area where only THK5351 was accumulated.Conclusions: THK5351 accumulated in glioblastomas to a greater degree than that of other tracers, making it useful for discriminating between healthy and malignant tissues.
RT-1 Treatment results of salvage gamma knife stereotactic radiosurgery and bevacizumab (AVAgamma therapy) for recurrent malignant glioma
Authors: Sato Kenichi , Asanome Taku , Ishida Yuuki , Sugio Hironori , Nakamura Hirohiko 
Published: December 2021

Abstract
Purpose: We report the treatment results of AVAgamma therapy combining gamma knife (GK) and bevacizumab for recurrent malignant glioma. Subjects: From August 2013 to January 2021, 71 patients (Grade 2:8 patients, Grade3:16 patients, Grade 4:47 patients) with recurrent malignant glioma treated with AVAgamma therapy as salvage therapy at the time of relapse after initial treatment. The average age is 55.7 years, with 44 men and 27 women. The tumor volume is 150 ml or less, and KPS is 40% or more as the indication of AVAgamma therapy. When the irradiation volume of the gamma knife was 15 ml or less, the marginal dose was 20 to 26 Gy, and when the irradiation volume was 15 ml or more, the marginal dose was 12 to 15 Gy in two divided doses.The mean therapeutic borderline dose was 24 Gy. Bevacizumab was administered 10 mg / kg or 15 mg / kg 1 to 10 times after GK. Methods: Median progression-free survival (mPFS) from AVAgamma treatment, median survival (mOS), and mOS from initial treatment were examined and compared with mOS in the RPA classification of recurrent glioma. Results: In relapsing glioma RPA classification, NABTT CNC class 2 mOS is 17.2 months, class 3 mOS is 3.8 months, class 5 mOS is 5.6 months, class 6 mOS is 6.4 months, but mOS from AVAgamma therapy is 18 months in class 3, 11 months in class 5, 9 months in class 6. The survival time has been extended in class3, class5, class6. Discussion: By AVAgamma therapy, it was thought that recurrent lesions were locally controlled and life prognosis was prolonged. Conclusion: AVAgamma therapy is thought to prolong the survival of recurrent malignant glioma and play an important role as salvage treatment.
MPC-2 Clinical course and prognosis of lower-grade glioma, IDH wildtype and pTERT mutant
Authors: Takahashi Yoshinobu , Takeuchi Hayato , Tanigawa Seisuke , Okamoto Takanari , Hashimoto Naoya 
Published: December 2021

Abstract
Background and Purpose: In the cIMPACT-Now update 3, it was proposed that grade 2 astrocytic gliomas without IDH-mutations and grade 3 astrocytic gliomas with TERT promoter mutations should be designated as diffuse IDH wildtype astrocytic glioma with molecular features of WHO grade IV glioblastoma. Therefore, we investigated whether this group of tumors actually corresponds to grade IV prognostically in cases that we encountered ourselves. Cases and Methods: Among the 65 patients having primary astrocytic glioma who were operated in our hospital from January 2016 to March 2021, the prognostic values of seven patients with lower-grade glioma, IDH wildtype, and pTERT mutant were investigated. Results: Among the seven patients, the median age was 59 years (50–66 years). Four of them had anaplastic astrocytoma, two had diffuse astrocytoma, and no tumor lesion could be identified upon histological examination for one patient. The male-to-female ratio was 1:6. MGMT methylation was observed in two patients (29%). The median survival was 20 months, with a significantly worse prognosis when compared with lower-grade glioma without the TERT promoter mutation (13 patients: median survival 40 months), but a better prognosis when compared with glioblastoma (45 patients: median survival 13 months) (Log-rank p = 0.0051). Conclusion: Although EGFR amplification, combined whole chromosome 7 gain, and whole chromosome 10 loss were not examined, the prognostic value of lower-grade glioma, IDH wildtype, and pTERT mutant was not as poor as that of glioblastoma. Further investigation is required to confirm whether these groups of tumors should be treated in the same way as grade IV glioblastoma.
MPC-13 The evaluation of the shift of trend in lower grade glioma diagnoses based on each era`s criteria
Authors: Pareira Eriel Sandika , Shibuya Makoto , Ohara Kentaro , Nakagawa Yu , Kanazawa Tokunori , Kamamoto Dai , Yoshida Kazunari , Sasaki Hikaru 
Published: December 2021

Abstract
It is found that molecular characteristics in lower grade gliomas (LrGGs) such as codeletion of 1p/19q and IDH mutation was found to be more accurate to predict the patient`s clinical outcome compared to morphological diagnoses alone. Since the revision WHO2016 classification of LrGGs, molecular characteristics were implemented as diagnostic standard for LrGGs diagnoses. In the other hand, morphological diagnostic standard before WHO2016 classification era was determined by different considerations and therapeutic strategies. The malignancy grades were also majorly determined by morphological diagnoses only. This study re-evaluated 20 years of LrGG cases in single institution based on WHO2007 morphological criteria and compared them to the original institutional diagnoses from each era. The study samples were originally grade II-III diffuse glioma-diagnosed cases resected from 1990 to 2016. Biopsy cases were excluded. IDH mutation was analyzed by Sanger sequence and 1p/19 codeletion status was analyzed by Comparative Genome Hybridization (CGH). As the result 93 cases were collected and based on original diagnoses, more than 50% cases are astrocytomas. Compared to re-assessment by morphological diagnoses (WHO 2007), case numbers of astrocytoma diagnoses are decreased whereas oligodendroglioma and oligoastrocytoma case numbers are increased. But, based on WHO2016 criteria, the case number of astrocytomas is again found to be increased. From comparison between original institutional diagnoses and re-assessment results, it is found that there is a shift of trend from astrocytoma to oligodendroglioma and from grade II to grade III. Comparison between morphological diagnoses (WHO2007) and molecular (WHO2016) found that astrocytoma diagnoses remain unchanged meanwhile 45% of oligodendroglioma diagnoses were shifted into astrocytomas. There is a probability that there are high frequency of morphologically diagnosed oligodendroglioma tumors which are having molecular characteristics of astrocytoma. There is a trend that diagnosed grade II LrGGs are actually grade III based on re-assessment diagnosis.