bluuebunny/crossref_metadata_2025_split huggingface dataset:
IL-1 TERT PROMOTER C228T MUTATION IN NEURAL PROGENITORS CONFERS GROWTH ADVANTAGE FOLLOWING TELOMERE SHORTENING IN VIVO
Authors: Furnari Frank , Miki Shunichiro , Koga Tomoyuki , Mckinney Andrew M , Parisian Alison D , Tadokoro Takahiro , Vadla Raghavendra , Masala Martin , Hevner Robert F , Costello Joseph F 
Published: December 2022

Abstract
Heterozygous TERT (Telomerase reverse transcriptase) promoter mutations (TPMs) facilitate TERT expression and are the most frequent mutation in glioblastoma (GBM). A recent analysis revealed this mutation is one of the earliest events in gliomagenesis, however no appropriate human models have been engineered to study the role of this mutation in the initiation of these tumors. To address this, we established GBM models by introducing the heterozygous TPM in human induced pluripotent stem cells (hiPSCs) using a two-step targeting approach in the context of GBM genetic alterations, CDKN2A/B and PTEN deletion, and EGFRvIII overexpression. Orthotopic injection of neuronal precursor cells (NPCs) derived from hiPSCs with TPM into immunodeficient mice did not enhance tumorigenesis compared to TERT promoter wild type (TPW) NPCs at initial in vivo passage which we attribute to relatively long telomeres. We further show that the TPM mutation recruited GA-Binding Protein (GABPA) and engendered low-level TERT expression, resulting in enhanced tumorigenesis upon secondary passage and maintenance of short telomere length as has been reported in human GBM. RNA sequencing of harvested tumors grown as secondary spheres demonstrated upregulated proliferation and mitosis pathway signatures in TPM cells, consistent with their increased in vitro proliferation relative to TPW counterparts. Finally, when secondary TPM and TPW sphere cultures were reinjected into mice, only the TPM led to tumor formation. In summary, our novel GBM model illustrates a growth advantage imparted by heterozygous TPMs in the context of GBM driver mutations relative to isogenic controls, and thereby allows for the identification and validation of TERT promoter-specific vulnerabilities in a genetically accurate background.
IL-2 TUMOR TREATING FIELDS: IMPROVING THE ODDS FOR PATIENTS WITH GLIOBLASTOMA
Authors: Hottinger Andreas F 
Published: December 2022

Abstract
Tumor treating fields (TTFields) is a novel, noninvasive regional antimitotic treatment modality approved for use in newly diagnosed glioblastoma (GBM). Nowadays, it is an integral part of the standard management of GBM. TTFields therapy delivers intermediate frequency (100-300 kHz), low intensity (1-3 V/cm), alternating electric fields to the tumor using transducer arrays placed on the scalp. TTFields disrupt mitotic spindle formation, block cell division and disrupt intracellular constituents, inducing apoptosis, autophagy and immune mediated cell death, as well as impairment of cell migration and DNA repair. A phase III trial of TTFields therapy in combination with maintenance temozolomide has established that TTFields are associated with minimal toxicity and result in a significant improvement of progression free survival and overall survival. Importantly, it also significantly increases the percentage of long-term survivors while maintaining the quality of life of the patients. Recent work has focused on a number of key parameters to better understand which patients are most likely to benefit from this new therapeutic approach. In this presentation, we will review the basics of TTFields therapy and the available clinical evidence that justify its use in GBM. We will also discuss how to best integrate this novel therapeutic approach in the current management of patients with newly diagnosed and progressing glioblastoma, highlighting how this was performed in the Swiss Institutions. We will also review and discuss recent work that analyzed the pertinence of TTFields in specific subgroups of patients, analyze patterns of progression under TTFields and discuss ongoing translational and clinical research.
IL-3 DISCONNECTING BRAIN TUMOR NETWORKS FOR IMPROVED THERAPIES
Authors: Winkler Frank 
Published: December 2022

Abstract
Integration into communicating tumor cell networks is a way how the entire brain tumor organism can progress in the brain, and resist therapies. It started with our discovery of ultra-long membrane protrusions, tumor microtube (TM), in tumor cells from glioblastomas and other incurable adult and pediatric glioma entities (Osswald et al., Nature 2015). These TMs are used for very effective brain invasion, and later interconnect single tumor cells to communicating and resistant multicellular networks, but also glioma cells to neurons in the brain, with neuron-glioma synapses stimulating glioma growth(Venkataramani et al., Nature 2019) and invasion (Venkataramani et al., Cell 2022). Increasing formation of these homotypic and heterotypic networks is seen with increasing glioma malignancy: lowest in low-grade oligodendrogliomas, and highest in glioblastomas and K27M mutated gliomas. The genetic reduction of GAP-43, a crucial neurodevelopmental factor that drives TM formation and function, not only deprived glioblastoma cells from the ability to form functional tumor networks, but also made radiotherapy much more effective, by and large eradicating experimental tumors from the mouse brain, which is typically not possible with radiotherapy alone. Consistent with the concept of tumor cell resilience by network integration, radiotherapy and also chemotherapy (Weil et al., Neuro-Oncology 2017) preferentially killed the unconnected glioblastoma cells, leaving the tumor cell networks largely intact. Damage to the tumor network by surgical measures induced a self-healing response. Taken together, integration into multicellular, highly functional, communicating and resilient networks is not only a feature of the nervous system, but also of incurable, most aggressive brain tumors. In this talk, clinical concepts that originate from these discoveries are presented, including a network disconnection strategy currently tested in the German MecMeth trial (EudraCT2021-000708-39), and the AMPAR inhibitor perampanel as a potential inhibitor of neuron-glioma synapses. Furthermore, new basic and translational developments in the field of brain tumor networks are presented and discussed.
IL-4 CHALLENGES FOR MANAGEMENT OF PRIMARY CNS LYMPHOMA
Authors: Nagane Motoo 
Published: December 2022

Abstract
Primary central nervous system lymphoma (PCNSL) affects primarily elderly patients and comprises 5% of all primary brain tumors with predominant histology of diffuse large B-cell lymphoma (DLBCL). Whole brain radiotherapy (WBRT) does not provide durable remission, rather is deeply involved in development of leukoencephalopathy with delayed neurotoxicity, especially in elderly patients. BBB-penetrating high-dose methotrexate (HD-MTX)-based multiagent immunochemotherapies have been extensively explored and have shown high activities as induction regimens, followed by consolidation therapies such as high-dose chemotherapy with autologous stem-cell transplant (HDC/ASCT). Recent progress in understanding molecular pathogenesis of PCNSL has shed light on developing novel molecular targeted therapies against key signaling molecules such as Bruton’s tyrosine kinase (BTK) and pathways leading to constitutive activation of NF-kB signaling. In this lecture, standard of care for PCNSL with its molecular landscape and issues to be pursuit to further improve outcome of PCNSL treatment will be discussed.
IL-5 Targeted Therapies for Nervous System Tumors – Progress, Pitfalls, and Prospects
Authors: Batchelor Tracy 
Published: December 2022

Abstract
The molecular genetic understanding of nervous system tumors has expanded rapidly offering insight into potentially targetable oncogenic driver alterations. In monogenic tumor susceptibility syndromes such as tuberous sclerosis, neurofibromatosis type 1, and von Hippel Lindau syndrome targeted drugs have demonstrated efficacy and are now approved in the United States for the treatment of subependymal giant cell astrocytoma, plexiform neurofibroma, and hemangioblastoma, respectively. Some genetic alterations like BRAF V600E mutations or neurotrophic receptor tyrosine kinase (NTRK) fusions, occur across multiple cancers, including certain types of gliomas. Dabrafenib in combination with trametinib is approved for use in gliomas that harbor BRAF V600E mutations and larotrectinib is approved in gliomas that harbor certain NTRK fusions. In pediatric low-grade astrocytoma, one of the most common solid tumors of childhood, BRAF truncation-fusion events may render these tumors susceptible to tovorafenib, a type 2 RAF inhibitor, which is under study in clinical trials. Mutations in the isocitrate dehydrogenase (IDH) gene occur in the majority of low-grade and anaplastic gliomas, create specific metabolic vulnerabilities, and several IDH-mutant targeting strategies are under investigation. Glioblastoma is characterized by intratumoral molecular heterogeneity so strategies that target single genetic alterations may not be as effective as in other types of gliomas although a number of novel targeted strategies have been advanced to clinical trials. Other types of nervous system tumors such as medulloblastoma, meningioma, primary central nervous system diffuse large B-cell lymphoma, and craniopharyngioma harbor targetable genetic alterations and clinical trials are ongoing. Finally, metastatic brain tumors may harbor targetable genetic alterations that may differ from the primary site of cancer highlighting the importance of biopsy and molecular analysis of the brain metastases in order to enroll patients in clinical trials of targeted therapies.
The Personality Divide Between Citizens and Politicians: The Case of the Four Largest Spanish Parties
Authors: Galais Carol , Coller Xavier 
Published: December 2022

Abstract
Despite the alleged increasing importance given to politicians’ personalities, the similarities and differences between citizens and politicians regarding their personality traits have been insufficiently studied. This research analyses the personality similarities and differences between citizens and politicians in Spain across party allegiances and ideologies. For this, we use two representative surveys for citizens and MPs. Our results show that Spanish politicians are a more homogeneous population—regarding their personality traits—than Spanish citizens, and that Spanish MPs are more sociable and imaginative and less lazy and artistic than the average citizen, which is consistent with a ‘politician’s personality’.
Toward a systems view on RNA-binding proteins and associated RNAs in plants: Guilt by association
Authors: Mateos Julieta L , Staiger Dorothee 
Published: December 2022

Abstract
RNA-binding proteins (RBPs) have a broad impact on most biochemical, physiological, and developmental processes in a plant’s life. RBPs engage in an on-off relationship with their RNA partners, accompanying virtually every stage in RNA processing and function. While the function of a plethora of RBPs in plant development and stress responses has been described, we are lacking a systems-level understanding of components in RNA-based regulation. Novel techniques have substantially enlarged the compendium of proteins with experimental evidence for binding to RNAs in the cell, the RNA-binding proteome. Furthermore, ribonomics methods have been adapted for use in plants to profile the in vivo binding repertoire of RBPs genome-wide. Here, we discuss how recent technological achievements have provided novel insights into the mode of action of plant RBPs at a genome-wide scale. Furthermore, we touch upon two emerging topics, the connection of RBPs to phase separation in the cell and to extracellular RNAs. Finally, we define open questions to be addressed to move toward an integrated understanding of RBP function.
Calcyclin-binding protein-promoted degradation of MdFRUCTOKINASE2 regulates sugar homeostasis in apple
Authors: Su Jing , Jiao Tiantian , Liu Xi , Zhu Lingcheng , Ma Baiquan , Ma Fengwang , Li Mingjun 
Published: December 2022

Abstract
Fructokinase (FRK) activates fructose through phosphorylation, which sends the activated fructose into primary metabolism and regulates fructose signaling capabilities in plants. The apple (Malus × domestica) FRK gene MdFRK2 shows especially high affinity to fructose, and its overexpression decreases fructose levels in the leaves of young plants. However, in the current study of mature plants, fruits of transgenic apple trees overexpressing MdFRK2 accumulated a higher level of fructose than wild-type (WT) fruits (at both young and mature stages). Transgenic apple trees with high mRNA MdFRK2 expression showed no significant differences in MdFRK2 protein abundance or FRK enzyme activity compared to WT in mature leaves, young fruits, and mature fruits. Immunoprecipitation–mass spectrometry analysis identified an skp1, cullin, F-box (SCF) E3 ubiquitin ligase, calcyclin-binding protein (CacyBP), that interacted with MdFRK2. RNA-sequencing analysis provided evidence for ubiquitin-mediated post-transcriptional regulation of MdFRK2 protein for the maintenance of fructose homeostasis in mature leaves and fruits. Further analyses suggested an MdCacyBP–MdFRK2 regulatory module, in which MdCacyBP interacts with and ubiquitinates MdFRK2 to facilitate its degradation by the 26S proteasome, thus decreasing the FRK enzyme activity to elevate fructose concentration in transgenic apple trees. This result uncovered an important mechanism underlying plant fructose homeostasis in different organs through regulating the MdFRK2 protein level via ubiquitination and degradation. Our study provides usable data for the future improvement of apple flavor and expands our understanding of the molecular mechanisms underlying plant fructose content and signaling regulation.
Fatty acid amide hydrolase and 9-lipoxygenase modulate cotton seedling growth by ethanolamide oxylipin levels
Authors: Arias-Gaguancela Omar , Aziz Mina , Chapman Kent D 
Published: December 2022

Abstract
Polyunsaturated N-acylethanolamines (NAEs) can be hydrolyzed by fatty acid amide hydrolase (FAAH) or oxidized by lipoxygenase (LOX). In Arabidopsis (Arabidopsis thaliana), the 9-LOX product of linoleoylethanolamide, namely, 9-hydroxy linoleoylethanolamide (9-NAE-HOD), is reported to negatively regulate seedling development during secondary dormancy. In upland cotton (Gossypium hirsutum L.), six putative FAAH genes (from two diverged groups) and six potential 9-LOX genes are present; however, their involvement in 9-NAE-HOD metabolism and its regulation of seedling development remain unexplored. Here, we report that in cotton plants, two specific FAAH isoforms (GhFAAH Ib and GhFAAH IIb) are needed for hydrolysis of certain endogenous NAEs. Virus-induced gene silencing (VIGS) of either or both FAAHs led to reduced seedling growth and this coincided with reduced amidohydrolase activities and elevated quantities of endogenous 9-NAE-HOD. Transcripts of GhLOX21 were consistently elevated in FAAH-silenced tissues, and co-silencing of GhLOX21 and GhFAAH (Ib and/or IIb) led to reversal of seedling growth to normal levels (comparable with no silencing). This was concomitant with reductions in the levels of 9-NAE-HOD, but not of 13-NAE-HOD. Pharmacological experiments corroborated the genetic and biochemical evidence, demonstrating that direct application of 9-NAE-HOD, but not 13-NAE-HOD or their corresponding free fatty acid oxylipins, inhibited the growth of cotton seedlings. Additionally, VIGS of GhLOX21 in cotton lines overexpressing AtFAAH exhibited enhanced growth and no detectable 9-NAE-HOD. Altogether, we conclude that the growth of cotton seedlings involves fine-tuning of 9-NAE-HOD levels via FAAH-mediated hydrolysis and LOX-mediated production, expanding the mechanistic understanding of plant growth modulation by NAE oxylipins to a perennial crop species.
The staphylococcal biofilm protein Aap mediates cell–cell adhesion through mechanically distinct homophilic and lectin interactions
Authors: Wang Can , Chantraine Constance , Viljoen Albertus , Herr Andrew B , Fey Paul D , Horswill Alexander R , Mathelié-Guinlet Marion , Dufrêne Yves F 
Published: December 2022

Abstract
The accumulation phase of staphylococcal biofilms relies on both the production of an extracellular polysaccharide matrix and the expression of bacterial surface proteins. A prototypical example of such adhesive proteins is the long multidomain protein Aap (accumulation-associated protein) from Staphylococcus epidermidis, which mediates zinc-dependent homophilic interactions between Aap B-repeat regions through molecular forces that have not been investigated yet. Here, we unravel the remarkable mechanical strength of single Aap–Aap homophilic bonds between living bacteria and we demonstrate that intercellular adhesion also involves sugar binding through the lectin domain of the Aap A region. We find that the mechanical force needed to unfold individual β-sheet-rich G5-E domains from the Aap B-repeat regions is very high, ranging from 300 up to 1,000 pN at high loading rates, indicating these are extremely stable. This high mechanostability provides a means to the cells to form highly adhesive and cohesive biofilms capable of sustaining high physiological shear stress. Importantly, we identify a previously undescribed role of Aap in bacterial–bacterial adhesion, that is, heterophilic sugar binding by a specific lectin domain located in the N-terminal A region, which might be important to establish initial contacts between cells before strong homophilic bonds come into play. This study emphasizes the remarkable mechanical and binding properties of Aap as well as its wide diversity of adhesive functions.
Delocalization and re-entrant localization of flat-band states in non-Hermitian disordered lattice models with flat bands
Authors: Kim Sangbum , Kim Kihong 
Published: December 2022

Abstract
We present a numerical study of Anderson localization in disordered non-Hermitian lattice models with flat bands. Specifically, we consider 1D stub and 2D kagome lattices that have a random scalar potential and a uniform imaginary vector potential and calculate the spectra of the complex energy, the participation ratio, and the winding number as a function of the strength of the imaginary vector potential, h. The flat-band states are found to show a double transition from localized to delocalized and back to localized states with h, in contrast to the dispersive-band states going through a single delocalization transition. When h is sufficiently small, all flat-band states are localized. As h increases above a certain critical value h1, some pairs of flat-band states become delocalized. The participation ratio associated with them increases substantially and their winding numbers become nonzero. As h increases further, more and more flat-band states get delocalized until the fraction of the delocalized states reaches a maximum. For larger h values, a re-entrant localization takes place and, at another critical value h2, all flat-band states return to compact localized states with very small participation ratios and zero winding numbers. This re-entrant localization transition, which is due to the interplay among disorder, non-hermiticity, and the flat band, is a phenomenon occurring in many models having an imaginary vector potential and a flat band simultaneously. We explore the spatial characteristics of the flat-band states by calculating the local density distribution.
Elevated Systemic Levels of Markers Reflecting Intestinal Barrier Dysfunction and Inflammasome Activation Are Correlated in Severe Mental Illness
Authors: Jensen Søren B , Sheikh Mashhood A , Akkouh Ibrahim A , Szabo Attila , O’Connell Kevin S , Lekva Tove , Engh John A , Agartz Ingrid , Elvsåshagen Torbjørn , Ormerod Monica B E G , Weibell Melissa A , Johnsen Erik , Kroken Rune A , Melle Ingrid , Drange Ole K , Nærland Terje , Vaaler Arne E , Westlye Lars T , Aukrust Pål , Djurovic Srdjan , Eiel Steen Nils , Andreassen Ole A , Ueland Thor 
Published: December 2022

Abstract

Background and Hypothesis
Gut microbiota alterations have been reported in severe mental illness (SMI) but fewer studies have probed for signs of gut barrier disruption and inflammation. We hypothesized that gut leakage of microbial products due to intestinal inflammation could contribute to systemic inflammasome activation in SMI.

Study Design
We measured plasma levels of the chemokine CCL25 and soluble mucosal vascular addressin cell adhesion molecule-1 (sMAdCAM-1) as markers of T cell homing, adhesion and inflammation in the gut, lipopolysaccharide binding protein (LBP) and intestinal fatty acid binding protein (I-FABP) as markers of bacterial translocation and gut barrier dysfunction, in a large SMI cohort (n = 567) including schizophrenia (SCZ, n = 389) and affective disorder (AFF, n = 178), relative to healthy controls (HC, n = 418). We assessed associations with plasma IL-18 and IL-18BPa and leukocyte mRNA expression of NLRP3 and NLRC4 as markers of inflammasome activation.

Study Results
Our main findings were: (1) higher levels of sMAdCAM-1 (P = .002), I-FABP (P = 7.6E−11), CCL25 (P = 9.6E−05) and LBP (P = 2.6E−04) in SMI compared to HC in age, sex, BMI, CRP and freezer storage time adjusted analysis; (2) the highest levels of sMAdCAM-1 and CCL25 (both P = 2.6E−04) were observed in SCZ and I-FABP (P = 2.5E−10) and LBP (3) in AFF; and (3), I-FABP correlated with IL-18BPa levels and LBP correlated with NLRC4.

Conclusions
Our findings support that intestinal barrier inflammation and dysfunction in SMI could contribute to systemic inflammation through inflammasome activation.
Integration of genome-scale data identifies candidate sleep regulators
Authors: Lee Yin Yeng , Endale Mehari , Wu Gang , Ruben Marc D , Francey Lauren J , Morris Andrew R , Choo Natalie Y , Anafi Ron C , Smith David F , Liu Andrew C , Hogenesch John B 
Published: December 2022

AbstractStudy ObjectivesGenetics impacts sleep, yet, the molecular mechanisms underlying sleep regulation remain elusive. In this study, we built machine learning models to predict sleep genes based on their similarity to genes that are known to regulate sleep.MethodsWe trained a prediction model on thousands of published datasets, representing circadian, immune, sleep deprivation, and many other processes, using a manually curated list of 109 sleep genes.ResultsOur predictions fit with prior knowledge of sleep regulation and identified key genes and pathways to pursue in follow-up studies. As an example, we focused on the NF-κB pathway and showed that chronic activation of NF-κB in a genetic mouse model impacted the sleep-wake patterns.ConclusionOur study highlights the power of machine learning in integrating prior knowledge and genome-wide data to study genetic regulation of complex behaviors such as sleep.