bluuebunny/crossref_metadata_2025_split huggingface dataset:
Differential Exhumation of the Eastern Cordillera in the Central Andes: Evidence for South‐Verging Backthrusting (Abancay Deflection, Peru)
Authors: Gérard Benjamin , Robert Xavier , Audin Laurence , Valla Pierre G. , Bernet Matthias , Gautheron Cécile 
Published: March 2021

AbstractLocated at the northern tip of the Altiplano, the Abancay Deflection marks abruptly the latitudinal segmentation of the Central Andes spreading over the Altiplano to the south and the Eastern Cordillera northward. The striking morphological contrast between the low‐relief Altiplano and the high‐relief Eastern Cordillera makes this area a well‐suited place to determine spatiotemporal variations in surface and/or rock uplift and discuss the latest phase of the formation of the Central Andes. Here, we aim to quantify exhumation and uplift patterns in the Abancay Deflection since 40 Ma and present new apatite (U–Th)/He and fission track data from four altitudinal profiles and additional individual samples. Age–elevation relationships and thermal modeling both document that the Abancay Deflection experienced a moderate, spatially uniform, and steady exhumation at 0.2 ± 0.1 km/Myr between 40 and ∼5 Ma implying common large‐scale exhumation mechanism(s). From ∼5 Ma, while the northern part of the Eastern Cordillera and the Altiplano registered similar ongoing slow exhumation, the southern part of the Eastern Cordillera experienced one order‐of‐magnitude of exhumation acceleration (1.2 ± 0.4 km/Myr). This differential exhumation since ∼5 Ma implies active tectonics, river capture, and incision affecting the southern Eastern Cordillera. 3D thermokinematic modeling favors a tectonic decoupling between the Altiplano and the Eastern Cordillera through backthrusting activity of the Apurimac fault. We speculate that the Abancay Deflection, with its “bulls‐eye” structure and significant exhumation rate since 5 Ma, may represent an Andean protosyntaxis, similar to the syntaxes described in the Himalaya or Alaska.
Mineral Dissolution and Precipitation Under Stress: Model Formulation and Application to Metamorphic Reactions
Authors: Malvoisin Benjamin , Baumgartner Lukas P. 
Published: March 2021

AbstractReactions in the Earth's crust occur through a dissolution‐precipitation process in the presence of fluid. Dissolution releases aqueous species which are transported to the locus of precipitation. This replacement process generates creep deformation (i.e., dissolution‐precipitation creep) due to volume change during reaction and stress‐controlled mass re‐distribution in the rock. Reaction under stress also modifies the rock microstructure and the pressure record during metamorphism. A quantitative model for dissolution‐precipitation creep is developed here by considering both dissolution and precipitation at grain interfaces to simulate replacement reactions under stress. A new creep law is obtained for pressure solution, allowing for the reaction‐ and the diffusion‐controlled cases to be modeled with a single expression. It is extended to replacement reactions by introducing volume change during reaction. Deformation mechanism maps are generated with the new creep law, indicating that, when fluid is present, dissolution‐precipitation creep is the dominant deformation mechanism in the Earth's crust. Numerical model reveals that grain shape preferred orientation only develops near thermodynamic equilibrium. This is consistent with measurements of porphyroblasts preferred orientation in rocks from the Nufenen Pass (Switzerland) having experienced prograde metamorphism. Kinetics play a key role on the thermodynamic pressure of metamorphic reaction. Near the equilibrium, reaction is controlled by either σ1 or σ3 depending on the total volume change during reaction whereas it is controlled by the mean stress far from the equilibrium.
How Much Did the Colombian Andes Rise by the Collision of the Caribbean Oceanic Plateau?
Authors: León Santiago , Monsalve Gaspar , Bustamante Camilo 
Published: March 2021

AbstractThe quantification of topographic growth at convergent margins is of primary importance to assessing the linkages between tectonic processes and landscape evolution. Traditionally, this task has relied on the applicability of conventional paleobotanical and isotopic methods to estimate paleoelevations, which is not always straightforward. Here, we use recent calibrations based on trace elements of arc‐related magmatic rocks to estimate crustal thickening and surface uplift of the northern Colombian Andes during the early Andean orogeny at ca. 70‐60 Ma. Increased Sr/Y and (La/Yb)N ratios of arc‐related intrusives suggest a ∼20 km crustal thickening that was probably accompanied by an isostatically compensated topographic uplift of up to ∼2 km along the proto‐Central Cordillera and the Santa Marta Range. This kilometer‐scale uplift was coeval with a regional shift from marine to continental deposition in foreland basins and was triggered by the collision of the Caribbean oceanic plateau.
Activation of Nm23-H1 to suppress breast cancer metastasis via redox regulation
Authors: Kim Bokyung , Lee Kong-Joo 
Published: March 2021

AbstractNon-metastatic protein 23 H1 (Nm23-H1), a housekeeping enzyme, is a nucleoside diphosphate kinase-A (NDPK-A). It was the first identified metastasis suppressor protein. Nm23-H1 prolongs disease-free survival and is associated with a good prognosis in breast cancer patients. However, the molecular mechanisms underlying the role of Nm23-H1 in biological processes are still not well understood. This is a review of recent studies focusing on controlling NDPK activity based on the redox regulation of Nm23-H1, structural, and functional changes associated with the oxidation of cysteine residues, and the relationship between NDPK activity and cancer metastasis. Further understanding of the redox regulation of the NDPK function will likely provide a new perspective for developing new strategies for the activation of NDPK-A in suppressing cancer metastasis.
High prevalence of TP53 loss and whole-genome doubling in early-onset colorectal cancer
Authors: Kim Jeong Eun , Choi Jaeyong , Sung Chang-Ohk , Hong Yong Sang , Kim Sun Young , Lee Hyunjung , Kim Tae Won , Kim Jong-Il 
Published: March 2021

AbstractThe global incidence of early-onset colorectal cancer (EO-CRC) is rapidly rising. However, the reason for this rise in incidence as well as the genomic characteristics of EO-CRC remain largely unknown. We performed whole-exome sequencing in 47 cases of EO-CRC and targeted deep sequencing in 833 cases of CRC. Mutational profiles of EO-CRC were compared with previously published large-scale studies. EO-CRC and The Cancer Genome Atlas (TCGA) data were further investigated according to copy number profiles and mutation timing. We classified colorectal cancer into three subgroups: the hypermutated group consisted of mutations in POLE and mismatch repair genes; the whole-genome doubling group had early functional loss of TP53 that led to whole-genome doubling and focal oncogene amplification; the genome-stable group had mutations in APC and KRAS, similar to conventional colon cancer. Among non-hypermutated samples, whole-genome doubling was more prevalent in early-onset than in late-onset disease (54% vs 38%, Fisher’s exact P = 0.04). More than half of non-hypermutated EO-CRC cases involved early TP53 mutation and whole-genome doubling, which led to notable differences in mutation frequencies between age groups. Alternative carcinogenesis involving genomic instability via loss of TP53 may be related to the rise in EO-CRC.
Genetic and clinical characteristics of treatment-resistant depression using primary care records in two UK cohorts
Authors: Fabbri Chiara , Hagenaars Saskia P. , John Catherine , Williams Alexander T. , Shrine Nick , Moles Louise , Hanscombe Ken B. , Serretti Alessandro , Shepherd David J. , Free Robert C. , Wain Louise V. , Tobin Martin D. , Lewis Cathryn M. 
Published: March 2021

AbstractTreatment-resistant depression (TRD) is a major contributor to the disability caused by major depressive disorder (MDD). Primary care electronic health records provide an easily accessible approach to investigate TRD clinical and genetic characteristics. MDD defined from primary care records in UK Biobank (UKB) and EXCEED studies was compared with other measures of depression and tested for association with MDD polygenic risk score (PRS). Using prescribing records, TRD was defined from at least two switches between antidepressant drugs, each prescribed for at least 6 weeks. Clinical-demographic characteristics, SNP-based heritability (h2SNP) and genetic overlap with psychiatric and non-psychiatric traits were compared in TRD and non-TRD MDD cases. In 230,096 and 8926 UKB and EXCEED participants with primary care data, respectively, the prevalence of MDD was 8.7% and 14.2%, of which 13.2% and 13.5% was TRD, respectively. In both cohorts, MDD defined from primary care records was strongly associated with MDD PRS, and in UKB it showed overlap of 71–88% with other MDD definitions. In UKB, TRD vs healthy controls and non-TRD vs healthy controls h2SNP was comparable (0.25 [SE = 0.04] and 0.19 [SE = 0.02], respectively). TRD vs non-TRD was positively associated with the PRS of attention deficit hyperactivity disorder, with lower socio-economic status, obesity, higher neuroticism and other unfavourable clinical characteristics. This study demonstrated that MDD and TRD can be reliably defined using primary care records and provides the first large scale population assessment of the genetic, clinical and demographic characteristics of TRD.
Pediatric subspecialty telemedicine use from the patient and provider perspective
Authors: Pooni Rajdeep , Pageler Natalie M. , Sandborg Christy , Lee Tzielan 
Published: March 2021

Abstract
Background
To characterize telemedicine use among pediatric subspecialties with respect to clinical uses of telemedicine, provider experience, and patient perceptions during the COVID-19 pandemic.

Methods
We performed a mixed-methods study of telemedicine visits across pediatric endocrinology, nephrology, orthopedic surgery, and rheumatology at a large children’s hospital. We used deductive analysis to review observational data from 40 video visits. Providers and patients/caregivers were surveyed around areas of satisfaction and communication.

Results
We found adaptations of telemedicine including shared-screen use and provider-guided parent procedures among others. All providers felt that it was safest for their patients to conduct visits by video, and 72.7% reported completing some component of a clinical exam. Patients rated the areas of being respected by the clinical staff/provider and showing care and concern highly, and the mean overall satisfaction was 86.7 ± 19.3%.

Conclusions
Telemedicine has been used to deliver care to pediatric patients during the pandemic, and we found that patients were satisfied with the telemedicine visits during this stressful time and that providers were able to innovate during visits. Telemedicine is a tool that can be successfully adapted to patient and provider needs, but further studies are needed to fully explore its integration in pediatric subspecialty care.

Impact

This study describes telemedicine use at the height of the COVID-19 pandemic from both a provider and patient perspective, in four different pediatric subspecialties.

Prior to COVID-19, pediatric telehealth landscape analysis suggested that many pediatric specialty practices had pilot telehealth programs, but there are few published studies evaluating telemedicine performance through the simultaneous patient and provider experience as part of standard care.

We describe novel uses and adaptations of telemedicine during a time of rapid deployment in pediatric specialty care.
EVI1 dysregulation: impact on biology and therapy of myeloid malignancies
Authors: Birdwell Christine , Fiskus Warren , Kadia Tapan M. , DiNardo Courtney D. , Mill Christopher P. , Bhalla Kapil N. 
Published: March 2021

AbstractEcotropic viral integration site 1 (Evi1) was discovered in 1988 as a common site of ecotropic viral integration resulting in myeloid malignancies in mice. EVI1 is an oncogenic zinc-finger transcription factor whose overexpression contributes to disease progression and an aggressive phenotype, correlating with poor clinical outcome in myeloid malignancies. Despite progress in understanding the biology of EVI1 dysregulation, significant improvements in therapeutic outcome remain elusive. Here, we highlight advances in understanding EVI1 biology and discuss how this new knowledge informs development of novel therapeutic interventions. EVI1 is overexpression is correlated with poor outcome in some epithelial cancers. However, the focus of this review is the genetic lesions, biology, and current therapeutics of myeloid malignancies overexpressing EVI1.
Skeleton-vasculature chain reaction: a novel insight into the mystery of homeostasis
Authors: Chen Ming , Li Yi , Huang Xiang , Gu Ya , Li Shang , Yin Pengbin , Zhang Licheng , Tang Peifu 
Published: March 2021

AbstractAngiogenesis and osteogenesis are coupled. However, the cellular and molecular regulation of these processes remains to be further investigated. Both tissues have recently been recognized as endocrine organs, which has stimulated research interest in the screening and functional identification of novel paracrine factors from both tissues. This review aims to elaborate on the novelty and significance of endocrine regulatory loops between bone and the vasculature. In addition, research progress related to the bone vasculature, vessel-related skeletal diseases, pathological conditions, and angiogenesis-targeted therapeutic strategies are also summarized. With respect to future perspectives, new techniques such as single-cell sequencing, which can be used to show the cellular diversity and plasticity of both tissues, are facilitating progress in this field. Moreover, extracellular vesicle-mediated nuclear acid communication deserves further investigation. In conclusion, a deeper understanding of the cellular and molecular regulation of angiogenesis and osteogenesis coupling may offer an opportunity to identify new therapeutic targets.
Engineered cells as glioblastoma therapeutics
Authors: Ramanathan Aparna , Lorimer Ian A. J. 
Published: March 2021

AbstractIn spite of significant recent advances in our understanding of the genetics and cell biology of glioblastoma, to date, this has not led to improved treatments for this cancer. In addition to small molecule, antibody, and engineered virus approaches, engineered cells are also being explored as glioblastoma therapeutics. This includes CAR-T cells, CAR-NK cells, as well as engineered neural stem cells and mesenchymal stem cells. Here we review the state of this field, starting with clinical trial studies. These have established the feasibility and safety of engineered cell therapies for glioblastoma and show some evidence for activity. Next, we review the preclinical literature and compare the strengths and weaknesses of various starting cell types for engineered cell therapies. Finally, we discuss future directions for this nascent but promising modality for glioblastoma therapy.
PARsylated transcription factor EB (TFEB) regulates the expression of a subset of Wnt target genes by forming a complex with β-catenin-TCF/LEF1
Authors: Kim Soyoung , Song Gahyeon , Lee Taebok , Kim Minseong , Kim Jeongrae , Kwon Hyeryun , Kim Jiyoung , Jeong Wonyoung , Lee Ukjin , Na Chaebin , Kang Sangwon , Kim Wantae , Seong Je Kyung , Jho Eek-hoon 
Published: March 2021

AbstractWnt signaling is mainly transduced by β-catenin via regulation of the β-catenin destruction complex containing Axin, APC, and GSK3β. Transcription factor EB (TFEB) is a well-known master regulator of autophagy and lysosomal biogenesis processes. TFEB’s nuclear localization and transcriptional activity are also regulated by various upstream signals. In this study, we found that Wnt signaling induces the nuclear localization of TFEB and the expression of Wnt target genes is regulated by TFEB-β-catenin-TCF/LEF1 as well as β-catenin-TCF/LEF1 complexes. Our biochemical data revealed that TFEB is a part of the β-catenin destruction complex, and destabilization of the destruction complex by knockdown of either Axin or APC causes nuclear localization of TFEB. Interestingly, RNA-sequencing analysis revealed that about 27% of Wnt3a-induced genes were TFEB dependent. However, these “TFEB mediated Wnt target genes” were different from TFEB target genes involved in autophagy and lysosomal biogenesis processes. Mechanistically, we found that Tankyrase (TNKS) PARsylates TFEB with Wnt ON signaling, and the nuclear localized PARsylated TFEB forms a complex with β-catenin-TCF/LEF1 to induce the “TFEB mediated Wnt target genes”. Finally, we found that in various types of cancer, the levels of TFEB mediated Wnt target genes exhibit strong correlations with the level of Axin2, which represents the activity of Wnt signaling. Overall, our data suggest that Wnt signaling induces the expression of a subset of genes that are distinct from previously known genes regulated by the β-catenin-TCF/LEF1 complex or TFEB, by forming a transcription factor complex consisting of PARsylated TFEB and β-catenin-TCF/LEF1.
FGF21 facilitates autophagy in prostate cancer cells by inhibiting the PI3K–Akt–mTOR signaling pathway
Authors: Dai Han , Hu Wenjing , Zhang Lianying , Jiang Feiyu , Mao Xiongmin , Yang Gangyi , Li Ling 
Published: March 2021

AbstractFibroblast growth factor 21 (FGF21) plays an important role in regulating glucose and lipid metabolism, but its role in cancer is less well-studied. We aimed to investigate the action of FGF21 in the development of prostate cancer (PCa). Herein, we found that FGF21 expression was markedly downregulated in PCa tissues and cell lines. FGF21 inhibited the proliferation and clone formation of LNCaP cells (a PCa cell line) and promoted apoptosis. FGF21 also inhibited PCa cell migration and invasiveness. The Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses revealed that FGF21 was related to autophagy and the phosphatidylinositol 3-kinase–Akt kinase–mammalian target of rapamycin (PI3K–Akt–mTOR) pathway. Mechanistically, FGF21 promoted autophagy in LNCaP cells by inhibiting the PI3K–Akt–mTOR–70S6K pathway. In addition, FGF21 inhibited PCa tumorigenesis in vivo in nude mice. Altogether, our findings show that FGF21 inhibits PCa cell proliferation and promoted apoptosis in PCa cells through facilitated autophagy. Therefore, FGF21 might be a potential novel target in PCa therapy.
Non-canonical role of wild-type SEC23B in the cellular stress response pathway
Authors: Yehia Lamis , Liu Darren , Fu Shuai , Iyer Pranav , Eng Charis 
Published: March 2021

AbstractWhile germline recessive loss-of-function mutations in SEC23B in humans cause a rare form of anaemia, heterozygous change-of-function mutations result in increased predisposition to cancer. SEC23B encodes SEC23 homologue B, a component of coat protein complex II (COPII), which canonically transports proteins from the endoplasmic reticulum (ER) to the Golgi. Despite the association of SEC23B with anaemia and cancer, the precise pathophysiology of these phenotypic outcomes remains unknown. Recently, we reported that mutant SEC23B has non-canonical COPII-independent function, particularly within the ER stress and ribosome biogenesis pathways, and that may contribute to the pathobiology of cancer predisposition. In this study, we hypothesized that wild-type SEC23B has a baseline function within such cellular stress response pathways, with the mutant protein reflecting exaggerated effects. Here, we show that the wild-type SEC23B protein localizes to the nucleus in addition to classical distribution at the ER/Golgi interface and identify multiple putative nuclear localization and export signals regulating nuclear–cytoplasmic transport. Unexpectedly, we show that, independently of COPII, wild-type SEC23B can also localize to cell nucleoli under proteasome inhibition conditions, with distinct distribution patterns compared to mutant cells. Unbiased proteomic analyses through mass spectrometry further revealed that wild-type SEC23B interacts with a subset of nuclear proteins, in addition to central proteins in the ER stress, protein ubiquitination, and EIF2 signalling pathways. We validate the genotype-specific differential SEC23B–UBA52 (ribosomal protein RPL40) interaction. Finally, utilizing patient-derived lymphoblastoid cell lines harbouring either wild-type or mutant SEC23B, we show that SEC23B levels increase in response to ER stress, further corroborating its role as a cellular stress response sensor and/or effector. Overall, these observations suggest that SEC23B, irrespective of mutation status, has unexplored roles in the cellular stress response pathway, with implications relevant to cancer and beyond that, CDAII and normal cell biology.
The Sumo proteome of proliferating and neuronal-differentiating cells reveals Utf1 among key Sumo targets involved in neurogenesis
Authors: Correa-Vázquez Juan F. , Juárez-Vicente Francisco , García-Gutiérrez Pablo , Barysch Sina V. , Melchior Frauke , García-Domínguez Mario 
Published: March 2021

AbstractPost-translational modification by covalent attachment of the Small ubiquitin-like modifier (Sumo) polypeptide regulates a multitude of processes in vertebrates. Despite demonstrated roles of Sumo in the development and function of the nervous system, the identification of key factors displaying a sumoylation-dependent activity during neurogenesis remains elusive. Through a SILAC (stable isotope labeling by/with amino acids in cell culture)-based proteomic approach, we have identified the Sumo proteome of the model cell line P19 under proliferation and neuronal differentiation conditions. More than 300 proteins were identified as putative Sumo targets differentially associated with one or the other condition. A group of proteins of interest were validated and investigated in functional studies. Among these, Utf1 was revealed as a new Sumo target. Gain-of-function experiments demonstrated marked differences between the effects on neurogenesis of overexpressing wild-type and sumoylation mutant versions of the selected proteins. While sumoylation of Prox1, Sall4a, Trim24, and Utf1 was associated with a positive effect on neurogenesis in P19 cells, sumoylation of Kctd15 was associated with a negative effect. Prox1, Sall4a, and Kctd15 were further analyzed in the vertebrate neural tube of living embryos, with similar results. Finally, a detailed analysis of Utf1 showed the sumoylation dependence of Utf1 function in controlling the expression of bivalent genes. Interestingly, this effect seems to rely on two mechanisms: sumoylation modulates binding of Utf1 to the chromatin and mediates recruitment of the messenger RNA-decapping enzyme Dcp1a through a conserved SIM (Sumo-interacting motif). Altogether, our results indicate that the combined sumoylation status of key proteins determines the proper progress of neurogenesis.