bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical significance of STEAP1 extracellular vesicles in prostate cancer
Authors: Khanna Karan , Salmond Nikki , Lynn Kalan S. , Leong Hon S. , Williams Karla C. 
Published: February 2021

AbstractBackgroundExtracellular vesicles (EVs) are cell-derived lipid bilayer enclosed structures shed from the plasma membrane by all cell types. Evidence of EV presence in biological fluids has led to considerable efforts focused on identifying their cargo and determining their utility as a non-invasive diagnostic platform for cancer. In this study, we identify circulating STEAP1 (six-transmembrane epithelial antigen of the prostate 1)-positive EVs in the plasma of healthy males and prostate cancer patients and evaluate its diagnostic and prognostic significance.MethodsSTEAP1 was identified on EVs in prostate cancer patient plasma. EVs were validated using electron microscopy, Western blot, nanoparticle tracking analysis, and nanoscale flow cytometry. STEAP1-positive EVs were quantified for 121 males with prostate cancer and 55 healthy age-matched control males. An evaluation of STEAP1 in prostate cancer tissue was also performed using established prostate cancer cohort data (TCGA, MSKCC, and SU2C/PCF Dream Team).ResultsEvaluation of STEAP1-positive EVs by nanoscale flow cytometry identified a significant increase in prostate cancer patient plasma compared to healthy males. However, no association was found between total STEAP1 EV levels and disease recurrence or overall survival. Cohort data from prostate cancer tissue also found STEAP1 to be elevated in prostate cancer while no significant association with recurrence or overall survival was identified.ConclusionsSTEAP1 is known to be enriched on the cells of the prostate with potential clinical significance in prostate cancer. Our results identify and quantitate STEAP1-positive EVs in plasma and provide rationale for a STEAP1 EV-based liquid biopsy as a diagnostic strategy in prostate cancer.
Impact of family history on oncological outcomes in primary therapy for localized prostate cancer patients: a systematic review and meta-analysis
Authors: Urabe Fumihiko , Kimura Shoji , Yamamoto Shutaro , Tashiro Kojiro , Kimura Takahiro , Egawa Shin 
Published: February 2021

Abstract
Background
The influence of family history on oncological outcomes of prostate cancer remains controversial. We conducted a systematic literature review and meta-analysis to investigate the impact of family history of localized prostate cancer on oncological outcomes.

Methods
On May 2020, we systematically searched MEDLINE, the Cochrane library, and Scopus for studies that compared patients who had localized prostate cancer with or without a positive family history of prostate cancer. Our aim was to evaluate the association of family history with biochemical recurrence-free survival, cancer-specific survival, and overall survival by means of a multivariate Cox regression analysis.

Results
Eleven studies with 39,716 patients were included in the systematic review, and eight studies with 33,027 patients for the meta-analysis. A positive family history was not associated with worse biochemical recurrence-free survival (pooled HR: 0.96; 95% CI: 0.79–1.17) or cancer-specific survival (pooled HR: 1.1; 95% CI: 0.52–2.35). Subgroup analyses showed no association between positive family history and poor biochemical recurrence-free survival in prostate cancer patients treated with radical prostatectomy (pooled HR: 0.99; 95% CI: 0.76–1.31) or radiation therapy (pooled HR: 0.93; 95% CI: 0.67–1.30).

Conclusions
This meta-analysis indicated that family history of prostate cancer does not increase the risk of biochemical recurrence or cancer-specific mortality in localized prostate cancer patients.
Resolving cryptic species complexes in marine protists: phylogenetic haplotype networks meet global DNA metabarcoding datasets
Authors: De Luca Daniele , Piredda Roberta , Sarno Diana , Kooistra Wiebe H C F 
Published: February 2021

Abstract
Marine protists have traditionally been assumed to be lowly diverse and cosmopolitan. Yet, several recent studies have shown that many protist species actually consist of cryptic complexes of species whose members are often restricted to particular biogeographic regions. Nonetheless, detection of cryptic species is usually hampered by sampling coverage and application of methods (e.g. phylogenetic trees) that are not well suited to identify relatively recent divergence and ongoing gene flow. In this paper, we show how these issues can be overcome by inferring phylogenetic haplotype networks from global metabarcoding datasets. We use the Chaetoceros curvisetus (Bacillariophyta) species complex as study case. Using two complementary metabarcoding datasets (Ocean Sampling Day and Tara Oceans), we equally resolve the cryptic complex in terms of number of inferred species. We detect new hypothetical species in both datasets. Gene flow between most of species is absent, but no barcoding gap exists. Some species have restricted distribution patterns whereas others are widely distributed. Closely related taxa occupy contrasting biogeographic regions, suggesting that geographic and ecological differentiation drive speciation. In conclusion, we show the potential of the analysis of metabarcoding data with evolutionary approaches for systematic and phylogeographic studies of marine protists.
Interspecies bacterial competition regulates community assembly in the C. elegans intestine
Authors: Ortiz Anthony , Vega Nicole M , Ratzke Christoph , Gore Jeff 
Published: February 2021

Abstract
From insects to mammals, a large variety of animals hold in their intestines complex bacterial communities that play an important role in health and disease. To further our understanding of how intestinal bacterial communities assemble and function, we study the C. elegans microbiota with a bottom-up approach by feeding this nematode with bacterial monocultures as well as mixtures of two to eight bacterial species. We find that bacteria colonizing well in monoculture do not always do well in co-cultures due to interspecies bacterial interactions. Moreover, as community diversity increases, the ability to colonize the worm gut in monoculture becomes less important than interspecies interactions for determining community assembly. To explore the role of host–microbe adaptation, we compare bacteria isolated from C. elegans intestines and non-native isolates, and we find that the success of colonization is determined more by a species’ taxonomy than by the isolation source. Lastly, by comparing the assembled microbiotas in two C. elegans mutants, we find that innate immunity via the p38 MAPK pathway decreases bacterial abundances yet has little influence on microbiota composition. These results highlight that bacterial interspecies interactions, more so than host–microbe adaptation or gut environmental filtering, play a dominant role in the assembly of the C. elegans microbiota.
Balance between promiscuity and specificity in phage λ host range
Authors: Andrews Bryan , Fields Stanley 
Published: February 2021

Abstract
As hosts acquire resistance to viruses, viruses must overcome that resistance to re-establish infectivity, or go extinct. Despite the significant hurdles associated with adapting to a resistant host, viruses are evolutionarily successful and maintain stable coevolutionary relationships with their hosts. To investigate the factors underlying how pathogens adapt to their hosts, we performed a deep mutational scan of the region of the λ tail fiber tip protein that mediates contact with the receptor on λ’s host, Escherichia coli. Phages harboring amino acid substitutions were subjected to selection for infectivity on wild type E. coli, revealing a highly restrictive fitness landscape, in which most substitutions completely abrogate function. A subset of positions that are tolerant of mutation in this assay, but diverse over evolutionary time, are associated with host range expansion. Imposing selection for phage infectivity on three λ-resistant hosts, each harboring a different missense mutation in the λ receptor, reveals hundreds of adaptive variants in λ. We distinguish λ variants that confer promiscuity, a general ability to overcome host resistance, from those that drive host-specific infectivity. Both processes may be important in driving adaptation to a novel host.
Identification of a long non-coding RNA regulator of liver carcinoma cell survival
Authors: Rybakova Yulia , Gonzalez John T. , Bogorad Roman , Chauhan Vikash P. , Dong Yize L. , Whittaker Charles A. , Zatsepin Timofei , Koteliansky Victor , Anderson Daniel G. 
Published: February 2021

AbstractGenomic studies have significantly improved our understanding of hepatocellular carcinoma (HCC) biology and have led to the discovery of multiple protein-coding genes driving hepatocarcinogenesis. In addition, these studies have identified thousands of new non-coding transcripts deregulated in HCC. We hypothesize that some of these transcripts may be involved in disease progression. Long non-coding RNAs are a large class of non-coding transcripts which participate in the regulation of virtually all cellular functions. However, a majority of lncRNAs remain dramatically understudied. Here, we applied a pooled shRNA-based screen to identify lncRNAs essential for HCC cell survival. We validated our screening results using RNAi, CRISPRi, and antisense oligonucleotides. We found a lncRNA, termed ASTILCS, that is critical for HCC cell growth and is overexpressed in tumors from HCC patients. We demonstrated that HCC cell death upon ASTILCS knockdown is associated with apoptosis induction and downregulation of a neighboring gene, protein tyrosine kinase 2 (PTK2), a crucial protein for HCC cell survival. Taken together, our study describes a new, non-coding RNA regulator of HCC.
SChLAP1 promotes prostate cancer development through interacting with EZH2 to mediate promoter methylation modification of multiple miRNAs of chromosome 5 with a DNMT3a-feedback loop
Authors: Huang Kai , Tang Yuxin 
Published: February 2021

AbstractThis study aimed to investigate the mechanism of SChLAP1 (second chromosome locus associated with prostate-1) on microRNA expression in prostate cancer. Differential expression of lncRNAs and microRNA prostate cancer cells were predicted by informatics and confirmed by qRT-PCR. SChLAP1-interacting proteins were characterized by RNA pull-down combined with western blotting, which was verified using RIP and qPCR analysis. Then ChIP assay and DNA pull-down were used to validate the binding of DNMT3a and HEK27me3 with miRNA gene promoters. Target genes of miRNAs were bioinformatically predicted and validated by dual-luciferase reporter assays. The tumorigenicity of prostate cancer cells was assessed using the cancer cell line-based xenograft (CDX) model. We found that SChLAP1 expression was significantly elevated in prostate cancer tissues and cell lines, which was negatively correlated with miR-340 expression. SChLAP1 directly binds with EZH2 and repressed multiple miRNA expression on chromosome 5 including the miR-340-3p in prostate cancer cells through recruiting H3K27me3 to mediate promoter methylation modification of miR-340-5p/miR-143-3p/miR-145-5p to suppress gene transcription. Moreover, DNMT3a was one of the common target genes of miR-340-5p/miR-143-3p/miR-145-5p in prostate cancer cells. And SChLAP1/EZH2 could also promote prostate cancer tumor development via the interaction of microRNA-DNMT3a signaling pathways in xenograft nude mice. Altogether, our results suggest that SChLAP1 enhanced the proliferation, migration, and tumorigenicity of prostate cancer cells through interacting with EZH2 to recruit H2K27me3 and mediate promoter methylation modification of miR-340-5p/miR-143-3p/miR-145-5p with a DNMT3a-feedback loop.
TOM20-mediated transfer of Bcl2 from ER to MAM and mitochondria upon induction of apoptosis
Authors: Lalier Lisenn , Mignard Vincent , Joalland Marie-Pierre , Lanoé Didier , Cartron Pierre-François , Manon Stéphen , Vallette François M. 
Published: February 2021

AbstractIn this work, we have explored the subcellular localization of Bcl2, a major antiapoptotic protein. In U251 glioma cells, we found that Bcl2 is localized mainly in the ER and is translocated to MAM and mitochondria upon induction of apoptosis; this mitochondrial transfer was not restricted to the demonstrator cell line, even if cell-specific modulations exist. We found that the Bcl2/mitochondria interaction is controlled by TOM20, a protein that belongs to the protein import machinery of the mitochondrial outer membrane. The expression of a small domain of interaction of TOM20 with Bcl2 potentiates its anti-apoptotic properties, which suggests that the Bcl2–TOM20 interaction is proapoptotic. The role of MAM and TOM20 in Bcl2 apoptotic mitochondrial localization and function has been confirmed in a yeast model in which the ER–mitochondria encounter structure (ERMES) complex (required for MAM stability in yeast) has been disrupted. Bcl2–TOM20 interaction is thus an additional player in the control of apoptosis.
Glycogen synthase kinase 3β inhibition synergizes with PARP inhibitors through the induction of homologous recombination deficiency in colorectal cancer
Authors: Zhang Ning , Tian Yu-Nan , Zhou Li-Na , Li Meng-Zhu , Chen Hua-Dong , Song Shan-Shan , Huan Xia-Juan , Bao Xu-Bin , Zhang Ao , Miao Ze-Hong , He Jin-Xue 
Published: February 2021

AbstractMonotherapy with poly ADP-ribose polymerase (PARP) inhibitors results in a limited objective response rate (≤60% in most cases) in patients with homologous recombination repair (HRR)-deficient cancer, which suggests a high rate of resistance in this subset of patients to PARP inhibitors (PARPi). To overcome resistance to PARPi and to broaden their clinical use, we performed high-throughput screening of 99 anticancer drugs in combination with PARPi to identify potential therapeutic combinations. Here, we found that GSK3 inhibitors (GSK3i) exhibited a strong synergistic effect with PARPi in a panel of colorectal cancer (CRC) cell lines with diverse genetic backgrounds. The combination of GSK3β and PARP inhibition causes replication stress and DNA double-strand breaks, resulting in increased anaphase bridges and abnormal spindles. Mechanistically, inhibition or genetic depletion of GSK3β was found to impair the HRR of DNA and reduce the mRNA and protein level of BRCA1. Finally, we demonstrated that inhibition or depletion of GSK3β could enhance the in vivo sensitivity to simmiparib without toxicity. Our results provide a mechanistic understanding of the combination of PARP and GSK3 inhibition, and support the clinical development of this combination therapy for CRC patients.
MCT8 deficiency in a patient with a novel frameshift variant in the SLC16A2 gene
Authors: Wakabayashi Kei , Osaka Hitoshi , Kojima Karin , Imaizumi Taichi , Yamamoto Toshiyuki , Yamagata Takanori 
Published: February 2021

AbstractMCT8 deficiency is an X-linked recessive disorder. We report the case of a 2-year-old Japanese boy with MCT8 deficiency caused by a novel frameshift variant, NM_006517.5(SLC16A2_v001):c.966dup [p.(Ile323Hisfs*57)]. He presented no head control and spoke no meaningful words, indicating severe developmental delay. Although missense or in-frame mutations of SLC16A2 are usually related to milder phenotypes and later-onset pyramidal signs, loss-of-function mutations are expected to cause severe clinical symptoms.
Asymmetric opening of the homopentameric 5-HT3A serotonin receptor in lipid bilayers
Authors: Zhang Yingyi , Dijkman Patricia M. , Zou Rongfeng , Zandl-Lang Martina , Sanchez Ricardo M. , Eckhardt-Strelau Luise , Köfeler Harald , Vogel Horst , Yuan Shuguang , Kudryashev Mikhail 
Published: February 2021

AbstractPentameric ligand-gated ion channels (pLGICs) of the Cys-loop receptor family are key players in fast signal transduction throughout the nervous system. They have been shown to be modulated by the lipid environment, however the underlying mechanism is not well understood. We report three structures of the Cys-loop 5-HT3A serotonin receptor (5HT3R) reconstituted into saposin-based lipid bilayer discs: a symmetric and an asymmetric apo state, and an asymmetric agonist-bound state. In comparison to previously published 5HT3R conformations in detergent, the lipid bilayer stabilises the receptor in a more tightly packed, ‘coupled’ state, involving a cluster of highly conserved residues. In consequence, the agonist-bound receptor conformation adopts a wide-open pore capable of conducting sodium ions in unbiased molecular dynamics (MD) simulations. Taken together, we provide a structural basis for the modulation of 5HT3R by the membrane environment, and a model for asymmetric activation of the receptor.
Climate change, not human population growth, correlates with Late Quaternary megafauna declines in North America
Authors: Stewart Mathew , Carleton W. Christopher , Groucutt Huw S. 
Published: February 2021

AbstractThe disappearance of many North American megafauna at the end of the Pleistocene is a contentious topic. While the proposed causes for megafaunal extinction are varied, most researchers fall into three broad camps emphasizing human overhunting, climate change, or some combination of the two. Understanding the cause of megafaunal extinctions requires the analysis of through-time relationships between climate change and megafauna and human population dynamics. To do so, many researchers have used summed probability density functions (SPDFs) as a proxy for through-time fluctuations in human and megafauna population sizes. SPDFs, however, conflate process variation with the chronological uncertainty inherent in radiocarbon dates. Recently, a new Bayesian regression technique was developed that overcomes this problem—Radiocarbon-dated Event-Count (REC) Modelling. Here we employ REC models to test whether declines in North American megafauna species could be best explained by climate changes, increases in human population densities, or both, using the largest available database of megafauna and human radiocarbon dates. Our results suggest that there is currently no evidence for a persistent through-time relationship between human and megafauna population levels in North America. There is, however, evidence that decreases in global temperature correlated with megafauna population declines.
Biological and therapeutic implications of a unique subtype of NPM1 mutated AML
Authors: Mer Arvind Singh , Heath Emily M. , Madani Tonekaboni Seyed Ali , Dogan-Artun Nergiz , Nair Sisira Kadambat , Murison Alex , Garcia-Prat Laura , Shlush Liran , Hurren Rose , Voisin Veronique , Bader Gary D. , Nislow Corey , Rantalainen Mattias , Lehmann Soren , Gower Mark , Guidos Cynthia J. , Lupien Mathieu , Dick John E. , Minden Mark D. , Schimmer Aaron D. , Haibe-Kains Benjamin 
Published: February 2021

AbstractIn acute myeloid leukemia (AML), molecular heterogeneity across patients constitutes a major challenge for prognosis and therapy. AML with NPM1 mutation is a distinct genetic entity in the revised World Health Organization classification. However, differing patterns of co-mutation and response to therapy within this group necessitate further stratification. Here we report two distinct subtypes within NPM1 mutated AML patients, which we label as primitive and committed based on the respective presence or absence of a stem cell signature. Using gene expression (RNA-seq), epigenomic (ATAC-seq) and immunophenotyping (CyToF) analysis, we associate each subtype with specific molecular characteristics, disease differentiation state and patient survival. Using ex vivo drug sensitivity profiling, we show a differential drug response of the subtypes to specific kinase inhibitors, irrespective of the FLT3-ITD status. Differential drug responses of the primitive and committed subtype are validated in an independent AML cohort. Our results highlight heterogeneity among NPM1 mutated AML patient samples based on stemness and suggest that the addition of kinase inhibitors to the treatment of cases with the primitive signature, lacking FLT3-ITD, could have therapeutic benefit.
Bridging scales in disordered porous media by mapping molecular dynamics onto intermittent Brownian motion
Authors: Bousige Colin , Levitz Pierre , Coasne Benoit 
Published: February 2021

AbstractOwing to their complex morphology and surface, disordered nanoporous media possess a rich diffusion landscape leading to specific transport phenomena. The unique diffusion mechanisms in such solids stem from restricted pore relocation and ill-defined surface boundaries. While diffusion fundamentals in simple geometries are well-established, fluids in complex materials challenge existing frameworks. Here, we invoke the intermittent surface/pore diffusion formalism to map molecular dynamics onto random walk in disordered media. Our hierarchical strategy allows bridging microscopic/mesoscopic dynamics with parameters obtained from simple laws. The residence and relocation times – tA, tB – are shown to derive from pore size d and temperature-rescaled surface interaction ε/kBT. tA obeys a transition state theory with a barrier ~ε/kBT and a prefactor ~10−12 s corrected for pore diameter d. tB scales with d which is rationalized through a cutoff in the relocation first passage distribution. This approach provides a formalism to predict any fluid diffusion in complex media using parameters available to simple experiments.
Bistability and time crystals in long-ranged directed percolation
Authors: Pizzi Andrea , Nunnenkamp Andreas , Knolle Johannes 
Published: February 2021

AbstractStochastic processes govern the time evolution of a huge variety of realistic systems throughout the sciences. A minimal description of noisy many-particle systems within a Markovian picture and with a notion of spatial dimension is given by probabilistic cellular automata, which typically feature time-independent and short-ranged update rules. Here, we propose a simple cellular automaton with power-law interactions that gives rise to a bistable phase of long-ranged directed percolation whose long-time behaviour is not only dictated by the system dynamics, but also by the initial conditions. In the presence of a periodic modulation of the update rules, we find that the system responds with a period larger than that of the modulation for an exponentially (in system size) long time. This breaking of discrete time translation symmetry of the underlying dynamics is enabled by a self-correcting mechanism of the long-ranged interactions which compensates noise-induced imperfections. Our work thus provides a firm example of a classical discrete time crystal phase of matter and paves the way for the study of novel non-equilibrium phases in the unexplored field of driven probabilistic cellular automata.