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Deepti Diwan, Jogender Mehla, James W Nelson, Gregory J Zipfel
Controllable and reproducible animal models of aneurysmal subarachnoid hemorrhage (SAH) are crucial for the systematic study of the pathophysiology and treatment of this debilitating condition. Despite the variety of animal models of SAH currently available, attempts to translate promising therapeutic strategies from preclinical studies to humans have largely failed. This failure is likely due, at least in part, to poor replication of pathology and disabilities in these preclinical models, especially the long-term neurocognitive deficits that drive poor quality of life / return to work in SAH survivors...
April 2, 2024: Research Square
#22
Justin R Wheelock, Nicole M Long
Memory brain states may influence how we experience an event. Memory encoding and retrieval constitute neurally dissociable brain states that individuals can selectively engage based on top-down goals. To the extent that memory states linger in time - as suggested by prior behavioral work - memory states may influence not only the current experience, but also subsequent stimuli and judgments. Thus lingering memory states may have broad influences on cognition, yet this account has not been directly tested utilizing neural measures of memory states...
April 9, 2024: bioRxiv
#23
Rodrigo Romero, Tinyi Chu, Tania J González-Robles, Perianne Smith, Yubin Xie, Harmanpreet Kaur, Sara Yoder, Huiyong Zhao, Chenyi Mao, Wenfei Kang, Maria V Pulina, Kayla E Lawrence, Anuradha Gopalan, Samir Zaidi, Kwangmin Yoo, Jungmin Choi, Ning Fan, Olivia Gerstner, Wouter R Karthaus, Elisa DeStanchina, Kelly V Ruggles, Peter M K Westcott, Ronan Chaligné, Dana Pe'er, Charles L Sawyers
Lineage plasticity is a recognized hallmark of cancer progression that can shape therapy outcomes. The underlying cellular and molecular mechanisms mediating lineage plasticity remain poorly understood. Here, we describe a versatile in vivo platform to identify and interrogate the molecular determinants of neuroendocrine lineage transformation at different stages of prostate cancer progression. Adenocarcinomas reliably develop following orthotopic transplantation of primary mouse prostate organoids acutely engineered with human-relevant driver alterations (e...
April 11, 2024: bioRxiv
#24
Noor Radde, Genevieve A Mortensen, Diya Bhat, Shireen Shah, Joseph J Clements, Sean P Leonard, Matthew J McGuffie, Dennis M Mishler, Jeffrey E Barrick
Engineered DNA will slow the growth of a host cell if it redirects limiting resources or otherwise interferes with homeostasis. Populations of engineered cells can rapidly become dominated by "escape mutants" that evolve to alleviate this burden by inactivating the intended function. Synthetic biologists working with bacteria rely on genetic parts and devices encoded on plasmids, but the burden of different engineered DNA sequences is rarely characterized. We measured how 301 BioBricks on high-copy plasmids affected the growth rate of Escherichia coli ...
April 8, 2024: bioRxiv
#25
Sarah E Hickson, Jennifer L Hyde
UNLABELLED: Venezuelan equine encephalitis virus (VEEV) is a mosquito-borne +ssRNA virus belonging to the Togaviridae . VEEV is found throughout Central and South America and is responsible for periodic epidemic/epizootic outbreaks of febrile and encephalitic disease in equines and humans. Endemic/enzootic VEEV is transmitted between Culex mosquitoes and sylvatic rodents, whereas epidemic/epizootic VEEV is transmitted between mosquitoes and equids, which serve as amplification hosts during outbreaks...
April 9, 2024: bioRxiv
#26
Daniel Hui, Scott Dudek, Krzysztof Kiryluk, Theresa L Walunas, Iftikhar J Kullo, Wei-Qi Wei, Hemant K Tiwari, Josh F Peterson, Wendy K Chung, Brittney Davis, Atlas Khan, Leah Kottyan, Nita A Limdi, Qiping Feng, Megan J Puckelwartz, Chunhua Weng, Johanna L Smith, Elizabeth W Karlson, Regeneron Genetics Center, Gail P Jarvik, Marylyn D Ritchie
Apart from ancestry, personal or environmental covariates may contribute to differences in polygenic score (PGS) performance. We analyzed effects of covariate stratification and interaction on body mass index (BMI) PGS (PGS BMI ) across four cohorts of European (N=491,111) and African (N=21,612) ancestry. Stratifying on binary covariates and quintiles for continuous covariates, 18/62 covariates had significant and replicable R 2 differences among strata. Covariates with the largest differences included age, sex, blood lipids, physical activity, and alcohol consumption, with R 2 being nearly double between best and worst performing quintiles for certain covariates...
April 10, 2024: medRxiv
#27
Gabriella Rice, Olivia Farrelly, Sixia Huang, Paola Kuri, Ezra Curtis, Lisa Ohman, Ning Li, Christopher Lengner, Vivian Lee, Panteleimon Rompolas
Adult tissues with high cellular turnover require a balance between stem cell renewal and differentiation, yet the mechanisms underlying this equilibrium are unclear. The cornea exhibits a polarized lateral flow of progenitors from the peripheral stem cell niche to the center; attributed to differences in cellular fate. To identify genes that are critical for regulating the asymmetric fates of limbal stem cells and their transient amplified progeny in the central cornea, we utilized an in vivo cell cycle reporter to isolate proliferating basal cells across the anterior ocular surface epithelium and perform single-cell transcriptional analysis...
April 11, 2024: bioRxiv
#28
Heterozygous Eif4nif1 Stop Gain Mice Replicate the Primary Ovarian Insufficiency Phenotype in Women.
Mika Moriwaki, Lihua Liu, Emma R James, Neal Tolley, Ashley M O'Connora, Benjamin Emery, Kenneth Ivan Aston, Robert A Campbell, Corrine K Welt
We created the c.1286C>G stop-gain mutation found in a family with primary ovarian insufficiency (POI) at age 30 years. The Eif4enif1 C57/Bl6 transgenic mouse model contained a floxed exon 10-19 cassette with a conditional knock-in cassette containing the c.1286C>G stop-gain mutation in exon 10. The hybrid offspring of CMV- Cre mice with Eif4enif1 WT/flx mice were designated Eif4enif1 WT/ Δ for simplicity. A subset of female heterozygotes ( Eif4enif1 WT/ Δ ) had no litters. In those with litters, the final litter was earlier (5...
April 11, 2024: bioRxiv
#29
C Caggiano, M Morselli, X Qian, B Celona, M Thompson, S Wani, A Tosevska, K Taraszka, G Heuer, S Ngo, F Steyn, P Nestor, L Wallace, P McCombe, S Heggie, K Thorpe, C McElligott, G English, A Henders, R Henderson, C Lomen-Hoerth, N Wray, A McRae, M Pellegrini, F Garton, N Zaitlen
Cell-free DNA (cfDNA) is increasingly recognized as a promising biomarker candidate for disease monitoring. However, its utility in neurodegenerative diseases, like amyotrophic lateral sclerosis (ALS), remains underexplored. Existing biomarker discovery approaches are tailored to a specific disease context or are too expensive to be clinically practical. Here, we address these challenges through a new approach combining advances in molecular and computational technologies. First, we develop statistical tools to select tissue-informative DNA methylation sites relevant to a disease process of interest...
April 10, 2024: medRxiv
#30
Rajula Elango, Namrata Nilavar, Andrew G Li, Erin E Duffey, Yuning Jiang, Daniel Nguyen, Abdulkadir Abakir, Nicholas A Willis, Jonathan Houseley, Ralph Scully
Collision of a replication fork with a DNA nick is thought to generate a one-ended break, fostering genomic instability. Collision of the opposing converging fork with the nick could, in principle, form a second DNA end, enabling conservative repair by homologous recombination (HR). To study mechanisms of nickase-induced HR, we developed the Flp recombinase "step arrest" nickase in mammalian cells. Flp-nickase-induced HR entails two-ended, BRCA2/RAD51-dependent short tract gene conversion (STGC), BRCA2/RAD51-independent long tract gene conversion, and discoordinated two-ended invasions...
April 10, 2024: bioRxiv
#31
Harrison Watters, Abia Fazili, Lauren Daley, Alex Belden, T J LaGrow, Taylor Bolt, Psyche Loui, Shella Keilholz
The intrinsic dynamics of human brain activity display a recurring pattern of anti-correlated activity between the default mode network (DMN), associated with internal processing and mentation, and task positive regions, associated with externally directed attention. In human functional magnetic resonance imaging (fMRI) data, this anti-correlated pattern is detectable on the infraslow timescale (<0.1 Hz) as a quasi-periodic pattern (QPP). While the DMN is implicated in creativity and musicality in traditional time-averaged functional connectivity studies, no one has yet explored how creative training may alter dynamic spatiotemporal patterns involving the DMN such as QPPs...
April 9, 2024: bioRxiv
#32
Amjad Dabi, Daniel Schrider
Simulations are an essential tool in all areas of population genetic research, used in tasks such as the validation of theoretical analysis and the study of complex evolutionary models. Forward-in-time simulations are especially flexible, allowing for various types of natural selection, complex genetic architectures, and non-Wright-Fisher dynamics. However, their intense computational requirements can be prohibitive to simulating large populations and genomes. A popular method to alleviate this burden is to scale down the population size by some scaling factor while scaling up the mutation rate, selection coefficients, and recombination rate by the same factor...
April 18, 2024: bioRxiv
#33
Patrick M Laughlin, Kimberly Young, Giovanni Gonzalez-Gutierrez, Joseph C Y Wang, Adam Zlotnick
SARS-CoV-2 Nucleocapsid protein ( N ) is a viral structural protein that packages the 30kb genomic RNA inside virions and forms condensates within infected cells through liquid-liquid phase separation ( LLPS ). N, in both soluble and condensed forms, has accessory roles in the viral life cycle including genome replication and immunosuppression. The ability to perform these tasks depends on phase separation and its reversibility. The conditions that stabilize and destabilize N condensates and the role of N-N interactions are poorly understood...
April 11, 2024: bioRxiv
#34
Kristin M Kotewicz, Mengyun Zhang, Seongok Kim, Meghan S Martin, Atish Roy Chowdhury, Albert Tai, Rebecca A Scheck, Ralph R Isberg
The Legionella pneumophila Sde family of translocated proteins promotes host tubular endoplasmic reticulum (ER) rearrangements that are tightly linked to phosphoribosyl-ubiquitin (pR-Ub) modification of Reticulon 4 (Rtn4). Sde proteins have two additional activities of unclear relevance to the infection process: K63 linkage-specific deubiquitination and phosphoribosyl modification of polyubiquitin (pR-Ub). We show here that the deubiquitination activity (DUB) stimulates ER rearrangements while pR-Ub protects the replication vacuole from cytosolic surveillance by autophagy...
April 8, 2024: bioRxiv
#35
Ran Yang, Olivia Hunker, Marleigh Wise, Franziska Bleichert
The loading of replicative helicases constitutes an obligatory step in the assembly of DNA replication machineries. In eukaryotes, the MCM2-7 replicative helicase motor is deposited onto DNA by the origin recognition complex (ORC) and co-loader proteins as a head-to-head MCM double hexamer to license replication origins. Although extensively studied in the budding yeast model system, the mechanisms of origin licensing in higher eukaryotes remain poorly defined. Here, we use biochemical reconstitution and electron microscopy (EM) to reconstruct the human MCM loading pathway...
April 10, 2024: bioRxiv
#36
Claire D James, Rachel L Lewis, Alexis L Fakunmoju, Austin J Witt, Aya H Youssef, Xu Wang, Nabiha M Rais, Apurva Tadimari Prabhakar, Raymonde Otoa, Molly L Bristol
UNLABELLED: Currently, there are no specific antiviral therapeutic approaches targeting Human papillomaviruses (HPVs), which cause around 5% of all human cancers. Specific antiviral reagents are particularly needed for HPV-related oropharyngeal cancers (HPV + OPCs) whose incidence is increasing and for which there are no early diagnostic tools available. We and others have demonstrated that the estrogen receptor alpha (ERα) is overexpressed in HPV + OPCs, compared to HPV-negative cancers in this region, and that these elevated levels are associated with an improved disease outcome...
April 12, 2024: bioRxiv
#37
JOURNAL ARTICLE
Ottavia De Simoni, Melania Scarpa, Ignazio Castagliuolo, Astghik Stepanyan, Imerio Angriman, Andromachi Kotsafti, Camilla Nacci, Federico Scognamiglio, Silvia Negro, Antonella D'Angelo, Valentina Chiminazzo, Gianluca Businello, Cesare Ruffolo, Roberta Salmaso, Boris Franzato, Mario Gruppo, Pierluigi Pilati, Antonio Scapinello, Anna Pozza, Tommaso Stecca, Marco Massani, Ivana Cataldo, Stefano Brignola, Angelo Paolo Dei Tos, Carlotta Ceccon, Vincenza Guzzardo, Chiara Vignotto, Luca Facci, Isacco Maretto, Marco Agostini, Francesco Marchegiani, Giulia Becherucci, Maurizio Zizzo, Giovanni Bordignon, Roberto Merenda, Giovanni Pirozzolo, Alfonso Recordare, Giulia Pozza, Mario Godina, Isabella Mondi, Daunia Verdi, Corrado Da Lio, Licia Laurino, Luca Saadeh, Giorgio Rivella, Silvio Guerriero, Chiara Romiti, Giuseppe Portale, Chiara Cipollari, Ylenia Camilla Spolverato, Giulia Noaro, Roberto Cola, Salvatore Candioli, Laura Gavagna, Fabio Ricagna, Monica Ortenzi, Mario Guerrieri, Giovanni Tagliente, Monica Tomassi, Umberto Tedeschi, Beatrice Salmaso, Gianluca Buzzi, Dario Parini, Daniela Prando, Matteo Zuin, Francesca Bergamo, Vittorina Zagonel, Andrea Porzionato, Francesco Cavallin, Barbara Di Camillo, Loretta Di Cristoforo, Quoc Riccardo Bao, Salvatore Pucciarelli, Romeo Bardini, Gaya Spolverato, Matteo Fassan, Marco Scarpa
BACKGROUND: Long-term daily use of aspirin reduces incidence and mortality due to colorectal cancer (CRC). This study aimed to analyze the effect of aspirin on the tumor microenvironment, systemic immunity, and on the healthy mucosa surrounding cancer. METHODS: Patients with a diagnosis of CRC operated on from 2015 to 2019 were retrospectively analyzed (METACCRE cohort). Expression of mRNA of immune surveillance-related genes (PD-L1, CD80, CD86, HLA I, and HLA II) in CRC primary cells treated with aspirin were extracted from Gene Expression Omnibus-deposited public database (GSE76583)...
April 22, 2024: Cancer
#38
JOURNAL ARTICLE
Negar Janani, Kendra A Young, Greg Kinney, Matthew Strand, John E Hokanson, Yaning Liu, Troy Butler, Erin Austin
The genome-wide association studies (GWAS) typically use linear or logistic regression models to identify associations between phenotypes (traits) and genotypes (genetic variants) of interest. However, the use of regression with the additive assumption has potential limitations. First, the normality assumption of residuals is the one that is rarely seen in practice, and deviation from normality increases the Type-I error rate. Second, building a model based on such an assumption ignores genetic structures, like, dominant, recessive, and protective-risk cases...
April 21, 2024: Genetic Epidemiology
#39
JOURNAL ARTICLE
Seongjun Park, Boram An, SeonJoo Park
BACKGROUND: Corydalis DC., the largest genus in the family Papaveraceae, comprises > 465 species. Complete plastid genomes (plastomes) of Corydalis show evolutionary changes, including syntenic arrangements, gene losses and duplications, and IR boundary shifts. However, little is known about the evolution of the mitochondrial genome (mitogenome) in Corydalis. Both the organelle genomes and transcriptomes are needed to better understand the relationships between the patterns of evolution in mitochondrial and plastid genomes...
April 22, 2024: BMC Plant Biology
#40
JOURNAL ARTICLE
Xinru Wang, Jiankang Wang, Xianchun Xia, Xiaowan Xu, Lingli Li, Shuanghe Cao, Yuanfeng Hao, Luyan Zhang
Linkage maps are essential for genetic mapping of phenotypic traits, gene map-based cloning, and marker-assisted selection in breeding applications. Construction of a high-quality saturated map requires high-quality genotypic data on a large number of molecular markers. Errors in genotyping cannot be completely avoided, no matter what platform is used. When genotyping error reaches a threshold level, it will seriously affect the accuracy of the constructed map and the reliability of consequent genetic studies...
April 22, 2024: BMC Plant Biology
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