bluuebunny/crossref_metadata_2025_split huggingface dataset:
Local-Scale phylodynamics reveal differential community impact of SARS-CoV-2 in metropolitan US county
Authors: Paredes Miguel I. , Perofsky Amanda C. , Frisbie Lauren , Moncla Louise H. , Roychoudhury Pavitra , Xie Hong , Mohamed Bakhash Shah A. , Kong Kevin , Arnould Isabel , Nguyen Tien V. , Wendm Seffir T. , Hajian Pooneh , Ellis Sean , Mathias Patrick C. , Greninger Alexander L. , Starita Lea M. , Frazar Chris D. , Ryke Erica , Zhong Weizhi , Gamboa Luis , Threlkeld Machiko , Lee Jover , Stone Jeremy , McDermot Evan , Truong Melissa , Shendure Jay , Oltean Hanna N. , Viboud Cécile , Chu Helen , Müller Nicola F. , Bedford Trevor 
Published: December 2022

AbstractSARS-CoV-2 transmission is largely driven by heterogeneous dynamics at a local scale, leaving local health departments to design interventions with limited information. We analyzed SARS-CoV-2 genomes sampled between February 2020 and March 2022 jointly with epidemiological and cell phone mobility data to investigate fine scale spatiotemporal SARS-CoV-2 transmission dynamics in King County, Washington, a diverse, metropolitan US county. We applied an approximate structured coalescent approach to model transmission within and between North King County and South King County alongside the rate of outside introductions into the county. Our phylodynamic analyses reveal that following stay-at-home orders, the epidemic trajectories of North and South King County began to diverge. We find that South King County consistently had more reported and estimated cases, COVID-19 hospitalizations, and longer persistence of local viral transmission when compared to North King County, where viral importations from outside drove a larger proportion of new cases. Using mobility and demographic data, we also find that South King County experienced a more modest and less sustained reduction in mobility following stay-at-home orders than North King County, while also bearing more socioeconomic inequities that might contribute to a disproportionate burden of SARS-CoV-2 transmission. Overall, our findings suggest a role for local-scale phylodynamics in understanding the heterogeneous transmission landscape.One Sentence SummaryAnalysis of SARS-CoV-2 genomes in King County, Washington show that diverse areas in the same metropolitan region can have different epidemic dynamics.
Oral aspirin for preventing colorectal adenoma recurrence: a systematic review and network meta-analysis of randomized controlled trials
Authors: Hoang Khanh Dinh , Chen Jin-Hua , Huang Tsai-Wei , Kang Yi-No , Chen Chiehfeng 
Published: December 2022

AbstractColorectal adenomas have the potential of malignant transformation if left untreated. Multiple randomized controlled trials have been performed to evaluate the efficacy of aspirin in preventing colorectal adenoma recurrence in a population with a history of colorectal adenoma but not colorectal cancer, however, the relationship between aspirin dose and colorectal adenoma recurrence remains unclear. We conducted pairwise meta-analysis, meta-regression, trial sequential analysis, and network meta-analysis of all eligible studies. The ROB 2.0 tool was used to assess the risk of bias in the studies. The confidence in network meta-analysis (CINeMA) approach was used to evaluate the confidence of the network meta-analysis results. The network meta-analysis included eight RCTs (nine reports), comprising four on aspirin (low or high dose) alone and four on aspirin combined with another medication, all compared with placebo. In the network meta-analysis, low-dose aspirin (LDA <300 mg per day) was more effective than high-dose aspirin (HDA ≥300 mg per day) and placebo, with risk ratios of 0.76 (95% CI: 0.58 to 0.99) and 0.7 (95% CI: 0.54 to 0.91), respectively. LDA was the optimal treatment relative to HDA and placebo (P-score = 0.99). In the trial sequential analysis, LDA was only more effective than placebo when the number of included participants exceeded the optimal information size; this was not the case for HDA. LDA has statistically significant efficacy for colorectal adenoma prevention, but compared with HDA, its efficacy remains uncertain. Further trials are therefore required.
Multi-omics on truncatingASXL1mutations in Bohring Opitz syndrome identify dysregulation of canonical and non-canonical Wnt signaling
Authors: Lin Isabella , Wei Angela , Awamleh Zain , Singh Meghna , Ning Aileen , Herrera Analeyla , Russell Bianca , Weksberg Rosanna , Arboleda Valerie A. 
Published: December 2022

ABSTRACTASXL1(Additional sex combs-like 1) plays key roles in epigenetic regulation of early developmental gene expression.De novotruncating mutations inASXL1cause Bohring-Opitz syndrome (BOS, OMIM #605039), a rare neurodevelopmental condition characterized by severe intellectual disabilities, characteristic facial features, hypertrichosis, increased risk of Wilms tumor, and variable congenital anomalies including heart defects and severe skeletal defects giving rise to a typical ‘BOS posture’. These BOS-causingASXL1variants are also high-prevalence somatic driver mutations in acute myeloid leukemia (AML). We use primary cells from BOS individuals (n = 18) and controls (n = 49) to dissect gene regulatory changes caused byASXL1mutations using comprehensive multi-omics assays for chromatin accessibility (ATAC-seq), DNA methylation, histone methylation binding, and transcriptome in peripheral blood and skin fibroblasts. Our data shows that regardless of cell type,ASXL1mutations drive strong cross-tissue effects that disrupt multiple layers of the epigenome. The data showed a broad activation of canonical Wnt signaling at the transcriptional and protein levels and upregulation ofVANGL2, a planar cell polarity pathway protein that acts through non-canonical Wnt signaling to direct tissue patterning and cell migration. This multi-omics approach identifies the core impact ofASXL1mutations and therapeutic targets for BOS and myeloid leukemias.Brief summaryGermlineASXL1mutations that cause Bohring Optiz syndrome disrupt the epigenome and dysregulate gene expression resulting in activation of canonical and non-canonical Wnt signaling pathways.
The Kelch13 compartment is a hub of highly divergent vesicle trafficking proteins in malaria parasites
Authors: Schmidt Sabine , Wichers-Misterek Jan Stephan , Behrens Hannah Michaela , Birnbaum Jakob , Henshall Isabelle G. , Dröge Jana , Jonscher Ernst , Flemming Sven , Castro-Peña Carolina , Mesén-Ramírez Paolo , Spielmann Tobias 
Published: December 2022

ABSTRACTSingle amino acid changes in the parasite protein Kelch13 (K13) result in reduced susceptibility ofP. falciparumparasites to artemisinin and its derivatives (ART). Recent work indicated that K13 and other proteins co-localising with K13 (K13 compartment proteins) are involved in the endocytic uptake of host cell cytosol (HCCU) and that a reduction in HCCU results in ART resistance. HCCU is critical for parasite survival but is poorly understood, with the K13 compartment proteins among the few proteins so far functionally linked to this process. Here we further defined the composition of the K13 compartment by analysing more hits from a previous BioID, showing that MyoF and MCA2 as well as Kelch13 interaction candidate (KIC) 11 and 12 are found at this site. Functional analyses, tests for ART susceptibility as well as comparisons of structural similarities using AlphaFold2 predictions of these and previously identified proteins showed that canonical vesicle trafficking and endocytosis domains were frequent in proteins involved in resistance or endocytosis (or both), comprising one group of K13 compartment proteins. While this strengthened the link of the K13 compartment to endocytosis, many proteins of this group showed unusual domain combinations and large parasite-specific regions, indicating a high level of taxon-specific adaptation of this process. Another group of K13 compartment proteins did not influence endocytosis or ART susceptibility and lacked detectable vesicle trafficking domains. We here identified the first protein of this group that is important for asexual blood stage development and showed that it likely is involved in invasion. Overall, this work identified novel proteins functioning in endocytosis and at the K13 compartment. Together with comparisons of structural predictions it provides a repertoire of functional domains at the K13 compartment that indicate a high level of adaption of endocytosis in malaria parasites.
Cytidine deaminase regulates mitochondrial biogenesis in pancreatic cancer cells
Authors: Frances Audrey , Lumeau Audrey , Stuani Lucille , Gayral Marion , Saland Estelle , Bery Nicolas , Pagan Delphine , Hanoun Naima , Torrisani Jérôme , Lemarié Anthony , Portais Jean-Charles , Buscail Louis , Dusetti Nelson , Sarry Jean-Emmanuel , Cordelier Pierre 
Published: December 2022

ABSTRACTDespite tremendous efforts from the scientific community, pancreatic ductal adenocarcinoma (PDAC) is still a deadly disease and will soon become the second cause of death by cancer worldwide1. When surgery is not possible, therapeutic options are few and ineffective2. Patients are most often treated with Folfirinox or gemcitabine chemotherapy, that extends survival in weeks to months. Cytidine deaminase (CDA) catalyzes the irreversible hydrolytic deamination of cytidine and deoxycytidine to uridine and deoxyuridine to fuel RNA and DNA synthesis3. CDA also deaminates and neutralizes deoxycytidine-based therapies, and as such, has been identified as a major contributor of tumor chemoresistance, especially to gemcitabine in PDAC3. We previously identified that CDA is elevated in PDAC tumors at diagnosis and that CDA exerts an unexpected role on DNA replication that can be exploited for therapeutic intervention4. Very recently, CDA was associated with cellular metabolism5. Here, we show that CDA promotes mitochondrial biogenesis and oxidative phosphorylation independently of its deaminase activity. This uncloaks novel therapeutic vulnerabilities in primary cancer cells that overexpress this protein. This study shines a new light on the tumoral potential of CDA in PDAC.
Discovery and remodeling ofVibrio natriegensas a microbial platform for efficient formic acid biorefinery
Authors: Tian Jinzhong , Deng Wangshuying , Zhang Ziwen , Xu Jiaqi , Zhao Guoping , Yang Sheng , Jiang Weihong , Gu Yang 
Published: December 2022

AbstractFormic acid (FA), an organic one-carbon source that is easily produced from CO2, has emerged as a promising CO2-equivalent feedstock for one-carbon biorefinery. However, developing efficient formatotrophs for an economically competitive FA utilization system remains a grand challenge. Here, we discovered that the gram-negative bacteriumVibrio natriegenshas exceptional FA tolerance and metabolic capacity natively. This strain was then remodeled by rewiring the serine cycle and the TCA cycle which resulted in a non-native closed loop (S-TCA) for enhancing FA assimilation. The rational design generated a powerful metabolic sink that enabled rapid emergence of the evolved strains with further significantly improved performance in using FA as the major or sole carbon source. Furthermore, the introduction of a foreign indigoidine-forming pathway into the best-performingV. natriegensstrain (S-TCA-2.0) led to production of 29.0 g·L-1indigoidine and consumption of 233.7 g·L-1formate within 72 h, achieving an order of magnitude higher formate consumption rate (3.2 g·L-1·h-1) than the reported highest level in microorganisms. This work represents a significant step towards the development of industrially viable microorganisms for FA biorefinery.
Encoding social preference by interhemispheric neurons in the Insula
Authors: Glangetas Christelle , Ladevèze Elodie , Guillaumin Adriane , Gauthier Manon , Doudnikoff Evelyne , Bézard Erwan , Taupignon Anne , Baufreton Jérôme , Georges François 
Published: December 2022

AbstractThe Insula is a multisensory relay that participates in socio-emotional processing through multiple projections to sensory, cognitive, emotional, and motivational regions. Interestingly, the Insula interhemispheric projection to the contralateral Insula is a strong but understudied projection. Using cutting-edge neuroanatomy,ex vivoandin vivoelectrophysiology associated with specific circuit manipulation, we unraveled the nature and role of Insula interhemispheric communication in social and anxiety processing in mice. In this study, we 1) characterized the anatomical and molecular profile of the interhemispheric neurons of the Insula, 2) highlighted that stimulation of this neuronal subpopulation triggers excitation in the Insula interhemispheric circuit 3) uncovered their engagement in social processing. In conclusion, this study demonstrates that interhemispheric neurons of the Insula constitute a unique class of Insula neurons and proposes new meaningful insights into the neuronal mechanisms underlying social behavior.
Heterologous expression ofPtAAS1reveals the metabolic potential of the common plant metabolite phenylacetaldehyde for auxin synthesisin planta
Authors: Günther Jan , Halitschke Rayko , Gershenzon Jonathan , Burow Meike 
Published: December 2022

AbstractAromatic aldehydes and amines are common plant metabolites involved in several specialized metabolite biosynthesis pathways. Recently, we showed that the aromatic aldehyde synthase PtAAS1 and the aromatic amino acid decarboxylase PtAADC1 contribute to the herbivory-induced formation of volatile 2-phenylethanol and its glucoside 2-phenylethyl-β-D-glucopyranoside inPopulus trichocarpa. To gain insights into alternative metabolic fates of phenylacetaldehyde and 2-phenylethylamine beyond alcohol and alcohol glucoside formation, we expressedPtAAS1andPtAADC1heterologously inNicotiana benthamianaand analyzed plant extracts using untargeted LC-qTOF-MS analysis. While the metabolomes ofPtAADC1-expressing plants did not significantly differ from those of control plants, expression ofPtAAS1resulted in the accumulation of phenylacetic acid (PAA) and PAA-amino acid conjugates, identified as PAA-aspartate and PAA-glutamate. Moreover, targeted LC-MS/MS analysis showed thatPtAAS1-expressing plants accumulated significant amounts of free PAA. The measurement of PAA and PAA-Asp in undamaged and herbivory-damaged poplar leaves revealed significantly induced accumulation of PAA-Asp while levels of free PAA remained unaltered by herbivore treatment. Sequence comparisons and transcriptome analysis showed that members of a small gene family comprising five putative auxin-amido synthetaseGH3genes potentially involved in the conjugation of auxins like PAA with amino acids were significantly upregulated upon herbivory inP. trichocarpaleaves. Overall, our data indicates that phenylacetaldehyde generated by poplar PtAAS1 serves as a hub metabolite linking the biosynthesis of volatile, non-volatile herbivory-induced specialized metabolites, and phytohormones, suggesting that growth and defense are balanced on a metabolic level.
Restriction-modification systems have shaped the evolution and distribution of plasmids across bacteria
Authors: Shaw Liam P. , Rocha Eduardo P. C. , MacLean R. Craig 
Published: December 2022

AbstractMany novel traits such as antibiotic resistance are spread by plasmids between species. Yet plasmids have different host ranges. Restriction-modification systems (R-M systems) are by far the most abundant bacterial defense system and therefore represent one of the key barriers to plasmid spread. However, their effect on plasmid evolution and host range has been neglected. Here we analyse the avoidance of targets of the most abundant R-M systems (Type II) for complete genomes and plasmids across bacterial diversity. For the most common target length (6 bp) we show that target avoidance is strongly correlated with the taxonomic distribution of R-M systems and is greater in plasmid genes than core genes. We find stronger avoidance of R-M targets in plasmids which are smaller and have a broader host range. Our results suggest two different evolutionary strategies for plasmids: small plasmids primarily adapt to R-M systems by tuning their sequence composition, and large plasmids primarily adapt through the carriage of additional genes protecting from restriction. Our work provides systematic evidence that R-M systems are important barriers to plasmid transfer and have left their mark on plasmids over long evolutionary time.
Stabilization of V1 interneuron-motor neuron connectivity ameliorates motor phenotype in a mouse model of ALS
Authors: Mora Santiago , von Huth Friis Rasmus , Stuckert Anna , Noes-Holt Gith , Montañana-Rosell Roser , Sørensen Andreas Toft , Selvan Raghavendra , Allodi Ilary 
Published: December 2022

AbstractLoss of connectivity between spinal V1 inhibitory inter-neurons and motor neurons is found early in disease in the SOD1G93AALS mice. Such changes in premotor inputs can contribute to homeostatic imbalance of vulnerable motor neurons. Here, we show, for the first time, that stabilization of V1 synapses by overexpression of the Extended Synap-totagmin 1 presynaptic organizer increases motor neuron survival and ameliorates motor phenotypes, demonstrating that interneurons can be a potential target to attenuate ALS symptoms.
Single-step genome-wide association study for susceptibility toTeratosphaeria nubilosaand precocity of vegetative phase change inEucalyptus globulus
Authors: Quezada Marianella , Giorello Facundo , Da Silva Cecilia , Aguilar Ignacio , Balmelli Gustavo 
Published: December 2022

AbstractMycosphaerella leaf disease (MLD) is one of the most prevalent foliar diseases ofE. globulusplantations around the world. Since resistance management strategies have not been effective in commercial plantations, breeding to develop more resistant genotypes is the most promising strategy. Available genomic information can be used to detect genomic regions associated with resistance to MLD, which could significantly speed up the process of genetic improvement. In this study, we investigated the genetic basis of MLD resistance in a breeding population ofE. globuluswhich was genotyped with the EUChip60K SNP array. Resistance to MLD was evaluated for resistance of the juvenile foliage, as defoliation and leaf spot severity, and for precocity of change to resistant adult foliage. Genome-wide association studies (GWAS) were carried out applying four Single-SNP models, a Genomic Best Linear Unbiased Prediction (GBLUP-GWAS) approach, and a Single-step genome-wide association study (ssGWAS). The Single-SNP and GBLUP-GWAS models detected 13 and 16 SNP-trait associations in chromosomes 2, 3 y 11; whereas the ssGWAS detected 66 SNP-trait associations in the same chromosomes, and additional significant SNP-trait associations in chromosomes 5 to 9 for the precocity of phase change (proportion of adult foliage). For this trait, the two main regions in chromosomes 3 and 11 were identified for the three approaches. The SNPs identified in these regions were positioned near the key miRNA genes,miR156.5andmiR157.4, which have a main role in the regulation of the timing of vegetative change, and also in the response to environmental stresses in plants. Our results outlined that ssG-WAS was more powerful in detecting regions that affect resistance than conventional GWAS approaches. Additionally, suggest a polygenic genetic architecture for the heteroblastic transition inE. globulusand identified useful SNP markers for the development of marker-assisted selection strategies for resistance.
Co-occurring mutations in the POLE exonuclease and non-exonuclease domains define a unique subset of highly mutagenic tumors
Authors: Shah Shreya M. , Demidova Elena V. , Ringenbach Salena , Faezov Bulat , Andrake Mark , Mur Pilar , Viana-Errasti Julen , Xiu Joanne , Swensen Jeffrey , Valle Laura , Dunbrack Roland L. , Hall Michael J. , Arora Sanjeevani 
Published: December 2022

AbstractSomaticPOLEmutations in the exonuclease domain (ExoD) are prevalent in colorectal cancer (CRC), endometrial cancer (EC), and others and typically lead to dramatically increased tumor mutation burden (TMB). To understand whether non-ExoD mutations also play a role in mutagenesis, we assessed TMB in 447/14541POLE-mutated CRCs, ECs, and ovarian cancers (OC) based on classification TMB-High (TMB-H) or TMB-Low (TMB-L). TMB-H tumors were segregated as ‘POLEExoD driver’, ‘POLEExoD driver plusPOLEVariant’, and ‘POLEVariant TMB-H’. Intriguingly, TMB was highest in tumors bearing ‘POLEExoD driver plusPOLEVariant’ (p<0.001 in CRC and EC, p<0.05 in OC). Integrated analysis of AlphaFold2-modeled POLE models and quantitative estimate of stability indicated that multiple variants had significant impact on functionality. These data indicate that co-occurringPOLEvariants categorize a unique subset ofPOLE-driven tumors defined by ultra-high TMB, which has implications for abundance of tumor neoantigens, therapeutic response, and patient outcomes.SignificanceSomaticPOLEExoD driver mutations cause proofreading deficiency that induces high tumor mutation burden (TMB). This study defines a novel modifier role for non-ExoD mutations inPOLEExoD-driven tumors, associated with ultra-high TMB. These data may inform acquisition of tumor neoantigens, tumor classification, therapeutic response, and patient outcomes.
Cell non-autonomous control of autophagy and metabolism by glial cells
Authors: Metcalf Melissa G. , Monshietehadi Samira , Sahay Arushi , Frakes Ashley E. , Durieux Jenni , Velichkovska Martina , Mena Cesar , Farinas Amelia , Sanchez Melissa , Dillin Andrew 
Published: December 2022

SUMMARYGlia are the protectors of the nervous system, providing neurons with support and protection from cytotoxic insults. We previously discovered that four astrocyte-like glia can regulate organismal proteostasis and longevity inC. elegans. Expression of the UPRERtranscription factor, XBP-1s, in these glia increases stress resistance, longevity, and activates the UPRERin intestinal cells via neuropeptides. Autophagy, a key regulator of metabolism and aging, has been described as a cell autonomous process. Surprisingly, we find that glial XBP-1s enhances proteostasis and longevity by cell non-autonomously reprogramming organismal lipid metabolism and activating autophagy. Glial XBP-1s regulates the activation of another transcription factor, HLH-30/TFEB, in the intestine. HLH-30 activates intestinal autophagy, increases intestinal lipid catabolism, and upregulates a robust transcriptional program. Our study reveals a novel role for glia in regulating peripheral lipid metabolism, autophagy, and organellar health through peripheral activation of HLH-30 and autophagy.