bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hypomethylation of miR-17-92 cluster in lupus T cells and no significant role for genetic factors in the lupus-associated DNA methylation signature
Authors: Coit Patrick , Roopnarinesingh Xiavan , Ortiz-Fernandez Lourdes , Maksimowicz-McKinnon Kathleen , Lewis Emily E. , Merrill Joan T. , McCune W. Joseph , Wren Jonathan D. , Sawalha Amr H. 
Published: February 2022

AbstractObjectivesEpigenetic dysregulation plays an important role in the pathogenesis of lupus, a systemic autoimmune disease characterized by autoantibody production. Lupus T cells demonstrate aberrant DNA methylation patterns dominated by hypomethylation of interferon-regulated genes. The objective of this study was to identify additional disease-associated DNA methylation changes in naïve CD4+ T cells from an extended cohort of lupus patients and determine the genetic contribution to epigenetic changes characteristic of lupus.MethodsGenome-wide DNA methylation was assessed in naïve CD4+ T cells isolated from a cohort of 74 lupus patients and 74 age-, sex-, and race-matched healthy controls. We applied a trend deviation analysis approach, comparing methylation data in our cohort to methylation data from over 16,500 samples to characterize lupus-associated DNA methylation patterns. Methylation quantitative trait loci (meQTL) analysis was used to determine genetic contribution to lupus-associated DNA methylation changes.ResultsIn addition to the previously reported epigenetic signature in interferon-regulated genes, we observed hypomethylation of the promoter regions of microRNA (miRNA) genes in the miR-17-92 cluster in lupus patients. Members of this miRNA cluster play an important role in regulating T cell proliferation and differentiation. Expression of two miRNAs within this cluster, miR-19b1 and miR-18a, showed a significant positive correlation with disease activity in lupus patients. meQTL were identified by integrating genome-wide DNA methylation profiles with genotyping data in lupus patients and controls. Patient meQTL show overlap with genetic risk loci for lupus. However, less than 1% of differentially methylated CpG sites in lupus patients were associated with an meQTL, suggesting minimal genetic contribution to lupus-associated epigenotypes.ConclusionThe lupus defining epigenetic signature, characterized by robust hypomethylation of interferon-regulated genes, does not appear to be determined by genetic factors. Hypomethylation of the miR-17-92 cluster that plays an important role in T cell activation is a novel epigenetic locus for lupus.
Prepronociceptin-expressing neurons in the extended amygdala signal darting away from an aversive odor
Authors: Ung Randall L. , Ortiz-Juza Maria M. , Curtis Vincent R. , Alghorazi Rizk A. , Velazquez-Hernandez Geronimo , Ring Ayden , Garcia-Reyes Ruben A. , Stuber Garret D. , Zhou Pengcheng , Kato Hiroyuki K. , Pégard Nicolas C. , Rodriguez-Romaguera Jose 
Published: February 2022

ABSTRACTDysregulation in the neural circuitry that encodes physiological arousal responses is thought to contribute to the manifestation of the maladaptive behaviors observed in neuropsychiatric disorders. We previously found that prepronociceptin-expressing neurons in the bed nucleus of the stria terminalis (PnocBNST neurons) modulate rapid changes in physiological arousal upon presentation of motivationally salient stimuli (Rodriguez-Romaguera et al., 2020). However, whether PnocBNST neurons are necessary to regulate behavioral actions to motivationally salient stimuli is still unknown. Here, we investigated the role of PnocBNST neurons in encoding behavioral responses to motivationally salient stimuli using in vivo calcium imaging and optogenetic approaches in freely behaving mice. We find that the bulk activity of PnocBNST neurons increases when mice are near an aversive odor in comparison to a rewarding odor. However, optogenetic inhibition of PnocBNST neurons does not affect the amount of time mice spend near an aversive odor. Further analysis revealed that a subgroup of PnocBNST neurons that correlate with proximity to the aversive odor also correlate to darting away from the same aversive odor. Since these two behaviors are opposite to each other and since we previously found PnocBNST neurons correlate with arousal responses, we believe these results may be due in part to the encoding of arousal responses that occur when mice approach and dart away from aversive stimuli.
Honey bees change the microbiota of pollen
Authors: Prado Alberto , Barret Matthieu , Vaissière Bernard E. , Torres-Cortes Gloria 
Published: February 2022

AbstractPollen, as all other plant tissues, harbors different microorganisms. As honey bees (Apis mellifera) collect and pack pollen they add regurgitated nectar to moisten and glue the pollen grains, possibly changing the microbial composition. In this study, we compared the microbiota of cleanBrassica napuspollen with that of bee-worked corbicular pollen. We found that by working pollen, bees increase the bacterial diversity of pollen, by adding honey bee symbionts such asBombella, Frischella, GilliamellaandSnodgrassella, bee pathogens asSpiroplasmaand nectar dwellingLactobacillusto the new pollen microbiota. The bee gut is an important source of inoculum of the corbicular pollen microbiota. We discuss the implications of these findings and propose future research avenues.
Antibacterial effects of propolis and brood comb extracts on the causative agent of European Foulbrood (Melissococcus plutonius) in honey bees (Apis mellifera)
Authors: Murray Stephanie K. , Kurkul Colin M. , Mularo Andrew J. , Hale Vanessa L. , Adams Rachelle M. M. , Johnson Reed M. 
Published: February 2022

AbstractAmong a long list of parasites and pathogens that threaten the European honey bee (Apis mellifera), European Foulbrood (EFB) has become an urgent apiary disease, as epidemic outbreaks are becoming increasingly common. EFB is a bacterial disease of larval honey bees, caused by a gram-positive, anaerobic bacterium,Melissococcus plutonius. The most effective current treatment for EFB, oxytetracycline hydrochloride, can disrupt the bee microbiome, cause bee mortality and residues may persist in honey harvested for human consumption. In this study, we explore the efficacy of more sustainable bee-derived solutions, including propolis, honey comb and brood comb ethanol extracts. Using a series of dilutions of these extracts, we determined the minimum inhibitory concertation (MIC) of each bee-derived product onM. plutonius, as well as two model bacterial species,Staphylococcus saprophyticus(gram-positive) andEscherichia coli(gram-negative). Overall, we found that propolis extract was most effective at inhibiting growth of gram-positive bacteria, and thatM. plutoniouswas also susceptible to honey comb (MIC = 16.00 mg/mL) and brood comb (MIC = 45.33 mg/mL) extracts, but at much higher concentrations than that of propolis (MIC = 1.14 mg/mL).
Different transcriptional responses by the CRISPRa system in distinct types of heterochromatin in Drosophila melanogaster
Authors: Ortega-Yáñez Andrea , Cruz-Ruiz Samantha , Vázquez Martha , Zurita Mario 
Published: February 2022

AbstractTranscription factors (TFs) activate gene expression by binding to elements close to promoters or enhancers. Some TFs can bind to heterochromatic regions to initiate gene activation, suggesting that if a TF is able to bind to any type of heterochromatin, it can activate transcription. To investigate this possibility, we used the CRISPRa system based on dCas9-VPR as an artificial TF in Drosophila. dCas9-VPR was targeted to the TAHRE subtelomeric element, an example of constitutive heterochromatin, and to promoters and enhancers of the HOX Ultrabithorax (Ubx) and Sex Combs Reduced (Scr) genes in the context of facultative heterochromatin. dCas9-VPR robustly activated TAHRE transcription, showing that although this element is heterochromatic, dCas9-VPR was sufficient to activate its expression. In the case of HOX gene promoters, although these genes are epigenetically silenced by Polycomb complexes, both were ectopically activated. When the artificial TF was directed to enhancers, we found that the expression pattern was different compared to the effect on the promoters. In the case of the Scr upstream enhancer, dCas9-VPR activated the gene ectopically but with less expressivity; however, ectopic activation also occurred in different cells. In the case of the bxI enhancer located in the third intron of Ubx, the presence of dCas9-VPR is capable of increasing transcription initiation while simultaneously blocking transcription elongation, generating a lack of functional phenotype. Our results show that transcription can be activated in any type of heterochromatin by CRISPRa; nevertheless, its effect on transcription is subject to the intrinsic characteristics of each gene or regulatory element.SignificanceWhether transcription only depends on activating factors binding to chromatin, even though it is found in a silent state as heterochromatin, remains an open question. In this work, we addressed this question using the CRISPRa system via dCas9-VPR as a synthetic transcriptional activator in Drosophila. This activator was directed to a constitutive heterochromatin element and to promoters and enhancers of two HOX genes, which in the tissues where they are not expressed, are present as facultative heterochromatin. In all cases, the CRISPRa system was able to activate transcription, showing that its sole presence is sufficient for this to occur. Although transcription in constitutive heterochromatin was very robust, in the case of promoters and enhancers of HOX genes, the degree of expressivity, penetrance and ectopic effect was different between promoters and enhancers. These results indicate that the presence of a synthetic activator can activate transcription by binding to transcriptional regulatory elements; however, its effect depends on the particular characteristics of each one. These results show how artificial transcription factors can be used to understand transcription regulation at the organismal level.
period Translation as a Core Mechanism Controlling Temperature Compensation in an Animal Circadian Clock
Authors: Itoh Taichi Q. , Yildirim Evrim , Surabhi Satya , Braun Rosemary , Allada Ravi 
Published: February 2022

AbstractThe most enigmatic of the canonical properties of circadian clocks is temperature compensation where circadian period length is stable across a wide temperature range despite the temperature dependence of most biochemical reactions. While the core mechanisms of circadian clocks have been well described, the molecular mechanisms of temperature compensation are poorly understood especially in animals. A major gap is the lack of temperature compensation mutants that do not themselves unambiguously affect the temperature dependence of the encoded protein. Here we show that null alleles of two genes encoding components of a complex important for translation of the core clock component period in circadian pacemaker neurons robustly alter the temperature dependence of circadian behavioral period length. These changes are accompanied by parallel temperature dependent changes in oscillations of the PER protein and are consistent with the model that these translation factors mediate the temperature-dependence of PER translation. Consistent with findings from modeling studies, we find that translation of the key negative feedback factor PER plays an instrumental role in temperature compensation.
Using a transection paradigm to enhance the repair mechanisms of an investigational human cell therapy
Authors: Chau Monica J. , Quintero Jorge E. , Monje Paula V. , Voss S. Randal , Welleford Andrew S. , Gerhardt Greg A. , van Horne Craig 
Published: February 2022

AbstractOne promising strategy in cell therapies for Parkinson’s Disease (PD) is to harness a patient’s own cells to provide neuroprotection in areas of the brain affected by neurodegeneration. No treatment exists to replace cells in the brain. Thus, our goal has been to support sick neurons and slow neurodegeneration by transplanting living repair tissue from the peripheral nervous system into the substantia nigra of those with PD. Our group has pioneered the transplantation of transection-activated sural nerve fascicles into the brain of human subjects with PD. Our experience in sural nerve transplantation through FDA-regulated clinical trials has supported the safety and feasibility of this approach. We are among the first to collect human sural nerve both before and after transection and to perform single nuclei RNA sequencing to determine the cell types present. We collected nerve tissue before and approximately 2 weeks after sural nerve transection for immunoassays from 15 participants, and collected from two additional participants for single nuclei RNA sequencing. We quantified the expression of key neuroprotective and anti-apoptotic genes along with their corresponding protein levels using immunoassays. The single nuclei data clustered into 10 distinctive groups defined on the basis of previously published cell type-specific genes. Transection-induced reparative peripheral nerve tissue showed RNA expression of neuroprotective factors and anti-apoptotic factors across multiple cell types after nerve injury induction. Key proteins of interest (BDNF, GDNF, beta-NGF, PDGFB, and VEGF) were significantly upregulated in reparative tissue compared to naïve. These results provide insight on this repair tissue’s utility as a neuroprotective cell therapy.Clinical TrialClinicaltrials.gov (Trial registration number NCT02369003)https://clinicaltrials.gov/ct2/show/NCT02369003).
SKOR1 mediates FER kinase-dependent invasive growth of breast cancer cells
Authors: Sluimer Lilian , Bullock Esme , Rätze Max , Enserink Lotte , Overbeeke Celine , Hornsveld Marten , Brunton Valerie G. , Derksen Patrick W.B. , Tavares Sandra 
Published: February 2022

AbstractHigh expression of the tyrosine kinase FER is an independent prognostic factor that correlates with poor survival in breast cancer patients. To investigate whether the kinase activity is essential for FER oncogenic properties, we developed an ATP analogue-sensitive knock-in allele (FERASKI). Specific FER kinase inhibition in MDA-MD-231 cells reduces migration, invasion, and metastasis in a mouse model of breast cancer. Using the FERASKI system, we identify SKI family transcriptional corepressor 1 (SKOR1) as a direct FER kinase substrate. SKOR1 loss phenocopies FER inhibition, leading to impaired proliferation, migration and invasion, and inhibition of breast cancer growth and metastasis formation in mice. We show that the candidate FER phosphorylation residue, SKOR1-Y234, is essential for FER-dependent tumor progression features. Finally, our work suggests that the SKOR1-Y234 residue promotes Smad2/3 signaling through SKOR1 binding to Smad3 attenuation.Our study thus identifies SKOR1 as a mediator of FER-dependent breast cancer progression, advocating FER kinase inhibition as a candidate strategy to treat high-grade breast cancers.SummaryThe SKI FAMILY TRANSCRIPTIONAL COREPRESSOR 1 (SKOR1) has been mainly associated with neuronal development. Now, Sluimer et al. identify SKOR1 as a new substrate of the oncogenic tyrosine kinase FER, and a driver of TNBC progression.
Complete sequence of a 641-kb insertion of mitochondrial DNA in the Arabidopsis thaliana nuclear genome
Authors: Fields Peter D. , Waneka Gus , Naish Matthew , Schatz Michael C. , Henderson Ian R. , Sloan Daniel B. 
Published: February 2022

ABSTRACTIntracellular transfers of mitochondrial DNA continue to shape nuclear genomes. Chromosome 2 of the model plant Arabidopsis thaliana contains one of the largest known nuclear insertions of mitochondrial DNA (numts). Estimated at over 600 kb in size, this numt is larger than the entire Arabidopsis mitochondrial genome. The primary Arabidopsis nuclear reference genome contains less than half of the numt because of its structural complexity and repetitiveness. Recent datasets generated with improved long-read sequencing technologies (PacBio HiFi) provide an opportunity to finally determine the accurate sequence and structure of this numt. We performed a de novo assembly using sequencing data from recent initiatives to span the Arabidopsis centromeres, producing a gap-free sequence of the Chromosome 2 numt, which is 641-kb in length and has 99.933% nucleotide sequence identity with the actual mitochondrial genome. The numt assembly is consistent with the repetitive structure previously predicted from fiber-based fluorescent in situ hybridization. Nanopore sequencing data indicate that the numt has high levels of cytosine methylation, helping to explain its biased spectrum of nucleotide sequence divergence and supporting previous inferences that it is transcriptionally inactive. The original numt insertion appears to have involved multiple mitochondrial DNA copies with alternative structures that subsequently underwent an additional duplication event within the nuclear genome. This work provides insights into numt evolution, addresses one of the last unresolved regions of the Arabidopsis reference genome, and represents a resource for distinguishing between highly similar numt and mitochondrial sequences in studies of transcription, epigenetic modifications, and de novo mutations.Significance statementNuclear genomes are riddled with insertions of mitochondrial DNA. The model plant Arabidopsis has one of largest of these insertions ever identified, which at over 600-kb in size represents one of the last unresolved regions in the Arabidopsis genome more than 20 years after the insertion was first identified. This study reports the complete sequence of this region, providing insights into the origins and subsequent evolution of the mitochondrial DNA insertion and a resource for distinguishing between the actual mitochondrial genome and this nuclear copy in functional studies.
Characterization of Arabian Peninsula whole exomes: exploring high inbreeding features
Authors: Ferreira Joana C. , Alshamali Farida , Pereira Luisa , Fernandes Veronica 
Published: February 2022

AbstractThe exome (WES) capture enriched for UTRs on 90 Arabian Peninsula (AP) populations contributed nearly 20,000 new variants from a total over 145,000 total variants. Almost half of these variants were in UTR3, reflecting the low effort we have dedicated to cataloguing these regions, which can bear an important proportion of functional variants, as being discovered in genome-wide association studies. By applying several pathogenic predicting tools, we have demonstrated the high burden in potentially deleterious variants (especially in nonsynonymous and UTR variants located in genes that have been associated mainly with neurologic disease and congenital malformations) contained in AP WES, and the burden was as high as the consanguinity level (inferred as sum of runs of homozygosity, SROH) increased. Arabians had twice SROH values in relation to Europeans and East Asians, and within AP, Saudi Arabia had the highest values and Oman the lowest. We must pursuit cataloguing diversity in populations with high consanguinity, as the potentially pathogenic variants are not eliminated by genetic drift as much as in less consanguineous populations.
Dynamic Sex Differences in Appetitive and Reactive Aggression
Authors: Aubry Antonio , Burnett C. Joseph , Goodwin Nastacia L. , Li Long , Navarrete Jovana , Zhang Yizhe , Tsai Valerie , Durand-de Cuttoli Romain , Golden Sam A. , Russo Scott J. 
Published: February 2022

AbstractAggression is an evolutionarily conserved, adaptive component of social behavior. Studies in male mice illustrate that aggression is influenced by numerous factors including the degree to which an individual finds aggression rewarding and will work for access to attack and subordinate mice. While such studies have expanded our understanding of the molecular and circuit mechanisms of male aggression very little is known about female aggression, owed in part to limited availability of valid mouse models in females. Here we use an ethologically relevant model of male vs. female aggression by pair housing adult male and female outbred CFW mice with opposite sex cage mates. We assess reactive (defensive) aggression in the resident intruder (RI) test and appetitive (rewarding) aggression in the aggression conditioned place preference (CPP) and operant self-administration (SA) tests. Our results show dramatic sex differences in both qualitative and quantitative aspects of reactive vs. appetitive aggression. Males exhibit more wrestling and less investigative behavior during RI, find aggression rewarding and will work for access to a subordinate to attack. Females exhibit more bites, alternate between aggressive behaviors and investigative behaviors more readily during RI, however, they do not find aggression to be rewarding or reinforcing. These results establish sex differences in aggression in mice, providing an important resource for the field to better understand the circuit and molecular mechanisms of aggression in both sexes.
Influence of claustrum on cortex varies by area, layer, and cell type
Authors: McBride Ethan G. , Gandhi Saurabh R. , Kuyat Jacqulyn R. , Ollerenshaw Douglas R. , Arkhipov Anton , Koch Christof , Olsen Shawn R. 
Published: February 2022

SUMMARYThe claustrum is a small subcortical structure with widespread connections with disparate regions of the cortex. These far-reaching projections have led to many hypotheses concerning its function. However, we know little about how claustrum input affects neural activity in cortex, particularly beyond frontal areas. Here, using optogenetics and multi-regional Neuropixels recordings from over 15,000 neurons in awake mice, we demonstrate that the effect of claustrum input differs depending on brain area, layer, and cell type. Brief claustrum stimulation produces approximately 1 spike per claustrum neuron, which affects many fast-spiking (FS; putative inhibitory) but very few regular-spiking (RS; putative excitatory) cortical neurons. Prolonged claustrum stimulation affects many more cortical FS and RS neurons. More inhibition occurs in frontal regions and deeper layers, while more excitation occurs in posterior regions and superficial layers. These differences imply that the function of claustrum input to cortex depends on the area, supporting the idea that claustro-cortical circuits are organized into functional modules.