bluuebunny/crossref_metadata_2025_split huggingface dataset:
No evidence that LSD microdosing affects recall or the balance between distracter resistance and updating
Authors: Fallon Sean James 
Published: December 2021

AbstractThe effect of low doses (<=20 μg) of LSD on working memory, in the absence of altered states of consciousness, remain largely unexplored. Given its possible effects on serotonin 5-HT2A receptors and dopaminergic signalling, it could be hypothesised that LSD microdoses modulate working memory recall. Moreover, in line with computational models, LSD microdoses could exert antagonistic effects on distracter resistance and updating. Here, we tested this hypothesis in a randomised double-blind, placebo-controlled study comparing three different LSD microdoses (5 μg, 10μg and 20μg) with placebo. After capsule administration, participants performed a modified delay-match-to-sample (DMTS) dopamine-sensitive task. The standard DMTS task was modified to include novel items in the delay period between encoding and probe. These novel items either had to be ignored or updated into working memory. There was no evidence that LSD microdoses affected the accuracy or efficiency of working memory recall and there was no evidence for differential effects on ignoring or updating. Due to the small sample of participants, these results are preliminary and larger studies are required to establish whether LSD microdoses affect short-term recall.
Differential mobility and self-association of Arc/Arg3.1 in the cytoplasm and nucleus of living cells
Authors: Hedde Per Niklas , Barylko Barbara , Binns Derk D. , Jameson David M. , Albanesi Joseph P. 
Published: December 2021

ABSTRACTArc, also known as Arg3.1, is an activity-dependent immediate-early gene product that plays essential roles in memory consolidation. A pool of Arc is located in the postsynaptic cytoplasm, where it promotes AMPA receptor endocytosis and cytoskeletal remodeling. However, Arc is also found in the nucleus, a major portion being associated with promyelocytic leukemia nuclear bodies (PML-NBs). Nuclear Arc has been implicated in epigenetic control of gene transcription associated with learning and memory. In this study, we use a battery of fluorescence nanoimaging approaches to characterize the behavior of Arc in living cells. Our results indicate that in the cytoplasm, Arc exists predominantly as monomers and dimers associated with slowly diffusing particles. In contrast, nuclear Arc is almost exclusively monomeric and displays a higher diffusivity than cytoplasmic Arc. We further show that Arc moves freely and rapidly between PML-NBs and the nucleoplasm, and that its movement within PML-NBs is relatively unobstructed.
Spectral distribution dynamics across different attentional priority states
Authors: Pietrelli Mattia , Samaha Jason , Postle Bradley R. 
Published: December 2021

AbstractAnticipatory covert spatial attention improves performance on tests of visual detection and discrimination, and shifts are accompanied by decreases and increases of alpha-band power at EEG electrodes corresponding to the attended and unattended location, respectively. Although the increase at the unattended location is often interpreted as an active mechanism (e.g., inhibiting processing at the unattended location), most experiments cannot rule out the alternative possibility that it is a secondary consequence of selection elsewhere. To adjudicate between these accounts, we designed a Posner-style cuing task in which male and female human participants made orientation judgments of targets appearing at one of four locations: up, down, right, or left. Critically, trials were blocked such that within a block the locations along one meridian alternated in status between attended and unattended, and targets never appeared at the other two, making them irrelevant. Analyses of the concurrently measured EEG signal were carried out on traditional narrowband alpha (8-14 Hz), as well as on two components resulting from the decomposition of this signal: periodic alpha; and the slope of the aperiodic 1/f-like component. Although data from right-left blocks replicated the familiar pattern of lateralized asymmetry in narrowband alpha power, with neither alpha signal could we find evidence for any difference in the time course at unattended versus irrelevant locations, an outcome consistent with the secondary-consequence interpretation of attention-related dynamics in the alpha band. Additionally, 1/f slope was lower at attended and unattended locations, relative to irrelevant, suggesting a tonic adjustment of physiological state.
Contextual control of conditioned pain tolerance and endogenous analgesic systems: Evidence for sex-based differences in endogenous opioid engagement
Authors: Trask Sydney , Mogil Jeffrey S. , Helmstetter Fred J. , Stucky Cheryl L. , Sadler Katelyn E. 
Published: December 2021

AbstractThe mechanisms underlying the transition from acute to chronic pain are unclear but may involve the persistence or strengthening of pain memories acquired in part through associative learning. Contextual cues, which comprise the surrounding environment where events occur, were recently described as a critical regulator of pain memory; both rodents and humans exhibit increased pain sensitivity in environments recently associated with a single painful experience. It is unknown, however, how repeated exposure to an acute painful unconditioned stimulus in a distinct context modifies pain sensitivity or the expectation of pain in that environment. To answer this question, we conditioned mice to associate distinct contexts with either repeated administration of a mild visceral pain stimulus (intraperitoneal injection of acetic acid) or vehicle injection over the course of three days. On the final day of experiments animals received either an acid injection or vehicle injection prior to being placed into both contexts. In this way, contextual control of pain sensitivity and pain expectation could be tested respectively. Both male and female mice developed context-dependent conditional pain tolerance, a phenomenon mediated by endogenous opioid signaling. However, when expecting the presentation of a painful stimulus in a given context, males exhibited conditional hypersensitivity whereas females exhibited endogenous opioid-mediated conditional analgesia. Successful determination of the brain circuits involved in this sexually dimorphic anticipatory response may allow for the manipulation of pain memories, which may contribute to the development of chronic pain states.
A chromosomal inversion may facilitate adaptation despite periodic gene flow in a freshwater fish
Authors: Thorstensen Matt J. , Euclide Peter T. , Jeffrey Jennifer D. , Shi Yue , Treberg Jason R. , Watkinson Douglas A. , Enders Eva C. , Larson Wesley A. , Kobayashi Yasuhiro , Jeffries Ken M. 
Published: December 2021

AbstractDifferences in genomic architecture between populations, such as chromosomal inversions, may play an important role in facilitating adaptation despite opportunities for gene flow. One system where chromosomal inversions may be important for eco-evolutionary dynamics are in freshwater fishes, which often live in heterogenous environments characterized by varying levels of connectivity and varying opportunities for gene flow. In the present study, reduced representation sequencing was used to study possible adaptation in n = 345 walleye (Sander vitreus) from three North American waterbodies: Cedar Bluff Reservoir (Kansas, USA), Lake Manitoba (Manitoba, Canada), and Lake Winnipeg (Manitoba, Canada). Haplotype and outlier-based tests revealed a putative chromosomal inversion that contained three expressed genes and was nearly fixed for alternate genotypes in each Canadian lake. These patterns exist despite several opportunities for gene flow between these proximate Canadian lakes, suggesting that the inversion may be important for facilitating adaptive divergence between the two lakes despite gene flow. Our study illuminates the importance of genomic architecture for facilitating local adaptation in freshwater fishes. Furthermore, our results provide additional evidence that inversions may facilitate local adaptation in many organisms that inhabit connected but heterogenous environments.
Phage resistance accompanies reduced fitness of uropathogenicE. coliin the urinary environment
Authors: Zulk Jacob J. , Clark Justin R. , Ottinger Samantha , Ballard Mallory B. , Mejia Marlyd E. , Mercado-Evans Vicki , Heckmann Emmaline R. , Sanchez Belkys C. , Trautner Barbara W. , Maresso Anthony W. , Patras Kathryn A. 
Published: December 2021

ABSTRACTUrinary tract infections (UTIs) are among the most common infections treated worldwide each year and are primarily caused by uropathogenicE. coli(UPEC). Rising rates of antibiotic resistance among uropathogens have spurred consideration of alternative strategies such as bacteriophage (phage) therapy; however, phage-bacterial interactions within the urinary environment are poorly defined. Here, we assess the activity of two phages, HP3 and ES17, against clinical UPEC isolates usingin vitroandin vivomodels of UTI. In both bacteriologic medium and pooled human urine, we identified phage resistance arising within the first 6-8 hours of coincubation. Whole genome sequencing revealed that UPEC resistant to HP3 and ES17 harbored mutations in genes involved in lipopolysaccharide (LPS) biosynthesis. These mutations coincided with severalin vitrophenotypes, including alterations to adherence to and invasion of human bladder epithelial HTB-9 cells, and increased biofilm formation. Interestingly, these phage-resistant UPEC demonstrated reduced growth in pooled human urine, which could be partially rescued by nutrient supplementation, and were more sensitive to several outer membrane targeting antibiotics than parental strains. Additionally, these phage-resistant UPEC were attenuated in a murine UTI model. In total, our findings suggest that while resistance to phages, such as LPS-targeted HP3 and ES17, may readily arise in the urinary environment, phage resistance is accompanied by fitness costs rendering UPEC more susceptible to host immunity or antibiotics.IMPORTANCEUTIs are one of the most common causes of outpatient antibiotic use, and rising antibiotic resistance threatens the ability to control these infections unless alternative treatments are developed. Bacteriophage (phage) therapy is gaining renewed interest, however, much like antibiotics, bacteria can readily become resistant to phage. For successful UTI treatment, we must predict how bacteria will evade killing by phage and identify the downstream consequences of phage-resistant bacterial infections. In our current study, we found that while phage-resistant mutant bacteria quickly emerged, these mutations left bacteria less capable of growing in human urine and colonizing the murine bladder. These results suggest that phage therapy poses a viable UTI treatment if phage resistance confers fitness costs for the uropathogen. These results have implications for developing cocktails of phage with multiple different bacterial targets, each of which is only evaded at the cost of bacterial fitness.
Historical biogeography of early diverging termite lineages (Isoptera: Teletisoptera)
Authors: Wang Menglin , Hellemans Simon , Šobotník Jan , Arora Jigyasa , Buček Aleš , Sillam-Dussès David , Clitheroe Crystal , Lu Tomer , Lo Nathan , Engel Michael S. , Roisin Yves , Evans Theodore A. , Bourguignon Thomas 
Published: December 2021

AbstractTermites are social cockroaches distributed throughout warm temperate and tropical ecosystems. The ancestor of modern termites (crown-Isoptera) occurred during the earliest Cretaceous, approximately 140 million years ago, suggesting that both vicariance through continental drift and overseas dispersal may have shaped the distribution of early diverging termite lineages. We reconstruct the historical biogeography of three early diverging termite families – Stolotermitidae, Hodotermitidae, and Archotermopsidae – using the nuclear rRNA genes and mitochondrial genomes of 27 samples. Our analyses confirmed the monophyly of Stolotermitidae + Hodotermitidae + Archotermopsidae (clade Teletisoptera), with Stolotermitidae diverging from a monophyletic Hodotermitidae + Archotermopsidae approximately 100.3 Ma (94.3–110.4 Ma, 95% HPD), and with Archotermopsidae paraphyletic to a monophyletic Hodotermitidae. The Oriental Archotermopsis and the Nearctic Zootermopsis diverged 50.8 Ma (40.7–61.4 Ma, 95% HPD) before land connections between the Palearctic region and North America ceased to exist. The African Hodotermes + Microhodotermes diverged from Anacanthotermes, a genus found in Africa and Asia, 32.1 Ma (24.8–39.9 Ma, 95% HPD), and the most recent common ancestor of Anacanthotermes lived 10.7 Ma (7.3–14.3 Ma, 95% HPD), suggesting that Anacanthotermes dispersed to Asia using the land bridge connecting Africa and Eurasia ∼18–20 Ma. In contrast, the common ancestors of modern Porotermes and Stolotermes lived 20.2 Ma (15.7–25.1 Ma, 95% HPD) and 26.6 Ma (18.3–35.6 Ma, 95% HPD), respectively, indicating that the presence of these genera in South America, Africa, and Australia involved over-water dispersals. Our results suggest that early diverging termite lineages acquired their current distribution through a combination of over-water dispersals and dispersal via land bridges. We clarify the classification by resolving the paraphyly of Archotermopsidae, restricting the family to Archotermopsis and Zootermopsis, and elevating Hodotermopsinae (Hodotermopsis) as Hodotermopsidae (status novum).
Nucleophagy contributes to genome stability though TOP2cc and nucleolar components degradation
Authors: Muciño-Hernández Gabriel , Cárdenas Adán Oswaldo Guerrero , Merchant-Larios Horacio , Castro-Obregón Susana 
Published: December 2021

ABSTRACTThe nuclear architecture of mammalian cells can be altered as a consequence of anomalous accumulation of nuclear proteins or genomic alterations. Most of the knowledge about nuclear dynamics comes from studies on cancerous cells. How normal, healthy cells maintain genome stability avoiding accumulation of nuclear damaged material is less understood. Here we describe that primary mouse embryonic fibroblasts develop a basal level of nuclear buds and micronuclei, which increase after Etoposide-induced DNA Double-Stranded Breaks. These nuclear buds and micronuclei co-localize with autophagic proteins BECN1 and LC3 and with acidic vesicles, suggesting their clearance by nucleophagy. Some of the nuclear alterations also contain autophagic proteins and Type II DNA Topoisomerases (TOP2A and TOP2B), or nucleolar protein Fibrillarin, implying they are also targets of nucleophagy. We propose that a basal nucleophagy contributes to genome and nuclear stability and also in response to DNA damage and nucleolar stress.
ABCA1 causes an asymmetric cholesterol distribution to regulate intracellular cholesterol homeostasis
Authors: Ogasawara Fumihiko , Ueda Kazumitsu 
Published: December 2021

AbstractCholesterol is a major and essential component of the mammalian cell plasma membrane (PM) and the loss of cholesterol homeostasis leads to various pathologies. Cellular cholesterol uptake and synthesis are regulated by a cholesterol sensor in the endoplasmic reticulum (ER). However, it remains unclear how the PM cholesterol level is sensed. Here we show that the sensing depends on ATP-binding cassette A1 (ABCA1) and Aster-A, which cooperatively maintain the asymmetric transbilayer cholesterol distribution in the PM. ABCA1 translocates (flops) cholesterol from the inner to the outer leaflet of the PM to maintain a low inner cholesterol level. When the inner cholesterol level exceeds a threshold, Aster-A is recruited to the PM-ER contact site to transfer cholesterol to the ER. These results show unknown synergy between ABCA1 and Aster-A in intracellular cholesterol homeostasis.
Comprehensive mapping of the alternative polyadenylation site usage and its dynamics at single cell resolution
Authors: Wang Junliang , Chen Wei , Hou Wenhong , Hong Ni , Zhong Hanbing , Ni Ting , Qi Yuanming , Jin Wenfei 
Published: December 2021

AbstractAlternative polyadenylation (APA) plays an important role in post-transcriptional gene regulation such as transcript stability and translation efficiency. However, our knowledge about APA dynamics at single cell level is largely unexplored. Here we developed single cell polyadenylation sequencing (scPolyA-seq), a strand-specific approach for sequencing 3’ end of transcripts, to investigate the landscape of APA at single cell level. By analyzing several cell lines, we found many genes using multiple polyA sites in bulk data are prone to use only one polyA site in each single cell. Interestingly, cell cycle was significantly enriched in genes showing high variation of polyA site usages. We further identified 414 genes showing polyA site usage switch after cell synchronization. Genes showing cell cycle associated polyA site usage switch were grouped into 6 clusters, with cell phase specific functional categories enriched in each cluster. Furthermore, scPolyA-seq could facilitate study of APA in various biological processes.
Lactococcus lactis sb. cremoris orchestrates signal events in the gut epithelium via TLR2 to promote tissue restitution
Authors: Naudin Crystal R. , Owens Joshua A. , Askew Lauren C. , Khan Ramsha Nabihah , Scharer Christopher D. , Matthews Jason D. , Luo Liping , Kim Jiyoung , Reedy April R. , Barbian Maria E. , Jones Rheinallt M. 
Published: December 2021

AbstractThe use of beneficial bacteria to promote gastrointestinal heath is widely practiced, however, the mechanisms whereby many of these microbes elicit their beneficial effects remain elusive. Previously, we conducted a screen for the discovery of novel beneficial microbes and identified the potent cytoprotective effects of a strain of Lactococcus lactis subsp. cremoris. Here, we show that dietary supplementation with L. lactis subsp. cremoris induced transcript enrichment of a set of genes within the colon whose functions are associated with host cell and microbe interactions. Specifically, L. lactis subsp. cremoris induced the expression of tlr2, which we show was required for L. lactis subsp. cremoris to elicit its beneficial effects on the intestine. L. lactis subsp. cremoris did not confer beneficial effects in mice deficient in TLR-2, or deficient in its adaptor protein Myd88 in chronic gut injury models. In addition to cytoprotection, culture supernatant from L. lactis subsp. cremoris accelerated epithelial migration in a cultured epithelial cell scratch wound assay; and effect that was abrogated by a TLR-2 antagonist. Furthermore, L. lactis subsp. cremoris accelerated epithelial tissue restitution following the infliction of a colonic wound biopsy in a TLR-2 and Myd88-dependent manner. Within colonic wounds, L. lactis subsp. cremoris induced the activation of signaling pathways that function in tissue restitution following injury, including the ERK signaling pathway, and of focal adhesion complex (FAC) proteins. Together, these data demonstrate that L. lactis subsp. cremoris signals via the TLR2/MyD88-axis to confer cytoprotection and accelarated tissue restituion in the gut epithelium. These data point to evolving adaptations where beneficial gut microbes moduate innate immune signaling to excert positive influnces on host physiology.
Mutational switch-backs can accelerate evolution of Francisella to a combination of ciprofloxacin and doxycycline
Authors: Mehta Heer H. , Ibarra David , Marx Christopher J. , Miller Craig R. , Shamoo Yousif 
Published: December 2021

AbstractCombination antimicrobial therapy has been considered a promising strategy to combat the evolution of antimicrobial resistance. Francisella tularensis is the causative agent of tularemia and in addition to being found in the nature, is recognized as a threat agent that requires vigilance. We investigated the evolutionary outcome of adapting the Live Vaccine Strain (LVS) of Francisella to two non-interacting drugs, ciprofloxacin and doxycycline, individually, sequentially, and in combination. Despite their individual efficacies and independence of mechanisms, evolution to the combination appeared to progress faster than evolution to the two drugs sequentially. We conducted a longitudinal mutational analysis of the populations evolving to the drug combination, genetically reconstructed the identified evolutionary pathway, and carried out biochemical validation. We discovered that, after the appearance of an initial weak generalist mutation (FupA/B), each successive mutation alternated between adaptation to one drug or the other. In combination, these mutations allowed the population to more efficiently ascend the fitness peak through a series of evolutionary switch-backs. Clonal interference, weak pleiotropy, and positive epistasis also contributed to combinatorial evolution. This finding suggests that, under some selection conditions, the use of non-interacting drug pairs as a treatment strategy may result in a more rapid ascent to multi-drug resistance and serves as a cautionary tale.Author summaryThe antimicrobial resistance crisis requires the use of novel treatment strategies to prevent or delay the emergence of resistance. Combinations of drugs offer one strategy to delay resistance, but the efficacy of such drug combinations depends on the evolutionary response of the organism. Using experimental evolution, we show that under some conditions, a potential drug combination does not delay the onset of resistance in bacteria responsible for causing tularemia, Francisella. In fact, they evolve resistance to the combination faster than when the two drugs are applied sequentially. This result is surprising and concerning: using this drug combination in a hospital setting could lead to simultaneous emergence of resistance to two antibiotics. Employing whole genome sequencing, we identified the molecular mechanism leading to evolution of resistance to the combination. The mechanism is similar to the switch-back route used by hikers while scaling steep mountains i.e., instead of simultaneously acquiring mutations conferring resistance to both drugs, the bacteria acquire mutations to each drug in alternating manner. Rather than scaling the steep mountain directly, the bacteria ascend the mountain by a series of evolutionary switch-backs to gain elevation and in doing so, they get to the top more efficiently.