bluuebunny/crossref_metadata_2025_split huggingface dataset:
Vhl deletion inDmp1-expressing cells alters MEP metabolism and promotes stress erythropoiesis
Authors: Emery Janna M. , Chicana Betsabel , Taglinao Hanna , Ponce Citlaly , Donham Cristine , Padmore Hawa , Sebastian Aimy , Trasti Scott L. , Manilay Jennifer O. 
Published: July 2023

ABSTRACTIn recent years, general hypoxia-inducible factor (HIF)-prolyl hydroxylase (PHD) enzyme inhibitors have been developed for the treatment of anemia due to renal disease and osteoporosis. However, it remains a challenge to target the HIF signaling pathway without dysregulating the skeletal and hematopoietic system. Here, we examined the effects ofVhldeletion in bone by performing longitudinal analyses ofVhlcKO mice at 3, 6, 10, and 24 weeks of age, where at 10 and 24 weeks of age, high bone mass and splenomegaly are present. Using flow cytometry, we observed increased frequency (%) of CD71loTER119hiFSCloorthochromatophilic erythroblasts and reticulocytes in 10- and 24-week-oldVhlcKO bone marrow (BM), which correlated with elevated erythropoietin levels in the BM and increased number of red blood cells in circulation. The absolute numbers of myeloerythroid progenitors (MEPs) in the BM were significantly reduced at 24 weeks. Bulk RNA-Seq of the MEPs showed upregulation ofEpas1(Hif1a)andEfnb2(Hif2a)inVhlcKO MEPs, consistent with a response to hypoxia, and genes involved in erythrocyte development, actin filament organization, and response to glucose. Additionally, histological analysis ofVhlcKO spleens revealed red pulp hyperplasia and the presence of megakaryocytes, both of which are features of extramedullary hematopoiesis (EMH). EMH in the spleen was correlated with the presence of mature stress erythroid progenitors, suggesting that stress erythropoiesis is occurring to compensate for the BM microenvironmental irregularities. Our studies implicate that HIF-driven alterations in skeletal homeostasis can accelerate erythropoiesis.Key Points• Dysregulation of HIF signaling in Dmp1+ bone cells induces stress erythropoiesis.• Skeletal homeostasis modulates erythropoiesis.
Complementary cognitive roles for D2-MSNs and D1-MSNs during interval timing
Authors: Bruce R. Austin , Weber Matthew A. , Bova Alexandra S. , Volkman Rachael A. , Jacobs Casey E. , Sivakumar Kartik , Stutt Hannah R , Kim Young-cho , Curtu Rodica , Narayanan Nandakumar S. 
Published: July 2023

AbstractThe role of striatal pathways in cognitive processing is unclear. We studied dorsomedial striatal cognitive processing during interval timing, an elementary cognitive task that requires mice to estimate intervals of several seconds and involves working memory for temporal rules as well as attention to the passage of time. We harnessed optogenetic tagging to record from striatal D2- dopamine receptor-expressing medium spiny neurons (D2-MSNs) in the indirect pathway and from D1-dopamine receptor-expressing MSNs (D1-MSNs) in the direct pathway. We found that D2-MSNs and D1-MSNs exhibited distinct dynamics over temporal intervals as quantified by principal component analyses and trial-by-trial generalized linear models. MSN recordings helped construct and constrain a four-parameter drift-diffusion computational model in which MSN ensemble activity represented the accumulation of temporal evidence. This model predicted that disrupting either D2-MSNs or D1-MSNs would increase interval timing response times and alter MSN firing. In line with this prediction, we found that optogenetic inhibition or pharmacological disruption of either D2-MSNs or D1-MSNs increased interval timing response times. Pharmacologically disrupting D2-MSNs or D1-MSNs also changed MSN dynamics and degraded trial-by-trial temporal decoding. Together, our findings demonstrate that D2-MSNs and D1-MSNs had opposing dynamics yet played complementary cognitive roles, implying that striatal direct and indirect pathways work together to shape temporal control of action. These data provide novel insight into basal ganglia cognitive operations beyond movement and have implications for human striatal diseases and therapies targeting striatal pathways.
Progress Towards UNAIDS’s 95-95-95 Targets in Zimbabwe: Sociodemographic Constraints and Geospatial Heterogeneity
Authors: Chowdhury MD Tuhin , Bershteyn Anna , Milali Masabho , Citron Daniel , Nyimbili Sulani , Musuka Godfrey , Cuadros Diego F 
Published: July 2023

AbstractThe HIV/AIDS epidemic remains critical in sub-Saharan Africa, with UNAIDS establishing “95-95-95” targets to optimize HIV care. Using the Zimbabwe Population-based HIV Impact Assessment (ZIMPHIA) geospatial data, this study aimed to identify patterns in these targets and determinants impacting the HIV care continuum in underserved Zimbabwean communities. Analysis techniques, including Gaussian kernel interpolation, optimized hotspot, and multivariate geospatial k-means clustering, were utilized to establish spatial patterns and cluster regional HIV care continuum needs. Further, we investigated healthcare availability, access, and social determinants and scrutinized the association between socio-demographic and behavioral covariates with HIV care outcomes. Dispar-ities in progress toward the “95-95-95” targets were noted across different regions, with each target demonstrating unique geographic patterns, resulting in four distinct clusters with specific HIV care needs. Key factors associated with gaps in achieving targets included younger age, male sex, employment, and minority or no religious affiliation. Our study uncovers significant spatial heterogeneity in the HIV care continuum in Zimbabwe, with unique regional patterns in “95-95-95” targets. The spatial analysis of the UNAIDS targets presented here could prove instrumental in designing effective control strategies by identifying vulnerable communities that are falling short of these targets and require intensified efforts. Our result provides insights for designing region-specific interventions and enhancing community-level factors, emphasizing the need to address regional gaps and improve HIV care outcomes in vulnerable communities lagging behind.
The reach of reactivation: Effects of consciously-triggered versus unconsciously-triggered reactivation of associative memory
Authors: Tal Amir , Schechtman Eitan , Caughran Bruce , Paller Ken A , Davachi Lila 
Published: July 2023

AbstractNewly formed memories are not passively stored for future retrieval; rather, they are reactivated offline and thereby strengthened and transformed. However, reactivation is not a uniform process: it occurs throughout different states of consciousness, including conscious rehearsal during wakefulness and unconscious processing during both wakefulness and sleep. In this study, we explore the consequences of reactivation during conscious and unconscious awake states. Forty-one participants learned associations consisting of adjective-object-position triads. Objects were clustered into distinct semantic groups (e.g., multiple fruits, vehicles, musical instruments) which allowed us to examine the consequences of reactivation on semantically-related memories. After an extensive learning phase, some triads were reactivated consciously, through cued retrieval, or unconsciously, through subliminal priming. In both conditions, the adjective was used as the cue. Reactivation impacted memory for the most distal association (i.e., the spatial position of associated objects) in a consciousness-dependent and memory-strength-dependent manner. First, conscious reactivation of a triad resulted in a weakening of other semantically related memories, but only those that were initially more accurate (i.e., memories with lower pre-reactivation spatial errors). This is similar to what has been previously demonstrated in studies employing retrieval-induced forgetting designs. Unconscious reactivation, on the other hand, benefited memory selectively for weak cued items. Semantically linked associations were not impaired, but rather integrated with the reactivated memory. Taken together, our results demonstrate that conscious and unconscious reactivation of memories during wakefulness have qualitatively different consequences on memory for distal associations. Effects are memory-strength-dependent, as has been shown for reactivation during sleep. Results support a consciousness-dependent inhibition account, according to which unconscious reactivation involves less inhibitory dynamics than conscious reactivation, thus allowing more liberal spread of activation. Our findings set the stage for additional exploration into the role of consciousness in memory structuring.
The relationships between genetic ancestry, somatic mutation frequency, and histologic subtypes in high-grade endometrial cancer
Authors: Bremseth-Vining Ryan , Borda Victor , Craig Douglas , Ruterbusch Julie J. , Boerner Julie , Fucinari Juliana , Ali-Fehmi Rouba , Elshaikh Mohamed , Abdallah Hassan , Maxwell G. Larry , Darcy Kathleen M. , Dyson Gregory , Conrads Thomas , Bateman Nicholas W. , Cote Michele L. , O’Connor Timothy D. 
Published: July 2023

AbstractHigh-grade endometrial cancer, like numerous other cancer types, exhibits clear racial disparities in the United States for both the incidence and outcomes of the disease. While institutional factors are likely the primary contributor to these disparities, other underlying causes cannot be ignored (i.e., molecular, genetic, and histopathologic factors). This study seeks to interrogate the role that germline genetic influences, specifically genetic ancestry, may play in contributing to characteristics of high-grade endometrial cancer. This is mainly accomplished by examining the relationship between local ancestry inferences and somatic mutation frequency as well as histologic subtypes. An association between clinical characteristics and patient survival was also interrogated, and while global ancestry was seen to have no significant effect, tumor mutation burden (TMB) did impact patient survival. Here, we identify associations between local ancestry segments on chromosomes 1 and 14 and an increased TMB in self-described (SD) Black patients. We also highlight a complex relationship between heterozygous ancestry combinations within genomic regions (i.e., [European/African] vs. [African/African]) and an increase in local somatic mutation frequency.Furthermore, we explore the relationship between local ancestry and histologic subtype. We identify one region (chr9q32) wherein the African/European local ancestry diplotype was associated with a higher incidence of serous carcinoma. We also underline a difference in somatic mutation frequency between endometrioid and serous carcinoma. While highly exploratory, these findings begin to characterize the complex relationship between genetic ancestry and characteristics of high-grade endometrial cancer, which may impact patient survival.
Shared GABA transmission pathology in dopamine agonist- and antagonist-induced dyskinesia
Authors: Abe Yoshifumi , Yagishita Sho , Sano Hiromi , Sugiura Yuki , Dantsuji Masanori , Suzuki Toru , Mochizuki Ayako , Yoshimaru Daisuke , Hata Junichi , Matsumoto Mami , Taira Shu , Takeuchi Hiroyoshi , Okano Hideyuki , Ohno Nobuhiko , Suematsu Makoto , Inoue Tomio , Nambu Atsushi , Watanabe Masahiko , Tanaka Kenji F 
Published: July 2023

SummaryDyskinesia is involuntary movement caused by long-term medication with dopamine-related agents: the dopamine agonist, L-DOPA, to treat Parkinson’s disease (L-DOPA-induced dyskinesia [LID]) or dopamine antagonists to treat schizophrenia (tardive dyskinesia [TD]). However, it remains unknown why distinct types of medications for distinct neuropsychiatric disorders induce similar involuntary movements. Here, we searched for a shared structural footprint using magnetic resonance imaging-based macroscopic screening and super-resolution microscopy-based microscopic identification. We identified the enlarged axon terminals of striatal medium spiny neurons in both LID and TD model mice. The striatal overexpression of vesicular gamma-aminobutyric acid transporter (VGAT) was necessary and sufficient for modeling these structural changes; VGAT levels gated the functional and behavioral alterations in dyskinesia models. Our findings indicate that lowered type 2 dopamine receptor signaling with repetitive dopamine fluctuations is a common cause of VGAT overexpression and late-onset dyskinesia formation, and that reducing dopamine fluctuation rescues dyskinesia pathology via VGAT downregulation.HighlightsEnhancement of GABAergic transmission is a shared mechanism between LID and TD.VGAT levels in MSNs govern the structure and function of MSN presynaptic terminals.Gain and loss of VGAT function in MSNs exacerbates and ameliorates dyskinesia.Lowered D2 signaling with repetitive DA fluctuations causes VGAT overexpression.Graphical abstract
Artificial selection improves pollutant degradation by bacterial communities
Authors: Arias-Sánchez Flor I. , Vessman Björn , Haym Alice , Alberti Géraldine , Mitri Sara 
Published: July 2023

AbstractArtificial selection is a promising way to improve microbial community functions, but previous experiments have only shown moderate success. Here, we experimentally evaluate a new method that was inspired by genetic algorithms to artificially select small bacterial communities of known species composition based on their degradation of an industrial pollutant. Starting from 29 randomly generated four-species communities, we repeatedly grew communities for four days, selected the 10 best-degrading communities, and rearranged them into 29 new communities composed of four species of equal ratios whose species compositions resembled those of the most successful communities from the previous round. The best community after 18 such rounds of selection degraded the pollutant better than the best community in the first round. It featured member species that degrade well, species that degrade badly alone but improve community degradation, and free-rider species that did not contribute to community degradation. Most species in the evolved communities did not differ significantly from their ancestors in their phenotype, suggesting that genetic evolution plays a small role at this time scale. These experiments show that artificial selection on microbial communities can work in principle, and inform on how to improve future experiments.
An active neural mechanism for relational learning and fast knowledge reassembly
Authors: Miconi Thomas , Kay Kenneth 
Published: July 2023

AbstractHow do we gain general insights from limited novel experiences? Humans and animals have a striking ability to learn relationships between experienced items, enabling efficient generalization and rapid assimilation of new information. One fundamental instance of such relational learning is transitive inference (learnA>BandB>C, inferA>C), which can be quickly and globally reorganized upon learning a new item (learnA>B>CandD>E>F, thenC>D, and inferB>E). Despite considerable study, neural mechanisms of transitive inference and fast reassembly of existing knowledge remain elusive. Here we adopt a meta-learning (“learning-to-learn”) approach. We train artificial neural networks, endowed with synaptic plasticity and neuromodulation, to be able to learn novel orderings of arbitrary stimuli from repeated presentation of stimulus pairs. We then obtain a complete mechanistic understanding of this discovered neural learning algorithm. Remarkably, this learning involves active cognition: items from previous trials are selectively reinstated in working memory, enabling delayed, self-generated learning and knowledge reassembly. These findings identify a new mechanism for relational learning and insight, suggest new interpretations of neural activity in cognitive tasks, and highlight a novel approach to discovering neural mechanisms capable of supporting cognitive behaviors.
CRISPR-Based Genome Editing inHarmonia Axyridis
Authors: Partosh Tamir , Davidovitz Michael , Firer Noa , Pines Gur 
Published: July 2023

AbstractHarmonia axyridis(Pallas), commonly known as the Asian lady beetle, is a native insect species of Asia that has been intentionally introduced to various regions for biocontrol purposes. However, its widespread presence beyond its original release sites suggests a high degree of invasiveness. Previous studies have employed double-stranded RNA techniques to investigate the functional genomics of this species. In this study, we utilized the CRISPR-Cas9 approach to achieve precise genome editing inH. axyridis. Specifically, we targeted two distinct genes known to exhibit visible phenotypic effects. While the knockout of thelaccase2gene resulted in an early-detectable phenotype but also in lethality, we successfully established a viable and genetically stable mutant colony by disrupting thescarletgene. Our findings contribute to the expanding knowledge of genetic manipulation inH. axyridisand provide insights into its potential for future research and practical applications for biocontrol and invasive species management.
Chromatin-associated RNA Dictates the ecDNA Interactome in the Nucleus
Authors: Liang Zhengyu , Gilbreath Collin , Liu Wenyue , Wang Yan , Zhang Michael Q. , Zhang Dong-Er , Wu Sihan , Fu Xiang-Dong 
Published: July 2023

ABSTRACTExtrachromosomal DNA (ecDNA) promotes cancer by driving copy number heterogeneity and amplifying oncogenes along with functional enhancers. More recent studies suggest two additional mechanisms for further enhancing their oncogenic potential, one via forming ecDNA hubs to augment oncogene expression1and the other through acting as portable enhancers totrans-activate target genes2. However, it has remained entirely elusive about how ecDNA explores the three-dimensional space of the nucleus and whether different ecDNA have distinct interacting mechanisms. Here, by profiling the DNA-DNA and DNA-RNA interactomes in tumor cells harboring different types of ecDNAs in comparison with similarly amplified homogenously staining regions (HSRs) in the chromosome, we show that specific ecDNA interactome is dictated by ecDNA-borne nascent RNA. We demonstrate that the ecDNA co-amplifyingPVT1andMYCutilize nascent noncodingPVT1transcripts to mediate specifictrans-activation of both ecDNA and chromosomal genes. In contrast, the ecDNA amplifyingEGFRis weak in this property because of more efficient splicing to remove chromatin-associated nascent RNA. These findings reveal a noncoding RNA-orchestrated program hijacked by cancer cells to enhance the functional impact of amplified oncogenes and associated regulatory elements.
Whole Genome Assembly of a HybridTrypanosoma cruziStrain Assembled with Nanopore Sequencing Alone
Authors: Hakim Jill M.C. , Gutierrez Guarnizo Sneider A , Machaca Edith Málaga , Gilman Robert H. , Mugnier Monica R. 
Published: July 2023

AbstractTrypanosoma cruziis the causative agent of Chagas disease, which causes 10,000 deaths per year. Despite the high mortality caused by the pathogen, relatively few parasite genomes have been assembled to date; even some commonly used laboratory strains do not have publicly available genome assemblies. This is at least partially due toT. cruzi’s highly complex and highly repetitive genome: while describing the variation in genome content and structure is critical to better understandingT. cruzibiology and the mechanisms that underlie Chagas disease, the complexity of the genome defies investigation using traditional short read sequencing methods. Here, we have generated a high-quality whole genome assembly of the hybrid Tulahuen strain, a commercially available Type VI strain, using long read Nanopore sequencing without short read scaffolding. Using automated tools and manual curation for annotation, we report a genome with 25% repeat regions, 17% variable multigene family members, and 27% transposable elements. Notably, we find that regions with transposable elements are significantly enriched for surface proteins, and that on average surface proteins are closer to transposable elements compared to other coding regions. This finding supports a possible mechanism for diversification of surface proteins in which mobile genetic elements such as transposons facilitate recombination within the gene family. This work demonstrates the feasibility of nanopore sequencing to resolve complex regions ofT. cruzigenomes, and with these resolved regions, provides support for a possible mechanism for genomic diversification.
Calcium-sensitive subthreshold oscillations and electrical coupling in principal cells of mouse dorsal cochlear nucleus
Authors: Hong H , Moore LA , Apostolides PF , Trussell LO 
Published: July 2023

ABSTRACTIn higher sensory brain regions, slow oscillations (0.5-5 Hz) associated with quiet wakefulness and attention modulate multisensory integration, predictive coding, and perception. Although often assumed to originate via thalamocortical mechanisms, the extent to which sub-cortical sensory pathways are independently capable of slow oscillatory activity is unclear. We find that in the first station for auditory processing, the cochlear nucleus, fusiform cells from juvenile mice (of either sex) generate robust 1-2 Hz oscillations in membrane potential and exhibit electrical resonance. Such oscillations were absent prior to the onset of hearing, intrinsically generated by hyperpolarization-activated cyclic nucleotide-gated (HCN) and persistent Na+conductances (NaP) interacting with passive membrane properties, and reflected the intrinsic resonance properties of fusiform cells. Cx36-containing gap junctions facilitated oscillation strength and promoted pairwise synchrony of oscillations between neighboring neurons. The strength of oscillations were strikingly sensitive to external Ca2+, disappearing at concentrations > 1.7 mM, due in part to the shunting effect of small-conductance calcium-activated potassium (SK) channels. This effect explains their apparent absence in previousin vitrostudies of cochlear nucleus which routinely employed high-Ca2+extracellular solution. In contrast, oscillations were amplified in reduced Ca2+solutions, due to relief of suppression by Ca2+of Na+channel gating. Our results thus reveal mechanisms for synchronous oscillatory activity in auditory brainstem, suggesting that slow oscillations, and by extension their perceptual effects, may originate at the earliest stages of sensory processing.SIGNIFICANCE STATEMENT (120 words max.)Many studies show that electrical activity in higher brain regions is regulated by brain oscillations. Here we show that such oscillatory activity can arise even in the first levels of auditory processing in the cochlear nucleus of the brainstem (fusiform cells), and is generated not by neural networks but by the biophysical properties of individual neurons. Oscillations are highly sensitive to external Ca2+due to interplay of multiple ionic conductances. Gap junctions between cells allows for amplification and synchrony of such activity. Oscillations are absent in pre-hearing neurons, suggesting that sound activity might be important for their emergence. We propose that such early-level oscillations may serve to enhance signaling associated with particular environmental stimuli.