bluuebunny/crossref_metadata_2025_split huggingface dataset:
mRNA nuclear clustering leads to a difference in mutant huntingtin mRNA and protein silencing by siRNAsin vivo
Authors: Allen Sarah , O’Reilly Daniel , Miller Rachael , Sapp Ellen , Summers Ashley , Paquette Joseph , Moreno Dimas Echeverria , Bramato Brianna , McHugh Nicholas , Yamada Ken , Aronin Neil , DiFiglia Marian , Khvorova Anastasia 
Published: April 2024

AbstractHuntington’s disease (HD) is an autosomal dominant neurodegenerative disease caused by CAG repeat expansion in the first exon of the huntingtin gene (HTT). Oligonucleotide therapeutics, such as short interfering RNA (siRNA), reduce levels of huntingtin mRNA and proteinin vivoand are considered a viable therapeutic strategy. However, the extent to which they silence HTT mRNA in the nucleus is not established. We synthesized siRNA cross-reactive to mouse (wild-type)Httand human (mutant)HTTin a di-valent scaffold and delivered to two mouse models of HD. In both models, di-valent siRNA sustained lowering of wild-typeHtt, but not mutantHTTmRNA expression in striatum and cortex. Near-complete silencing of both mutant HTT protein and wild-type Htt protein was observed in both models. Subsequent fluorescent in situ hybridization (FISH) analysis shows that di-valent siRNA acts predominantly on cytoplasmic mutantHTTtranscripts, leaving clustered mutantHTTtranscripts in the nucleus largely intact in treated HD mouse brains. The observed differences between mRNA and protein levels, exaggerated in the case of extended repeats, might apply to other repeat-associated neurological disorders.
HIF-1α is Required to Differentiate the Neonatal Macrophage Secretome from Adults
Authors: Becker Amanda , Filipp Mallory , Lantz Connor , Glinton Kristofor , Thorp Edward B. 
Published: April 2024

AbstractThe immune response to stress diverges with age, with neonatal macrophages implicated in tissue regeneration versus tissue scarring and maladaptive inflammation in adults. Integral to the macrophage stress response is the recognition of hypoxia and pathogen-associated molecular patterns (PAMPs), which are often coupled. The age-specific, cell-intrinsic nature of this stress response remains vague. To uncover age-defined divergences in macrophage crosstalk potential after exposure to hypoxia and PAMPs, we interrogated the secreted proteomes of neonatal versus adult macrophages via non-biased mass spectrometry. Through this approach, we newly identified age-specific signatures in the secretomes of neonatal versus adult macrophages in response to hypoxia and the prototypical PAMP, lipopolysaccharide (LPS). Neonatal macrophages polarized to an anti-inflammatory, regenerative phenotype protective against apoptosis and oxidative stress, dependent onhypoxia inducible transcription factor-1α(HIF-1α).In contrast, adult macrophages adopted a pro-inflammatory, glycolytic phenotypic signature consistent with pathogen killing. Taken together, these data uncover fundamental age andHIF-1αdependent macrophage programs that may be targeted to calibrate the innate immune response during stress and inflammation.
Group composition and its ontogenetic changes in marine pelagic fishes
Authors: Furuichi Sho , Suzuki Masahiro , Kamimura Yasuhiro , Yukami Ryuji 
Published: April 2024

ABSTRACTGroup living is a widespread phenomenon among animals and an important trait in fishes. Understanding group composition and its dynamics is fundamental for elucidating ecological and evolutionary processes in natural populations of gregarious animal species, including fishes, but our knowledge of group composition in marine fishes is limited. Here, we examined group composition and its ontogenetic change in two marine fishes, Japanese sardine (Sardinops melanostictus) and chub mackerel (Scomber japonicus). We found that, at the juvenile stage, groups were composed of individuals with similar body length, age, and growth history. At the sub-adult stage, although body length within a group remained similar, the within-group similarity in age and growth history decreased, approaching the level expected when groups were randomly composed. Therefore, during the early life history, individuals form groups with those spawned at approximately the same time and place (i.e., those from the same batch). As they develop, however, individuals of various origins intermingle and selectively form groups with others exhibiting similar phenotypes. We further found that environmental and geographical factors were also related to the body size and age of individuals distributed. This indicates that Japanese sardine and chub mackerel exhibit phenotype-specific and growth-stage-specific habitat use, which also contributes to the formation and maintenance of structured groups. Our findings provide valuable information on group composition, its ontogenetic change, and its underlying mechanisms in marine fishes, for which the information is limited. These insights may help to clarify ecological and evolutionary processes such as population dynamics, density-dependent phenomena, and the evolution of grouping behaviour in small pelagic fishes.
Involvement of neurons in the non-human primate anterior striatum in proactive inhibition
Authors: Yoshida Atsushi , Hikosaka Okihide 
Published: April 2024

AbstractBehaving as desired requires selecting the appropriate behavior and inhibiting the selection of inappropriate behavior. This inhibitory function involves multiple processes, such as reactive and proactive inhibition, instead of a single process. In this study, macaque monkeys were required to perform a task in which they had to sequentially select (accept) or refuse (reject) a choice. Neural activity was recorded from the anterior striatum, which is considered to be involved in behavioral inhibition, focusing on the distinction between proactive and reactive inhibitions. We identified neurons with significant activity changes during the rejection of bad objects. Cluster analysis revealed three distinct groups, of which one showed obviously increased activity during object rejection, suggesting its involvement in proactive inhibition. This activity pattern was consistent irrespective of the rejection method, indicating a role beyond mere saccadic suppression. Furthermore, minimal activity changes during the fixation task indicated that these neurons were not primarily involved in reactive inhibition. In conclusion, these findings suggest that the anterior striatum plays a crucial role in cognitive control and orchestrates goal-directed behavior through proactive inhibition, which may be critical in understanding the mechanisms of behavioral inhibition dysfunction that occur in patients with basal ganglia disease.
Morphology and synapse topography optimize linear encoding of synapse numbers inDrosophilalooming responsive descending neurons
Authors: Moreno-Sanchez Anthony , Vasserman Alexander N. , Jang HyoJong , Hina Bryce W. , von Reyn Catherine R. , Ausborn Jessica 
Published: April 2024

ABSTRACTSynapses are often precisely organized on dendritic arbors, yet the role of synaptic topography in dendritic integration remains poorly understood. Utilizing electron microscopy (EM) connectomics we investigate synaptic topography inDrosophila melanogasterlooming circuits, focusing on retinotopically tuned visual projection neurons (VPNs) that synapse onto descending neurons (DNs). Synapses of a given VPN type project to non-overlapping regions on DN dendrites. Within these spatially constrained clusters, synapses are not retinotopically organized, but instead adopt near random distributions. To investigate how this organization strategy impacts DN integration, we developed multicompartment models of DNs fitted to experimental data and using precise EM morphologies and synapse locations. We find that DN dendrite morphologies normalize EPSP amplitudes of individual synaptic inputs and that near random distributions of synapses ensure linear encoding of synapse numbers from individual VPNs. These findings illuminate how synaptic topography influences dendritic integration and suggest that linear encoding of synapse numbers may be a default strategy established through connectivity and passive neuron properties, upon which active properties and plasticity can then tune as needed.
Comparison of therapeutic effects between pulsed field ablation and cryoballoon ablation in the treatment of atrial fibrillation: a systematic review and meta-analysis
Authors: Wan Yun , Zeng Shuting , Liu FuWei , Gao Xin , Li Weidong , Liu Kaifeng , He Jie , Ji Jianqing , Luo Jun 
Published: April 2024

AbstractBackgroundPulmonary vein isolation (PVI) is the cornerstone of atrial fibrillation (AF) ablation surgery. Cryoballoon ablation (CBA), a conventional thermal ablation technique, enjoys widespread clinical application. In contrast, Pulsed field ablation (PFA) is a novel non thermal ablation technique for the treatment of atrial fibrillation (AF) patients, with safety comparable to traditional thermal ablation surgery. The present study aims to evaluate and compare the procedural efficiency and safety profiles of PFA and CBA in the management of AF.MethodWe performed a systematic search across PubMed, the Cochrane Library, and Embase databases, encompassing the literature up to February 2024, to inform our systematic review and meta-analysis. When assessing outcome indicators, the risk ratio (RR) and its corresponding 95% confidence interval (CI) were calculated for dichotomous variables. For continuous variables, the mean difference (MD) and the associated 95% CI were determined. In this context, an RR less than 1 and an MD less than 0 were considered advantageous for the PFA group.ResultIn this analysis, nine observational studies encompassing 2,875 patients with AF were included. Among these, 38% (n=1105) were treated with PFA, while 62% (n=1,770) received CBA. The results indicated that PFA was associated with a significantly shorter surgical duration compared to CBA, with a mean difference (MD) of -10.49 minutes (95% CI [-15.50, -5.49];p<0.0001). Additionally, the PFA group exhibited a reduced risk of perioperative complications relative to the CBA group, with a risk ratio (RR) of 0.52 (95% CI 0.30-0.89;p=0.02). Nevertheless, no statistically significant differences were observed when comparing the two treatment cohorts concerning fluorescence irradiation time (MD 0.71; 95% CI [-0.45, 1.86];p=0.23) and the recurrence of atrial arrhythmias during follow-up (RR 0.95; 95% CI 0.78-1.14;p=0.57).ConclusionThe outcomes of this investigation reveal that PFA holds a relative advantage over CBA in certain respects, notably by reducing both surgical duration and the incidence of perioperative complications. However, no significant distinction was identified between the two modalities concerning the duration of fluorescence irradiation or the rate of atrial arrhythmia recurrence. To enhance the robustness of these estimates, further research is needed, especially by incorporating additional randomized controlled trials.
Angelica keiskeileaves extract attenuates psychosocial stress in overcrowding-subjected rats
Authors: Siswanto Ferbian Milas 
Published: April 2024

ABSTRACTAngelica keiskeiis currently used as a popular functional food with various beneficial effects, including antioxidant, anti-obesity, anti-tumor, anti-diabetic, and anti-bacterial. A recentin vitrostudy reported thatA. keiskeiinhibits monoamine oxidases (MAOs), suggesting the antidepressant property ofA. keiskei. However,in vivostudies on laboratory animals subjected to psychosocial stress have not been conducted. In this study, the effects of anA. keiskeileaves extract (AKE) on rats undergoing chronic social overcrowding stress were explored. Six-month-old male and female Wistar rats were housed in groups of three in 12 × 12 × 18 cm cages (overcrowding) for twenty-eight days. Both male and female rats were divided into two groups (N = 10); control group received oral distilled water, whilst the other group (treatment group) received 20 mg/kgBW/day of AKE supplementation. The results showed that AKE-treated rats exhibited lower anxiety- and depressive-related behaviors than that of control stressed rats. AKE significantly decreased corticosterone and increased testosterone and estrogen levels in stressed rats. Additionally, brain tissue MDA and TNF-alpha levels were reduced, while brain neurotransmitter 5-HT and antioxidant SOD levels were elevated by the AKE. These findings suggest, for the first time, that AKE could alleviate overcrowding stress-induced behavioral, neuroendocrine, antioxidant, and inflammatory dysfunctions.A. keiskeileaves extract could potentially be used as an agonist to reduce stress and depression.GRAPHICAL ABSTRACT
Developmental defects in ectodermal appendages caused by missense mutation inedaraddgene in thenfrmangrove killifish,Kryptolebias marmoratus
Authors: Saud Hussein A. , O’Neill Paul A. , Ring Brian C. , Kudoh Tetsuhiro 
Published: April 2024

AbstractFrom an ENU-mutated mangrove killifish line R228, we have identified and isolated a novel mutant line, no-fin-ray/nfrin which fin ray development is largely reduced. Besides the reduction of the fin, thenfrmutant also exhibited other phenotype associated with ectodermal cell lineages including loss of scales, deformation in the gill structure such as decreasing the number of gill filaments, the reduction in the number of jaw teeth, pharyngeal teeth and gill rakers. Illumina RNAseq with 12 embryos each from mutants, siblings and the parental WT strain Hon9 identified a mutation in theedaraddin a highly conserved C-terminal death domain. Edaradd is known as a cytoplasmic accessory protein for the Ectodysplasin A (EDA) signalling pathway. To confirm the crucial role ofedaraddduring fin development, CRISPR RNAs were designed to knock out the gene in another killifish species, Arabian killifish. Indeed, Arabian killifishedaraddcrispants showed a potent reduction of the fin development with 100% frequency. Furthermore,EDAcrispants also showed identical phenotypes to that ofedaraddcrispants, confirming the fin defect in the mutants/crispants is caused by the signalling pathway of theEDAin the killifish species. These data demonstrate a powerful genetic approach using isogenic self-fertilising mangrove killifish as a tool for identifying mutants and their mutation, and revealed the crucial role ofedaraddin the fish fin development and other ectoderm derived epithelial tissues.
Causal Debiasing for Unknown Bias in Histopathology - A Colon Cancer Use Case
Authors: Correa-Medero Ramón , Pai Rish , Ebare Kingsley , Buchanan Daniel , Jenkins Mark A , Phipps Amanda I. , Newcomb Polly A. , Gallinger Steven , Grant Robert , Le marchand Loic , Banerjee Imon 
Published: April 2024

Advancement of AI has opened new possibility for accurate diagnosis and prognosis using digital histopathology slides which not only saves hours of expert effort but also makes the estimation more standardized and accurate. However, preserving the AI model performance on the external sites is an extremely challenging problem in the histopathology domain which is primarily due to the difference in data acquisition and/or sampling bias. Although, AI models can also learn spurious correlation, they provide unequal performance across validation population. While it is crucial to detect and remove the bias from the AI model before the clinical application, the cause of the bias is often unknown. We proposed a Causal Survival model that can reduce the effect of unknown bias by leveraging the causal reasoning framework. We use the model to predict recurrence-free survival for the colorectal cancer patients using quantitative histopathology features from seven geographically distributed sites and achieve equalized performance compared to the baseline traditional Cox Proportional Hazards and DeepSurvival model. Through ablation study, we demonstrated benefit of novel addition of latent probability adjustment and auxiliary losses. Although detection of cause of unknown bias is unsolved, we proposed a causal debiasing solution to reduce the bias and improve the AI model generalizibility on the histopathology domain across sites.
Paranormal believers are quicker but less accurate in rejecting the presence of the target in conjunction visual search compared to skeptics
Authors: Akbari Fatemeh , Asivandzadehchaharmahali Samaneh , Narmashiri Abdolvahed 
Published: April 2024

AbstractRecent studies have shown that paranormal believers may exhibit cognitive dysfunctions, yet their performance in conjunction with visual search has not been understood. To address this issue, we examined the performance of both paranormal believers and skeptics in a conjunction visual search task, paying particular attention to their search time and accuracy across different set sizes in both target-present (TP) and target-absent (TA) trials. In our study, believers demonstrated a tendency toward speed but also displayed carelessness compared to skeptics when rejecting the presence of the target. Conversely, skeptics exhibited slower search times but demonstrated greater accuracy both in rejecting the presence of the target and in finding it. Overall, our findings suggest that believers were quicker and less accurate in rejecting the presence of the target in conjunction visual search compared to skeptics, highlighting potential differences in cognitive processing between skeptics and believers.Significant statementOur study investigates the performance of paranormal believers and skeptics in conjunction with visual search tasks, shedding light on potential differences in cognitive processing between the two groups. While believers demonstrate faster search times, they also display greater carelessness compared to skeptics when rejecting the target’s presence. In contrast, skeptics exhibit slower search times but higher accuracy in both rejecting and finding the target. These findings underscore the importance of considering individual belief systems in understanding cognitive performance in conjunction with visual tasks.
Thrombospondins 1 and 4 undergo coordinated transport to multicore cytotoxic granules to regulate SMAP biogenesis and function in CTL-mediated cytotoxicity
Authors: Cassioli Chiara , Capitani Nagaja , Staton Claire C. , Schirra Claudia , Finetti Francesca , Onnis Anna , Alawar Nadia , Tu Szu-Min , Lopresti Ludovica , Tatangelo Vanessa , Tangredi Carmela , Valvo Salvatore , Chang Hsin-Fang , Miccoli Annachiara , Compeer Ewaldus B. , Nicholls Jemma , Blazar Bruce , Marotta Giuseppe , Wood Matthew J. A. , Trentin Livio , Patrussi Laura , Dustin Michael L. , Becherer Ute , Baldari Cosima T. 
Published: April 2024

AbstractSupramolecular Attack Particles (SMAPs) are particulate entities, characterized by a cytotoxic core enriched in granzymes and perforin surrounded by a glycoproteic shell, released by CTLs and NK cells. Prior proteomic analysis identified thrombospondin-1 (TSP-1) and thrombospondin-4 (TSP-4) as putative components of SMAPs. While TSP-1 has been validated as a component of the SMAP shell and shown to contribute significantly to CTL-mediated killing, the expression and function of TSP-4 in CTLs, and its interplay with TSP-1 in SMAP biogenesis and function, has not been investigated as yet. Here we demonstrate that TSP-4 and TSP-1 have a complementary expression profile during in vitro human CD8+T cell differentiation to CTLs and sequentially localize to lytic granules (LG), with TSP-4 being required for TSP-1 association with LGs. Correlative light microscopy identified the TSP-enriched LGs as the SMAP-containing multicore granules. We show by STED microscopy a heterogeneity among TSP-enriched LGs, the most abundant population being positive for both TSP-4 and TSP-1. We also show that TSP-1 and TSP-4 are co-released in association with SMAPs at immune synapses formed on planar supported lipid bilayers, as assessed by dSTORM imaging. Finally, we provide evidence that TSP-4 is required for CTL- and SMAP-mediated cell killing. Of note, we found that chronic lymphocytic leukemia (CLL) cell supernatants, which suppress CTL mediated killing, also suppress expression of TSP-4 as well as of cytolytic effectors and impair SMAP biogenesis. These results identify TSP-4 as a key player in SMAP structure and activity and suggest that SMAPs may be a new target for immune suppression by CLL.
The signalling axis CDK12-BRCA1 mediates dinaciclib associated radiosensitivity through p53-mediated cellular senescence
Authors: Flores Natalia García , Fernández-Aroca Diego M. , Garnés-García Cristina , Domínguez-Calvo Andrés , Sabater Sebastia , Andrés Ignacio , Jiménez-Suárez Jaime , Fernández-Aroca Pablo , Cimas Francisco , de Cárcer Guillermo , Belandia Borja , Palmero Ignacio , Huertas Pablo , Ruiz-Hidalgo María José , Prieto Ricardo Sánchez 
Published: April 2024

AbstractPan-CDK inhibitors are a new class of targeted therapies that can act on multiple CDKs, with dinaciclib being one of the most promising compounds. Although used as monotherapy, an interesting approach could be to combine it with radiotherapy. Here we show that dinaciclib increases radiosensitivity in some experimental models of lung and colon cancer (A549 or HCT 116) but not in others (H1299 or HT-29). Dinaciclib did not alter responses such as ATM signalling, apoptosis or cell cycle profiling after ionising radiation exposure that have been described for other CDK inhibitors. Mechanistically, inhibition of CDK12 by dinaciclib abolishes BRCA1 expression, which blocks homologous recombination (HR), leaving only the non-homologous end joining repair process (NHEJ), which ultimately promotes the induction of ionising radiation-associated cellular senescence in a p53-dependent manner, explaining the lack of effect observed in some experimental models. In conclusion, our report explains the molecular mechanism involved in this novel therapeutic effect of dinaciclib and provides a rationale for more selective and personalised chemo/radiotherapy treatment according to the genetic background of the tumour.Highlights➢Dinaciclib is a radiosensitising agent in lung and colon cancer cell lines.➢Dinaciclib promotes radiosensitivity by inhibiting CDK12 leading to a decrease in BRCA1 expression.➢Lack of BRCA1 blocks homologous recombination response to DNA damage, enhancing ionising radiation-associated senescence in a p53-dependent fashion.➢The combination of dinaciclib plus radiotherapy could be a novel treatment for tumours holding functional BRCA1 and p53 signalling.
Genetic tuning of intrinsically photosensitive retinal ganglion cell subtype identity to drive visual behavior
Authors: Aranda Marcos L. , Bhoi Jacob D. , Parra Omar A. Payán , Lee Seul Ki , Yamada Tomoko , Yang Yue , Schmidt Tiffany M. 
Published: April 2024

AbstractThe melanopsin-expressing, intrinsically photosensitive retinal ganglion cells (ipRGCs) comprise a subset of the ∼40 retinal ganglion cell types in the mouse retina and drive a diverse array of light-evoked behaviors from circadian photoentrainment to pupil constriction to contrast sensitivity for visual perception. Central to the ability of ipRGCs to control this diverse array of behaviors is the distinct complement of morphophysiological features and gene expression patterns found in the M1-M6 ipRGC subtypes. However, the genetic regulatory programs that give rise to subtypes of ipRGCs are unknown. Here, we identify the transcription factor Brn3b (Pou4f2) as a key genetic regulator that shapes the unique functions of ipRGC subtypes and their diverse downstream visual behaviors.