Miracle-dz/UniFAR-FTUs huggingface dataset:
Hippocampal Reactivation Extends for Several Hours Following Novel Experience

New memories are believed to be consolidated over several hours of post-task sleep. The reactivation or “replay” of hippocampal cell assemblies has been proposed to provide a key mechanism for this process. However, previous studies have indicated that such replay is restricted to the first 10–30 min of post-task sleep, suggesting that it has a limited role in memory consolidation. We performed long-duration recordings in sleeping and behaving male rats and applied methods for evaluating the reactivation of neurons in pairs as well as in larger ensembles while controlling for the continued activation of ensembles already present during pre-task sleep (“preplay”). We found that cell assemblies reactivate for up to 10 h, with a half-maximum timescale of ∼6 h, in sleep following novel experience, even when corrected for preplay. We further confirmed similarly prolonged reactivation in post-task sleep of rats in other datasets that used behavior in novel environments. In contrast, we saw limited reactivation in sleep following behavior in familiar environments. Overall, our findings reconcile the duration of replay with the timescale attributed to cellular memory consolidation and provide strong support for an integral role of replay in memory. SIGNIFICANCE STATEMENT Neurons that are active during an experience reactivate again afterward during rest and sleep. This replay of ensembles of neurons has been proposed to help strengthen memories, but it has also been reported that replay occurs only in the first 10–30 min of sleep, suggesting a circumscribed role. We performed long-duration recordings in the hippocampus of rats and found that replay persists for several hours in sleep following novel experience, far beyond the limits found in previous reports based on shorter recordings. These findings reconcile the duration of replay with the hours-long timescales attributed to memory consolidation.
Tumor Microenvironment Remodeling by Intratumoral Oncolytic Vaccinia Virus Enhances the Efficacy of Immune-Checkpoint Blockade

Purpose: Cancer immunotherapy is a potent treatment modality, but its clinical benefit depends on the tumor's immune profile. Here, we used mJX-594 (JX), a targeted and GM-CSF–armed oncolytic vaccinia virus, as a strategy to remodel the tumor microenvironment (TME) and subsequently increase sensitivity to αPD-1 and/or αCTLA-4 immunotherapy. Experimental Design: The remodeling of the TME was determined using histologic, flow-cytometric, and NanoString immune profiling analyses. JX was intratumorally injected into implanted Renca kidney tumors or MMTV-PyMT transgenic mouse breast cancers with or without αPD-1 and/or αCTLA-4. Various combination regimens were used to evaluate immunotherapeutic anticancer responses. Results: Intratumoral injection of JX remodeled the TME through dynamic changes in the immune system, as shown by increased tumor-infiltrating T cells and upregulation of immune-related gene signatures. This remodeling induced conversion of a noninflamed tumor into an inflamed tumor. JX virotherapy led to enhanced abscopal effects in distant tumors, with increased intratumoral infiltration of CD8+ T cells. A depletion study revealed that GM-CSF is an indispensable regulator of anticancer efficacy of JX. Dual-combination therapy with intratumoral JX and systemic αPD-1 or αCTLA-4 further enhanced the anticancer immune response, regardless of various treatment schedules. Of note, triple combination immunotherapy with JX, αPD-1, and αCTLA-4 elicited the most potent anticancer immunity and induced complete tumor regression and long-term overall survival. Conclusions: Our results show that intratumoral JX treatment induces dramatic remodeling of the TME and more potently suppresses cancer progression with immune-checkpoint blockades by overcoming resistance to immunotherapy.
Accuracy of Nodal Staging and Outcomes of Lymphadenectomy for Non-metastatic Renal Cell Carcinoma: An Analysis of the National Cancer Database.

Lymph node dissection (LND) plays a critical role in multiple urologic malignancies [1–4]. Lymph node (LN) involvement in renal cell carcinoma (RCC) is typically associated with a poor prognosis [5]. While LND may provide diagnostic information in RCC, the therapeutic benefit remains controversial [6–10]. Several studies have suggested that LND does not confer a survival advantage in RCC patients, even in high-risk patients or those with clinical lymphadenopathy [7, 9, 10]. Conversely, other studies have found that a small subset of pN1M0 RCC patients with isolated nodal disease may have a durable long-term survival benefit after LND [6, 8] Currently, the American Urologic Association (AUA) guideline on localized renal cancer recommends performing a LND in the setting of regional lymphadenopathy [11]. Thus, we sought to examine the accuracy of clinical staging by examining the relationship between clinical lymph node (cLN) status and pathologic lymph node (pLN) status among patients who received a LND at the time of kidney surgery. We also aimed to characterize contemporary LND practice patterns and to analyze survival outcomes after LND.
Pharmacotherapy for acute migraines in children and adolescents

ABSTRACT Introduction: Migraine is increasingly recognized as an extremely burdensome and disabling disorder in both children and adolescents. A proper treatment plan is needed to improve the quality of life of both children and families as well as to minimize the risk of disease progression. Areas covered: This review focuses on the current pharmacotherapy for acute migraine in pediatric populations, taking into account specific considerations for those drugs tested in randomized, placebo-controlled trials (RCTs). Expert opinion: A large number of RCTs have documented the efficacy, tolerability, and safety of different compounds. Triptans appears more effective than placebo but results are variable and inconsistent. Almotriptan and rizatriptan are effective as oral formulations, as well as sumatriptan and zolmitriptan as both oral and nasal spray formulations. Adding non-steroidal anti-inflammatory drugs (NSAIDs) reinforces triptan’s effectiveness. Furthermore, small RCTs have documented both the efficacy of ibuprofen and the ineffectiveness of acetaminophen. Naproxen, ketoprofen, diclofenac, and indomethacin – NSAIDs effective in acute migraines in adults – should be tested also in pediatric subjects. Furthermore, the authors suggest that dopamine receptor antagonists should be considered in cases of severe migraines. Lastly, better designed RCTs are needed to fine-tune current therapeutic resources.
A stability-reversibility map unifies elasticity, plasticity, yielding, and jamming in hard sphere glasses

A stability-reversibility map unifies the response of amorphous solids to volume and shear deformations. Amorphous solids, such as glasses, have complex responses to deformations, with substantial consequences in material design and applications. In this respect, two intertwined aspects are important: stability and reversibility. It is crucial to understand, on the one hand, how a glass may become unstable due to increased plasticity under shear deformations, and, on the other hand, to what extent the response is reversible, meaning how much a system is able to recover the original configuration once the perturbation is released. Here, we focus on assemblies of hard spheres as the simplest model of amorphous solids such as colloidal glasses and granular matter. We prepare glass states quenched from equilibrium supercooled liquid states, which are obtained by using the swap Monte Carlo algorithm and correspond to a wide range of structural relaxation time scales. We exhaustively map out their stability and reversibility under volume and shear strains using extensive numerical simulations. The region on the volume-shear strain phase diagram where the original glass state remains solid is bounded by the shear yielding and the shear jamming lines that meet at a yielding-jamming crossover point. This solid phase can be further divided into two subphases: the stable glass phase, where the system deforms purely elastically and is totally reversible, and the marginal glass phase, where it experiences stochastic plastic deformations at mesoscopic scales and is partially irreversible. The details of the stability-reversibility map depend strongly on the quality of annealing of the glass. This study provides a unified framework for understanding elasticity, plasticity, yielding, and jamming in amorphous solids.
Environmental and individual predictors of 25(OH)D concentrations measured from neonatal dried blood spots in Denmark: the D-tect study.

Environmental factors such as sunshine hours, temperature and UV radiation (UVR) are known to influence seasonal fluctuations in vitamin D concentrations. However, currently there is poor understanding regarding the environmental factors or individual characteristics that best predict neonatal 25-hydroxyvitamin D (25(OH)D) concentrations. The aims of this study were to (1) identify environmental and individual determinants of 25(OH)D concentrations in newborns and (2) investigate whether environmental factors and individual characteristics could be used as proxy measures for neonatal 25(OH)D concentrations. 25-Hydroxyvitamin D3 (25(OH)D3) was measured from neonatal dried blood spots (DBS) of 1182 individuals born between 1993 and 2002. Monthly aggregated data on daily number of sunshine hours, temperature and UVR, available from 1993, were retrieved from the Danish Meteorological Institute. The individual predictors were obtained from the Danish National Birth register, and Statistics Denmark. The optimal model to predict 25(OH)D3 concentrations from neonatal DBS was the one including the following variables: UVR, temperature, maternal education, maternal smoking during pregnancy, gestational age at birth and parity. This model explained 30 % of the variation of 25(OH)D3 in the neonatal DBS. Ambient UVR in the month before the birth month was the best single-item predictor of neonatal 25(OH)D3, accounting for 24 % of its variance. Although this prediction model cannot substitute for actual blood measurements, it might prove useful in cohort studies ranking individuals in groups according to 25(OH)D3 status.
Non-motor Symptoms in Patients with Parkinson’s Disease: A Cross-sectional Survey

Background In multiple studies around the globe, non-motor symptoms (NMS) have been identified as a source of immense disability in patients with Parkinson’s disease (PD). However, there is a scarcity of data from Asia. This is the first study of the Pakistani population to assess the impact of NMS in PD on patients. Objectives To determine the frequency of NMS of PD in the Pakistani population and compare it with existing data. Methods In this cross-sectional survey, patient demographics were retrospectively collected from a tertiary care hospital neurology database. This study population comprised 97 patients at different stages of PD who presented to the neurology outpatient department. Disease severity was assessed using the Hoehn and Yahr scale. The NMS questionnaire was employed to identify the presence of NMS. Medical records were reviewed for demographic data and recent treatment history. Results The mean age was 67 years (76.3% of patients had adult onset PD and 23.7% had young onset PD). The NMS with the highest frequencies were nocturia (77.3%), urinary urgency (61.9%), constipation (59.8%), dementia (58.8%), insomnia (52.6%), and orthostatic hypotension (52.6%). The earliest manifestations of NMS were nocturia, forgetfulness, low mood, and orthostatic hypotension. Sleep abnormalities, falling episodes, and hallucinations are prevalent among patients with advanced disease. Conclusion There is a higher frequency of NMS present in the Pakistani population as compared to existing data in other populations.
Multiple chromosomal rearrangements in a hybrid zone between Littorina saxatilis ecotypes

Both classical and recent studies suggest that chromosomal inversion polymorphisms are important in adaptation and speciation. However, biases in discovery and reporting of inversions make it difficult to assess their prevalence and biological importance. Here, we use an approach based on linkage disequilibrium among markers genotyped for samples collected across a transect between contrasting habitats to detect chromosomal rearrangements de novo. We report 17 polymorphic rearrangements in a single locality for the coastal marine snail, Littorina saxatilis. Patterns of diversity in the field and of recombination in controlled crosses provide strong evidence that at least the majority of these rearrangements are inversions. Most show clinal changes in frequency between habitats, suggestive of divergent selection, but only one appears to be fixed for different arrangements in the two habitats. Consistent with widespread evidence for balancing selection on inversion polymorphisms, we argue that a combination of heterosis and divergent selection can explain the observed patterns and should be considered in other systems spanning environmental gradients.
Putative contributions of the sex chromosome proteins SOX3 and SRY to neurodevelopmental disorders

The male‐biased prevalence of certain neurodevelopmental disorders and the sex‐biased outcomes associated with stress exposure during gestation have been previously described. Here, we hypothesized that genes distinctively targeted by only one or both homologous proteins highly conserved across therian mammals, SOX3 and SRY, could induce sexual adaptive changes that result in a differential risk for neurodevelopmental disorders. ChIP‐seq/chip data showed that SOX3/SRY gene targets were expressed in different brain cell types in mice. We used orthologous human genes in rodent genomes to extend the number of SOX3/SRY set (1,721). These genes were later found to be enriched in five modules of coexpressed genes during the early and mid‐gestation periods (FDR < 0.05), independent of sexual hormones. Genes with differential expression (24, p < 0.0001) and methylation (40, p < 0.047) between sexes were overrepresented in this set. Exclusive SOX3 or SRY target genes were more associated with the late gestational and postnatal periods. Using autism as a model sex‐biased disorder, the SOX3/SRY set was enriched in autism gene databases (FDR ≤ 0.05), and there were more de novo variations from the male autism spectrum disorder (ASD) samples under the SRY peaks compared to the random peaks (p < 0.024). The comparison of coexpressed networks of SOX3/SRY target genes between male autism and control samples revealed low preservation in gene modules related to stress response (99 genes) and neurogenesis (78 genes). This study provides evidence that while SOX3 is a regulatory mechanism for both sexes, the male‐exclusive SRY also plays a role in gene regulation, suggesting a potential mechanism for sex bias in ASD.
Neurobiological responses in the adolescent striatum to being ‘tested’

&NA; While emerging research implicates the striatum in adolescents' ability to learn from feedback, little is known about how motivational contexts, such as emphasizing the evaluative nature of learning tasks, modulate adolescents' striatal learning. We used functional magnetic resonance imaging during a feedback‐based learning task, in conjunction with a within‐subject evaluative threat manipulation, to determine whether evaluation threat influences behavioral and neural responses to feedback in adolescents. On average, adolescents were less sensitive than adults to the evaluation threat. In the adolescents, the effect of evaluation threat on performance was tracked with the striatal response to performance feedback during the evaluation threat condition, such that greater striatal sensitivity correlated with greater gains in learning performance. Our findings suggest that variability in how adolescents respond to a contextual threat of evaluation and associated striatal sensitivity can facilitate enhanced learning.
Investigating the Relationship between Cerebral Blood Flow and Cognitive Function in Hemodialysis Patients.

BACKGROUND The immediate and longer-term effects of hemodialysis on cerebral circulation, cerebral structure, and cognitive function are poorly understood. METHODS In a prospective observational cohort study of 97 adults (median age 59 years) receiving chronic hemodialysis, we used transcranial Doppler ultrasound to measure cerebral arterial mean flow velocity (MFV) throughout dialysis. Using a well validated neuropsychological protocol, we assessed cognitive function during and off dialysis and after 12 months of treatment. We also used brain magnetic resonance imaging (MRI) to assess atrophy, white matter hyperintensities (WMHs), and diffusion parameters, and tested correlations between MFV, cognitive scores, and changes on MRI. RESULTS MFV declined significantly during dialysis, correlating with ultrafiltrate volumes. Percentage of decline in MFV correlated with intradialytic decline in cognitive function, including global function, executive function, and verbal fluency. At follow-up, 73 patients were available for repeat testing, 34 of whom underwent repeat MRI. In a subgroup of patients followed for 12 months of continued dialysis, percentage of decline in MFV correlated significantly with lower global and executive function and with progression of WMH burden (a marker of small vessel disease). Twelve of 15 patients who received renal transplants during follow-up had both early and follow-up off-dialysis assessments. After transplant, patients' memory (on a delayed recall test) improved significantly; increased fractional anisotropy of white matter (a measure of cerebral diffusion) in these patients correlated with improving executive function. CONCLUSIONS Patients undergoing hemodialysis experience transient decline in cerebral blood flow, correlating with intradialytic cognitive dysfunction. Progressive cerebrovascular disease occurred in those continuing dialysis, but not in transplanted patients. Cognitive function and cerebral diffusion improved after transplant.
Role of miR‐486‐5p in regulating renal cell carcinoma cell proliferation and apoptosis via TGF‐β–activated kinase 1

Renal cell carcinoma (RCC) is a common kidney tumor in adults. The role of miR‐486‐5p in RCC is unknown. The aim of our study was to identify new targets regulated by miR‐486‐5p in RCC, to obtain a deeper insight into the network and to better understand the role of these microRNAs and their targets in carcinogenesis of RCC. We performed a series of tests and found consistently lower expression levels of miR‐486‐5p in kidney cancer cells. Restoration of miR‐486‐5p expression in RCC cells could lead to the suppression of cell proliferation and the increase of cell apoptosis. Further studies demonstrated that TGF‐β–activated kinase 1 was a target gene of miR‐486‐5p in kidney cancer cells. It was also shown that C‐C motif chemokine ligand 2 (CCL2) from tumor‐associated macrophages downregulated miR‐486‐5p expression, and miR‐486‐5p inhibited RCC cell proliferation and apoptosis resistance induced by CCL2. The study demonstrates that there are potential diagnosis and therapy values of miR‐486‐5p in RCC.
Reward improves response inhibition by enhancing attentional capture

&NA; Reward plays a crucial role in enhancing response inhibition. While it is generally assumed that the process of response inhibition involves attentional capture and the stopping of action, it is unclear whether this reflects a direct impact of reward on response inhibition or rather an indirect mediation via attentional capture. Here, we employed a revised stop‐signal task (SST) that separated these two cognitive elements, by including a continue signal that required the same motor response as in go trials, but also attention to a cue, as in stop trials. We first confirmed the engagement of the right inferior frontal gyrus (IFG) during stop and continue trials, both of which required the attentional capture of the task‐relevant cue, but only one of which required motor inhibition. The pre‐supplementary motor area (pre‐SMA) was specifically activated by the contrast of the stop trials with the continue trials. The results indicated that the IFG played an important role in attentional capture by unexpected stimuli, while the pre‐SMA was responsible for the direct control of motor inhibition. Behavioral performance of the SST was improved by reward, and moreover, reward induced an increase in IFG activity. In addition, this advantageous reward effect was associated with enhanced connectivity between the anterior cingulate cortex and the IFG. These results indicated that the reward facilitation effect on response inhibition was indirect, occurring via a change in attentional processing. The present data confirm the specific function of the IFG and pre‐SMA in response inhibition and provide straightforward evidence that reward can increase attentional capture‐related activation in the IFG, which in turn improves the performance of response inhibition.
Integrin Subunit beta 8 (ITGB8) Upregulation Is an Independent Predictor of Unfavorable Survival of High-Grade Serous Ovarian Carcinoma Patients

Background ITGB8 encodes a β subunit of integrin (integrin β8), which is upregulated in some types of cancer. In the current study, we examined the expression profile of ITGB8 in serous ovarian cancer (SOVC) and investigated its potential as an independent prognostic indicator for overall survival (OS) and recurrence-free survival (RFS) in high-grade SOVC. Material/Methods A secondary study was conducted based on genomic and survival data in large online databases, including the Gene Expression Omnibus (GEO), the Human Protein Atlas (HPA), and the Cancer Genome Atlas-Ovarian cancer (TCGA-OV). Kaplan-Meier curves were generated to evaluate the association between ITGB8 expression and OS/RFS. Univariate and multivariate analysis were performed with the Cox regression model. Results ITGB8 was significantly upregulated in ovarian cancer tissues compared to that in normal ovary tissues. High-grade SOVC patients with high ITGB8 expression had significantly shorter OS and RFS compared to their low-expression counterparts. Increased ITGB8 expression might be an independent prognostic indicator of unfavorable OS (HR: 1.424, 95%CI: 1.228–1.653, p<0.001) and RFS (HR: 2.167, 95%CI: 1.507–3.114, p<0.001) in high-grade SOVC. DNA amplification was frequent (149/509, 29.3%) in high-grade SOVC patients and was associated with increased ITGB8 expression compared to the copy-neutral cases. Conclusions ITGB8 expression might be a valuable prognostic biomarker in high-grade SOVC, the expression of which might be regulated by its DNA copy numbers.