Miracle-dz/UniFAR-FTUs huggingface dataset:
Learning as an Important Privilege: A Life Span Perspective with Implications for Successful Aging

Research has demonstrated the cognitive and mental health benefits of learning new skills and content across the life span, enhancing knowledge as well as cognitive performance. We argue that the importance of this learning – which is not available equally to all – goes beyond the cognitive and mental health benefits. Learning is important for not only the maintenance, but also enhancement of functional independence in a dynamic environment, such as changes induced by the COVID-19 pandemic and technological advances. Learning difficult skills and content is a privilege because the opportunities for learning are neither guaranteed nor universal, and it requires personal and social engagement, time, motivation, and societal support. This paper highlights the importance of considering learning new skills and content as an important privilege across the life span and argues that this privilege becomes increasingly exclusionary as individuals age, when social and infrastructural support for learning decreases. We highlight research on the potential positive and negative impacts of retirement, when accessibility to learning opportunities may vary, and research on learning barriers due to low expectations and limited resources from poverty. We conclude that addressing barriers to lifelong learning would advance theories on life span cognitive development and raise the bar for successful aging. In doing so, our society might imagine and achieve previously unrealized gains in life span cognitive development, through late adulthood.
Four long noncoding RNAs act as biomarkers in lung adenocarcinoma

Abstract Introduction Lung adenocarcinoma (LUAD) is currently one of the most common malignant tumors worldwide. However, there is a lack of long noncoding RNA (lncRNA)-based effective markers for predicting the prognosis of LUAD patients. We identified four lncRNAs that can effectively predict the prognosis of LUAD patients. Methods We used data gene expression profile for 446 patients from The Cancer Genome Atlas database. The patients were randomly divided into a training set and a test set. Significant lncRNAs were identified by univariate regression. Then, multivariate regression was used to identify lncRNAs significantly associated with the survival rate. We constructed four-lncRNA risk formulas for LUAD patients and divided patients into high-risk and low-risk groups. Identified lncRNAs subsequently verified in the test set, and the clinical independence of the lncRNA model was evaluated by stratified analysis. Then mutated genes were identified in the high-risk and low-risk groups. Enrichment analysis was used to determine the relationships between lncRNAs and co-expressed genes. Finally, the accuracy of the model was verified using external database. Results A four-lncRNA signature (AC018629.1, AC122134.1, AC119424.1, and AL138789.1) has been verified in the training and test sets to be significantly associated with the overall survival of LUAD patients. Conclusions The present study demonstrated that identified four-lncRNA signature can be used as an independent prognostic biomarker for the prediction of survival of LUAD patients.
Interval‐induced metabolic perturbation determines tissue fluid shifts into skeletal muscle

Intense interval exercise has proven to be as effective as traditional endurance exercise in improving maximal oxygen uptake. Shared by these two exercise regimes is an acute reduction in plasma volume, which is a suggested stimulus behind exercise‐induced increases in blood volume and maximal oxygen uptake. This study aimed to link exercise‐induced metabolic perturbation with volume shifts into skeletal muscle tissue. Ten healthy subjects (mean age 33 ± 8 years, 5 males and 5 females) performed three 30 s all‐out sprints on a cycle ergometer. Upon cessation of exercise magnetic resonance imaging, 31Phosphorus magnetic resonance spectroscopy and blood samples were used to measure changes in muscle volume, intramuscular energy metabolites and plasma volume. Compared to pre‐exercise, muscle volume increased from 1147.1 ± 35.6 ml to 1283.3 ± 11.0 ml 8 min post‐exercise. At 30 min post‐exercise, muscle volume was still higher than pre‐exercise (1147.1 ± 35.6 vs. 1222.2 ± 6.8 ml). Plasma volume decreased by 16 ± 3% immediately post‐exercise and recovered back to – 5 ± 6% after 30 min. Principal component analysis of exercise performance, muscle and plasma volume changes as well as changes in intramuscular energy metabolites showed generally strong correlations between metabolic and physiological variables. The strongest predictor for the volume shifts of muscle and plasma was the magnitude of glucose‐6‐phosphate accumulation post‐exercise. Interval training leads to large metabolic and hemodynamic perturbations with accumulation of glucose‐6‐phosphate as a possible key event in the fluid flux between the vascular compartment and muscle tissue.
Arterial stiffness is not acutely modified by consumption of a caffeinated soft drink sweetened with high‐fructose corn syrup in young healthy adults

We tested the hypothesis that ingestion of a caffeinated soft drink sweetened with high‐fructose corn syrup acutely increases arterial stiffness. In a randomized counterbalanced, crossover design, fourteen healthy adults (25 ± 3 years, 6 women) reported to the laboratory for two experimental visits where 500 ml of tap water (H2O) or 500 ml of Mountain Dew® (a caffeinated soft drink sweetened with high‐fructose corn syrup (HFCS)) were consumed. Arterial stiffness (carotid‐to‐femoral pulse wave velocity (cfPWV)), peripheral and central blood pressures were measured pre‐consumption, 30 min post‐consumption, and 120 min post‐consumption. Prior to each measurement period, beat‐to‐beat hemodynamic measures were collected. Changes in heart rate, blood pressure, and cardiac output from pre‐consumption did not differ between trials at any timepoint (p ≥ 0.06). Moreover, changes in peripheral or central blood pressures from pre‐consumption did not differ between trials (p ≥ 0.84). Likewise, changes in cfPWV from pre‐consumption to 30 min post‐consumption (HFCS: 0.2 ± 0.3 m/s, H2O: 0.0 ± 0.3 m/s, p = 0.34) and 120 min post‐consumption (HFCS: 0.3 ± 0.4 m/s, H2O: 0.2 ± 0.3 m/s, p = 0.77) did not differ. Changes in aortic augmentation pressure, augmentation index, augmentation index corrected to a heart rate of 75 bpm, and reflection magnitude did not differ between conditions at 30 min post‐ (p ≥ 0.55) or 120 min post‐ (p ≥ 0.18) consumption. In healthy young adults, ingesting 500 ml of a commercially available caffeinated soft drink sweetened with high‐fructose corn syrup does not acutely change indices of arterial stiffness and wave reflection.
Topoisomerase I Essentiality, DnaA-Independent Chromosomal Replication, and Transcription-Replication Conflict in Escherichia coli

In all life forms, double-helical DNA exists in a topologically supercoiled state. The enzymes DNA gyrase and topoisomerase I act, respectively, to introduce and to relax negative DNA supercoils in Escherichia coli. ABSTRACT Topoisomerase I (Topo I) of Escherichia coli, encoded by topA, acts to relax negative supercoils in DNA. Topo I deficiency results in hypernegative supercoiling, formation of transcription-associated RNA-DNA hybrids (R-loops), and DnaA- and oriC-independent constitutive stable DNA replication (cSDR), but some uncertainty persists as to whether topA is essential for viability in E. coli and related enterobacteria. Here, we show that several topA alleles, including ΔtopA, confer lethality in derivatives of wild-type E. coli strain MG1655. Viability in the absence of Topo I was restored with two perturbations, neither of which reversed the hypernegative supercoiling phenotype: (i) in a reduced-genome strain (MDS42) or (ii) by an RNA polymerase (RNAP) mutation, rpoB*35, that has been reported to alleviate the deleterious consequences of RNAP backtracking and transcription-replication conflicts. Four phenotypes related to cSDR were identified for topA mutants: (i) one of the topA alleles rescued ΔdnaA lethality; (ii) in dnaA+ derivatives, Topo I deficiency generated a characteristic copy number peak in the terminus region of the chromosome; (iii) topA was synthetically lethal with rnhA (encoding RNase HI, whose deficiency also confers cSDR); and (iv) topA rnhA synthetic lethality was itself rescued by ΔdnaA. We propose that the terminal lethal consequence of hypernegative DNA supercoiling in E. coli topA mutants is RNAP backtracking during transcription elongation and associated R-loop formation, which in turn leads to transcription-replication conflicts and to cSDR. IMPORTANCE In all life forms, double-helical DNA exists in a topologically supercoiled state. The enzymes DNA gyrase and topoisomerase I act, respectively, to introduce and to relax negative DNA supercoils in Escherichia coli. That gyrase deficiency leads to bacterial death is well established, but the essentiality of topoisomerase I for viability has been less certain. This study confirms that topoisomerase I is essential for E. coli viability and suggests that in its absence, aberrant chromosomal DNA replication and excessive transcription-replication conflicts occur that are responsible for lethality.
Principles of mRNA targeting and regulation via the Arabidopsis m6A-binding proteins ECT2 and ECT3

Gene regulation dependent on N6-methyladenosine (m6A) in mRNA involves RNA-binding proteins that recognize m6A through a YTH domain. The Arabidopsis YTH-domain protein ECT2 is thought to influence mRNA 3’-end formation via binding to URU(m6A)Y sites, an unexpected conclusion given that ECT2 functions require its m6A binding activity, and that RR(m6A)CH is the m6A consensus site in all eukaryotes. Here, we apply the orthogonal techniques individual nucleotide-resolution UV-crosslinking and immunoprecipitation (iCLIP) and HyperTRIBE to define high-quality target sets of the YTH-domain proteins ECT2 and ECT3. The results show that in vivo, ECT2 does in fact bind to RR(m6A)CH. URUAY and other pyrimidine-rich motifs are enriched around, but not at m6A-sites, reflecting a preference for N6-adenosine methylation of RRACH islands in pyrimidine-rich regions. Such regions may also be implicated in ECT2-binding. In particular, a series of properties unique to the URUAY motif suggest that URUAY-type sequences act as sites of competition between unknown RNA-binding proteins and the intrinsically disordered region of ECT2. We also show that the abundance of many ECT2/3 mRNA targets is decreased in meristematic cells devoid of ECT2/3/4-activity. In contrast, loss of ECT2/3/4 activity has no effect on polyadenylation site usage in ECT2/3 targets, consistent with the exclusive cytoplasmic localization of ECT2 observed by super-resolution confocal microscopy. Our study reconciles conflicting results between genetic observations on N6-adenosine methylation and ECT2/3/4 function on the one side, and ECT2 target identification on the other, and point to regulation of cytoplasmic mRNA function, including abundance, as a mechanism of plant YTHDF action.
Genetic diversity of the LILRB1 and LILRB2 coding regions in an admixed Brazilian population sample

Leukocyte Immunoglobulin (Ig)-like Receptors (LILR) LILRB1 and LILRB2 play a pivotal role in maintaining self-tolerance and modulating the immune response through interaction with classical and non-classical Human Leukocyte Antigen (HLA) molecules. Although both diversity and natural selection patterns over HLA genes have been extensively evaluated, little information is available concerning the genetic diversity and selection signatures on the LIRB1/2 regions. Therefore, we identified the LILRB1/2 genetic diversity using next-generation sequencing in a population sample comprising 528 healthy control individuals from São Paulo State, Brazil. We identified 58 LILRB1 Single Nucleotide Variants (SNVs), which gave rise to 13 haplotypes with at least 1% of frequency. For LILRB2, we identified 41 SNVs arranged into 11 haplotypes with frequencies above 1%. We found evidence of either positive or purifying selection on LILRB1/2 coding regions. Some residues in both proteins showed to be under the effect of positive selection, suggesting that amino acid replacements in these proteins resulted in beneficial functional changes. Finally, we have shown that allelic variation (six and five amino acid exchanges in LILRB1 and LILRB2, respectively) affects the structure and/or stability of both molecules. Nonetheless, LILRB2 has shown higher average stability, with no D1/D2 residue affecting protein structure. Taken together, our findings demonstrate that LILRB1 and LILRB2 are highly polymorphic and provide strong evidence supporting the directional selection regime hypothesis.
Pairing to the microRNA 3′ region occurs through two alternative binding modes, with affinity shaped by nucleotide identity as well as pairing position

MicroRNAs (miRNAs), in association with Argonaute (AGO) proteins, direct repression by pairing to sites within mRNAs. Compared to pairing preferences of the miRNA seed region (nucleotides 2–8), preferences of the miRNA 3′ region are poorly understood, due to the sparsity of measured affinities for the many pairing possibilities. We used RNA bind-n-seq with purified AGO2–miRNA complexes to measure relative affinities of >1,000 3′-pairing architectures for each miRNA. In some cases, optimal 3′ pairing increased affinity by >500-fold. Some miRNAs had two high-affinity 3′-pairing modes—one of which included additional nucleotides bridging seed and 3′ pairing to enable high-affinity pairing to miRNA nucleotide 11. The affinity of binding and the position of optimal pairing both tracked with the occurrence of G or oligo(G/C) nucleotides within the miRNA. These and other results advance understanding of miRNA targeting, providing insight into how optimal 3′ pairing is determined for each miRNA. HIGHLIGHTS RNA bind-n-seq reveals relative affinities of >1,000 3′-pairing architectures Two distinct 3′-binding modes can enhance affinity, by >500-fold in some instances G and oligo(G/C) residues help define the miRNA 3′ segment most critical for pairing Seed mismatch identity can influence the contribution of compensatory 3′ pairing
Personality-specific pathways from peer victimization to adolescent alcohol misuse: A multilevel longitudinal moderated mediation analysis

Peer victimization is common in adolescence and have been associated with a broad variety of psychopathology and alcohol use. The present study assessed whether peer victimization has a time-varying effect on alcohol use through internalizing and externalizing symptoms and whether this indirect association throughout time is moderated by personality. This 5-year longitudinal study (3,800 grade 7 adolescents) used Bayesian multilevel moderated mediation models: independent variable was peer victimization; moderators were four personality dimensions (anxiety sensitivity, hopelessness, impulsivity, and sensation seeking); internalizing symptoms (anxiety, depressive symptoms) and externalizing symptoms (conduct, hyperactivity problems) were the mediators; and alcohol use, the outcome. Results indicated significant between, within, and lagged effects on alcohol use through internalizing and externalizing symptoms. There was significant between and within effects on alcohol use through internalizing symptoms for adolescents with high anxiety sensitivity and hopelessness, and significant between, within, and lagged effects on alcohol use through externalizing for adolescents with high impulsivity and sensation seeking. These findings implicate two risk pathways that account for how peer victimization enhances alcohol use risk and emphasize the importance of personality profiles that can shape the immediate and long-term consequences of victimization.
Developmental series of gene expression clarifies maternal mRNA provisioning and maternal-to-zygotic transition in the reef-building coral Montipora capitata

Background Maternal mRNA provisioning of oocytes regulates early embryogenesis. Maternal transcripts are degraded as zygotic genome activation (ZGA) intensifies, a phenomenon known as the maternal-to-zygotic transition (MZT). Here, we examine gene expression over nine developmental stages in the Pacific rice coral, Montipora capitata, from eggs and embryos at 1, 4, 9, 14, 22, and 36 hours-post-fertilization (hpf), as well as swimming larvae (9d), and adult colonies. Results Weighted Gene Coexpression Network Analysis revealed four expression peaks, identifying the maternal complement, two waves of the MZT, and adult expression. Gene ontology enrichment revealed maternal mRNAs are dominated by cell division, methylation, biosynthesis, metabolism, and protein/RNA processing and transport functions. The first MZT wave occurs from ∼4-14 hpf and is enriched in terms related to biosynthesis, methylation, cell division, and transcription. In contrast, functional enrichment in the second MZT wave, or ZGA, from 22 hpf-9dpf, includes ion/peptide transport and cell signaling. Finally, adult expression is enriched for functions related to signaling, metabolism, and ion/peptide transport. Our proposed MZT timing is further supported by expression of enzymes involved in zygotic transcriptional repression (Kaiso) and activation (Sox2), which peak at 14 hpf and 22 hpf, respectively. Further, DNA methylation writing (DNMT3a) and removing enzymes (TET1) peak and remain stable past ∼4 hpf, indicating that methylome programming occurs before 4 hpf. Conclusions Our high-resolution insight into the coral maternal mRNA and MZT provides essential information regarding setting the stage for, and the sensitivity of, developmental success and parental carryover effects under increasing environmental stress.
Hybridisation boosts dispersal of two contrasted ecotypes in a grass species

In the absence of strong reproductive barriers, genetic exchanges between closely related groups of organisms with different adaptations have well-documented beneficial and detrimental consequences. In plants, pollen-mediated exchanges affect the sorting of alleles across physical landscapes, and influence rates of hybridisation. How these dynamics affect the emergence and spread of novel ecological strategies remains only partially understood. We use phylogenomics and population genomics to retrace the origin of two geographically overlapping ecotypes of the African grass Alloteropsis angusta. We report the existence of a previously undescribed ecotype inhabiting miombo woodlands and grasslands. The two ecotypes have divergent nuclear genomes. However, the seed-transported chloroplast genomes are consistently shared by distinct ecotypes inhabiting the same region. These patterns suggest that the nuclear genome of one ecotype can reach the seeds of the other via pollen movements, with strong selection subsequently sorting nuclear alleles by habitat. The contrasting ecotypes of A. angusta can use each other as a gateway to new locations across a large part of Africa. Coupled with newly discovered hybridisation with the sister species A. semialata, our results show that hybridisation can facilitate the geographical dispersal of distinct ecotypes of the same grass species.
Predicting the genomic resolution of bulk segregant analysis

Bulk segregant analysis (BSA) is a technique for identifying the genetic loci that underlie phenotypic trait differences. The basic approach of this method is to compare two pools of individuals from the opposing tails of the phenotypic distribution, sampled from an interbred population. Each pool is sequenced and scanned for alleles that show divergent frequencies between the pools, indicating potential association with the observed trait differences. BSA has already been successfully applied to the mapping of various quantitative trait loci in organisms ranging from yeast to maize. However, these studies have typically suffered from rather low mapping resolution, and we still lack a detailed understanding of how this resolution is affected by experimental parameters. Here, we use coalescence theory to calculate the expected genomic resolution of BSA. We first show that in an idealized interbreeding population of infinite size, the expected length of the mapped region is inversely proportional to the recombination rate, the number of generations of interbreeding, and the number of genomes sampled, as intuitively expected. In a finite population, coalescence events in the genealogy of the sample reduce the number of potentially informative recombination events during interbreeding, thereby increasing the length of the mapped region. This is incorporated into our theory by an effective population size parameter that specifies the pairwise coalescence rate of the interbreeding population. The mapping resolution predicted by our theory closely matches numerical simulations. Furthermore, we show that the approach can easily be extended to modifications of the crossing scheme. Our framework enables researchers to predict the expected power of their mapping experiments, and to evaluate how their experimental design could be tuned to optimize mapping resolution.
A cortico-hippocampal scaffold for representing and recalling lifelike events

Real-world events are complex, featuring elements that may be unique to, or shared across, multiple situations. In the present study, we used fMRI to identify how different event components are represented in real-time and during memory retrieval. Twenty participants viewed and recalled eight videos depicting real-world events, combining people, contexts, and context types. Multi-voxel pattern similarity analyses revealed specific ‘person’ representations, persistent across contexts, in regions of an Anterior-Temporal Network. Conversely, we found specific ‘context’ representations, persistent across people, in regions of a Posterior-Medial Network. We also found schema-like generalization across contexts in medial prefrontal cortex, and episodic specificity in the hippocampus. Event patterns were reinstated during recall, and hippocampal reinstatement predicted the number of details retrieved. Finally, we observed distinct representational timescales across the hippocampus and cortical regions. These findings reveal mechanisms for scaffolding different aspects of lifelike event representations in cortico-hippocampal networks as experiences are observed and recalled.
FAN1 nuclease activity affects CAG expansion and age at onset of Huntington’s disease

The age at onset of motor symptoms in Huntington’s disease (HD) is driven by HTT CAG repeat length but modified by other genes. We used exome sequencing of 683 HD patients with extremes of onset or phenotype relative to CAG length to identify rare variants associated with clinical effect. We identified damaging coding variants in candidate modifier genes from prior genome-wide association studies associated with altered HD onset or severity. Variants in FAN1 clustered in its DNA-binding and nuclease domains and were associated predominantly with earlier onset HD. Nuclease activities of these variants correlated with residual age at motor onset of HD. Mutating endogenous FAN1 to a nuclease-inactive form in an induced pluripotent stem cell model of HD led to rates of CAG expansion comparable to those observed with complete FAN1 knock out. Together, these data implicate FAN1 nuclease activity in slowing somatic repeat expansion and hence onset of HD.