The Effects of a Novel Non-catechol Dopamine Partial Agonist on Working Memory in the Aged Rhesus Monkey

Aged-related declines in cognition, especially working memory and executive function, begin in middle-age and these abilities are known to be mediated by the prefrontal cortex (PFC) and more specifically the dopamine (DA) system within the PFC. In both humans and monkeys, there is significant evidence that the PFC is the first cortical region to change with age and the PFC appears to be particularly vulnerable to age-related loss of dopamine (DA). Therefore, the DA system is a strong candidate for therapeutic intervention to slow or reverse age related declines in cognition. In the present study, we administered a novel selective, potent, non-catechol DA D1 R agonist PF-6294 (Pfizer, Inc.) to aged female rhesus monkeys and assessed their performance on two benchmark tasks of working memory – the Delayed Non-match to Sample Task (DNMS) and Delayed Recognition Span Task (DRST). The DNMS task was administered first with the standard 10 s delay and then with 5 min delays, with and without distractors. The DRST was administered each day with four trials with unique sequences and one trial of a repeated sequence to assess evidence learning and retention. Overall, there was no significant effect of drug on performance on any aspect of the DNMS task. In contrast, we demonstrated that a middle range dose of PF-6294 significantly increased memory span on the DRST on the first and last days of testing and by the last day of testing the increased memory span was driven by the performance on the repeated trials.

Telomere Roles in Fungal Genome Evolution and Adaptation

Telomeres form the ends of linear chromosomes and usually comprise protein complexes that bind to simple repeated sequence motifs that are added to the 3′ ends of DNA by the telomerase reverse transcriptase (TERT). One of the primary functions attributed to telomeres is to solve the “end-replication problem” which, if left unaddressed, would cause gradual, inexorable attrition of sequences from the chromosome ends and, eventually, loss of viability. Telomere-binding proteins also protect the chromosome from 5′ to 3′ exonuclease action, and disguise the chromosome ends from the double-strand break repair machinery whose illegitimate action potentially generates catastrophic chromosome aberrations. Telomeres are of special interest in the blast fungus, Pyricularia, because the adjacent regions are enriched in genes controlling interactions with host plants, and the chromosome ends show enhanced polymorphism and genetic instability. Previously, we showed that telomere instability in some P. oryzae strains is caused by novel retrotransposons (MoTeRs) that insert in telomere repeats, generating interstitial telomere sequences that drive frequent, break-induced rearrangements. Here, we sought to gain further insight on telomeric involvement in shaping Pyricularia genome architecture by characterizing sequence polymorphisms at chromosome ends, and surrounding internalized MoTeR loci (relics) and interstitial telomere repeats. This provided evidence that telomere dynamics have played historical, and likely ongoing, roles in shaping the Pyricularia genome. We further demonstrate that even telomeres lacking MoTeR insertions are poorly preserved, such that the telomere-adjacent sequences exhibit frequent presence/absence polymorphism, as well as exchanges with the genome interior. Using TERT knockout experiments, we characterized chromosomal responses to failed telomere maintenance which suggested that much of the MoTeR relic-/interstitial telomere-associated polymorphism could be driven by compromised telomere function. Finally, we describe three possible examples of a phenomenon known as “Adaptive Telomere Failure,” where spontaneous losses of telomere maintenance drive rapid accumulation of sequence polymorphism with possible adaptive advantages. Together, our data suggest that telomere maintenance is frequently compromised in Pyricularia but the chromosome alterations resulting from telomere failure are not as catastrophic as prior research would predict, and may, in fact, be potent drivers of adaptive polymorphism.

Improved Cell Selectivity of Pseudin-2 via Substitution in the Leucine-Zipper Motif: In Vitro and In Vivo Antifungal Activity

Several antimicrobial peptides (AMPs) have been discovered, developed, and purified from natural sources and peptide engineering; however, the clinical applications of these AMPs are limited owing to their lack of abundance and side effects related to cytotoxicity, immunogenicity, and hemolytic activity. Accordingly, to improve cell selectivity for pseudin-2, an AMP from Pseudis paradoxa skin, in mammalian cells and pathogenic fungi, the sequence of pseudin-2 was modified by alanine or lysine at each position of two amino acids within the leucine-zipper motif. Alanine-substituted variants were highly selective toward fungi over HaCaT and erythrocytes and maintained their antifungal activities and mode of action (membranolysis). However, the antifungal activities of lysine-substituted peptides were reduced, and the compound could penetrate into fungal cells, followed by induction of mitochondrial reactive oxygen species and cell death. In vivo antifungal assays of analogous peptide showed excellent antifungal efficiency in a Candida tropicalis skin infection mouse model. Our results demonstrated the usefulness of selective amino acid substitution in the repeated sequence of the leucine-zipper motif for the design of AMPs with potent antimicrobial activities and low toxicity.

DASRS Rest: Um Algoritmo Eficiente de Detecção de Anomalias em Tempo Real para Data Centers

A grande quantidade de equipamentos, com diferentes configurações, e atualizações constantes de software e hardware em data centers, tornam difícil o uso de sistemas de monitoração baseados na configuração de thresholds. Este artigo propõe utilizar detecção de anomalias para prevenção de falhas e apresenta o algoritmo Decreased Anomaly Score by Repeated Sequence (DASRS) Rest, que detecta anomalias sem exigir conhecimento prévio do serviço monitorado. Avaliamos o desempenho do DASRS Rest utilizando o framework Numenta Anomaly Benchmark (NAB). O algoritmo proposto possui bons resultados de acurácia, o menor consumo de memória e é o mais rápido, quando comparado com diversos algoritmos do estado da arte.

Complete Genome Sequence of the Naegleria fowleri (Strain LEE) Closed Circular Extrachromosomal Ribosomal DNA Element

ABSTRACT The circular extrachromosomal ribosomal DNA (rDNA) element of Naegleria fowleri strain LEE was molecularly cloned and fully sequenced. The element comprises 15,786 bp and contains a single copy of the organism’s rDNA cistron. The nonribosomal sequence contains five potential open reading frames, two large direct repeat sequences, and numerous smaller repeated-sequence regions.

Development of a karyotype associated with the genome map and its applications in identification and characterization of chromosomes in peanut

Background Chromosomal structural variants are important materials for crop breeding and genetic research. Oligo fluorescence in situ hybridization (oligo FISH) is a useful tool for the identification of chromosomal structural variants. Results We developed 114 new repetitive oligos based on genome-wide tandem repeats (TRs) using genomic reference sequences of the cultivar Tifrunner and the diploid species Arachis ipaensis by bioinformatics and FISH. These oligo probes were positioned and classified into 28 types. Signals produced by representative probes from eight types were in the secondary constriction, middle arm, and terminal regions; signals of four probe types were on the B subgenome; and one probe being able to produce signals on only one pair of chromosomes could be used to recognize a special genome or chromosomes of peanut. Based on new and previous oligo probes, we developed a cocktail Multiplex #3 including FAM modified TIF-439, TIF-185-1, TIF-134-3, TIF-165-3, and TAMRA modified Ipa-1162, Ipa-1137, DP-1, and DP-5, which combined with the total genomic DNA of A. duranensis and A. ipaensis probes, and 45S rDNA and 5S rDNA probes to establish a karyotype associated with the genome map of peanut and identify 14 chromosomal structural variants. Conclusions The new oligo probes are useful and convenient for distinguishing peanut chromosomes or specific segments of peanut chromosomes. Comparisons of oligo sites in the karyotype and chromosome plots of electronic location revealed the characteristics of repeated sequences, and showed that the assembly of repeated sequence in peanut genomic reference sequence was incomplete. We therefor demonstrated the great potentials of the new oligo probes in facilitating chromosome identification and characterization, and provided novel materials for further study and genetic improvement of peanut.

Capacity of short-term memory in dyslexia is reduced due to less efficient utilization of items’ long-term frequency

Dyslexia, defined as a specific impairment in decoding the written script, is the most widespread learning difficulty. However, individuals with dyslexia (IDDs) also consistently manifest reduced short-term memory (STM) capacity, typically measured by Digit Span or non-word repetition tasks. In this paper we report two experiments which test the effect of item frequency and the effect of a repeated sequence on the performance in STM tasks in good readers and in IDDs. IDDs’ performance benefited less from item frequency, revealing poor use of long-term single item statistics. This pattern suggests that the amply reported shorter verbal spans in dyslexia may in fact reflect their impaired sensitivity to items’ long-term frequency. For repeated sequence learning, we found no significant deficit among IDDs, even when a sensitive paradigm and a robust measure were used.

The B-side of Xist

Female mammals express the long noncoding X inactivation-specific transcript (Xist) RNA to initiate X chromosome inactivation (XCI) that eventually results in the formation of the Barr body. Xist encompasses half a dozen repeated sequence stretches containing motifs for RNA-binding proteins that recruit effector complexes with functions for silencing genes and establishing a repressive chromatin configuration. Functional characterization of these effector proteins unveils the cooperation of a number of pathways to repress genes on the inactive X chromosome. Mechanistic insights can be extended to other noncoding RNAs with similar structure and open avenues for the design of new therapies to switch off gene expression. Here we review recent advances in the understanding of Xist and on this basis try to synthesize a model for the initiation of XCI.

IW And-type state in IM Eridani

IW And stars are a recently recognized group of dwarf novae which are characterized by a repeated sequence of brightening from a standstill-like phase with damping oscillations followed by a deep dip. Kimura et al. (2019, PASJ, submitted) recently proposed a model based on thermal-viscous disk instability in a tilted disk to reproduce the IW And-type characteristics. IM Eri experienced the IW And-type phase in 2018 and we recorded three cycles of the (damping) oscillation phase terminated by brightening. We identified two periods during the IW And-type state: 4–5 d small-amplitude (often damping) oscillations and a 34–43 d long cycle. This behavior is typical for an IW And-type star. The object gradually brightened within the long cycle before the next brightening, which terminated the (damping) oscillation phase. This observation agrees with the increasing disk mass during the long cycle predicted by the Kimura et al. model of thermal-viscous disk instability in a tilted disk. We did not, however, succeed in detecting negative superhumps, which are considered to be the signature of a tilted disk.

THE AGING BRAIN AND MOTOR LEARNING

The effect of aging on motor learning is poorly understood. This study investigated response time and patterns of brain activation induced over the course of a bimanual motor learning task in three age groups. Twenty-two cognitively unimpaired participants (32%women) were grouped into Young (<35,n=6), Middle-Age (36-59,n=10), and Old (60+,n=6). A self-paced bimanual motor learning task was performed during fMRI. The task consisted of using 2 capital and 2 lower case letters in strings of 16 cues with 6 novel alternating with 6 repeated sequence blocks. To assess learning, a repeated measures ANOVA tested whether average time per slide differed over time between novel and sequence conditions. Voxel-wise changes in brain activation between novel and sequence conditions over time were examined using a within-subject repeated measures model. Faster initial time per slide was associated with younger age (p0.05). Old had increased brain activation in repeated sequence than novel conditions in right postcentral and superior parietal regions during the early half of the task compared to the second half (p0.05). We found behavioral evidence of motor learning in Middle-Age and Old, but not Young, perhaps because younger individuals performed quickly and learned sequence almost immediately. Among older individuals, sequence-specific learning in parietal regions challenges the view that it is mediated by only motor areas.