Targeted deletion of miR-132/-212 impairs memory and alters the hippocampal transcriptome

miR-132 and miR-212 are structurally related microRNAs that have been found to exert powerful modulatory effects within the central nervous system (CNS). Notably, these microRNAs are tandomly processed from the same noncoding transcript, and share a common seed sequence: thus it has been difficult to assess the distinct contribution of each microRNA to gene expression within the CNS. Here, we employed a combination of conditional knockout and transgenic mouse models to examine the contribution of the miR-132/-212 gene locus to learning and memory, and then to assess the distinct effects that each microRNA has on hippocampal gene expression. Using a conditional deletion approach, we show that miR-132/-212 double-knockout mice exhibit significant cognitive deficits in spatial memory, recognition memory, and in tests of novel object recognition. Next, we utilized transgenic miR-132 and miR-212 overexpression mouse lines and the miR-132/-212 double-knockout line to explore the distinct effects of these two miRNAs on the transcriptional profile of the hippocampus. Illumina sequencing revealed that miR-132/-212 deletion increased the expression of 1138 genes; Venn analysis showed that 96 of these genes were also downregulated in mice overexpressing miR-132. Of the 58 genes that were decreased in animals overexpressing miR-212, only four of them were also increased in the knockout line. Functional gene ontology analysis of downregulated genes revealed significant enrichment of genes related to synaptic transmission, neuronal proliferation, and morphogenesis, processes known for their roles in learning, and memory formation. These data, coupled with previous studies, firmly establish a role for the miR-132/-212 gene locus as a key regulator of cognitive capacity. Further, although miR-132 and miR-212 share a seed sequence, these data indicate that these miRNAs do not exhibit strongly overlapping mRNA targeting profiles, thus indicating that these two genes may function in a complex, nonredundant manner to shape the transcriptional profile of the CNS. The dysregulation of miR-132/-212 expression could contribute to signaling mechanisms that are involved in an array of cognitive disorders

Prokaryote genome fluidity is dependent on effective population size

Many prokaryote species are known to have fluid genomes, with different strains varying markedly in accessory gene content through the combined action of gene loss, gene gain via lateral transfer, as well as gene duplication. However, the evolutionary forces determining genome fluidity are not yet well understood. We here for the first time systematically analyse the degree to which this distinctive genomic feature differs between bacterial species. We find that genome fluidity is positively correlated with synonymous nucleotide diversity of the core genome, a measure of effective population size Ne. No effects of genome size, phylogeny or homologous recombination rate on genome fluidity were found. Our findings are consistent with a scenario where accessory gene content turnover is for a large part dictated by neutral evolution

Multivariate word properties in fluency tasks reveal markers of Alzheimer’s dementia

Version of Record online: 12 October 2023INTRODUCTION Verbal fluency tasks are common in Alzheimer's disease (AD) assessments. Yet, standard valid response counts fail to reveal disease-specific semantic memory patterns. Here, we leveraged automated word-property analysis to capture neurocognitive markers of AD vis-à-vis behavioral variant frontotemporal dementia (bvFTD). METHODS Patients and healthy controls completed two fluency tasks. We counted valid responses and computed each word's frequency, granularity, neighborhood, length, familiarity, and imageability. These features were used for group-level discrimination, patient-level identification, and correlations with executive and neural (magnetic resonanance imaging [MRI], functional MRI [fMRI], electroencephalography [EEG]) patterns. RESULTS Valid responses revealed deficits in both disorders. Conversely, frequency, granularity, and neighborhood yielded robust group- and subject-level discrimination only in AD, also predicting executive outcomes. Disease-specific cortical thickness patterns were predicted by frequency in both disorders. Default-mode and salience network hypoconnectivity, and EEG beta hypoconnectivity, were predicted by frequency and granularity only in AD. DISCUSSION Word-property analysis of fluency can boost AD characterization and diagnosis. Highlights We report novel word-property analyses of verbal fluency in AD and bvFTD. Standard valid response counts captured deficits and brain patterns in both groups. Specific word properties (e.g., frequency, granularity) were altered only in AD. Such properties predicted cognitive and neural (MRI, fMRI, EEG) patterns in AD. Word-property analysis of fluency can boost AD characterization and diagnosis.National Institutes of Health, National Institutes of Aging, Grant/Award Numbers: R01AG057234, R01AG075775; ANID: FONDECYT Regular, Grant/Award Numbers: 1210176, 1210195, 1220995; FONDAP, Grant/Award Number: 15150012; PIA/ANILLOS, Grant/Award Number: ACT210096; FONDEF, Grant/Award Number: ID20I10152; GBHI, Alzheimer’s Association, and Alzheimer’s Society: Alzheimer’s Association GBHI, Grant/Award Number: ALZ UK-22-865742; Alzheimer’s Association, Grant/Award Number: SG-20-725707; Latin American Brain Health Institute (BrainLat), Universidad Adolfo Ibáñez, Santiago, Chile, Grant/Award Number: #BL-SRGP2021-01; Programa Interdisciplinario de Investigación Experimental en Comunicación y Cognición (PIIECC), Facultad de Humanidades, USACH; Takeda, Grant/Award Number: CW2680521; Rainwater Charitable Foundation; Tau Consortium; European Commission: H2020-MSCA-IF-GFMULTI-LAND, Grant/Award Number: 10102581

Analytical and toxicological aspects of nanomaterials in different product groups: Challenges and opportunities

The widespread integration of engineered nanomaterials into consumer and industrial products creates new challenges and requires innovative approaches in terms of design, testing, reliability, and safety of nanotechnology. The aim of this review article is to give an overview of different product groups in which nanomaterials are present and outline their safety aspects for consumers. Here, release of nanomaterials and related analytical challenges and solutions as well as toxicological considerations, such as dose-metrics, are discussed. Additionally, the utilization of engineered nanomaterials as pharmaceuticals or nutraceuticals to deliver and release cargo molecules is covered. Furthermore, critical pathways for human exposure to nanomaterials, namely inhalation and ingestion, are discussed in the context of risk assessment. Analysis of NMs in food, innovative medicine or food contact materials is discussed. Specific focus is on the presence and release of nanomaterials, including whether nanomaterials can migrate from polymer nanocomposites used in food contact materials. With regard to the toxicology and toxicokinetics of nanomaterials, aspects of dose metrics of inhalation toxicity as well as ingestion toxicology and comparison between in vitro and in vivo conclusions are considered. The definition of dose descriptors to be applied in toxicological testing is emphasized. In relation to potential exposure from different products, opportunities arising from the use of advanced analytical techniques in more unique scenarios such as release of nanomaterials from medical devices such as orthopedic implants are addressed. Alongside higher product performance and complexity, further challenges regarding material characterization and safety, as well as acceptance by the general public are expected

Cortical-Bone Fragility - Insights from sFRP4 Deficiency in Pyle's Disease

BACKGROUND Cortical-bone fragility is a common feature in osteoporosis that is linked to non - vertebral fractures. Regulation of cortical-bone homeostasis has proved elusive. The study of genetic disorders of the skeleton can yield insights that fuel experimental therapeutic approaches to the treatment of rare disorders and common skeletal ailments. METHODS We evaluated four patients with Pyle’s disease, a genetic disorder that is characterized by cortical-bone thinning, limb deformity, and fractures; two patients were examined by means of exome sequencing, and two were examined by means of Sanger se - quencing. After a candidate gene was identified, we generated a knockout mouse model that manifested the phenotype and studied the mechanisms responsible for altered bone architecture. RESULTS In all affected patients, we found biallelic truncating mutations in SFR P4 , the gene encoding secreted frizzled-related protein 4, a soluble Wnt inhibitor. Mice deficient in Sfrp4 , like persons with Pyle’s disease, have increased amounts of trabecular bone and unusually thin cortical bone, as a result of differential regulation of Wnt and bone morphogenetic protein (BMP) signaling in these two bone compartments. Treat - ment of Sfrp4- deficient mice with a soluble Bmp2 receptor (RAP-661) or with anti - bodies to sclerostin corrected the cortical-bone defect. CONCLUSIONS Our study showed that Pyle’s disease was caused by a deficiency of sFRP4, that cortical- bone and trabecular-bone homeostasis were governed by different mechanisms, and that sFRP4-mediated cross-regulation between Wnt and BMP signaling was critical for achieving proper cortical-bone thickness and stability. (Funded by the Swiss Na - tional Foundation and the National Institutes of Health.

The Formation and Evolution of Massive Stellar Clusters in IC 4662

We present a multiwavelength study of the formation of massive stellar clusters, their emergence from cocoons of gas and dust, and their feedback on surrounding matter. Using data that span from radio to optical wavelengths, including Spitzer and Hubble ACS observations, we examine the population of young star clusters in the central starburst region of the irregular Wolf-Rayet galaxy IC 4662. We model the radio-to-IR spectral energy distributions of embedded clusters to determine the properties of their HII regions and dust cocoons (sizes, masses, densities, temperatures), and use near-IR and optical data with mid-IR spectroscopy to constrain the properties of the embedded clusters themselves (mass, age, extinction, excitation, abundance). The two massive star-formation regions in IC 4662 are excited by stellar populations with ages of ~ 4 million years and masses of ~ 3 x 10^5 M_sun (assuming a Kroupa IMF). They have high excitation and sub-solar abundances, and they may actually be comprised of several massive clusters rather than the single monolithic massive compact objects known as Super Star Clusters (SSCs). Mid-IR spectra reveal that these clusters have very high extinctions, A_V ~ 20-25 mag, and that the dust in IC 4662 is well-mixed with the emitting gas, not in a foreground screen.Comment: 7 pages, 11 figures, to appear in proceedings of the conference "Young Massive Star Clusters: Initial Conditions and Environments ", held in Granada, Spain, September 200

Worldwide variations in artificial skyglow

Despite constituting a widespread and significant environmental change, understanding of artificial nighttime skyglow is extremely limited. Until now, published monitoring studies have been local or regional in scope, and typically of short duration. In this first major international compilation of monitoring data we answer several key questions about skyglow properties. Skyglow is observed to vary over four orders of magnitude, a range hundreds of times larger than was the case before artificial light. Nearly all of the study sites were polluted by artificial light. A non-linear relationship is observed between the sky brightness on clear and overcast nights, with a change in behavior near the rural to urban landuse transition. Overcast skies ranged from a third darker to almost 18 times brighter than clear. Clear sky radiances estimated by the World Atlas of Artificial Night Sky Brightness were found to be overestimated by ~25%; our dataset will play an important role in the calibration and ground truthing of future skyglow models. Most of the brightly lit sites darkened as the night progressed, typically by ~5% per hour. The great variation in skyglow radiance observed from site-to-site and with changing meteorological conditions underlines the need for a long-term international monitoring program

Investigations into the killing activity of an antimicrobial peptide active against extensively antibiotic-resistant K. pneumoniae and P. aeruginosa

SET-M33 is a multimeric antimicrobial peptide active against Gram-negative bacteria in vitro and in vivo. Insights into its killing mechanism could elucidate correlations with selectivity. SET-M33 showed concentration-dependent bactericidal activity against colistin-susceptible and resistant isolates of P. aeruginosa and K. pneumoniae. Scanning and transmission microscopy studies showed that SET-M33 generated cell blisters, blebs, membrane stacks and deep craters in K. pneumoniae and P. aeruginosa cells. NMR analysis and CD spectra in the presence of sodium dodecyl sulfate micelles showed a transition from an unstructured state to a stable α-helix, driving the peptide to arrange itself on the surface of micelles. SET-M33 kills Gram-negative bacteria after an initial interaction with bacterial LPS. The molecule becomes then embedded in the outer membrane surface, thereby impairing cell function. This activity of SET-M33, in contrast to other similar antimicrobial peptides such as colistin, does not generate resistant mutants after 24h of exposure, non-specific interactions or toxicity against eukaryotic cell membranes, suggesting that SET-M33 is a promising new option for the treatment of Gram-negative antibiotic-resistant infections