Cortical miR-709 links glutamatergic signaling to NREM sleep EEG slow waves in an activity-dependent manner.

MicroRNAs (miRNAs) are key post-transcriptional regulators of gene expression that have been implicated in a plethora of neuronal processes. Nevertheless, their role in regulating brain activity in the context of sleep has so far received little attention. To test their involvement, we deleted mature miRNAs in post-mitotic neurons at two developmental ages, i.e., in early adulthood using conditional Dicer knockout (cKO) mice and in adult mice using an inducible conditional Dicer cKO (icKO) line. In both models, electroencephalographic (EEG) activity was affected and the response to sleep deprivation (SD) altered; while the rapid-eye-movement sleep (REMS) rebound was compromised in both, the increase in EEG delta (1 to 4 Hz) power during non-REMS (NREMS) was smaller in cKO mice and larger in icKO mice compared to controls. We subsequently investigated the effects of SD on the forebrain miRNA transcriptome and found that the expression of 48 miRNAs was affected, and in particular that of the activity-dependent miR-709. In vivo inhibition of miR-709 in the brain increased EEG power during NREMS in the slow-delta (0.75 to 1.75 Hz) range, particularly after periods of prolonged wakefulness. Transcriptome analysis of primary cortical neurons in vitro revealed that miR-709 regulates genes involved in glutamatergic neurotransmission. A subset of these genes was also affected in the cortices of sleep-deprived, miR-709-inhibited mice. Our data implicate miRNAs in the regulation of EEG activity and indicate that miR-709 links neuronal activity during wakefulness to brain synchrony during sleep through the regulation of glutamatergic signaling

Deficiency of the miR-29a/b-1 cluster leads to ataxic features and cerebellar alterations in mice

miR-29 is expressed strongly in the brain and alterations in expression have been linked to several neurological disorders. To further explore the function of this miRNA in the brain, we generated miR-29a/b-1 knockout animals. Knockout mice develop a progressive disorder characterized by locomotor impairment and ataxia. The different members of the miR-29 family are strongly expressed in neurons of the olfactory bulb, the hippocampus and in the Purkinje cells of the cerebellum. Morphological analysis showed that Purkinje cells are smaller and display less dendritic arborisation compared to their wildtype littermates. In addition, a decreased number of parallel fibers form synapses on the Purkinje cells. We identified several mRNAs significantly up-regulated in the absence of the miR-29a/b-1 cluster. At the protein level, however, the voltage-gated potassium channel Kcnc3 (Kv3.3) was significantly up-regulated in the cerebella of the miR-29a/b knockout mice. Dysregulation of KCNC3 expression may contribute to the ataxic phenotype

Maternal Diet Quality During Pregnancy and Offspring Hepatic Fat in Early Childhood: The Healthy Start Study

Background: Overnutrition in utero may increase offspring risk of nonalcoholic fatty liver disease (NAFLD), but the specific contribution of maternal diet quality during pregnancy to this association remains understudied in humans. Objectives: This study aimed to examine the associations of maternal diet quality during pregnancy with offspring hepatic fat in early childhood (median: 5 y old, range: 4–8 y old). Methods: Data were from 278 mother–child pairs in the longitudinal, Colorado-based Healthy Start Study. Multiple 24-h recalls were collected from mothers during pregnancy on a monthly basis (median: 3 recalls, range: 1–8 recalls starting after enrollment), and used to estimate maternal usual nutrient intakes and dietary pattern scores [Healthy Eating Index-2010 (HEI-2010), Dietary Inflammatory Index (DII), and Relative Mediterranean Diet Score (rMED)]. Offspring hepatic fat was measured in early childhood by MRI. Associations of maternal dietary predictors during pregnancy with offspring log-transformed hepatic fat were assessed using linear regression models adjusted for offspring demographics, maternal/perinatal confounders, and maternal total energy intake. Results: Higher maternal fiber intake and rMED scores during pregnancy were associated with lower offspring hepatic fat in early childhood in fully adjusted models [Back-transformed β (95% CI): 0.82 (0.72, 0.94) per 5 g/1000 kcal fiber; 0.93 (0.88, 0.99) per 1 SD for rMED]. In contrast, higher maternal total sugar and added sugar intakes, and DII scores were associated with higher offspring hepatic fat [Back-transformed β (95% CI): 1.18 (1.05, 1.32) per 5% kcal/d added sugar; 1.08 (0.99, 1.18) per 1 SD for DII]. Analyses of dietary pattern subcomponents also revealed that lower maternal intakes of green vegetables and legumes and higher intake of “empty calories” were associated with higher offspring hepatic fat in early childhood. Conclusions: Poorer maternal diet quality during pregnancy was associated with greater offspring susceptibility to hepatic fat in early childhood. Our findings provide insights into potential perinatal targets for the primordial prevention of pediatric NAFLD

Evolutionary significance of phenotypic accommodation in novel environments: an empirical test of the Baldwin effect

When faced with changing environments, organisms rapidly mount physiological and behavioural responses, accommodating new environmental inputs in their functioning. The ubiquity of this process contrasts with our ignorance of its evolutionary significance: whereas within-generation accommodation of novel external inputs has clear fitness consequences, current evolutionary theory cannot easily link functional importance and inheritance of novel accommodations. One hundred and twelve years ago, J. M. Baldwin, H. F. Osborn and C. L. Morgan proposed a process (later termed the Baldwin effect) by which non-heritable developmental accommodation of novel inputs, which makes an organism fit in its current environment, can become internalized in a lineage and affect the course of evolution. The defining features of this process are initial overproduction of random (with respect to fitness) developmental variation, followed by within-generation accommodation of a subset of this variation by developmental or functional systems (‘organic selection’), ensuring the organism's fit and survival. Subsequent natural selection sorts among resultant developmental variants, which, if recurrent and consistently favoured, can be inherited when existing genetic variance includes developmental components of individual modifications or when the ability to accommodate novel inputs is itself heritable. Here, I show that this process is consistent with the origin of novel adaptations during colonization of North America by the house finch. The induction of developmental variation by novel environments of this species's expanding range was followed by homeostatic channelling, phenotypic accommodation and directional cross-generational transfer of a subset of induced developmental outcomes favoured by natural selection. These results emphasize three principal points. First, contemporary novel adaptations result mostly from reorganization of existing structures that shape newly expressed variation, giving natural selection an appearance of a creative force. Second, evolutionary innovations and maintenance of adaptations are different processes. Third, both the Baldwin and parental effects are probably a transient state in an evolutionary cycle connecting initial phenotypic retention of adaptive changes and their eventual genetic determination and, thus, the origin of adaptation and evolutionary change

The international EAACI/GA²LEN/EuroGuiDerm/APAAACI guideline for the definition, classification, diagnosis, and management of urticaria

This update and revision of the international guideline for urticaria was developed following the methods recommended by Cochrane and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) working group. It is a joint initiative of the Dermatology Section of the European Academy of Allergology and Clinical Immunology (EAACI), the Global Allergy and Asthma European Network (GA²LEN) and its Urticaria and Angioedema Centers of Reference and Excellence (UCAREs and ACAREs), the European Dermatology Forum (EDF; EuroGuiDerm), and the Asia Pacific Association of Allergy, Asthma and Clinical Immunology with the participation of 64 delegates of 50 national and international societies and from 31 countries. The consensus conference was held on 3 December 2020. This guideline was acknowledged and accepted by the European Union of Medical Specialists (UEMS). Urticaria is a frequent, mast cell–driven disease that presents with wheals, angioedema, or both. The lifetime prevalence for acute urticaria is approximately 20%. Chronic spontaneous or inducible urticaria is disabling, impairs quality of life, and affects performance at work and school. This updated version of the international guideline for urticaria covers the definition and classification of urticaria and outlines expert-guided and evidence-based diagnostic and therapeutic approaches for the different subtypes of urticaria. © 2021 GA²LEN. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd

The Biology of the Presenilin Complexes

APP proteolytic processing Alzheimer's Disease (AD) is characterized by the deposition of two kinds of abnormal protein aggregates, senile plaques and neurofibrillary tangles, and by neuronal dysfunction and cell loss in the brain. Senile plaques are primarily composed of extracellular deposits of hydrophobic 37-43 amino acid Aβ peptides. Aβ peptides are derived by successive enzymatic cleavages of the type I membrane protein, β-amyloid precursor protein (APP) (Haass and Selkoe 1993). APP is first cleaved close to the membrane in the extracellular domain by either α-or β-secretase, resulting in a release of soluble APP ectodomains, and residual membrane-tethered C-terminal protein stubs, termed C83 or C99, respectively (The numbers indicate the length of each carboxylterminal fragment). C83 and C99 are substrates for γ-secretase, an activity that generates p3 and Aβ peptides, respectively. γ-Secretase processes substrates at different positions within the membrane domain and thus, both Aβ and p3 have "ragged" termini. Aβ has been best studied in this regard and species between 37 and 43 amino acid residues have been identified. γ-Secretase cleavage of APP also releases the intracellular carboxy-terminal "APP intracellular domain" or "AICD". The function of both Aβ and AICD is the subject of intense investigations. Because Aβ42 is the primary constituent of the amyloid fibrils deposited in the AD brains, and mutations in APP and presenilin enhance the production of this peptide, γ-secretase cleavage of APP is a pivotal step in AD pathogenesis. It is striking that this proteolytic reaction occurs within the highly hydrophobic environment of the membrane. Identification of presenilin Genetic studies in familial AD (FAD) cases have identified disease-linked mutations in three genes that contribute to AD. The first pathogenic mutations in early-onset FAD families were found in the APP gene on chromosome 21 (Chartier-Harlin et al. 1991; Goate et al. 1991; Murrell et al. 1991). However, subsequent studies indicated that mutations in APP account only for a small fraction of FAD cases. Several genetic studies indicated a major locus for FAD on chromosome 14 in early onset autosomal dominant AD, and in 1995, the Presenilin1 (PS1) gene on chromosome 14 (14q24.3) was identified by positional cloning (Sherrington et al. 1995). Shortly thereafter, it was shown that mutations in the closely related PS2 gene on chromosome 1 (1q42.2) could cause FAD as well (Levy-Lahad et al. 1995; Rogaev et al. 1995). Studies in transgenic mice (Borchelt et al. 1996; Duff et al. 1996) and cultured cells (Citron et al. 1997; Scheuner et al. 1996; Tomita et al. 1997) have revealed that expression of FAD-linked PS variants elevates Aβ42/Aβ40 ratios. Moreover, transgenic mice that co-express FAD-mutant PS1 and APP develop amyloid plaques much earlier than age-matched mutant APP mice (Borchelt et al. 1997). Therefore, PS mutations cause a change in the Aβ42/40 ratio, but whether PS is directly involved in γ-secretase processing of APP was unclear. However, in PS-deficient neurons and fibroblasts, APP processing was greatly impaired, leading to the accumulation of the C83 and C99 APP fragments, the direct substrates of γ-secretase, and inhibition of Aβ (and p3) generation (De Strooper et al. 1998; Xia et al. 1998). Thus, PS are directly required for γ-secretase cleavage of APP. Overall, the findings imply that mutations in the substrate (APP) or in the proteolytic machinery (PS) result in similar changes in Aβ42 generation (Scheuner et al. 1996). This provides very strong support for the "amyloid cascade hypothesis". © 2007 Springer Science+Business Media, LLC. All rights reserved