The dynamic recruitment of TRBP to neuronal membranes mediates dendritogenesis during development

MicroRNAs are important regulators of local protein synthesis during neuronal development. We investigated the dynamic regulation of microRNA production and found that the majority of the microRNA‐generating complex, consisting of Dicer, TRBP, and PACT, specifically associates with intracellular membranes in developing neurons. Stimulation with brain‐derived neurotrophic factor (BDNF), which promotes dendritogenesis, caused the redistribution of TRBP from the endoplasmic reticulum into the cytoplasm, and its dissociation from Dicer, in a Ca²⁺‐dependent manner. As a result, the processing of a subset of neuronal precursor microRNAs, among them the dendritically localized pre‐miR16, was impaired. Decreased production of miR‐16‐5p, which targeted the BDNF mRNA itself, was rescued by expression of a membrane‐targeted TRBP. Moreover, miR‐16‐5p or membrane‐targeted TRBP expression blocked BDNF‐induced dendritogenesis, demonstrating the importance of neuronal TRBP dynamics for activity‐dependent neuronal development. We propose that neurons employ specialized mechanisms to modulate local gene expression in dendrites, via the dynamic regulation of microRNA biogenesis factors at intracellular membranes of the endoplasmic reticulum, which in turn is crucial for neuronal dendrite complexity and therefore neuronal circuit formation and function.     

Effects of vulture exclusion on carrion consumption by facultative scavengers

Vultures provide an essential ecosystem service through removal of carrion, but globally, many populations are collapsing and several species are threatened with extinction. Widespread declines in vulture populations could increase the availability of carrion to other organisms, but the ways facultative scavengers might respond to this increase have not been thoroughly explored. We aimed to determine whether facultative scavengers increase carrion consumption in the absence of vulture competition and whether they are capable of functionally replacing vultures in the removal of carrion biomass from the landscape. We experimentally excluded 65 rabbit carcasses from vultures during daylight hours and placed an additional 65 carcasses that were accessible to vultures in forested habitat in South Carolina, USA during summer (June–August). We used motion‐activated cameras to compare carrion use by facultative scavenging species between the experimental and control carcasses. Scavenging by facultative scavengers did not increase in the absence of competition with vultures. We found no difference in scavenger presence between control carcasses and those from which vultures were excluded. Eighty percent of carcasses from which vultures were excluded were not scavenged by vertebrates, compared to 5% of carcasses that were accessible to vultures. At the end of the 7‐day trials, there was a 10.1‐fold increase in the number of experimental carcasses that were not fully scavenged compared to controls. Facultative scavengers did not functionally replace vultures during summer in our study. This finding may have been influenced by the time of the year in which the study took place, the duration of the trials, and the spacing of carcass sites. Our results suggest that under the warm and humid conditions of our study, facultative scavengers would not compensate for loss of vultures. Carcasses would persist longer in the environment and consumption of carrion would likely shift from vertebrates to decomposers. Such changes could have substantial implications for disease transmission, nutrient cycling, and ecosystem functioning.     

Twelve fundamental life histories evolving through allocation‐dependent fecundity and survival

An organism's life history is closely interlinked with its allocation of energy between growth and reproduction at different life stages. Theoretical models have established that diminishing returns from reproductive investment promote strategies with simultaneous investment into growth and reproduction (indeterminate growth) over strategies with distinct phases of growth and reproduction (determinate growth). We extend this traditional, binary classification by showing that allocation‐dependent fecundity and mortality rates allow for a large diversity of optimal allocation schedules. By analyzing a model of organisms that allocate energy between growth and reproduction, we find twelve types of optimal allocation schedules, differing qualitatively in how reproductive allocation increases with body mass. These twelve optimal allocation schedules include types with different combinations of continuous and discontinuous increase in reproduction allocation, in which phases of continuous increase can be decelerating or accelerating. We furthermore investigate how this variation influences growth curves and the expected maximum life span and body size. Our study thus reveals new links between eco‐physiological constraints and life‐history evolution and underscores how allocation‐dependent fitness components may underlie biological diversity.     

integRATE: a desirability-based data integration framework for the prioritization of candidate genes across heterogeneous omics and its application to preterm birth

Background

The integration of high-quality, genome-wide analyses offers a robust approach to elucidating genetic factors involved in complex human diseases. Even though several methods exist to integrate heterogeneous omics data, most biologists still manually select candidate genes by examining the intersection of lists of candidates stemming from analyses of different types of omics data that have been generated by imposing hard (strict) thresholds on quantitative variables, such as P-values and fold changes, increasing the chance of missing potentially important candidates.

Methods

To better facilitate the unbiased integration of heterogeneous omics data collected from diverse platforms and samples, we propose a desirability function framework for identifying candidate genes with strong evidence across data types as targets for follow-up functional analysis. Our approach is targeted towards disease systems with sparse, heterogeneous omics data, so we tested it on one such pathology: spontaneous preterm birth (sPTB).

Results

We developed the software integRATE, which uses desirability functions to rank genes both within and across studies, identifying well-supported candidate genes according to the cumulative weight of biological evidence rather than based on imposition of hard thresholds of key variables. Integrating 10 sPTB omics studies identified both genes in pathways previously suspected to be involved in sPTB as well as novel genes never before linked to this syndrome. integRATE is available as an R package on GitHub (https://github.com/haleyeidem/integRATE).

Conclusions

Desirability-based data integration is a solution most applicable in biological research areas where omics data is especially heterogeneous and sparse, allowing for the prioritization of candidate genes that can be used to inform more targeted downstream functional analyses.

     

Socioecological Factors Affecting Range Defensibility Among Howler Monkeys

Range defensibility is defined as the ability of animals to efficiently move over an area to monitor and defend it. Therefore, range defensibility can help us understand the spatial structure of animal territoriality. We used howler monkeys (Alouatta spp.), a genus for which no agreement on the extent of their territoriality exists, to investigate the factors mediating range defensibility. We compared the defensibility index (D) across 63 groups of howler monkeys, representing 8 different species, based on a literature review. All species, except Alouatta palliata, were classified as potentially territorial according to D, although there was high variability within and among species. Group size had a positive effect on D, probably owing to the greater ability of groups to defend a territory as they become larger. Study area had a negative effect on D, perhaps suggesting that unlike small areas, large areas allow groups to have territories that do not require significant defense from neighbors. However, population density was the factor with the strongest effect on D, with greater monitoring of home ranges under high levels of competition. Our results suggest that howler monkeys are theoretically capable of maintaining a territory and suggest that animals can show a gradient in territoriality, which can be mediated by the competitive context in which it occurs.     

The role of AdipoR1 and AdipoR2 in liver fibrosis

Activation of the adiponectin (APN) signaling axis retards liver fibrosis. However, understanding of the role of AdipoR1 and AdipoR2 in mediating this response is still rudimentary. Here, we sought to elucidate the APN receptor responsible for limiting liver fibrosis by employing AdipoR1 and AdipoR2 knock-out mice in the carbon tetrachloride (CCl₄) model of liver fibrosis. In addition, we knocked down receptor function in primary hepatic stellate cells (HSCs) in vitro. Following the development of fibrosis, AdipoR1 and AdipoR2 KO mice had no quantitative difference in fibrosis by Sirius red staining. However, AdipoR2 KO mice had an enhanced fibrotic signature with increased Col1-α1, TGFß-1, TIMP-1, IL-10, MMP-2 and MMP-9. Knockdown of AdipoR1 or AdipoR2 in HSCs followed by APN treatment demonstrated that AdipoR1 and AdipoR2 did not affect proliferation or TIMP-1 gene expression, while AdipoR2 modulated Col1-α1 and α-SMA gene expression, HSC migration, and AMPK activity. These finding suggest that AdipoR2 is the major APN receptor on HSCs responsible for mediating its anti-fibrotic effects.     

The human MAPT locus generates circular RNAs

The microtubule-associated protein Tau, generated by the MAPT gene is involved in dozens of neurodegenerative conditions (“tauopathies”), including Alzheimer's disease (AD) and frontotemporal lobar degeneration/frontotemporal dementia (FTLD/FTD). The pre-mRNA of MAPT is well studied and its aberrant pre-mRNA splicing is associated with frontotemporal dementia. Using a PCR screen of RNA from human brain tissues, we found that the MAPT locus generates circular RNAs through a backsplicing mechanism from exon 12 to either exon 10 or 7. MAPT circular RNAs are localized in the cytosol and contain open reading frames encoding Tau protein fragments. The MAPT exon 10 is alternatively spliced and proteins involved in its regulation, such as CLK2, SRSF7/9G8, PP1 (protein phosphatase 1) and NIPP1 (nuclear inhibitor of PP1) reduce the abundance of the circular MAPT exon 12?→?10 backsplice RNA after being transfected into cultured HEK293 cells. In summary, we report the identification of new bona fide human brain RNAs produced from the MAPT locus. These may be a component of normal human brain Tau regulation and, since the circular RNAs could generate high molecular weight proteins with multiple microtubule binding sites, they could contribute to taupathies.     

How do the suprachiasmatic nuclei of the hypothalamus integrate photoperiodic information?

The suprachiasmatic nucleus of the hypothalamus (SCN) plays an essential role in the generation and maintenance of circadian rhythms in mammals. The SCN activity is also dependent upon the photoperiod. The duration of the SCN sensitive phase to light, in term of Fos induction, is variable and tied to the length of the night. The question is how and by which pathways can photoperiod influence SCN? It is possible following the theoretical model of evening and morning component of the clock that the SCN build itself the photoperiodic signal. That the SCN integrate the photoperiodic information through indirect neural or neuroendocrine pathways is also to consider. Data in favor of these different interpretations are presented.     

The 1.25 A crystal structure of sepiapterin reductase reveals its binding mode to pterins and brain neurotransmitters.

Sepiapterin reductase catalyses the last steps in the biosynthesis of tetrahydrobiopterin, the essential co-factor of aromatic amino acid hydroxylases and nitric oxide synthases. We have determined the crystal structure of mouse sepiapterin reductase by multiple isomorphous replacement at a resolution of 1.25 A in its ternary complex with oxaloacetate and NADP. The homodimeric structure reveals a single-domain alpha/beta-fold with a central four-helix bundle connecting two seven-stranded parallel beta-sheets, each sandwiched between two arrays of three helices. Ternary complexes with the substrate sepiapterin or the product tetrahydrobiopterin were studied. Each subunit contains a specific aspartate anchor (Asp258) for pterin-substrates, which positions the substrate side chain C1'-carbonyl group near Tyr171 OH and NADP C4'N. The catalytic mechanism of SR appears to consist of a NADPH-dependent proton transfer from Tyr171 to the substrate C1' and C2' carbonyl functions accompanied by stereospecific side chain isomerization. Complex structures with the inhibitor N-acetyl serotonin show the indoleamine bound such that both reductase and isomerase activity for pterins is inhibited, but reaction with a variety of carbonyl compounds is possible. The complex structure with N-acetyl serotonin suggests the possibility for a highly specific feedback regulatory mechanism between the formation of indoleamines and pteridines in vivo.