PAPP‐A: a new anti‐aging target?

This article focuses on the role of PAPP‐A in mammalian aging. It introduces PAPP‐A and a little of its history, briefly discusses the function of PAPP‐A in the insulin‐like growth factor (IGF) system and the regulators of PAPP‐A expression, and then reviews data concerning PAPP‐A in aging and age‐related diseases especially in regard to the PAPP‐A knockout (KO) mouse. The PAPP‐A KO mouse is a valuable new model to test hypotheses concerning the control of the tissue availability of IGF, independent from systemic levels, on healthspan as well as lifespan.     

Extended incubation recesses by alpine‐breeding Horned Larks: a strategy for dealing with inclement weather?

ABSTRACT Incubating birds can incur high energetic costs and, when faced with a trade‐off between incubation and foraging, parents may neglect their eggs in favor of their own somatic needs. Extended incubation recesses are an example of neglect, but they are often treated as outliers and largely overlooked in studies of incubation behavior. We studied incubation rhythms of Horned Larks (Eremophila alpestris) on Hudson Bay Mountain, British Columbia, Canada, during four breeding seasons. Incubation recesses averaged 10.92 ± 0.38 min (N= 4076 2‐h periods), but we observed 70 extended recesses, ranging from 59 to 387 min in duration, at 35 nests. Although rare (<1% of all daytime recesses), extended recesses occurred in all 4 yr, were longer and more frequent in colder years (60% occurred in the two coldest years), and often occurred during inclement weather (39% occurred during three storm events). Extended recesses did not appear to compensate for long attendance periods because extended recess duration was not correlated with the duration of previous on‐bouts (P= 0.10, N= 70) or the mean on‐bout duration of the previous 2‐h period (P= 0.36, N= 70). Rather, extended recesses seemed to reflect a shift in parental investment away from their eggs and toward self‐maintenance when faced with energetically stressful conditions. Extended recesses may have reduced embryo viability; egg‐hatching rates were 91 ± 2.4% for nests where females did not take extended recesses and 81 ± 4.2% for nests where females did take extended recesses (P= 0.02, N= 56 nests). Extended recesses during incubation are rare events, but they may represent an important mechanism that allows birds to breed successfully in energetically challenging conditions.     

Could circRNA be a new biomarker for pre‐eclampsia?

Pre‐eclampsia is a devastating complication of pregnancy which is characterized by hypertension and proteinuria in pregnant women. Pre‐eclampsia is important as it is the leading cause of death. Moreover, untreated pre‐eclampsia might lead to other lethal complications, for both fetus and mother. Pre‐eclampsia can also affect the quality of life in affected women. Despite a large number of risk factors for pre‐eclampsia, these risk factors are able to detect just 30% of women who are susceptible to pre‐eclampsia. Heterogeneous manifestations of pre‐eclampsia necessitate the discovery of potential biomarkers required for its early detection. Circular RNAs (circRNAs) are a type of RNA which are more abundant, specific, and highly organized compared with other types of RNA. Accordingly, circRNAs have been suggested as one of the potential biomarkers for different diseases. Recently, researchers have shown interest in the effects of circRNAs in pre‐eclampsia, although the current evidence is limited. The majority of obstetricians are probably not aware of circRNAs as a useful biomarker. Here, we aimed to summarize recent supporting evidence and assess the mechanisms by which circRNAs are involved in pre‐eclampsia.     

A new gene for Tourette's syndrome: a window into causal mechanisms?

Gilles de la Tourette syndrome (GTS) is a neurodevelopmental disorder characterized by impairing motor-vocal tics. Locating genetic loci by associating the phenotype with DNA translocations, inversions, gain or losses, State et al. identified SLITRK1 as a candidate gene in an individual with GTS and inv(13) (q31.1; q33.1). This gene was also associated with abnormal axonal-dendritic development in embryonic mouse cells. Although SLITRK1 is not a major causal gene for GTS, it can shed light on our understanding of the gene-based neural correlates of this disease.     

Obesity and triple‐negative‐breast‐cancer: Is apelin a new key target?

Epidemiological studies have shown that obese subjects have an increased risk of developing triple‐negative breast cancer (TNBC) and an overall reduced survival. However, the relation between obesity and TNBC remains difficult to understand. We hypothesize that apelin, an adipokine whose levels are increased in obesity, could be a major factor contributing to both tumour growth and metastatization in TNBC obese patients. We observed that development of obesity under high‐fat diet in TNBC tumour‐bearing mice significantly increased tumour growth. By showing no effect of high‐fat diet in obesity‐resistant mice, we demonstrated the necessity to develop obesity‐related disorders to increase tumour growth. Apelin mRNA expression was also increased in the subcutaneous adipose tissue and tumours of obese mice. We further highlighted that the reproduction of obesity‐related levels of apelin in lean mice led to an increased TNBC growth and brain metastases formation. Finally, injections of the apelinergic antagonist F13A to obese mice significantly reduced TNBC growth, suggesting that apelinergic system interference could be an interesting therapeutic strategy in the context of obesity and TNBC.     

Problems with essential fatty acids: time for a new paradigm?

The term ‘essential fatty acid’ is ambiguous and inappropriately inclusive or exclusive of many polyunsaturated fatty acids. When applied most rigidly to linoleate and -linolenate, this term excludes the now well accepted but conditional dietary need for two long chain polyunsaturates (arachidonate and docosahexaenoate) during infancy. In addition, because of the concomitant absence of dietary -linolenate, essential fatty acid deficiency is a seriously flawed model that has probably led to significantly overestimating linoleate requirements. Linoleate and -linolenate are more rapidly β-oxidized and less easily replaced in tissue lipids than the common ‘non-essential’ fatty acids (palmitate, stearate, oleate). Carbon from linoleate and -linolenate is recycled into palmitate and cholesterol in amounts frequently exceeding that used to make long chain polyunsaturates. These observations represent several problems with the concept of ‘essential fatty acid’, a term that connotes a more protected and important fatty acid than those which can be made endogenously. The metabolism of essential and non-essential fatty acids is clearly much more interconnected than previously understood. Replacing the term ‘essential fatty acid’ by existing but less biased terminology, i.e. polyunsaturates, ω3 or ω6 polyunsaturates, or naming the individual fatty acid(s) in question, would improve clarity and would potentially promote broader exploration of the functional and health attributes of polyunsaturated fatty acids.     

Will a 385 million year‐struggle for light become a struggle for water and for carbon? – How trees may cope with more frequent climate change‐type drought events

Trees are exceptional organisms that have evolved over some 385 million years and have overtaken other plants in order to harvest light first. However, this advantage comes with a cost: trees must transport water all the way up to their crowns and inherent physical limitations make them vulnerable to water deficits. Because climate change scenarios predict more frequent extreme drought events, trees will increasingly need to cope with water stress. Recent occurrences of climate change‐type droughts have had severe impacts on several forest ecosystems. Initial experimental studies have been undertaken and show that stomatal control of water loss hinders carbon assimilation and could lead to starvation during droughts. Other mechanisms of drought‐induced mortality are catastrophic xylem dysfunction, impeded long‐distance transport of carbohydrates (translocation) and also symplastic failure (cellular breakdown). However, direct empirical support is absent for either hypothesis. More experimental studies are necessary to increase our understanding of these processes and to resolve the mystery of drought‐related tree mortality. Instead of testing the validity of particular hypothesis as mechanisms of drought‐induced tree mortality, future research should aim at revealing the temporal dynamics of these mechanisms in different species and over a gradient of environmental conditions. Only such studies will reveal whether the struggle for light will become a struggle for water and/or for carbon in drought‐affected areas.     

Blocking autophagy to prevent parasite differentiation: a possible new strategy for fighting parasitic infections?

The genome of Trypanosoma cruzi was surveyed for autophagy-related genes. We have identified all the essential genes except for the Atg12 conjugation system and demonstrated functionality of the putative ATG4 and ATG8 homologs. TcAtg4.1 was primarily involved in the proteolytic processing of TcAtg8.1, the ATG8-homolog that was found to be localized to autophagosomal membranes during starvation. Autophagy was also found to be strongly upregulated during differentiation between developmental stages, a process that is essential for the propagation of the parasite. Based on our work, new strategies for treatment of Chagas disease, a chronic debilitating condition still without suitable chemotherapy, can be envisioned.     

Host‐cell lipid rafts: a safe door for micro‐organisms?

The lipid raft hypothesis proposed that these microdomains are small (10–200 nM), highly dynamic and enriched in cholesterol, glycosphingolipids and signalling phospholipids, which compartmentalize cellular processes. These membrane regions play crucial roles in signal transduction, phagocytosis and secretion, as well as pathogen adhesion/interaction. Throughout evolution, many pathogens have developed mechanisms to escape from the host immune system, some of which are based on the host membrane microdomain machinery. Thus lipid rafts might be exploited by pathogens as signalling and entry platforms. In this review, we summarize the role of lipid rafts as players in the overall invasion process used by different pathogens to escape from the host immune system.     

Flexibility in a changing arctic food web: Can rough‐legged buzzards cope with changing small rodent communities?

Indirect effects of climate change are often mediated by trophic interactions and consequences for individual species depend on how they are tied into the local food web. Here we show how the response of demographic rates of an arctic bird of prey to fluctuations in small rodent abundance changed when small rodent community composition and dynamics changed, possibly under the effect of climate warming. We observed the breeding biology of rough‐legged buzzards (Buteo lagopus) at the Erkuta Tundra Monitoring Site in southern Yamal, low arctic Russia, for 19 years (1999–2017). At the same time, data on small rodent abundance were collected and information on buzzard diet was obtained from pellet dissection. The small rodent community experienced a shift from high‐amplitude cycles to dampened fluctuations paralleled with a change in species composition toward less lemmings and more voles. Buzzards clearly preferred lemmings as prey. Breeding density of buzzards was positively related to small rodent abundance, but the shift in small rodent community lead to lower numbers relative to small rodent abundance. At the same time, after the change in small rodent community, the average number of fledglings was higher relative to small rodent abundance than earlier. These results suggest that the buzzard population adapted to a certain degree to the changes in the major resource, although at the same time density declined. The documented flexibility in the short‐term response of demographic rates to changes in structure and dynamics of key food web components make it difficult to predict how complex food webs will be transformed in a warmer Arctic. The degree of plasticity of functional responses is indeed likely to vary between species and between regions, depending also on the local food web context.     

From fever to immunity: A new role for IGFBP‐6?

Fever is a fundamental response to infection and a hallmark of inflammatory disease, which has been conserved and shaped through millions of years of natural selection. Although fever is able to stimulate both innate and adaptive immune responses, the very nature of all the molecular thermosensors, the timing and the detailed mechanisms translating a physical trigger into a fundamental biological response are incompletely understood. Here we discuss the consequence of hyperthermic stress in dendritic cells (DCs), and how the sole physical input is sensed as an alert stimulus triggering a complex transition in a very narrow temporal window. Importantly, we review recent findings demonstrating the significant and specific changes discovered in gene expression and in the metabolic phenotype associated with hyperthermia in DCs. Furthermore, we discuss the results that support a model based on a thermally induced autocrine signalling, which rewires and sets a metabolism checkpoint linked to immune activation of dendritic cells. Importantly, in this context, we highlight the novel regulatory functions discovered for IGFBP‐6 protein: induction of chemotaxis; capacity to increase oxidative burst and degranulation of neutrophils, ability to induce metabolic changes in DCs. Finally, we discuss the role of IGFBP‐6 in autoimmune disease and how novel mechanistic insights could lead to exploit thermal stress‐related mechanisms in the context of cancer therapy.     

5‐Hydroxymethylcytosine: a new kid on the epigenetic block?

The discovery of the Ten‐Eleven‐Translocation (TET) oxygenases that catalyze the hydroxylation of 5‐methylcytosine (5mC) to 5‐hydroxymethylcytosine (5hmC) has triggered an avalanche of studies aiming to resolve the role of 5hmC in gene regulation if any. Hitherto, TET1 is reported to bind to CpG‐island (CGI) and bivalent promoters in mouse embryonic stem cells, whereas binding at DNAseI hypersensitive sites (HS) had escaped previous analysis. Significant enrichment/accumulation of 5hmC but not 5mC can indeed be detected at bivalent promoters and at DNaseI‐HS. Surprisingly, however, 5hmC is not detected or present at very low levels at CGI promoters notwithstanding the presence of TET1. Our meta‐analysis of DNA methylation profiling points to potential issues with regard to the various methodologies that are part of the toolbox used to detect 5mC and 5hmC. Discrepancies between published studies and technical limitations prevent an unambiguous assignment of 5hmC as a ‘true’ epigenetic mark, that is, read and interpreted by other factors and/or as a transiently accumulating intermediary product of the conversion of 5mC to unmodified cytosines.     

Oligonucleotides with isopolar phosphonate internucleotide linkage: a new perspective for antisense compounds?

Several types of isopolar modified oligothymidylates and oligoadenylates (15 mers) with the phosphonate -O-P-CH2-O- internucleotide linkage were prepared. The modified oligonucleotides were subjected to the study of their hybridization properties, resistance against nucleases, and the ability to elicit RNase H activity.     

Rubisco activase: an enzyme with a temperature‐dependent dual function?

Heat treatment of intact spinach leaves was found to induce a unique thylakoid membrane association of an approximately 40 kDa stromal protein. This protein was identified as rubisco activase. Most of the rubisco activase was sequestered to the thylakoid membrane, particularly to the stroma-exposed regions, during the first 10 min of heat treatment at 42 degrees C. At lower temperatures (38-40 degrees C) the association of rubisco activase with the thylakoid membrane occurred more slowly. The temperature-dependent association of rubisco activase with the thylakoid membrane was due to a conformational change in the rubisco activase itself, not to heat-induced alterations in the thylakoid membrane. Association of the 41 kDa isoform of rubisco activase occurred first, followed by the binding of the 45 kDa isoform to the thylakoid membrane. Fractionation of thylakoid membranes revealed a specific association of rubisco activase with thylakoid-bound polysomes. Our results suggest a temperature-dependent dual function for rubisco activase. At optimal temperatures it functions in releasing inhibitory sugar phosphates from the active site of Rubisco. During a sudden and unexpected exposure of plants to heat stress, rubisco activase is likely to manifest a second role as a chaperone in association with thylakoid-bound ribosomes, possibly protecting, as a first aid, the thylakoid associated protein synthesis machinery against heat inactivation.     

‘Stick with your own kind,or hang with the locals?’ Implications of shoaling strategy for tropical reef fish on a range‐expansion frontline

Range shifts of tropical marine species to temperate latitudes are predicted to increase as a consequence of climate change. To date, the research focus on climate‐mediated range shifts has been predominately dealt with the physiological capacity of tropical species to cope with the thermal challenges imposed by temperate latitudes. Behavioural traits of individuals in the novel temperate environment have not previously been investigated, however, they are also likely to play a key role in determining the establishment success of individual species at the range‐expansion forefront. The aim of this study was to investigate the effect of shoaling strategy on the performance of juvenile tropical reef fishes that recruit annually to temperate waters off the south east coast of Australia. Specifically, we compared body‐size distributions and the seasonal decline in abundance through time of juvenile tropical fishes that shoaled with native temperate species (‘mixed’ shoals) to those that shoaled only with conspecifics (as would be the case in their tropical range). We found that shoaling with temperate native species benefitted juvenile tropical reef fishes, with individuals in ‘mixed’ shoals attaining larger body‐sizes over the season than those in ‘tropical‐only’ shoals. This benefit in terms of population body‐size distributions was accompanied by greater social cohesion of ‘mixed’ shoals across the season. Our results highlight the impact that sociality and behavioural plasticity are likely to play in determining the impact on native fish communities of climate‐induced range expansion of coral reef fishes.