Predators modify the temperature dependence of life‐history trade‐offs

Although life histories are shaped by temperature and predation, their joint influence on the interdependence of life‐history traits is poorly understood. Shifts in one life‐history trait often necessitate shifts in another—structured in some cases by trade‐offs—leading to differing life‐history strategies among environments. The offspring size–number trade‐off connects three traits whereby a constant reproductive allocation (R) constrains how the number (O) and size (S) of offspring change. Increasing temperature and size‐independent predation decrease size at and time to reproduction which can lower R through reduced time for resource accrual or size‐constrained fecundity. We investigated how O, S, and R in a clonal population of Daphnia magna change across their first three clutches with temperature and size‐independent predation risk. Early in ontogeny, increased temperature moved O and S along a trade‐off curve (constant R) toward fewer larger offspring. Later in ontogeny, increased temperature reduced R in the no‐predator treatment through disproportionate decreases in O relative to S. In the predation treatment, R likewise decreased at warmer temperatures but to a lesser degree and more readily traded off S for O whereby the third clutch showed a constant allocation strategy of O versus S with decreasing R. Ontogenetic shifts in S and O rotated in a counterclockwise fashion as temperature increased and more drastically under risk of predation. These results show that predation risk can alter the temperature dependence of traits and their interactions through trade‐offs.     

Label‐free imaging of healthy and infarcted fetal sheep hearts by two‐photon microscopy

Coronary heart disease is one of the largest causes of death worldwide, making this a significant health care issue. A critical problem for the adult human heart is that it does not undergo effective repair in response to damage, leaving patients with a poor prognosis. Unlike the adult, fetal hearts have the ability to repair after myocardial damage. Using two‐photon microscopy, we have visualised the morphological and metabolic changes following myocardial infarction in sheep fetuses, to characterise response to cardiac injury in a mammalian model. Following myocardial infarction, fetal hearts showed no significant increase in collagen deposition in the region of the infarction, when compared to either the surrounding tissue or shams. In contrast, metabolic activity (i. e. NAD(P)H and FAD) was significantly reduced in the region of myocardial infarction, when compared to either the surrounding tissue or sham hearts. For comparison, we also imaged two hearts from preadolescent sheep (sham and myocardial infarction) and showed highly ordered collagen deposition with decreased metabolic activity within the infarcted area. Therefore, two‐photon imaging had the capacity to image both morphological and metabolic changes in response to myocardial infarction and showed differences in the response with age. Picture : Two‐photon imaging of myocardial infarction ( b and d ) enabled the visualisation of increased collagen (blue; Em=431 nm) and changes in other tissue autofluorescence (green; Em=489–606 nm) in fetal ( a and b ) and preadolescent ( c and d ) hearts, compared to shams ( a and c ). The excitation wavelength was 840 nm. Scale bars: 10 μm.

     

ADHD symptoms in healthy adults are associated with stressful life events and negative memory bias

Stressful life events, especially Childhood Trauma, predict ADHD symptoms. Childhood Trauma and negatively biased memory are risk factors for affective disorders. The association of life events and bias with ADHD symptoms may inform about the etiology of ADHD. Memory bias was tested using a computer task in N = 675 healthy adults. Life events and ADHD symptoms were assessed using questionnaires. The mediation of the association between life events and ADHD symptoms by memory bias was examined. We explored the roles of different types of life events and of ADHD symptom clusters. Life events and memory bias were associated with overall ADHD symptoms as well as inattention and hyperactivity/impulsivity symptom clusters. Memory bias mediated the association of Lifetime Life Events, specifically Childhood Trauma, with ADHD symptoms. Negatively biased memory may be a cognitive marker of the effects of Childhood Trauma on the development and/or persistence of ADHD symptoms.     

A multiplatform strategy for the discovery of conventional monoclonal antibodies that inhibit the voltage-gated potassium channel Kv1.3

Identifying monoclonal antibodies that block human voltage-gated ion channels (VGICs) is a challenging endeavor exacerbated by difficulties in producing recombinant ion channel proteins in amounts that support drug discovery programs. We have developed a general strategy to address this challenge by combining high-level expression of recombinant VGICs in Tetrahymena thermophila with immunization of phylogenetically diverse species and unique screening tools that allow deep-mining for antibodies that could potentially bind functionally important regions of the protein. Using this approach, we targeted human Kv1.3, a voltage-gated potassium channel widely recognized as a therapeutic target for the treatment of a variety of T-cell mediated autoimmune diseases. Recombinant Kv1.3 was used to generate and recover 69 full-length anti-Kv1.3 mAbs from immunized chickens and llamas, of which 10 were able to inhibit Kv1.3 current. Select antibodies were shown to be potent (IC₅₀<10 nM) and specific for Kv1.3 over related Kv1 family members, hERG and hNav1.5.     

Glycine at hypoglossal motor nucleus: genioglossus activity, CO(2) responses, and the additive effects of GABA.

There is evidence for glycine and GABA(A)-receptor-mediated inhibition of hypoglossal motoneurons in vitro. However, comparable studies have not been performed in vivo, and the interactions of such mechanisms with integrative reflex respiratory control have also not been determined. This study tests the hypotheses that glycine at the hypoglossal motor nucleus (HMN) will suppress genioglossus (GG) muscle activity, even in the presence of hypercapnic respiratory stimulation, and the effects of glycine will be blocked by strychnine. We also determined whether coapplication of glycine and muscimol (GABA(A)- receptor agonist) to the HMN is additive in suppressing GG activity. Twenty-four urethane-anesthetized, tracheotomized, and vagotomized rats were studied. Diaphragm and GG activities, the electroencephalogram, and blood pressure were recorded. Microdialysis probes were implanted into the HMN for delivery of artificial cerebrospinal fluid (control), glycine (0.0001-10 mM), or muscimol (0.1 microM). Increasing glycine at the HMN produced graded suppression of GG activity (P < 0.001), although the GG still responded to stimulation with 7% inspired CO(2) (P = 0.002). Strychnine (0.1 mM) reversed the glycine-mediated suppression of GG activity, whereas combined glycine and muscimol were additive in GG muscle suppression. It remains to be determined whether the recruitment of such glycine and GABA mechanisms explains the periods of major GG suppression in behaviors such as rapid eye movement sleep.     

Are Girls Good and Boys Bad for Parental Longevity?

Using historical data from the Utah Population Database, this analysis finds significant, consistent, but small adverse mortality effects for mothers after age 50 who had mostly sons. Examination of age-dependent effects indicates that this association increases with mother’s age. Additionally, mothers who had mostly daughters faced mortality risks that increased with age. Offspring sex composition did not have a significant effect on paternal mortality. Interaction analyses were conducted to examine the effect of offspring sex composition with regard to historical period, residential location, socioeconomic status, and childhood survival. No other interactions were found to be statistically significant. Having mostly boys remained detrimental to maternal mortality regardless of childhood survival.

Synthesis, biological evaluation and molecular modelling of N-heterocyclic dipeptide aldehydes as selective calpain inhibitors

A series of N-heterocyclic dipeptide aldehydes 4-13 have been synthesised and evaluated as inhibitors of ovine calpain 1 (o-CAPN1) and ovine calpain 2 (o-CAPN2). 5-Formyl-pyrrole 9 (IC(50) values of 290 and 25nM against o-CAPN1 and o-CAPN2, respectively) was the most potent and selective o-CAPN2 inhibitor, displaying >11-fold selectivity. The amino acid sequences of o-CAPN1 and o-CAPN2 have been determined. Because of the lack of available structural information on the ovine calpains, in silico homology models of the active site cleft of o-CAPN1 and o-CAPN2 were developed based on human calpain 1 (h-CAPN1) X-ray crystal structure (PDB code 1ZCM). These models were used to rationalise the observed SAR for compounds 4-13 and the selectivity observed for 9. The o-CAPN2 selective inhibitor 9 (CAT0059) was assayed in an in vitro ovine lens culture system and shown to successfully protect the lens from calcium-induced opacification.