Review: Closing nutrient cycles for animal production - Current and future agroecological and socio-economic issues.

We face an urgent and complex challenge to produce large amounts of healthful animal and plant foods for an estimated 10 billion people by 2050 while maintaining essential ecosystem services. To compound this challenge, we must do so while not further degrading our environment and conserving essential nutrients such as copper, magnesium, phosphorus, selenium, and zinc that are in short supply for fertilization. Much good research has been done, but to meet this challenge, we need to greatly increase on-farm and watershed-scale research including on-farm evaluations and demonstrations of the putative best combinations of stewardship techniques over multiple years in real-world settings, which are backed by data on nutrient inputs, soil, air, and water chemistry (fluxes) and water discharge. We also need to work with farmers, specialists, and generalists in highly creative interdisciplinary teams that resist forming silos and that use combinations of techniques linked to agroecology and industrial ecology in combination with state-of-the-art engineering. Some of these research and demonstration farms need to be in catchments prone to pollution of aquatic and terrestrial ecosystems with nitrogen, phosphorus, and other nutrients. Some promising approaches include mixed crop-livestock systems, although these alone may not be productive enough without updating to meet the dietary needs of an estimated 10 billion people by 2050. Other approaches could be state-of-the-art multi-trophic production systems, which include several species of plants integrated into production with vertebrates (e.g., ruminants, pigs, poultry), invertebrates (e.g., insects, earthworms) and fish, shrimp, or crayfish to utilize wasted feed and excreta, and recycle nutrients back to the animals (via plants or invertebrates) in the systems. To cut costs and increase desirable outputs, we must recycle nutrients much better within our food production systems and produce both animal and plant foods more efficiently as nutrients cycle through systems.

Evolutionary divergence of the necroptosis effector MLKL.

The pseudokinase, MLKL (mixed-lineage kinase domain-like), is the most terminal obligatory component of the necroptosis cell death pathway known. Phosphorylation of the MLKL pseudokinase domain by the protein kinase, receptor interacting protein kinase-3 (RIPK3), is known to be the key step in MLKL activation. This phosphorylation event is believed to trigger a molecular switch, leading to exposure of the N-terminal four-helix bundle (4HB) domain of MLKL, its oligomerization, membrane translocation and ultimately cell death. To examine how well this process is evolutionarily conserved, we analysed the function of MLKL orthologues. Surprisingly, and unlike their mouse, horse and frog counterparts, human, chicken and stickleback 4HB domains were unable to induce cell death when expressed in murine fibroblasts. Forced dimerization of the human MLKL 4HB domain overcame this defect and triggered cell death in human and mouse cell lines. Furthermore, recombinant proteins from mouse, frog, human and chicken MLKL, all of which contained a 4HB domain, permeabilized liposomes, and were most effective on those designed to mimic plasma membrane composition. These studies demonstrate that the membrane-permeabilization function of the 4HB domain is evolutionarily conserved, but reveal that execution of necroptotic death by it relies on additional factors that are poorly conserved even among closely related species.

RIPK1- and RIPK3-induced cell death mode is determined by target availability.

Both receptor-interacting protein kinase 1 (RIPK1) and RIPK3 can signal cell death following death receptor ligation. To study the requirements for RIPK-triggered cell death in the absence of death receptor signaling, we engineered inducible versions of RIPK1 and RIPK3 that can be activated by dimerization with the antibiotic coumermycin. In the absence of TNF or other death ligands, expression and dimerization of RIPK1 was sufficient to cause cell death by caspase- or RIPK3-dependent mechanisms. Dimerized RIPK3 induced cell death by an MLKL-dependent mechanism but, surprisingly, also induced death mediated by FADD, caspase 8 and RIPK1. Catalytically active RIPK3 kinase domains were essential for MLKL-dependent but not for caspase 8-dependent death. When RIPK1 or RIPK3 proteins were dimerized, the mode of cell death was determined by the availability of downstream molecules such as FADD, caspase 8 and MLKL. These observations imply that rather than a 'switch' operating between the two modes of cell death, the final mechanism depends on levels of the respective signaling and effector proteins.

Anxiety, emotional security and the interpersonal behavior of individuals with social anxiety disorder.

BACKGROUND: Interpersonal functioning is central to social anxiety disorder (SAD). Empirical examinations of interpersonal behaviors in individuals with SAD have frequently relied on analogue samples, global retrospective reports and laboratory observation. Moreover, research has focused on avoidance and safety behaviors, neglecting potential links between SAD and affiliative behaviors. METHOD: The influence of situational anxiety and emotional security on interpersonal behaviors was examined for individuals with SAD (n=40) and matched normal controls (n=40). Participants monitored their behavior and affect in naturally occurring social interactions using an event-contingent recording procedure. RESULTS: Individuals with SAD reported higher levels of submissive behavior and lower levels of dominant behavior relative to controls. Consistent with cognitive-behavioral and evolutionary theories, elevated anxiety in specific events predicted increased submissiveness among individuals with SAD. Consistent with attachment theory, elevations in event-level emotional security were associated with increased affiliative behaviors (increased agreeable behavior and decreased quarrelsome behavior) among members of the SAD group. Results were not accounted for by concurrent elevations in sadness or between-group differences in the distribution of social partners. CONCLUSIONS: These findings are consistent with predictions based on several theoretical perspectives. Further, the present research documents naturally occurring interpersonal patterns of individuals with SAD and identifies conditions under which these individuals may view social interactions as opportunities for interpersonal connectedness.

Effects of L-histidine depletion and L-tyrosine/L-phenylalanine depletion on sensory and motor processes in healthy volunteers.

BACKGROUND AND PURPOSE: Animal studies show that histamine plays a role in cognitive functioning and that histamine H3-receptor antagonists, which increase histaminergic function through presynaptic receptors, improve cognitive performance in models of clinical cognitive deficits. In order to test such new drugs in humans, a model for cognitive impairments induced by low histaminergic functions would be useful. Studies with histamine H1-receptor antagonists have shown limitations as a model. Here we evaluated whether depletion of L-histidine, the precursor of histamine, was effective in altering measures associated with histamine in humans and the behavioural and electrophysiological (event-related-potentials) effects. EXPERIMENTAL APPROACH: Seventeen healthy volunteers completed a three-way, double-blind, crossover study with L-histidine depletion, L-tyrosine/L-phenylalanine depletion (active control) and placebo as treatments. Interactions with task manipulations in a choice reaction time task were studied. Task demands were increased using visual stimulus degradation and increased response complexity. In addition, subjective and objective measures of sedation and critical tracking task performance were assessed. KEY RESULTS: Measures of sedation and critical tracking task performance were not affected by treatment. L-histidine depletion was effective and enlarged the effect of response complexity as measured with the response-locked lateralized readiness potential onset latency. CONCLUSIONS AND IMPLICATIONS: L-histidine depletion affected response- but not stimulus-related processes, in contrast to the effects of H1-receptor antagonists which were previously found to affect primarily stimulus-related processes. L-histidine depletion is promising as a model for histamine-based cognitive impairment. However, these effects need to be confirmed by further studies.

Exposure to bright light is associated with positive social interaction and good mood over short time periods: A naturalistic study in mildly seasonal people.

Bright light is used to treat winter depression and might also have positive effects on mood in some healthy individuals. We examined possible links between bright light exposure and social interaction using naturalistic data. For 20 days in winter and/or summer, 48 mildly seasonal healthy individuals wore a light meter at the wrist and recorded in real-time their behaviours, mood, and perceptions of others during social interactions. Possible short-term effects of bright light were examined using the number of minutes, within any given morning, afternoon or evening, that people were exposed to light exceeding 1000 lux (average: 19.6min). Social interactions were labelled as having occurred under conditions of no, low or high bright light exposure. Independent of season, day, time, and location, participants reported less quarrelsome behaviours, more agreeable behaviours and better mood when exposed to high but not low levels of bright light. Given that the effects were seen only when exposure levels were above average, a minimum level of bright light may be necessary for its positive effects to occur. Daily exposure levels were generally low in both winter and summer. Spending more time outdoors and improving indoor lighting may help optimize everyday social behaviour and mood across seasons in people with mild seasonality.

Cortical trapping of alpha-[(11)C]methyl-l-tryptophan, an index of serotonin synthesis, is lower in females than males.

One neural system that may exhibit gender differences is serotonin (5-HT), a neurotransmitter implicated in the regulation of mood, cognitive processes, and impulse-control. However, most of the available evidence of gender-related differences in this system has been indirect and at times contradictory. The objective of the present study was to follow up on preliminary evidence that there are gender differences in brain regional 5-HT synthesis, as measured by trapping of alpha-[(11)C]methyl-l-tryptophan (alpha-[(11)C]MTrp). Sixty-minute dynamic scans were performed in healthy volunteers, 28 women and 31 men. Functional images of the brain trapping constant, used as a proxy for 5-HT synthesis, which correlate in the rat brain with tryptophan's conversion into 5-HT, were transferred to the standardized 3D space. The voxel based comparison was performed by Statistical Parametric Mapping with proportional normalization. There was lower normalized alpha-[(11)C]MTrp trapping in females than males throughout much of the cerebral cortex, including the left middle frontal gyrus, the bilateral inferior frontal gyrus, the bilateral precentral gyrus, the left supramarginal gyrus, the bilateral inferior parietal lobule, the left superior temporal gyrus, the bilateral posterior cingulate gyrus, and the bilateral precuneus. There were no regions in which the normalized trapping was significantly higher in females than in males. Gender differences in sub-cortical sites were not found. Women, compared to men, may have lower rates of this tracer trapping, used as a proxy for 5-HT synthesis, throughout much of the cerebral cortex which is likely related to differences in 5-HT synthesis because relative differences in the normalized trapping should be the same as those in 5-HT synthesis. These differences may be related, at least in part, to previously suggested gender differences in affect, cognitive processes, and susceptibility to 5-HT-related neuropsychiatric and neurological disorders.

Increasing blood oxygen increases an index of 5-HT synthesis in human brain as measured using alpha-[(11)C]methyl-L-tryptophan and positron emission tomography.

The main objective of this investigation was to test the hypothesis that brain serotonin (5-HT) synthesis, as measured by trapping of alpha-[(11)C]methyl-L-tryptophan (alpha-MTrp) using positron emission tomography (PET), can be modulated by changes in blood oxygen. The study involved six healthy participants (three male and three female), who breathed a 15% or 60% oxygen mixture starting 15 min before the injection of tracer and continuing during the entire acquisition period. Participants were injected with up to 12m Ci of alpha-MTrp. Two sets of PET images were acquired while the participants were breathing each of the oxygen mixtures and, after reconstruction, all images were converted into brain functional images illustrating the brain trapping constant K(*) (microL/g/min). The K(*) values were obtained for 12 regions of interest outlined on the magnetic resonance images. The K(*) values obtained at high and low blood oxygen content were compared by paired statistics using Tukey's post hoc correction. As there were no difference in plasma tryptophan concentrations, these K(*) values are directly related to regional 5-HT synthesis. The results showed highly significant increases (50% on average) in brain serotonin synthesis (K(*) values) at high (mean value of 223+/-41 mmHg) relative to low (mean value 77.1+/-7.7 mmHg) blood oxygen levels. This suggests that tryptophan hydroxylase is not saturated with oxygen in the living human brain and that increases in blood oxygen can elevate brain serotonin synthesis.

Bulimia nervosa with co-morbid avoidant personality disorder: behavioural characteristics and serotonergic function.

BACKGROUND: Separate lines of research link lowered serotonin tone to interpersonal submissiveness and bulimia nervosa (BN). We explored the impact of co-morbid avoidant personality disorder (APD), as a proxy for submissiveness, on behavioural inhibition and serotonin function in women with BN. METHOD: Participants included women with BN with co-morbid APD (BNA +, N = 13); women with BN but without APD (BNA-, N = 23), and control women with neither BN nor APD (N = 23). The women were assessed for psychopathological tendencies and eating disorder symptoms, and participated in a computerized laboratory task that measured behavioural inhibition and disinhibition. Participants also provided blood samples for measurement of serial prolactin responses following oral administration of the partial 5-HT agonist meta-chlorophenylpiperazine (m-CPP). RESULTS: The BNA+ group had higher scores than the other groups on self-report measures of submissiveness, social avoidance, restricted emotional expression, affective instability and self-harming behaviours. Compared with the other groups, the BNA+ group tended to be more inhibited under cues for punishment on the computerized task and to have blunted prolactin response following m-CPP. The bulimic groups did not differ from each other on current eating symptoms or on frequencies of other mental disorders. CONCLUSIONS: Findings indicate that women with BN and co-morbid APD may be characterized by interpersonal submissiveness and avoidance, affective instability, self-harm, behavioural inhibition in response to threat and lower sensitivity to serotonergic activation. These findings may indicate common, serotonergic factors, associated with social submissiveness, behavioural inhibition to threat and BN.

Effects of chewing gum on responses to routine painful procedures in children.

In infants, sweet taste and sucking on a pacifier both have analgesic effects. Animal studies suggest that sweet taste may involve opioids, while rhythmic oral movements, as with a pacifier, increase the release of serotonin, which is involved in the gating of nociceptive afferents. The present study was designed to see if these effects produce an analgesic effect in children. Two studies were performed, during blood draws in a pediatric test center in 7- to 12-year-old children, and during vaccination at school in 9- to 11-year-old children. Using unsweetened or sweetened chewing gum, there were four groups: control, sweet, chew, and sweet plus chew. Overall, there was no effect of either sweet taste or chewing on pain responses. However, in boys sweet taste tended to increase pain ratings, but only in conjunction with chewing, while in girls sweet taste tended to decrease pain ratings in conjunction with chewing and increased them in the absence of chewing. Ratings of pain intensity and affective state were correlated. Affective state before the painful stimulus was related to pain response in the girls and in the boys in the test center, but not in the schools. In the schools, the presence of peers may have influenced the ratings.

Study of the brain serotonergic system with labeled alpha-methyl-L-tryptophan.

alpha-Methyl-L-tryptophan (alpha-MTrp) is an artificial amino acid and an analog of tryptophan (Trp), the precursor of the neurotransmitter serotonin (5-HT). In this article we have summarized available data, which suggest that the measurement of the unidirectional uptake of alpha-MTrp and its conversion to 5-HT synthesis rates is a valid approach for the determination of brain 5-HT synthesis rates. The main feature on which the model is based is the trapping of labeled alpha-MTrp in brain tissue. An overview of opposing opinions, which suggest that there is a need for a metabolic conversion of tracer, is also presented and discussed critically. As with all biological modeling there is likely to be room for improvements of the proposed biological model. In addition, there are a limited number of clearly defined circumstances in which the method is confounded by the metabolism of labeled alpha-MTrp via the kynurenine pathway. Nonetheless, a significant body of evidence suggests that labeled alpha-MTrp is a useful tracer to study brain 5-HT synthesis in most circumstances. Calculation of 5-HT synthesis rates depends on the plasma-free tryptophan concentration, which, according to the balance of arguments in the literature, is a more appropriate parameter than the total-plasma tryptophan. The method, as proposed by us, can be used in conjunction with autoradiographic measurements in laboratory animals, and with positron emission tomography in large animals and humans. We review studies in animals looking at the normal control of 5-HT synthesis and the way in which it is altered by drugs, as well as initial studies investigating healthy humans and patients with neuropsychiatric disorders.

Association of serotonin and cortisol indices with childhood abuse in bulimia nervosa.

BACKGROUND: Bulimia nervosa (BN) is reported to co-occur with childhood abuse and alterations in central serotonin (5-hydroxytryptamine [5-HT]) and cortisol mechanisms. However, findings also link childhood abuse to anomalous 5-HT and cortisol function, and this motivated us to explore relationships between childhood abuse and neurobiological variations in BN. METHODS: Thirty-five bulimic and 25 nonbulimic women were assessed for childhood physical and sexual abuse, eating symptoms, and comorbid psychopathological tendencies. These women provided blood samples for measurement of platelet hydrogen-3-paroxetine binding and serial prolactin and cortisol responses following oral administration of the partial 5-HT agonist meta-chlorophenylpiperazine (m-CPP). RESULTS: Bulimic women showed markedly lower mean +/- SD density (B(max)) of paroxetine-binding sites (631.12 +/- 341.58) than did normal eaters (1213.00 +/- 628.74) (t(54) = -4.47; P =.001). Paroxetine binding did not vary with childhood abuse. In contrast, measures of peak change on prolactin levels after m-CPP administration (Delta-peak prolactin) indicated blunted response in abused bulimic women (7.26 +/- 7.06), nonabused bulimic women (5.62 +/- 3.95), and abused women who were normal eaters (5.73 +/- 5.19) compared with nonabused women who were normal eaters (13.57 +/- 9.94) (F(3,51) = 3.04, P =.04). Furthermore, individuals reporting childhood abuse showed decreased plasma cortisol levels relative to nonabused women who were normal eaters. CONCLUSION: Findings imply that BN and childhood abuse are both generally associated with reduced 5-HT tone but that childhood abuse may be somewhat more specifically linked to reduced cortisol levels (ie, hypothalamic-pituitary-adrenal axis) activity.

Self-destructiveness and serotonin function in bulimia nervosa.

Studies have linked bulimia nervosa (BN) to alterations in brain serotonin (5-hydroxytryptamine: 5-HT) activity and to heightened propensity for parasuicidality and self-injuriousness. The coincidence of self-destructiveness and 5-HT abnormality in BN is of interest, given documentation (in various populations) of an inverse association between 5-HT activity and potential for self-harm. The present study examined the connection between 5-HT status and self-destructiveness in BN. Structured interviews and self-report questionnaires were used to assess 40 bulimic and 21 normal-eater women for: (a) history of parasuicidal or self-injurious acts; and (b) mood and impulse-regulation problems. We then applied tests, presumed to reflect 5-HT function, of serial prolactin (PRL) and cortisol (CORT) responses after oral administration of the partial 5-HT agonist, meta-chlorophenylpiperazine (m-CPP). Relative to non-bulimic women, bulimic women (on average) showed blunting of PRL and CORT following m-CPP. The blunting of neuroendocrine responses was, however, most remarkable in bulimic women with a history of self-destructiveness. These findings suggest that some serotonergic anomalies reported in BN sufferers (i.e. reduced neuroendocrine response after m-CPP) may be most characteristic of individuals in the population showing clear-cut self-destructive potential.

The effect of tryptophan on social interaction in everyday life: a placebo-controlled study.

In monkeys increasing serotonin function enhances affiliative interactions and promotes the acquisition of dominance. To examine whether similar effects occur in humans, we treated 98 subjects for 12 days with the serotonin precursor tryptophan (1g TID) and for 12 days with placebo in a double-blind, cross over study. Agreeableness/quarrelsomeness and dominance/submission were measured using an event-contingent method, in which subjects reported on various behaviors during important social interactions throughout their day. Tryptophan decreased quarrelsome behavior, but only when placebo was given first, suggesting that a decrease in quarrelsomeness when tryptophan was given first may have carried over into the subsequent placebo period. Tryptophan increased dominant behavior, an effect that was independent of the order of treatment, the broad social context, and the subject's and partner's sex. Our results suggest that serotonin may enhance dominance in humans, as in monkeys, and illustrate the advantages of the event contingent methodology in studying the associations between biology and human social interaction.

Biogenic amine metabolites and thiamine in cerebrospinal fluid in heredo-degenerative ataxias.

BACKGROUND: The aims of the present study were: i) to measure levels of the dopamine metabolite homovanillic acid (HVA), the serotonin metabolite 5-hydroxindoleacetic acid (5HIAA) and precursor tryptophan, as well as the noradrenaline metabolite 3-methoxy-4-hydroxyphenylethylene glycol (MHPG) and thiamine in the cerebrospinal fluid (CSF) of patients with Friedreich's ataxia (FA), olivopontocerebellar atrophy (OPCA), and the autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSAC), as compared with sex- and age-matched control subjects. PATIENTS AND METHODS: CSF amine related compound levels and thiamine results were compared in 40 FA, 44 OPCA and nine ARSAC patients with those of 94 sex- and age-matched subjects. Neuroimaging (CT scans and single photon emission computed tomographies i.e. SPECT) were carried out in all patients and controls. Genetic studies were conducted on OPCA patients. CSF amine related compounds were measured by high performance liquid chromatography, whereas CSF thiamine levels were measured by a microbiological method. RESULTS: FA patients had significantly lower CSF HVA, 5HIAA and thiamine values than control patients and a trend for lower MHPG levels. In OPCA patients, CSF HVA, MHPG and thiamine values were markedly lower whereas CSF 5HIAA values showed only a trend towards lower levels; in ARSAC patients only thiamine and HVA CSF values were lower than those in control subjects. CONCLUSION: After presenting the relationships between neurochemical findings on one side, the degree of ataxia, the degree of cerebellar atrophy and the SPECT findings on the other, the authors concluded that replacement and neuroprotective clinical trials in these patients would have to include two or three drugs because the neurotransmitter deficiencies are multiple.

Brain Regional alpha-[11C]methyl-L-tryptophan trapping in impulsive subjects with borderline personality disorder.

OBJECTIVE: Neurotransmission of serotonin (or 5-hydroxytryptamine [5-HT]) is thought to be disturbed in patients exhibiting impulsive behaviors. However, until recently it has not been possible to test this hypothesis in the brains of living humans. METHOD: Unidirectional trapping of the 5-HT precursor analog alpha-[(11)C]methyl-L-tryptophan (alpha-[(11)C]MTrp) has been proposed as an index of 5-HT synthesis capacity. The authors measured brain regional alpha-[(11)C]MTrp trapping with positron emission tomography in medication-free subjects with borderline personality disorder (N=13) and a healthy comparison group (N=11). Impulsivity was assessed by using a laboratory measure of behavioral disinhibition, go/no-go commission errors. RESULTS: Compared to healthy men, the men with borderline personality disorder had significantly lower alpha-[(11)C]MTrp trapping in corticostriatal sites, including the medial frontal gyrus, anterior cingulate gyrus, superior temporal gyrus, and corpus striatum. In the women with borderline personality disorder, significantly lower alpha-[(11)C]MTrp trapping was seen in fewer regions, but in both men and women, negative correlations with impulsivity scores were identified in the medial frontal gyrus, anterior cingulate gyrus, temporal gyrus, and striatum. CONCLUSIONS: Low 5-HT synthesis capacity in corticostriatal pathways may contribute to the development of impulsive behaviors in persons with borderline personality disorder.

Contact and nutrient caregiving effects on newborn infant pain responses.

To understand how the 'caregiving context' could affect responses to procedural pain, the authors sought to determine whether (1) the combined effects of sweet taste and holding (caregiving contact) were greater than the effects of either alone, (2) any combined effects were additive or interactive, and (3) the interventions had similar effects on behavioral (crying and facial activity) and physiological (heart rate, vagal tone) responses to the heel-stick procedure in newborn infants in a randomized two-factorial intervention trial. Eighty-five normally developing newborn infants were studied with a mean gestational age of 39.4 weeks on the 2nd or 3rd day of life. Infants were randomized in blocks of eight to receive (1) no holding and water taste (control participants), (2) no holding and sucrose taste (sucrose group), (3) holding and water taste (holding group), or (4) holding and sucrose taste (holding and sucrose group). Crying was reduced significantly by taste and holding, and the interventions combined additively. Facial activity was only significantly reduced by holding. For physiological measures, the interventions interacted with each other and preintervention levels to reduce heart rate and lower vagal tone more during the procedure in infants in whom heart rate and vagal tone were higher before intervention. Consequently, sweet taste and holding interventions combined in complex ways when acting on different behavioral and physiological response systems to modify stressful pain experiences. The results suggest that providing a caregiving context when painful procedures are performed may be a simple and practical method of reducing pain experience in infants, and that no one measure captures these effects.