Effective Altruism as an Ethical Lens on Research Priorities.

Effective altruism is an ethical framework for identifying the greatest potential benefits from investments. Here, we apply effective altruism concepts to maximize research benefits through identification of priority stakeholders, pathosystems, and research questions and technologies. Priority stakeholders for research benefits may include smallholder farmers who have not yet attained the minimal standards set out by the United Nations Sustainable Development Goals; these farmers would often have the most to gain from better crop disease management, if their management problems are tractable. In wildlands, prioritization has been based on the risk of extirpating keystone species, protecting ecosystem services, and preserving wild resources of importance to vulnerable people. Pathosystems may be prioritized based on yield and quality loss, and also factors such as whether other researchers would be unlikely to replace the research efforts if efforts were withdrawn, such as in the case of orphan crops and orphan pathosystems. Research products that help build sustainable and resilient systems can be particularly beneficial. The "value of information" from research can be evaluated in epidemic networks and landscapes, to identify priority locations for both benefits to individuals and to constrain regional epidemics. As decision-making becomes more consolidated and more networked in digital agricultural systems, the range of ethical considerations expands. Low-likelihood but high-damage scenarios such as generalist doomsday pathogens may be research priorities because of the extreme potential cost. Regional microbiomes constitute a commons, and avoiding the "tragedy of the microbiome commons" may depend on shifting research products from "common pool goods" to "public goods" or other categories. We provide suggestions for how individual researchers and funders may make altruism-driven research more effective.[Formula: see text] Copyright © 2020 The Author(s). This is an open access article distributed under the CC BY 4.0 International license.

Lower cardiorespiratory fitness contributes to increased insulin resistance and fasting glycaemia in middle-aged South Asian compared with European men living in the UK.

AIMS/HYPOTHESIS: This study aimed to determine the extent to which increased insulin resistance and fasting glycaemia in South Asian men, compared with white European men, living in the UK, was due to lower cardiorespiratory fitness (maximal oxygen uptake [VO(2max)]) and physical activity. METHODS: One hundred South Asian and 100 age- and BMI-matched European men without diagnosed diabetes, aged 40-70 years, had fasted blood taken for measurement of glucose concentration, HOMA-estimated insulin resistance (HOMA(IR)), plus other risk factors, and underwent assessment of physical activity (using accelerometry), VO(2max), body size and composition, and demographic and other lifestyle factors. For 13 South Asian and one European man, HbA1c levels were >6.5% (>48 mmol/mol), indicating potential undiagnosed diabetes; these men were excluded from the analyses. Linear regression models were used to determine the extent to which body size and composition, fitness and physical activity variables explained differences in HOMA(IR) and fasting glucose between South Asian and European men. RESULTS: HOMA(IR) and fasting glucose were 67% (p < 0.001) and 3% (p < 0.018) higher, respectively, in South Asians than Europeans. Lower VO(2max), lower physical activity and greater total adiposity in South Asians individually explained 68% (95% CI 45%, 91%), 29% (11%, 46%) and 52% (30%, 80%), respectively, and together explained 83% (50%, 119%) (all p < 0.001) of the ethnic difference in HOMA(IR). Lower VO(2max) and greater total adiposity, respectively, explained 61% (9%, 111%) and 39% (9%, 76%) (combined effect 63% [8%, 115%]; all p < 0.05) of the ethnic difference in fasting glucose. CONCLUSIONS/INTERPRETATION: Lower cardiorespiratory fitness is a key factor associated with the excess insulin resistance and fasting glycaemia in middle-aged South Asian, compared with European, men living in the UK.

Neuron/glia relationships observed over intervals of several months in living mice.

Identified neurons and glial cells in a parasympathetic ganglion were observed in situ with video-enhanced microscopy at intervals of up to 130 d in adult mice. Whereas the number and position of glial cells associated with particular neurons did not change over several hours, progressive differences were evident over intervals of weeks to months. These changes involved differences in the location of glial nuclei on the neuronal surface, differences in the apparent number of glial nuclei associated with each neuron, and often both. When we examined the arrangement of neurons and glial cells in the electron microscope, we also found that presynaptic nerve terminals are more prevalent in the vicinity of glial nuclei than elsewhere on the neuronal surface. The fact that glial nuclei are associated with preganglionic endings, together with the finding that the position and number of glial nuclei associated with identified neurons gradually changes, is in accord with the recent observation that synapses on these neurons are normally subject to ongoing rearrangement (Purves, D., J. T. Voyvodic, L. Magrassi, and H. Yawo. 1987. Science (Wash. DC). 238:1122-1126). By the same token, the present results suggest that glial cells are involved in synaptic remodeling.

The distribution of synapses on a physiologically identified motor neuron in the central nervous system of the leech. An electron microscope study after the injection of the fluorescent dye procion yellow.

The fine structure of a physiologically identified motor neuron in the segmental ganglion of the leech central nervous system and the morphology of synapses on it were studied after injection of the fluorescent dye Procion yellow as a marker. The injected cell and its processes within the neuropil were located in thick or thin sections with fluorescence optics after initial fixation with glutaraldehyde and brief treatment with osmium tetroxide. The same or adjacent thin sections could then be examined in the electron microscope. Comparison with uninjected cells showed that the general features of the injected cell are retained although some organelles are distorted. The main features of the geometry of this neuron are the same from animal to animal: a single large process runs from the soma through the neuropil to bifurcate and enter the contralateral roots. Within the neuropil the main process gives off long branches (up to 150 micro), but these are greatly outnumbered by short branches and spines, one or a few microns in length, which were not appreciated in previous light microscope studies after injection of Procion yellow. Serial thin sections of selected areas along the main process within the neuropil showed that there are synapses on most of the shorter branches and spines; occasional synaptic contacts were also made on the main process itself and on longer branches. At least two morphologically distinct types of synapse could be recognized. A minimum estimate of the total number of synapses on the motor cell is 300, based on their occurrence in reconstructed segments.

Elimination of synapses in the developing nervous system.

Reduction of the number of axons that contact target cells may be a general feature of neural development. This process may underlie the progressively restricted malleability of the maturing nervous system.

Geometrical differences among homologous neurons in mammals.

The dendritic arbors of sympathetic neurons in different species of mammals vary systematically: the superior cervical ganglion cells of smaller mammals have fewer and less extensive dendrites than the homologous neurons in larger animals. This difference in dendritic complexity according to body size is reflected in the convergence of ganglionic innervation; the ganglion cells of progressively larger mammals are innervated by progressively more axons. These relations have implications both for the function of homologous neural systems in animals of different sizes and for the regulation of neuronal geometry during development.

Nerve terminal remodeling visualized in living mice by repeated examination of the same neuron.

The distribution of presynaptic endings on the surfaces of autonomic ganglion cells was mapped in living mice after intravenous administration of a styryl pyridinium dye. The staining and imaging techniques did not appear to damage the ganglion cells, or the synapses on them; these procedures could therefore be repeated after an arbitrary period. Observations of the same neurons at intervals of up to 3 weeks indicate that the pattern of preganglionic terminals on many of these nerve cells gradually changes.

The changing view of neural specificity.

The generation of specific patterns of neuronal connections has usually been regarded as a central problem in neurobiology. The prevailing view for many years has been that these connections are established by complementary recognition molecules on the pre- and postsynaptic cells (the chemoaffinity theory). Experimental results obtained in the past decade, however, indicate that the view that axon guidance and synaptogenesis proceed according to restrictive chemical markers is too narrow. Although a more rigid plan may prevail in some invertebrates, the formation of specific connections in vertebrates also involves competition between axon terminals, trophic feedback between pre- and postsynaptic cells, and modification of connections by functional activity.

The effects of color on brightness.

Observation of human subjects shows that the spectral returns of equiluminant colored surrounds govern the apparent brightness of achromatic test targets. The influence of color on brightness provides further evidence that perceptions of luminance are generated according to the empirical frequency of the possible sources of visual stimuli, and suggests a novel way of understanding color contrast and constancy.

Iterated patterns of brain circuitry (or how the cortex gets its spots)

The prominence of repeating patterns of circuitry in the mammalian brain has led to the general view that iterated modular units reflect a fundamental principle of cortical function. Here we argue that these intriguing patterns arise not because the functional organization of the brain demands them, but as an incidental consequence of the rules of synapse formation.

Is neural development Darwinian?

Gradually, and without much debate, the idea that the developing nervous system is in some sense darwinian has become one of the canons of neurobiology. In fact, there is little evidence to support this idea.

Neural activity and the development of the somatic sensory system.

Present thinking about the role of neural activity in the developing brain is based largely upon observations in the visual system. Attempts to generalize these findings in the somatic sensory system, however, have yielded perplexing results. Unlike the visual system, recent evidence suggests that activity plays a relatively minor role in establishing structural patterns in the primary somatic sensory cortex. Activity levels in the primary somatic sensory cortex are nonetheless highest in those regions that grow most during postnatal development, implying that activity promotes differential cortical growth.

Statistical modelling studies examining the dimensional structure of psychopathology experienced by adults with intellectual disabilities: Systematic review.

Diagnosing mental ill-health using categorical classification systems has limited validity for clinical practice and research. Dimensions of psychopathology have greater validity than categorical diagnoses in the general population, but dimensional models have not had a significant impact on our understanding of mental ill-health and problem behaviours experienced by adults with intellectual disabilities. This paper systematically reviews the methods and findings from intellectual disabilities studies that use statistical methods to identify dimensions of psychopathology from data collected using structured assessments of psychopathology. The PRISMA framework for systematic review was used to identify studies for inclusion. Study methods were compared to best-practice guidelines on the use of exploratory factor analysis. Data from the 20 studies included suggest that it is possible to use statistical methods to model dimensions of psychopathology experienced by adults with intellectual disabilities. However, none of the studies used methods recommended for the analysis of non-continuous psychopathology data and all 20 studies used statistical methods that produce unstable results that lack reliability. Statistical modelling is a promising methodology to improve our understanding of mental ill-health experienced by adults with intellectual disabilities but future studies should use robust statistical methods to build on the existing evidence base.

An empirical explanation of the cornsweet effect.

A long-standing puzzle in vision is the assignment of illusory brightness values to visual territories based on the characteristics of their edges (the Craik-O'Brien-Cornsweet effect). Here we show that the perception of the equiluminant territories flanking the Cornsweet edge varies according to whether these regions are more likely to be similarly illuminated surfaces having the same material properties or unequally illuminated surfaces with different properties. Thus, if the likelihood is increased that these territories are surfaces with similar reflectance properties under the same illuminant, the Craik-O'Brien-Cornsweet effect is diminished; conversely, if the likelihood is increased that the adjoining territories are differently reflective surfaces receiving different amounts of illumination, the effect is enhanced. These findings indicate that the Craik-O'Brien-Cornsweet effect is determined by the relative probabilities of the possible sources of the luminance profiles in the stimulus.

Ongoing electrical activity of superior cervical ganglion cells in mammals of different size.

The ongoing synaptic activity of superior cervical ganglion cells in adult mammals was examined in situ by intracellular recording in anesthetized mice, hamsters, rats, guinea pigs, and rabbits. The proportion of neurons exhibiting subthreshold and suprathreshold synaptic activity during a standard period of observation was least in a small mammal like the mouse (30%), intermediate among neurons of mammals of intermediate size such as the hamster and rat (48% and 45%, respectively), and greatest in the largest animals in the series, the guinea pig (89%) and rabbit (91%). Ganglion cells in all species fell silent after transection of the cervical trunk. The average frequency of synaptic activity among tonically active cells also increased with animal size, being least in the mouse (1.0/second) and greatest in the rabbit (6.4/second). This variation of ongoing synaptic activity in sympathetic ganglion cells may reflect the demands of progressively larger peripheral targets on relatively fixed populations of autonomic neurons.

Segmental organization of sympathetic preganglionic neurons in the mammalian spinal cord.

We have used retrograde transport of horseradish peroxidase to determine the distribution of the preganglionic cell bodies whose axons join particular rami of the thoracic spinal cord in a series of guinea pigs, and in a small number of hamsters and cats. In contrast to other recent studies, our results show that the neurons sending axons to a ramus are confined to a single segment at the corresponding spinal level. This segmental organization supports the idea that the rostro-caudal position of preganglionic cell bodies is one determinant of selective synapse formation between preganglionic axons and sympathetic ganglion cells.

Development of blobs in the visual cortex of macaques.

We have examined the area of the primary visual cortex and the number and size of blobs within it in 10 neonatal and 11 adult rhesus monkeys. The average area of the primary visual cortex (V1) increases from 919 mm2 in newborns to 1,069 mm2 in adult animals (16%). The number of blobs decreases per unit area from an average of 5.2/mm2 at birth to 4.3/mm2 in maturity (18%). As a consequence, the number of blobs remains approximately the same during maturation, at about 4,800/hemisphere. These observations correct a preliminary report on a subset of the animals studied here (Purves and LaMantia: Proc Natl Acad Sci 87:5765, '90), in which it appeared that blob number might increase between birth and maturity. As in other regions of the developing postnatal brain, we found no net loss of modular circuitry.

Clinical evaluation of serum tissue polypeptide-specific antigen (TPS) in non-small cell lung cancer.

M3 is an epitope of the tissue polypeptide antigen detectable in the serum by immunoradiometric assay. This epitope is referred to as tissue polypeptide-specific antigen (TPS). We examined the pretreatment TPS level of 160 non-small cell lung cancer (NSCLC) patients and 71 patients who suffered from non-malignant pulmonary diseases. The upper limit of normal values was 140 U/l. Using this cutoff, the sensitivity and specificity were 36 and 90%, respectively. The TPS was significantly higher in NSCLC patients with an advanced stage, a mediastinal lymph node involvement or a poor performance status. This level was significantly higher in the group of patients for whom the disease proved to progress during chemotherapy. In univariate analysis, patients with a high TPS level proved to have a shorter survival than patients with a TPS < or = 140 U/l. In Cox's model analysis, performance status, stage of the disease and serum TPS were the only significant prognostic variables. The low sensitivity of TPS precludes its use for diagnosis. However, the pretreatment TPS level adds information to the management of NSCLC inasmuch as it predicts a low sensitivity to chemotherapy and a poor prognosis.

The relevance of visual perception to cortical evolution and development.

The quality of brightness--perhaps the simplest visual attribute we perceive--appears to be determined probabilistically. In this empirical conception of the perception of light, the stimulus-induced activity of visual cortical neurons does not encode the retinal image or the properties of the stimulus per se, but associations (percepts) determined by the relative probabilities of the possible sources of the stimulus. If this theory is correct, the rationale for the prolonged postnatal construction of visual circuitry--and the evolution of this visual scheme--is to strengthen and/or create by activity-dependent feedback the empirically determined association on which vision depends.

Contextual control of conditioned responding in rats with dorsal hippocampal lesions.

The control exerted by contextual cues over classically conditioned responding was assessed for rats with electrolytic lesions of the dorsal hippocampus and sham-operated controls. In 3 experiments the rats received initial training with 2 reinforced cues, each presented in its own distinctive context, followed by a nonreinforced test in which the cues were presented in the other context. Both control and operated subjects showed context specificity, as evidenced by less vigorous responding to these cues than to cues presented on test in their original contexts. The groups did not differ in their ability to learn an explicit discrimination in which a given cue was reinforced in one context and nonreinforced in a different context (although the groups did differ on a simple autoshaping task). It is concluded that a special role for the hippocampus in the contextual control of conditioned responding still remains to be demonstrated.