Control of brain blood flow by capillaries: a simulation study in an anatomically accurate large human vascular network

In this paper, the variations in cerebral blood flow induced by global or localised capillary vasodilations are studied. The results demonstrate that pericyte-mediated regulation of blood flowat capillary level would be efficient for neuro-vascular coupling. By contrast to a regulation situated at the level of arterioles (Lorthois et al. 2011b), the changes in blood volume can be highly localised in space, with the potential to be as close as possible of areas of neuronal activation. However, the changes in blood flow are much more diffuse. This imposes limits on the ultimate spatial resolution of hemodynamically based brain functional imaging techniques

Signalling through AMPA receptors on oligodendrocyte precursors promotes myelination by enhancing oligodendrocyte survival

Myelin, made by oligodendrocytes, is essential for rapid information transfer in the central nervous system. Oligodendrocyte precursors (OPs) receive glutamatergic synaptic input from axons but how this affects their development is unclear. Murine OPs in white matter express AMPA receptor (AMPAR) subunits GluA2, GluA3 and GluA4. We generated mice in which OPs lack both GluA2 and GluA3, or all three subunits GluA2/3/4, which respectively reduced or abolished AMPAR-mediated input to OPs. In both double- and triple-knockouts OP proliferation and number were unchanged but ~25% fewer oligodendrocytes survived in the subcortical white matter during development. In triple knockouts, this shortfall persisted into adulthood. The oligodendrocyte deficit resulted in ~20% fewer myelin sheaths but the average length, number and thickness of myelin internodes made by individual oligodendrocytes appeared normal. Thus, AMPAR-mediated signalling from active axons stimulates myelin production in developing white matter by enhancing oligodendrocyte survival, without influencing myelin synthesis per se

Endogenous GABA controls oligodendrocyte lineage cell number, myelination, and CNS internode length

Adjusting the thickness and internodal length of the myelin sheath is a mechanism for tuning the conduction velocity of axons to match computational needs. Interactions between oligodendrocyte precursor cells (OPCs) and developing axons regulate the formation of myelin around axons. We now show, using organotypic cerebral cortex slices from mice expressing eGFP in Sox10-positive oligodendrocytes, that endogenously released GABA, acting on GABAA receptors, greatly reduces the number of oligodendrocyte lineage cells. The decrease in oligodendrocyte number correlates with a reduction in the amount of myelination but also an increase in internode length, a parameter previously thought to be set by the axon diameter or to be a property intrinsic to oligodendrocytes. Importantly, while TTX block of neuronal activity had no effect on oligodendrocyte lineage cell number when applied alone, it was able to completely abolish the effect of blocking GABAA receptors, suggesting that control of myelination by endogenous GABA may require a permissive factor to be released from axons. In contrast, block of AMPA/KA receptors had no effect on oligodendrocyte lineage cell number or myelination. These results imply that, during development, GABA can act as a local environmental cue to control myelination and thus influence the conduction velocity of action potentials within the CNS. GLIA 2017;65:309-321

Socio-Economic Instability and the Scaling of Energy Use with Population Size

The size of the human population is relevant to the development of a sustainable world, yet the forces setting growth or declines in the human population are poorly understood. Generally, population growth rates depend on whether new individuals compete for the same energy (leading to Malthusian or density-dependent growth) or help to generate new energy (leading to exponential and super-exponential growth). It has been hypothesized that exponential and super-exponential growth in humans has resulted from carrying capacity, which is in part determined by energy availability, keeping pace with or exceeding the rate of population growth. We evaluated the relationship between energy use and population size for countries with long records of both and the world as a whole to assess whether energy yields are consistent with the idea of an increasing carrying capacity. We find that on average energy use has indeed kept pace with population size over long time periods. We also show, however, that the energy-population scaling exponent plummets during, and its temporal variability increases preceding, periods of social, political, technological, and environmental change. We suggest that efforts to increase the reliability of future energy yields may be essential for stabilizing both population growth and the global socio-economic system

An Intact Kidney Slice Model to Investigate Vasa Recta Properties and Function in situ

Background: Medullary blood flow is via vasa recta capillaries, which possess contractile pericytes. In vitro studies using isolated descending vasa recta show that pericytes can constrict/dilate descending vasa recta when vasoactive substances are present. We describe a live kidney slice model in which pericyte-mediated vasa recta constriction/dilation can be visualized in situ. Methods: Confocal microscopy was used to image calcein, propidium iodide and Hoechst labelling in ‘live’ kidney slices, to determine tubular and vascular cell viability and morphology. DIC video-imaging of live kidney slices was employed to investigate pericyte-mediated real-time changes in vasa recta diameter. Results: Pericytes were identified on vasa recta and their morphology and density were characterized in the medulla. Pericyte-mediated changes in vasa recta diameter (10–30%) were evoked in response to bath application of vasoactive agents (norepinephrine, endothelin-1, angiotensin-II and prostaglandin E2) or by manipulating endogenous vasoactive signalling pathways (using tyramine, L-NAME, a cyclo-oxygenase (COX-1) inhibitor indomethacin, and ATP release). Conclusions: The live kidney slice model is a valid complementary technique for investigating vasa recta function in situ and the role of pericytes as regulators of vasa recta diameter. This technique may also be useful in exploring the role of tubulovascular crosstalk in regulation of medullary blood flow

Variation in helper effort among cooperatively breeding bird species is consistent with Hamilton's Rule.

Investment by helpers in cooperative breeding systems is extremely variable among species, but this variation is currently unexplained. Inclusive fitness theory predicts that, all else being equal, cooperative investment should correlate positively with the relatedness of helpers to the recipients of their care. We test this prediction in a comparative analysis of helper investment in 36 cooperatively breeding bird species. We show that species-specific helper contributions to cooperative brood care increase as the mean relatedness between helpers and recipients increases. Helper contributions are also related to the sex ratio of helpers, but neither group size nor the proportion of nests with helpers influence helper effort. Our findings support the hypothesis that variation in helping behaviour among cooperatively breeding birds is consistent with Hamilton's rule, indicating a key role for kin selection in the evolution of cooperative investment in social birds

Additional Saturday rehabilitation improves functional independence and quality of life and reduces length of stay: a randomised controlled trial

Background Many inpatients receive little or no rehabilitation on weekends. Our aim was to determine what effect providing additional Saturday rehabilitation during inpatient rehabilitation had on functional independence, quality of life and length of stay compared to 5 days per week of rehabilitation.MethodsThis was a multicenter, single-blind (assessors) randomized controlled trial with concealed allocation and 12-month follow-up conducted in two publically funded metropolitan inpatient rehabilitation facilities in Melbourne, Australia. Patients were eligible if they were adults (aged &ge;18 years) admitted for rehabilitation for any orthopedic, neurological or other disabling conditions excluding those admitted for slow stream rehabilitation/geriatric evaluation and management. Participants were randomly allocated to usual care Monday to Friday rehabilitation (control) or to Monday to Saturday rehabilitation (intervention). The additional Saturday rehabilitation comprised physiotherapy and occupational therapy. The primary outcomes were functional independence (functional independence measure (FIM); measured on an 18 to 126 point scale), health-related quality of life (EQ-5D utility index; measured on a 0 to 1 scale, and EQ-5D visual analog scale; measured on a 0 to 100 scale), and patient length of stay. Outcome measures were assessed on admission, discharge (primary endpoint), and at 6 and 12 months post discharge.ResultsWe randomly assigned 996 adults (mean (SD) age 74 (13) years) to Monday to Saturday rehabilitation (n&thinsp;=&thinsp;496) or usual care Monday to Friday rehabilitation (n&thinsp;=&thinsp;500). Relative to admission scores, intervention group participants had higher functional independence (mean difference (MD) 2.3, 95% confidence interval (CI) 0.5 to 4.1, P&thinsp;=&thinsp;0.01) and health-related quality of life (MD 0.04, 95% CI 0.01 to 0.07, P&thinsp;=&thinsp;0.009) on discharge and may have had a shorter length of stay by 2 days (95% CI 0 to 4, P&thinsp;=&thinsp;0.1) when compared to control group participants. Intervention group participants were 17% more likely to have achieved a clinically significant change in functional independence of 22 FIM points or more (risk ratio (RR) 1.17, 95% CI 1.03 to 1.34) and 18% more likely to have achieved a clinically significant change in health-related quality of life (RR 1.18, 95% CI 1.04 to 1.34) on discharge compared to the control group. There was some maintenance of effect for functional independence and health-related quality of life at 6-month follow-up but not at 12-month follow-up. There was no difference in the number of adverse events between the groups (incidence rate ratio&thinsp;=&thinsp;0.81, 95% CI 0.61 to 1.08).ConclusionsProviding an additional day of rehabilitation improved functional independence and health-related quality of life at discharge and may have reduced length of stay for patients receiving inpatient rehabilitation.&nbsp;</p

Image based machine learning for identification of macrophage subsets

Macrophages play a crucial rule in orchestrating immune responses against pathogens and foreign materials. Macrophages have remarkable plasticity in response to environmental cues and are able to acquire a spectrum of activation status, best exemplified by pro-inflammatory (M1) and anti-inflammatory (M2) phenotypes at the two ends of the spectrum. Characterisation of M1 and M2 subsets is usually carried out by quantification of multiple cell surface markers, transcription factors and cytokine profiles. These approaches are time consuming, require large numbers of cells and are resource intensive. In this study, we used machine learning algorithms to develop a simple and fast imaging-based approach that enables automated identification of different macrophage functional phenotypes using their cell size and morphology. Fluorescent microscopy was used to assess cell morphology of different cell types which were stained for nucleus and actin distribution using DAPI and phalloidin respectively. By only analysing their morphology we were able to identify M1 and M2 phenotypes effectively and could distinguish them from naïve macrophages and monocytes with an average accuracy of 90%. Thus we suggest high-content and automated image analysis can be used for fast phenotyping of functionally diverse cell populations with reasonable accuracy and without the need for using multiple markers