Underestimating Internal Variability Leads to Narrow Estimates of Climate System Properties

Probabilistic estimates of climate system properties often rely on the comparison of model simulations to observed temperature records and an estimate of the internal climate variability. In this study, we investigate the sensitivity of probability distributions for climate system properties in the Massachusetts Institute of Technology Earth System Model to the internal variability estimate. In particular, we derive probability distributions using the internal variability extracted from 25 different Coupled Model Intercomparison Project Phase 5 models. We further test the sensitivity by pooling variability estimates from models with similar characteristics. We find the distributions to be highly sensitive when estimating the internal variability from a single model. When merging the variability estimates across multiple models, the distributions tend to converge to a wider distribution for all properties. This suggests that using a single model to approximate the internal climate variability produces distributions that are too narrow and do not fully represent the uncertainty in the climate system property estimates

'Special K' and a loss of cell-to-cell adhesion in proximal tubule-derived epithelial cells: modulation of the adherens junction complex by ketamine

Ketamine, a mild hallucinogenic class C drug, is the fastest growing ‘party drug’ used by 16–24 year olds in the UK. As the recreational use of Ketamine increases we are beginning to see the signs of major renal and bladder complications. To date however, we know nothing of a role for Ketamine in modulating both structure and function of the human renal proximal tubule. In the current study we have used an established model cell line for human epithelial cells of the proximal tubule (HK2) to demonstrate that Ketamine evokes early changes in expression of proteins central to the adherens junction complex. Furthermore we use AFM single-cell force spectroscopy to assess if these changes functionally uncouple cells of the proximal tubule ahead of any overt loss in epithelial cell function. Our data suggests that Ketamine (24–48 hrs) produces gross changes in cell morphology and cytoskeletal architecture towards a fibrotic phenotype. These physical changes matched the concentration-dependent (0.1–1 mg/mL) cytotoxic effect of Ketamine and reflect a loss in expression of the key adherens junction proteins epithelial (E)- and neural (N)-cadherin and β-catenin. Down-regulation of protein expression does not involve the pro-fibrotic cytokine TGFβ, nor is it regulated by the usual increase in expression of Slug or Snail, the transcriptional regulators for E-cadherin. However, the loss in E-cadherin can be partially rescued pharmacologically by blocking p38 MAPK using SB203580. These data provide compelling evidence that Ketamine alters epithelial cell-to-cell adhesion and cell-coupling in the proximal kidney via a non-classical pro-fibrotic mechanism and the data provides the first indication that this illicit substance can have major implications on renal function. Understanding Ketamine-induced renal pathology may identify targets for future therapeutic intervention

Knowing urban informalities

How do Anglophone urban scholars know urban informalities? This article reviews three dominant ways of knowing urban informality, noting that, despite the profoundly rich insights they each provide, two critiques of the overall concept endure. These are that the concept is often imprecise, and that the contribution to knowing ‘the urban’ more generally remains clearly circumscribed to the ‘urban non-west’. In our view, these limitations curtail the possibilities of sharpening our understanding of the relationship to inequalities and injustices. We work with these critiques, suggesting that they represent two sides of the same problem, associated with binaries. In doing so, we build on the existing emphasis on practices and work across the three dominant ways of knowing urban informalities. This reveals that binaries are not held together magically and transparently so that each is the mirror opposite. Instead, the difference is constituted through unnamed aspects of common denominators – two of which we highlight (property rights and aesthetics) – and may be intrinsic to the way urban informality has come to develop. It is through the latent power relations that inhere in these common denominators that urban scholars can achieve greater conceptual precision and make different contributions to broader urban theory committed to challenging injustices

GABAergic nerve terminals decrease in the substantia nigra following hemitransections of the striatonigral and pallidonigral pathways.

Glutamic acid decarboxylase (GAD), the enzyme that synthesizes the neurotransmitter, GABA, was immunocytochemically localized in axon terminals as well as in small and medium-sized neurons of the rat substantia nigra. The pattern formed by GAD-containing axon terminals with the dendrites and somata of neurons in the substantia nigra was altered following ipsilateral hemitransections of the striatonigral and pallidonigral pathways. A marked reduction of GAD-positive terminals occurred throughout this brain region, but the ventral fifth of the pars reticulata showed a nearly normal pattern of GAD-positive axon terminals. The results of this investigation are consistent with results from biochemical studies which have indicated that the striatonigral and/or pallidonigral pathways are GABAergic. In addition, these results suggest that the residual GABAergic terminals remaining after hemitransection are derived from intrinsic neurons of the substantia nigra

Suppression of cathepsins B and L causes a proliferation of lysosomes and the formation of meganeurites in hippocampus.

Cultured hippocampal slices exhibited prominent ultrastructural features of brain aging after exposure to an inhibitor of cathepsins B and L. Six days of treatment with N-CBZ-L-phenylalanyl-L-alanine-diazomethylketone (ZPAD) resulted in a dramatic increase in the number of lysosomes in the perikarya of neurons and glial cells throughout the slices. Furthermore, lysosomes in CA1 and CA3 pyramidal cells were not restricted to the soma but instead were located throughout dendritic processes. Clusters of lysosomes were commonly found within bulging segments of proximal dendrites that were notable for an absence of microtubules and neurofilaments. Although pyknotic nuclei were sometimes encountered, most of the cells in slices exposed to ZPAD for 6 d appeared relatively normal. Slices given 7 d of recovery contained several unique features, compared with those processed immediately after incubation with the inhibitor. Cell bodies of CA1 neurons were largely cleared of the excess lysosomes but had gained fusiform, somatic extensions that were filled with fused lysosomes and related complex, dense bodies. These appendages, similar in form and content to structures previously referred to as "meganeurites," were not observed in CA3 neurons or granule cells. Because meganeurites were often interposed between cell body and axon, they have the potential to interfere with processes requiring axonal transport. It is suggested that inactivation of cathepsins B and L results in a proliferation of lysosomes and that meganeurite generation provides a means of storing residual catabolic organelles. The accumulated material could be eliminated by pinching off the meganeurite but, at least in some cases, this action would result in axotomy. Reduced cathepsin L activity, increased numbers of lysosomes, and the formation of meganeurites are all reported to occur during brain aging; thus, it is possible that the infusion of ZPAD into cultured slices sets in motion a greatly accelerated gerontological sequence

Computational neurorehabilitation: modeling plasticity and learning to predict recovery

Despite progress in using computational approaches to inform medicine and neuroscience in the last 30 years, there have been few attempts to model the mechanisms underlying sensorimotor rehabilitation. We argue that a fundamental understanding of neurologic recovery, and as a result accurate predictions at the individual level, will be facilitated by developing computational models of the salient neural processes, including plasticity and learning systems of the brain, and integrating them into a context specific to rehabilitation. Here, we therefore discuss Computational Neurorehabilitation, a newly emerging field aimed at modeling plasticity and motor learning to understand and improve movement recovery of individuals with neurologic impairment. We first explain how the emergence of robotics and wearable sensors for rehabilitation is providing data that make development and testing of such models increasingly feasible. We then review key aspects of plasticity and motor learning that such models will incorporate. We proceed by discussing how computational neurorehabilitation models relate to the current benchmark in rehabilitation modeling – regression-based, prognostic modeling. We then critically discuss the first computational neurorehabilitation models, which have primarily focused on modeling rehabilitation of the upper extremity after stroke, and show how even simple models have produced novel ideas for future investigation. Finally, we conclude with key directions for future research, anticipating that soon we will see the emergence of mechanistic models of motor recovery that are informed by clinical imaging results and driven by the actual movement content of rehabilitation therapy as well as wearable sensor-based records of daily activity

HTR4 gene structure and altered expression in the developing lung

Background: Meta-analyses of genome-wide association studies (GWAS) have identified single nucleotide polymorphisms (SNPs) spanning the 5-hydroxytryptamine receptor 4 (5-HT4R) gene (HTR4) associated with lung function. The aims of this study were to i) investigate the expression profile of HTR4 in adult and fetal lung tissue and cultured airway cells, ii) further define HTR4 gene structure and iii) explore the potential functional implications of key SNPs using a bioinformatic approach

Efficacy of Some Combination Regimens of Oral Hypoglycaemic Agents in Type 2 Diabetes Mellitus Patients

Purpose: To examine the efficacy of selected oral hypoglycaemic agent (OHA) regimens in a small group of patients receiving such treatment.Methods: This was a retrospective, observational study that involved patients who had been diagnosed with type 2 diabetes mellitus and undergoing routine follow-up at a teaching hospital. By reviewing patients’ medical records, changes in fasting blood glucose (FPG) and glycated haemoglobin (HbA1c) levels induced by several OHA cobmination regimens were documented. Target FPG and HbA1c were defined as 4.4 - 6.1 mmol/L and 6.5 %, respectively.Results: Based on the medical records of 156 patients reviewed, the combination of metformin and gliclazide was the most commonly prescribed regimen (63.46 %). The use of gliclazide + rosiglitazone + acarbose produced the greatest reduction in FPG and HbA1c (-4.80 mmol/L and -4.20 %, respectively), but the number of patients receiving this combination was too small to allow definitive conclusions to be made. More patients in the triple OHA group were able to achieve the desired glycaemic control than those in the dual OHA group (FPG, 44.44 % versus 41.18 %; HbA1c, 52.94 % versus 47.06 %), highlighting the important benefits conferred by the use of multiple OHAs.Conclusion: The efficacy of various OHA combinations varies, and adding a third drug to a dual-agent regimen further reduces FPG and HbA1c levels. Though gliclazide + rosiglitazone + acarbose produces the greatest reduction in FPG and HbA1c levels, larger studies are required to confirm these findings.Keywords: Type 2 Diabetes Mellitus, Oral Hypoglycaemic Agents, Fasting Plasma Glucose (FPG), Glycated Haemoglobin (HbA1c), Combination Therapy, Gliclazide, Rosiglitazone, Acarbos

Human kin detection

Natural selection has favored the evolution of behaviors that benefit not only one's genes, but also their copies in genetically related individuals. These behaviors include optimal outbreeding (choosing a mate that is neither too closely related, nor too distant), nepotism (helping kin), and spite (hurting non-kin at a personal cost), and all require some form of kin detection or kin recognition. Yet, kinship cannot be assessed directly; human kin detection relies on heuristic cues that take into account individuals' context (whether they were reared by our mother, or grew up in our home, or were given birth by our spouse), appearance (whether they smell or look like us), and ability to arouse certain feelings (whether we feel emotionally close to them). The uncertainties of kin detection, along with its dependence on social information, create ample opportunities for the evolution of deception and self-deception. For example, babies carry no unequivocal stamp of their biological father, but across cultures they are passionately claimed to resemble their mother's spouse; to the same effect, neutral' observers are greatly influenced by belief in relatedness when judging resemblance between strangers. Still, paternity uncertainty profoundly shapes human relationships, reducing not only the investment contributed by paternal versus maternal kin, but also prosocial behavior between individuals who are related through one or more males rather than females alone. Because of its relevance to racial discrimination and political preferences, the evolutionary pressure to prefer kin to non-kin has a manifold influence on society at large