Given the prevalence and societal impact of autism spectrum disorders (ASD), there is an urgent need to develop innovative preventative strategies and treatments to reduce the alarming number of ...cases and improve core symptoms for afflicted individuals. Translational efforts between clinical and preclinical research are needed to (i) identify and evaluate putative causes of ASD, (ii) determine the underlying neurobiological mechanisms, (iii) develop and test novel therapeutic approaches and (iv) ultimately translate basic research into safe and effective clinical practices. However, modeling a uniquely human brain disorder, such as ASD, will require sophisticated animal models that capitalize on unique advantages of diverse species including drosophila, zebra fish, mice, rats, and ultimately, species more closely related to humans, such as the nonhuman primate. Here we discuss the unique contributions of the rhesus monkey (Macaca mulatta) model to ongoing efforts to understand the neurobiology of the disorder, focusing on the convergence of brain and behavior outcome measures that parallel features of human ASD.
•Advanced animal models are needed to study complex brain disorders, such as ASD.•Rhesus monkeys demonstrate sophisticated social processing capabilities.•Brain regions implicated in social processing are well developed in rhesus monkeys.•This combination makes the rhesus monkey an invaluable preclinical tool for ASD.
The amygdala is a medial temporal lobe structure implicated in social and emotional regulation. In typical development (TD), the amygdala continues to increase volumetrically throughout childhood and ...into adulthood, while other brain structures are stable or decreasing in volume. In autism spectrum disorder (ASD), the amygdala undergoes rapid early growth, making it volumetrically larger in children with ASD compared to TD children. Here we explore: (a) if dendritic arborization in the amygdala follows the pattern of protracted growth in TD and early overgrowth in ASD and (b), if spine density in the amygdala in ASD cases differs from TD from youth to adulthood. The amygdala from 32 postmortem human brains (7–46 years of age) were stained using a Golgi‐Kopsch impregnation. Ten principal neurons per case were selected in the lateral nucleus and traced using Neurolucida software in their entirety. We found that both ASD and TD individuals show a similar pattern of increasing dendritic length with age well into adulthood. However, spine density is (a) greater in young ASD cases compared to age‐matched TD controls (<18 years old) and (b) decreases in the amygdala as people with ASD age into adulthood, a phenomenon not found in TD. Therefore, by adulthood, there is no observable difference in spine density in the amygdala between ASD and TD age‐matched adults (≥18 years old). Our findings highlight the unique growth trajectory of the amygdala and suggest that spine density may contribute to aberrant development and function of the amygdala in children with ASD.
Here we demonstrate the density of spines in the amygdala is greater in young children with ASD than typically developing peers. This phenomenon normalizes with age such that there is no difference in spine density between adults with ASD and typically developing adults.
In the past decades, Deep Learning (DL) frameworks have demonstrated excellent performance in modeling nonlinear interactions and are a promising technique to move beyond physics-based models. In ...this context, super-resolution techniques may present an accurate approach as subfilter-scale (SFS) closure model for Large Eddy Simulations (LES) in premixed combustion. However, DL models need to perform accurately in a variety of physical regimes and generalize well beyond their training conditions. In this work, a super-resolution Generative Adversarial Network (GAN) is proposed as closure model for the unresolved subfilter-stress and scalar-flux tensors of the filtered reactive Navier–Stokes equations solved in LES. The model trained on a premixed methane/air jet flame is evaluated a-priori on similar configurations at different Reynolds and Karlovitz numbers. The GAN generalizes well at both lower and higher Reynolds numbers and outperforms existing algebraic models when the ratio between the filter size and the Kolmogorov scale is preserved. Moreover, extrapolation at a higher Karlovitz number is investigated indicating that the ratio between the filter size and the thermal flame thickness may not need to be conserved in order to achieve high correlation in terms of SFS field. Generalization studies obtained on substantially different flame conditions indicate that successful predictive abilities are demonstrated if the generalization criterion is matched. Finally, the reconstruction of a scalar quantity, different from that used during the training, is evaluated, revealing that the model is able to reconstruct scalar fields with large gradients that have not been explicitly used in the training. The a-priori investigations carried out assess whether out-of-sample predictions are even feasible in the first place, providing insights into the quantities that need to be conserved for the model to perform well between different regimes, and represent a crucial step toward future embedding into LES numerical solvers.
In Europe, in addition to Borrelia burgdorferi sensu lato and tick-borne encephalitis (TBE) virus, other zoonotic pathogens, like B. miyamotoi, a species related to the relapsing fever spirochaetes, ...Candidatus Neoehrlichia mikurensis (N. mikurensis), Rickettsia helvetica, Rickettsia monacensis, and Anaplasma phagocytophilum have been reported in the ixodid tick Ixodes ricinus. No study was conducted to identify reservoir hosts for these pathogens. Here, we investigated the role played by wild rodents in the natural transmission cycle of B. miyamotoi, N. mikurensis, R. helvetica, R. monacensis, and A. phagocytophilum in Switzerland. In 2011 and 2012, small mammals were captured in an area where these pathogens occur in questing ticks. Ixodes ricinus ticks infesting captured small mammals were analysed after their moult by PCR followed by reverse line blot to detect the different pathogens. Xenodiagnostic larvae were used to evaluate the role of rodents as reservoirs and analysed after their moult. Most of the 108 captured rodents (95.4%) were infested by I. ricinus ticks; 4.9%, 3.9%, 24.0%, and 0% of the rodents were infested by Borrelia, N. mikurensis, Rickettsia spp., and A. phagocytophilum-infected larvae, respectively. Borrelia afzelii, B. miyamotoi, N. mikurensis, Rickettsia spp., and A. phagocytophilum were detected in 2.8%, 0.17%, 2.6%, 6.8%, and 0% of the ticks attached to rodents, respectively. Borrelia afzelii was transmitted by 4 rodents to 41.2% of the xenodiagnostic ticks, B. miyamotoi by 3 rodents to 23.8%, and N. mikurensis was transmitted by 6 rodents to 41.0% of the xenodiagnostic ticks. None of the tested rodent transmitted Rickettsia spp. or A. phagocytophilum to I. ricinus xenodiagnostic larvae. This study showed that rodents are reservoir hosts for B. miyamotoi and N. mikurensis in Europe.
Acid and metalliferous release occurring when sulfide (principally pyrite)-containing rock from mining activities and from natural environments is exposed to the elements is acknowledged as a major ...environmental problem. Acid rock drainage (ARD) management is both challenging and costly for operating and legacy mine sites. Current technological solutions are expensive and focused on treating ARD on release rather than preventing it at source. We describe here a viable, practical mechanism for reduced ARD through the formation of silicate-stabilized iron oxyhydroxide surface layers. Without silicate, oxidized pyrite particles form an overlayer of crystalline goethite or lepidocrocite with porous structure. With silicate addition, a smooth, continuous, coherent and apparently amorphous iron oxyhydroxide surface layer is observed, with consequent pyrite dissolution rates reduced by more than 90% at neutral pH. Silicate is structurally incorporated within this layer and inhibits the phase transformation from amorphous iron (oxy)hydroxide to goethite, resulting in pyrite surface passivation. This is confirmed by computational simulation, suggesting that silicate-doping of a pseudoamorphous iron oxyhydroxide (ferrihydrite structure) is thermodynamically more stable than the equivalent undoped structure. This mechanism and its controlling factors are described. As a consequence of the greatly reduced acid generation rate, neutralization from on-site available reactive silicate minerals may be used to maintain neutral pH, after initial limestone addition to achieve neutral pH, thus maintaining the integrity of these layers for effective ARD management.
Although up to 15% of patients with whiplash injury develop chronic headache, the basis and mechanisms of this posttraumatic headache are not well understood.
Thirty-two patients with posttraumatic ...headache following whiplash injury were investigated within 14 days after the accident and again after 3 months using magnetic resonance-based voxel-based morphometry. Twelve patients developed chronic headache lasting longer than 3 months and were studied a third time after 1 year.
Patients who developed chronic headache revealed decreases in gray matter in the anterior cingulate and dorsolateral prefrontal cortex after 3 months. These changes resolved after 1 year, in parallel to the cessation of headache. The same patients who developed chronic headache showed an increase of gray matter in antinociceptive brainstem centers, thalamus, and cerebellum 1 year after the accident.
We demonstrate adaptive gray matter changes of pain processing structures in patients with chronic posttraumatic headache in regard to neuronal plasticity, thus providing a biologically plausible basis for this common, disabling problem.
This paper contributes to the debate on anti-doping policies not by evaluating the policy itself but by evaluating the announcement of (new) policy measures. We develop a dynamic model for analyzing ...the effects of two different types of news shocks: (1) the preannouncement of improved drug testing technological opportunities and (2) the preannouncement of future increases in financial sanctions. We find that the anticipation of policy changes affects the behavior of potentially delinquent athletes. In both scenarios, our simulations show immediately reduced drug abuse among athletes. We conclude that authorities may consider news shocks as an anti-doping strategy.
To examine the mechanism by which metformin lowers endogenous glucose production in type 2 diabetic patients, we studied seven type 2 diabetic subjects, with fasting hyperglycemia (15.5 +/- 1.3 ...mmol/l), before and after 3 months of metformin treatment. Seven healthy subjects, matched for sex, age, and BMI, served as control subjects. Rates of net hepatic glycogenolysis, estimated by 13C nuclear magnetic resonance spectroscopy, were combined with estimates of contributions to glucose production of gluconeogenesis and glycogenolysis, measured by labeling of blood glucose by 2H from ingested 2H2O. Glucose production was measured using 6,6-2H2glucose. The rate of glucose production was twice as high in the diabetic subjects as in control subjects (0.70 +/- 0.05 vs. 0.36 +/- 0.03 mmol x m(-2) min(-1), P < 0.0001). Metformin reduced that rate by 24% (to 0.53 +/- 0.03 mmol x m(-2) x min(-1), P = 0.0009) and fasting plasma glucose concentration by 30% (to 10.8 +/- 0.9 mmol/l, P = 0.0002). The rate of gluconeogenesis was three times higher in the diabetic subjects than in the control subjects (0.59 +/- 0.03 vs. 0.18 +/- 0.03 mmol x m(-2) min(-1) and metformin reduced that rate by 36% (to 0.38 +/- 0.03 mmol x m(-2) x min(-1), P = 0.01). By the 2H2O method, there was a twofold increase in rates of gluconeogenesis in diabetic subjects (0.42 +/- 0.04 mmol m(-2) x min(-1), which decreased by 33% after metformin treatment (0.28 +/- 0.03 mmol x m(-2) x min(-1), P = 0.0002). There was no glycogen cycling in the control subjects, but in the diabetic subjects, glycogen cycling contributed to 25% of glucose production and explains the differences between the two methods used. In conclusion, patients with poorly controlled type 2 diabetes have increased rates of endogenous glucose production, which can be attributed to increased rates of gluconeogenesis. Metformin lowered the rate of glucose production in these patients through a reduction in gluconeogenesis.
•Lack of reliable epidemiological data concerning diabetic neuropathy.•Rapid lowering of blood glucose levels can worsen symptoms associated with diabetic neuropathy.•Findings from MR-neurography and ...histology suggest proximal primary nerve injury in diabetic polyneuropathy.•There are no specific treatment options for diabetic neuropathy, with the drugs commonly used showing inconsistent results.
A 62-year-old diabetologist diagnosed himself to have diabetes type-2, with an HbA1c of 9.5. Five months after lifestyle intervention and a multi-drug approach, HbA1c was 6.3, systolic blood pressure was below 135mmHg and BMI reduced to 27. But he suffered from severe painful diabetic neuropathy. Therefore he decided to visit his friend, a famous neuroscientist at an even more famous university. He asked him several plain questions: 1. What is the natural course of painful diabetic neuropathy? 2. Why do I have, despite almost normalizing HbA1c, more problems than before? 3. Are you sure my problems are due to diabetes or should we do a nerve biopsy? 4. Are there imaging techniques helpful for the diagnosis of this diabetic complication, starting in the distal nerve endings of the foot and slowly moving ahead? 5. Can you suggest any drug, specific and effective, for relieving painful diabetic neuropathy?
This review will use the experts’ answers to the questions of the diabetologist, not only to give a summary of the current knowledge, but even more to highlight areas of research needed for improving the fate of patients with painful diabetic neuropathy. Based on the unknowns, which exceed the knowns in diabetic neuropathy, a quest for more public support of research is made.
Premixed flames exhibit different asymptotic regimes of interaction between heat release and turbulence depending on their respective length scales. At high Karlovitz number, the dilatation caused by ...heat release does not have any relevant effect on turbulent kinetic energy with respect to non-reacting flow, while at low Karlovitz number, the mean shear is a sink of turbulent kinetic energy, and counter-gradient transport is observed. This latter phenomenon is not well captured by closure models commonly used in Large Eddy Simulations that are based on gradient diffusion. The massive amount of data available from Direct Numerical Simulation (DNS) opens the possibility to develop data-driven models able to represent physical mechanisms and non-linear features present in both these regimes. In this work, the databases are formed by DNSs of two planar hydrogen/air flames at different Karlovitz numbers corresponding to the two asymptotic regimes. In this context, the Generative Adversarial Network (GAN) gives the possibility to successfully recognize and reconstruct both gradient and counter-gradient phenomena if trained with databases where both regimes are included. Two GAN models were first trained each for a specific Karlovitz number and tested using the same dataset in order to verify the capability of the models to learn the features of a single asymptotic regime and assess its accuracy. In both cases, the GAN models were able to reconstruct the Reynolds stress subfilter scales accurately. Later, the GAN was trained with a mixture of both datasets to create a model containing physical knowledge of both combustion regimes. This model was able to reconstruct the subfilter scales for both cases capturing the interaction between heat release and turbulence closely to the DNS as shown from the turbulent kinetic budget and barycentric maps.
PDF
