Simultaneous Alteration of the Circadian Variation of Memory, Hippocampal Synaptic Plasticity, and Metabolism in a Triple Transgenic Mouse Model of Alzheimer's Disease.

Alzheimer's disease (AD) is characterized by progressive memory deficits accompanied by synaptic and metabolic deficits, namely of mitochondrial function. AD patients also display a disrupted circadian pattern. Thus, we now compared memory performance, synaptic plasticity, and mitochondria function in 24-week-old non-transgenic (non-Tg) and triple transgenic male mice modeling AD (3xTg-AD) at Zeitgeber 04 (ZT-4, inactive phase) and ZT-16 (active phase). Using the Morris water maze test to minimize the influence of circadian-associated locomotor activity, we observed a circadian variation in hippocampus-dependent learning performance in non-Tg mice, which was impaired in 3xTg-AD mice. 3xTg-AD mice also displayed a lack of circadian variation of their performance in the reversal spatial learning task. Additionally, the amplitude of hippocampal long-term potentiation also exhibited a circadian profile in non-Tg mice, which was not observed in 3xTg-AD mice. Moreover, cerebral cortical synaptosomes of non-Tg mice also displayed a circadian variation of FCCP-stimulated oxygen consumption as well as in mitochondrial calcium retention that were blunted in 3xTg-AD mice. In sum, this multidimensional study shows that the ability to maintain a circadian oscillation in brain behavior, synaptic plasticity, and synaptic mitochondria function are simultaneously impaired in 3xTg-AD mice, highlighting the effects of circadian misalignment in AD.

Endothelial dysfunction in people with depressive disorders: A systematic review and meta-analysis.

The study aimed to identify whether people diagnosed with depression have endothelial dysfunction, assessed by the technique of flow-mediated dilation (FMD), when compared to controls without depression. In addition, to verify whether people with depressive symptoms have impaired endothelial function when compared to controls without symptoms. Also to explore the potential moderators of the association between depression and endothelial dysfunction. Systematic review and meta-analysis. We searched PubMed, PsycINFO, Embase and Web of Science, from inception to April 16, 2021, for studies in people with depression and controls evaluating endothelial function through FMD. The primary outcome was the percentage of change in FMD. Comparative random effects meta-analysis, calculating the mean difference (MD) of the FMD between depressed and controls was performed. Potential sources of heterogeneity were explored by meta-regressions and subgroup analyses. The study protocol was registered with PROSPERO (CRD42020192070). Nine studies evaluating 1367 participants (379 depressed and 988 controls) (median age = 39.8 years, 44.9% men) were included. People with depression had lower FMD = -1.48% (95%CI = -2.62 to -0.33). High density lipoprotein (HDL) cholesterol levels moderated the effect (beta = -0.408, 95%CI = -0.776 to -0.040). Differences in FMD were found when assessment was done in the first minute after release of the occlusion, when using occlusion position in distal forearm, and when using occlusion pressure between 250 and 300 mmHg. Those with clinical depression (established by diagnostic instruments) presented the greatest dysfunction. Individuals with depression have a more impaired endothelial dysfunction when compared to controls. HDL cholesterol levels and differences in FMD assessment modalities moderate the difference.

Classification of the interictal state with hypsarrhythmia from Zika Virus Congenital Syndrome and of the ictal state from epilepsy in childhood without hypsarrhythmia in EEGs using entropy measures.

This paper intends to classify the interictal state with hypsarrhythmia in patients with Zika Virus Congenital Syndrome (ZVCS) and of the ictal state in patients with epilepsy in childhood without the presence of hypsarrhythmia. Hypsarrhythmia is a specific interictal chaotic morphology, and the correct distinction between these two EEG states is crucial to improving the cognitive development of these epileptic patients. The proposed approach was assessed using the proprietary database of Casa Ninar, which contains data regarding children from northeastern Brazil born with microcephaly caused by the Zika virus. We also used data from the CHB-MIT database. Fundamental rhythms of the EEG signal δ, θ, α, and ß were analyzed, and then decomposed by Discrete Wavelet Transform, in which 45 mother wavelet functions were tested to determine the most appropriate function to represent the EEG signals in the hypsarrhythmia interictal and ictal states. We extracted Shannon, Log Energy, Norm, and Sure entropy measures of the subbands as relevant features, and the combinations among them were applied in the state-of-the-art machine learning methods. The combination of Sure entropy with Shannon entropy, or with Log Energy and Norm, extracted from the δ rhythm, allowed for the best linear separability between the classes in most of the classifiers, obtaining 100% accuracy, sensitivity, and specificity.

Chronic hyperglycemia impairs hippocampal neurogenesis and memory in an Alzheimer's disease mouse model.

During aging, lifestyle-related factors shape the brain's response to insults and modulate the progression of neurodegenerative pathologies such as Alzheimer's disease (AD). This is the case for chronic hyperglycemia associated with type 2 diabetes, which reduces the brain's ability to handle the neurodegenerative burden associated with AD. However, the mechanisms behind the effects of chronic hyperglycemia in the context of AD are not fully understood. Here, we show that newly generated neurons in the hippocampal dentate gyrus of triple transgenic AD (3xTg-AD) mice present increased dendritic arborization and a number of synaptic puncta, which may constitute a compensatory mechanism allowing the animals to cope with a lower neurogenesis rate. Contrariwise, chronic hyperglycemia decreases the complexity and differentiation of 3xTg-AD newborn neurons and reduces the levels of ß-catenin, a key intrinsic modulator of neuronal maturation. Moreover, synaptic facilitation is depressed in hyperglycemic 3xTg-AD mice, accompanying the defective hippocampal-dependent memory. Our data suggest that hyperglycemia evokes cellular and functional alterations that accelerate the onset of AD-related symptoms, namely memory impairment.

Supercell calculations of the geometry and lattice energy of α-glycine crystal.

Evidence about the presence of glycine in the interstellar medium (ISM) has been motivating studies aiming the understanding of the chemical behavior of this amino acid in such environment. Since glycine is expected to be predominantly found in the ISM in solid phase, this work focuses on the search for a theoretical methodology for obtaining a molecular cluster for α-glycine that provides a good description of the geometry of the unit cell and lattice energy. Calculations have been performed using the B3LYP-D3, PBE0-D3, and WB97X-D3 functionals, with def2-SVP, def2-TZVP, def2-TZVPP, and def2-QZVPP basis sets for two models: (a) the unit cell, containing 4 glycine units, and (b) the 2 × 1 × 2 expanded cell, with 16 glycine units. Corrections for the basis set superposition error have also been applied. No significant changes in geometries and lattice energy predictions from the different functionals and basis sets have been observed for each model. Nevertheless, results obtained for the larger molecular cluster are in better agreement with the experimental data. The best lattice energy prediction, obtained for the 2 × 1 × 2 supercell at the B3LYP-gCP-D3/def2-TZVPP level, is - 15.35 kcal mol-1, with a root mean square deviation of the predicted Cartesian coordinates of the inner molecules (with respect to the experimental α-glycine unit cell geometry) of 0.966 Å. This methodology is finally recommended for future studies of similar molecular cluster, and the predicted geometry is proposed for further studies aiming to describe glycine surface reactions in the ISM.

Superior Effects of High-Intensity Interval vs. Moderate-Intensity Continuous Training on Endothelial Function and Cardiorespiratory Fitness in Patients With Type 1 Diabetes: A Randomized Controlled Trial.

This study aimed to compare the effect of high-intensity interval training (HIIT) with moderate-intensity continuous training (MCT) on endothelial function, oxidative stress and clinical fitness in patients with type 1 diabetes. Thirty-six type 1 diabetic patients (mean age 23.5 ± 6 years) were randomized into 3 groups: HIIT, MCT, and a non-exercising group (CON). Exercise was performed in a stationary cycle ergometers during 40 min, 3 times/week, for 8 weeks at 50-85% maximal heart rate (HRmax) in HIIT and 50% HRmax in MCT. Endothelial function was measured by flow-mediated dilation (FMD) [endothelium-dependent vasodilation (EDVD)], and smooth-muscle function by nitroglycerin-mediated dilation [endothelium-independent vasodilation (EIVD)]. Peak oxygen consumption (VO2peak) and oxidative stress markers were determined before and after training. Endothelial dysfunction was defined as an increase < 8% in vascular diameter after cuff release. The trial is registered at ClinicalTrials.gov, identifier: NCT03451201. Twenty-seven patients completed the 8-week protocol, 9 in each group (3 random dropouts per group). Mean baseline EDVD was similar in all groups. After training, mean absolute EDVD response improved from baseline in HIIT: + 5.5 ± 5.4%, (P = 0.0059), but remained unchanged in MCT: 0.2 ± 4.1% (P = 0.8593) and in CON: -2.6 ± 6.4% (P = 0.2635). EDVD increase was greater in HIIT vs. MCT (P = 0.0074) and CON (P = 0.0042) (ANOVA with Bonferroni). Baseline VO2peak was similar in all groups (P = 0.96). VO2peak increased 17.6% from baseline after HIIT (P = 0.0001), but only 3% after MCT (P = 0.055); no change was detected in CON (P = 0.63). EIVD was unchanged in all groups (P = 0.18). Glycemic control was similar in all groups. In patients with type 1 diabetes without microvascular complications, 8-week HIIT produced greater improvement in endothelial function and physical fitness than MCT at a similar glycemic control.

Empirical force field for cisplatin based on quantum dynamics data: case study of new parameterization scheme for coordination compounds.

Parameterization of molecular complexes containing a metallic compound, such as cisplatin, is challenging due to the unconventional coordination nature of the bonds which involve platinum atoms. In this work, we develop a new methodology of parameterization for such compounds based on quantum dynamics (QD) calculations. We show that the coordination bonds and angles are more flexible than in normal covalent compounds. The influence of explicit solvent is also shown to be crucial to determine the flexibility of cisplatin in quantum dynamics simulations. Two empirical topologies of cisplatin were produced by fitting its atomic fluctuations against QD in vacuum and QD with explicit first solvation shell of water molecules respectively. A third topology built in a standard way from the static optimized structure was used for comparison. The later one leads to an excessively rigid molecule and exhibits much smaller fluctuations of the bonds and angles than QD reveals. It is shown that accounting for the high flexibility of cisplatin molecule is needed for adequate description of its first hydration shell. MD simulations with flexible QD-based topology also reveal a significant decrease of the barrier of passive diffusion of cisplatin accross the model lipid bilayer. These results confirm that flexibility of organometallic compounds is an important feature to be considered in classical molecular dynamics topologies. Proposed methodology based on QD simulations provides a systematic way of building such topologies.

Epilepsy, hippocampal sclerosis and febrile seizures linked by common genetic variation around SCN1A.

Epilepsy comprises several syndromes, amongst the most common being mesial temporal lobe epilepsy with hippocampal sclerosis. Seizures in mesial temporal lobe epilepsy with hippocampal sclerosis are typically drug-resistant, and mesial temporal lobe epilepsy with hippocampal sclerosis is frequently associated with important co-morbidities, mandating the search for better understanding and treatment. The cause of mesial temporal lobe epilepsy with hippocampal sclerosis is unknown, but there is an association with childhood febrile seizures. Several rarer epilepsies featuring febrile seizures are caused by mutations in SCN1A, which encodes a brain-expressed sodium channel subunit targeted by many anti-epileptic drugs. We undertook a genome-wide association study in 1018 people with mesial temporal lobe epilepsy with hippocampal sclerosis and 7552 control subjects, with validation in an independent sample set comprising 959 people with mesial temporal lobe epilepsy with hippocampal sclerosis and 3591 control subjects. To dissect out variants related to a history of febrile seizures, we tested cases with mesial temporal lobe epilepsy with hippocampal sclerosis with (overall n = 757) and without (overall n = 803) a history of febrile seizures. Meta-analysis revealed a genome-wide significant association for mesial temporal lobe epilepsy with hippocampal sclerosis with febrile seizures at the sodium channel gene cluster on chromosome 2q24.3 [rs7587026, within an intron of the SCN1A gene, P = 3.36 × 10(-9), odds ratio (A) = 1.42, 95% confidence interval: 1.26-1.59]. In a cohort of 172 individuals with febrile seizures, who did not develop epilepsy during prospective follow-up to age 13 years, and 6456 controls, no association was found for rs7587026 and febrile seizures. These findings suggest SCN1A involvement in a common epilepsy syndrome, give new direction to biological understanding of mesial temporal lobe epilepsy with hippocampal sclerosis with febrile seizures, and open avenues for investigation of prognostic factors and possible prevention of epilepsy in some children with febrile seizures.