Connectome dysfunction in patients at clinical high risk for psychosis and modulation by oxytocin.

Abnormalities in functional brain networks (functional connectome) are increasingly implicated in people at Clinical High Risk for Psychosis (CHR-P). Intranasal oxytocin, a potential novel treatment for the CHR-P state, modulates network topology in healthy individuals. However, its connectomic effects in people at CHR-P remain unknown. Forty-seven men (30 CHR-P and 17 healthy controls) received acute challenges of both intranasal oxytocin 40 IU and placebo in two parallel randomised, double-blind, placebo-controlled cross-over studies which had similar but not identical designs. Multi-echo resting-state fMRI data was acquired at approximately 1 h post-dosing. Using a graph theoretical approach, the effects of group (CHR-P vs healthy control), treatment (oxytocin vs placebo) and respective interactions were tested on graph metrics describing the topology of the functional connectome. Group effects were observed in 12 regions (all pFDR < 0.05) most localised to the frontoparietal network. Treatment effects were found in 7 regions (all pFDR < 0.05) predominantly within the ventral attention network. Our major finding was that many effects of oxytocin on network topology differ across CHR-P and healthy individuals, with significant interaction effects observed in numerous subcortical regions strongly implicated in psychosis onset, such as the thalamus, pallidum and nucleus accumbens, and cortical regions which localised primarily to the default mode network (12 regions, all pFDR < 0.05). Collectively, our findings provide new insights on aberrant functional brain network organisation associated with psychosis risk and demonstrate, for the first time, that oxytocin modulates network topology in brain regions implicated in the pathophysiology of psychosis in a clinical status (CHR-P vs healthy control) specific manner.

Ligand Effects on the Spin Relaxation Dynamics and Coherent Manipulation of Organometallic La(II) Potential Qudits.

We present pulsed electron paramagnetic resonance (EPR) studies on three La(II) complexes, [K(2.2.2-cryptand)][La(Cp')3] (1), [K(2.2.2-cryptand)][La(Cp″)3] (2), and [K(2.2.2-cryptand)][La(Cptt)3] (3), which feature cyclopentadienyl derivatives as ligands [Cp' = C5H4SiMe3; Cp″ = C5H3(SiMe3)2; Cptt = C5H3(CMe3)2] and display a C3 symmetry. Long spin-lattice relaxation (T1) and phase memory (Tm) times are observed for all three compounds, but with significant variation in T1 among 1-3, with 3 being the slowest relaxing due to higher s-character of the SOMO. The dephasing times can be extended by more than an order of magnitude via dynamical decoupling experiments using a Carr-Purcell-Meiboom-Gill (CPMG) sequence, reaching 161 µs (5 K) for 3. Coherent spin manipulation is performed by the observation of Rabi quantum oscillations up to 80 K in this nuclear spin-rich environment (1H, 13C, and 29Si). The high nuclear spin of 139La (I = 7/2), and the ability to coherently manipulate all eight hyperfine transitions, makes these molecules promising candidates for application as qudits (multilevel quantum systems featuring d quantum states; d >2) for performing quantum operations within a single molecule. Application of HYSCORE techniques allows us to quantify the electron spin density at ligand nuclei and interrogate the role of functional groups to the electron spin relaxation properties.

Increased hippocampal blood flow in people at clinical high risk for psychosis and effects of cannabidiol.

BACKGROUND: Hippocampal hyperperfusion has been observed in people at Clinical High Risk for Psychosis (CHR), is associated with adverse longitudinal outcomes and represents a potential treatment target for novel pharmacotherapies. Whether cannabidiol (CBD) has ameliorative effects on hippocampal blood flow (rCBF) in CHR patients remains unknown. METHODS: Using a double-blind, parallel-group design, 33 CHR patients were randomized to a single oral 600 mg dose of CBD or placebo; 19 healthy controls did not receive any drug. Hippocampal rCBF was measured using Arterial Spin Labeling. We examined differences relating to CHR status (controls v. placebo), effects of CBD in CHR (placebo v. CBD) and linear between-group relationships, such that placebo > CBD > controls or controls > CBD > placebo, using a combination of hypothesis-driven and exploratory wholebrain analyses. RESULTS: Placebo-treated patients had significantly higher hippocampal rCBF bilaterally (all pFWE<0.01) compared to healthy controls. There were no suprathreshold effects in the CBD v. placebo contrast. However, we found a significant linear relationship in the right hippocampus (pFWE = 0.035) such that rCBF was highest in the placebo group, lowest in controls and intermediate in the CBD group. Exploratory wholebrain results replicated previous findings of hyperperfusion in the hippocampus, striatum and midbrain in CHR patients, and provided novel evidence of increased rCBF in inferior-temporal and lateral-occipital regions in patients under CBD compared to placebo. CONCLUSIONS: These findings suggest that hippocampal blood flow is elevated in the CHR state and may be partially normalized by a single dose of CBD. CBD therefore merits further investigation as a potential novel treatment for this population.

Influence of diimine bidentate ligand in the nitrosyl and nitro terpyridine ruthenium complex on the HSA/DNA interaction and antiviral activity.

Nitric oxide (NO) acts in different physiological processes, such as blood pressure control, antiparasitic activities, neurotransmission, and antitumor action. Among the exogenous NO donors, ruthenium nitrosyl/nitro complexes are potential candidates for prodrugs, due to their physicochemical properties, such as thermal and physiological pH stability. In this work, we proposed the synthesis and physical characterization of the new nitro terpyridine ruthenium (II) complexes of the type [RuII(L)(NO2)(tpy)]PF6 where tpy = 2,2':6',2″-terpyridine; L = 3,4-diaminobenzoic acid (bdq) or o-phenylenediamine (bd) and evaluation of influence of diimine bidentate ligand NH.NHq-R (R = H or COOH) in the HSA/DNA interaction as well as antiviral activity. The interactions between HSA and new nitro complexes [RuII(L)(NO2)(tpy)]+ were evaluated. The Ka values for the HSA-[RuII(bdq)(NO2)(tpy)]+ is 10 times bigger than HSA-[RuII(bd)(NO2)(tpy)]+. The sites of interaction between HSA and the complexes via synchronous fluorescence suppression indicate that the [RuII(bdq)(NO2)(tpy)]+ is found close to the Trp-241 residue, while the [RuII(bd)(NO2)(tpy)]+ complex is close to Tyr residues. The interaction with fish sperm fs-DNA using direct spectrophotometric titration (Kb) and ethidium bromide replacement (KSV and Kapp) showed weak interaction in the system fs-DNA-[RuII(bdq)(NO)(tpy)]+. Furthermore, fs-DNA-[RuII(bd)(NO2)(tpy)]+ and fs-DNA-[RuII(bd)(NO)(tpy)]3+ system showed higher intercalation constant. Circular dichroism spectra for fs-DNA-[RuII(bd)(NO2)(tpy)]+ and fs-DNA-[RuII(bd)(NO)(tpy)]3+, suggest semi-intercalative accompanied by major groove binding interaction modes. The [RuII(bd)(NO2)(tpy)]+ and [RuII(bd)(NO)(tpy)]3+ inhibit replication of Zika and Chikungunya viruses based in the nitric oxide release under S-nitrosylation reaction with cysteine viral.

Enhancing nerve regeneration in infraorbital nerve injury rat model: effects of vitamin B complex and photobiomodulation.

Orofacial nerve injuries may result in temporary or long-term loss of sensory function and decreased quality of life in patients. B vitamins are required for DNA synthesis and the repair and maintenance of phospholipids. In particular, vitamins B1, B6, and B12 are essential for neuronal function. Deficiency in vitamin B complex (VBC) has been linked to increased oxidative stress, inflammation and demyelination. Photobiomodulation (PBM) has antioxidant activity and is neuroprotective. In addition, a growing literature attests to the positive effects of PBM on nerve repair. To assess the effect of PBM and VBC on regenerative process we evaluated the expression of brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), myelin basic protein (MBP), laminin and neurofilaments (NFs) using Western blotting to identify regenerative pattern after chronic constriction injury of the infraorbital nerve (CCI IoN) treated by PBM, VBC or its combination. After CCI IoN, the rats were divided into six groups naive, sham, injured (CCI IoN), treated with photobiomodulation (904 nm, 6.23 J/cm2, CCI IoN + PBM), treated with VBC (containing B1, B6 and B12) 5 times, CCI IoN + VBC) and treated with PBM and VBC (CCI IoN + VBC + PBM). The treatments could revert low expression of BDNF, MBP and laminin. Also reverted the higher expression of neurofilaments and enhanced expression of NGF. PBM and VBC could accelerate injured infraorbital nerve repair in rats through reducing the expression of neurofilaments, increasing the expression of BDNF, laminin and MBP and overexpressing NGF. These data support the notion that the use of PBM and VBC may help in the treatment of nerve injuries. This finding has potential clinical applications.

The effects of propofol anaesthesia on molecular-enriched networks during resting-state and naturalistic listening.

Placing a patient in a state of anaesthesia is crucial for modern surgical practice. However, the mechanisms by which anaesthetic drugs, such as propofol, impart their effects on consciousness remain poorly understood. Propofol potentiates GABAergic transmission, which purportedly has direct actions on cortex as well as indirect actions via ascending neuromodulatory systems. Functional imaging studies to date have been limited in their ability to unravel how these effects on neurotransmission impact the system-level dynamics of the brain. Here, we leveraged advances in multi-modal imaging, Receptor-Enriched Analysis of functional Connectivity by Targets (REACT), to investigate how different levels of propofol-induced sedation alter neurotransmission-related functional connectivity (FC), both at rest and when individuals are exposed to naturalistic auditory stimulation. Propofol increased GABA-A- and noradrenaline transporter-enriched FC within occipital and somatosensory regions respectively. Additionally, during auditory stimulation, the network related to the dopamine transporter showed reduced FC within bilateral regions of temporal and mid/posterior cingulate cortices, with the right temporal cluster showing an interaction between auditory stimulation and level of consciousness. In bringing together these micro- and macro-scale systems, we provide support for both direct GABAergic and indirect noradrenergic and dopaminergic-related network changes under propofol sedation. Further, we delineate a cognition-related reconfiguration of the dopaminergic network, highlighting the utility of REACT to explore the molecular substrates of consciousness and cognition.

Exploring the neuroprotective effects of montelukast on brain inflammation and metabolism in a rat model of quinolinic acid-induced striatal neurotoxicity.

BACKGROUND: One intrastriatal administration of quinolinic acid (QA) in rats induces a lesion with features resembling those observed in Huntington's disease. Our aim is to evaluate the effects of the cysteinyl leukotriene receptor antagonist montelukast (MLK), which exhibited neuroprotection in different preclinical models of neurodegeneration, on QA-induced neuroinflammation and regional metabolic functions. METHODS: The right and left striatum of Sprague Dawley and athymic nude rats were injected with QA and vehicle (VEH), respectively. Starting from the day before QA injection, animals were treated with 1 or 10 mg/kg of MLK or VEH for 14 days. At 14 and 30 days post-lesion, animals were monitored with magnetic resonance imaging (MRI) and positron emission tomography (PET) using [18F]-VC701, a translocator protein (TSPO)-specific radiotracer. Striatal neuroinflammatory response was measured post-mortem in rats treated with 1 mg/kg of MLK by immunofluorescence. Rats treated with 10 mg/kg of MLK also underwent a [18F]-FDG PET study at baseline and 4 months after lesion. [18F]-FDG PET data were then used to assess metabolic connectivity between brain regions by applying a covariance analysis method. RESULTS: MLK treatment was not able to reduce the QA-induced increase in striatal TSPO PET signal and MRI lesion volume, where we only detected a trend towards reduction in animals treated with 10 mg/kg of MLK. Post-mortem immunofluorescence analysis revealed that MLK attenuated the increase in striatal markers of astrogliosis and activated microglia in the lesioned hemisphere. We also found a significant increase in a marker of anti-inflammatory activity (MannR) and a trend towards reduction in a marker of pro-inflammatory activity (iNOS) in the lesioned striatum of MLK-compared to VEH-treated rats. [18F]-FDG uptake was significantly reduced in the striatum and ipsilesional cortical regions of VEH-treated rats at 4 months after lesion. MLK administration preserved glucose metabolism in these cortical regions, but not in the striatum. Finally, MLK was able to counteract changes in metabolic connectivity and measures of network topology induced by QA, in both lesioned and non-lesioned hemispheres. CONCLUSIONS: Overall, MLK treatment produced a significant neuroprotective effect by reducing neuroinflammation assessed by immunofluorescence and preserving regional brain metabolism and metabolic connectivity from QA-induced neurotoxicity in cortical and subcortical regions.

Dereplication of Lantana trifolia L. leaves and fruits by UFLC-DAD-(+)-ESI-MS/MS and its antifungal and cytotoxic activities.

INTRODUCTION: Lantana trifolia L. (Verbenaceae) is a shrubby plant. In folk medicine, its leaves are used in the form of infusions and syrups to treat angina, coughs, and colds; they are also applied as tranquilizer. Previous studies have reported the antimicrobial potential of the compounds present in L. trifolia leaves. OBJECTIVES: To report the anti-Candida activities of the fractions obtained from the fruits and leaves of two L. trifolia specimens. METHODS: The L. trifolia fractions were submitted to UFLC-DAD-(+)-ESI-MS/MS, and the data were analyzed by using multivariate statistical tools (PCA, PLS-DA) and spectral similarity analyses based on molecular networking, which aided dereplication of the bioactive compounds. Additionally, NMR analyses were performed to confirm the chemical structure of some of the major compounds in the fractions. RESULTS: The ethyl acetate fractions presented MIC values lower than 100 µg mL-1 against the three Candida strains evaluated herein (C. albicans, C. tropicalis, and C. glabrata). Fractions FrPo AcOEt, FrPe AcOEt, and FrPe nBut had MIC values of 1.46, 2.93, and 2.93 µg mL-1 against C. glabrata, respectively. These values resembled the MIC value of amphotericin B, the positive control (0.5-1.0 µg mL-1), against this same strain. Cytotoxicity was measured and used to calculate the selectivity index. CONCLUSION: On the basis of our data, the most active fractions in the antifungal assay were more selective against C. glabrata than against non-infected cells. The analytical approach adopted here allowed us to annotate 29 compounds, nine of which were bioactive (PLS-DA results) and belong to the class of phenolic compounds.

Insights into the role of the cobalt(III)-thiosemicarbazone complex as a potential inhibitor of the Chikungunya virus nsP4.

Chikungunya virus (CHIKV) is the causative agent of chikungunya fever, a disease that can result in disability. Until now, there is no antiviral treatment against CHIKV, demonstrating that there is a need for development of new drugs. Studies have shown that thiosemicarbazones and their metal complexes possess biological activities, and their synthesis is simple, clean, versatile, and results in high yields. Here, we evaluated the mechanism of action (MOA) of a cobalt(III) thiosemicarbazone complex named [CoIII(L1)2]Cl based on its in vitro potent antiviral activity against CHIKV previously evaluated (80% of inhibition on replication). Furthermore, the complex has no toxicity in healthy cells, as confirmed by infecting BHK-21 cells with CHIKV-nanoluciferase in the presence of the compound, showing that [CoIII(L1)2]Cl inhibited CHIKV infection with the selective index of 3.26. [CoIII(L1)2]Cl presented a post-entry effect on viral replication, emphasized by the strong interaction of [CoIII(L1)2]Cl with CHIKV non-structural protein 4 (nsP4) in the microscale thermophoresis assay, suggesting a potential mode of action of this compound against CHIKV. Moreover, in silico analyses by molecular docking demonstrated potential interaction of [CoIII(L1)2]Cl with nsP4 through hydrogen bonds, hydrophobic and electrostatic interactions. The evaluation of ADME-Tox properties showed that [CoIII(L1)2]Cl presents appropriate lipophilicity, good human intestinal absorption, and has no toxicological effect as irritant, mutagenic, reproductive, and tumorigenic side effects.

An update on the development of antiviral against Mayaro virus: from molecules to potential viral targets.

Mayaro virus (MAYV), first isolated in 1954 in Trinidad and Tobago islands, is the causative agent of Mayaro fever, a disease characterized by fever, rashes, headaches, myalgia, and arthralgia. The infection can progress to a chronic condition in over 50% of cases, with persistent arthralgia, which can lead to the disability of the infected individuals. MAYV is mainly transmitted through the bite of the female Haemagogus spp. mosquito genus. However, studies demonstrate that Aedes aegypti is also a vector, contributing to the spread of MAYV beyond endemic areas, given the vast geographical distribution of the mosquito. Besides, the similarity of antigenic sites with other Alphavirus complicates the diagnoses of MAYV, contributing to underreporting of the disease. Nowadays, there are no antiviral drugs available to treat infected patients, being the clinical management based on analgesics and non-steroidal anti-inflammatory drugs. In this context, this review aims to summarize compounds that have demonstrated antiviral activity against MAYV in vitro, as well as discuss the potentiality of viral proteins as targets for the development of antiviral drugs against MAYV. Finally, through rationalization of the data presented herein, we wish to encourage further research encompassing these compounds as potential anti-MAYV drug candidates.

Photobiomodulation and vitamin B treatment alleviate both thermal and mechanical orofacial pain in rats.

PURPOSE: The present study investigates the efficacy of Photobiomodulation (PBM) and Vitamin B Complex (VBC) to relieve pain, both in separately and combined (PBM and VBC). METHODS: Rats with chronic constriction injury of the right infraorbital nerve (CCI-IoN) or Sham surgery were used. PBM was administered at a wavelength of 904 nm and energy density of 6.23 J/cm2 and VBC (containing B1, B6 and B12) subcutaneously, both separately and combined. Behavioral tests were performed to assess mechanical and thermal hypersensitivity before and after CCI and after PBM, VBC, or PBM + VBC. The expression of inflammatory proteins in the trigeminal ganglion and the immunohistochemical alterations of Periaqueductal Gray (PAG) astrocytes and microglia were examined following CCI and treatments. RESULTS: All testeds treatments reversed the painful behavior. The decrease in pain was accompanied by a decrease of Glial Fibrillary Acidic Protein (GFAP), a specific astrocytic marker, and Ionized calcium-binding adaptor molecule 1 (Iba-1), a marker of microglia, and decreased expression of Transient Receptor Potential Vanilloid 1 (TRPV1), Substance P, and Calcitonin Gene-Related Peptide (CGRP) induced by CCI-IoN in PAG and Trigeminal ganglion. Furthermore, both treatments showed a higher expression of Cannabinoid-type 1 (CB1) receptor in the trigeminal ganglion compared to CCI-IoN rats. Our results show that no difference was observed between groups. CONCLUSION: We showed that PBM or VBC regulates neuroinflammation and reduces inflammatory protein expression. However, the combination of PBM and VBC did not enhance the effectiveness of both therapies alone.

Precision-Driven Multi-Target Path Planning and Fine Position Error Estimation on a Dual-Movement-Mode Mobile Robot Using a Three-Parameter Error Model.

The multi-target path planning problem is a universal problem to mobile robots and mobile manipulators. The two movement modes of forward movement and rotation are universally implemented in integrated, commercially accessible mobile platforms used in logistics robots, construction robots, etc. Localization error in multi-target path tracking is one of the crucial measures in mobile robot applications. In this article, a precision-driven multi-target path planning is first proposed. According to the path's odometry error evaluation function, the precision-optimized path can be discovered. Then, a three-parameter odometry error model is proposed based on the dual movement mode. The error model describes localization errors in terms of the theoretical motion command values issued to the mobile robot, the forward moving distances, and the rotation angles. It appears that the three error parameters follow the normal distribution. The error model is finally validated using a mobile robot prototype. The error parameters can be identified by analyzing the actual moving trajectory of arbitrary movements. The experimental localization error is compared to the simulated localization error in order to validate the proposed error model and the precision-driven path planning method. The OptiTrack motion capture device was used to capture the prototype mobile robot's pose and position data.

Effects of the application of a food processing-based classification system in obese women: A randomized controlled pilot study.

Background: Obesity is one of the major public health problems worldwide and contributes to the onset of many diseases, especially the ones related to the metabolic syndrome. The new Dietary Guidelines for the Brazilian population bring a new food classification based on food processing and prioritizes the consumption of fresh or minimally processed foods. Aim: This study analyzed the effects of an educational intervention on obese women, on their weight loss, quality of life, components of the metabolic syndrome and pain. Methods: Randomized controlled pilot study, including 40 obese women, randomized into 2 groups: control group and intervention group. An educational intervention with 5 biweekly meetings of 90 min based on the Dietary Guidelines for the Brazilian population (2014) was carried out involving the intervention group. Parameters related to weight loss, quality of life (SF-36), pain (McGill), bioelectrical impedance analysis, cardiorespiratory fitness, and serum and clinical components of metabolic syndrome, as well as serum concentrations of cytokines were assessed. Results: Significantly decrease of body mass, waist and hip circumferences, basal metabolic rate, extracellular water, body capacitance, and body cell mass were observed in the intervention group after 3 months. Reduction of pain and improvement in quality of life and cardiorespiratory fitness were also observed in the intervention group. There were reductions in waist circumference and glycemia, components of metabolic syndrome. Conclusions: This study showed that the educational intervention can be associated with weight loss, increase in quality of life, reduction of pain, and better metabolic syndrome parameters in obese women.

Unravelling the Role of Habenula Subnuclei on Avoidance Response: Focus on Activation and Neuroinflammation.

Understanding the mechanisms responsible for anxiety disorders is a major challenge. Avoidance behavior is an essential feature of anxiety disorders. The two-way avoidance test is a preclinical model with two distinct subpopulations-the good and poor performers-based on the number of avoidance responses presented during testing. It is believed that the habenula subnuclei could be important for the elaboration of avoidance response with a distinct pattern of activation and neuroinflammation. The present study aimed to shed light on the habenula subnuclei signature in avoidance behavior, evaluating the pattern of neuronal activation using FOS expression and astrocyte density using GFAP immunoreactivity, and comparing control, good and poor performers. Our results showed that good performers had a decrease in FOS immunoreactivity (IR) in the superior part of the medial division of habenula (MHbS) and an increase in the marginal part of the lateral subdivision of lateral habenula (LHbLMg). Poor performers showed an increase in FOS in the basal part of the lateral subdivision of lateral habenula (LHbLB). Considering the astroglial immunoreactivity, the poor performers showed an increase in GFAP-IR in the inferior portion of the medial complex (MHbl), while the good performers showed a decrease in the oval part of the lateral part of the lateral complex (LHbLO) in comparison with the other groups. Taken together, our data suggest that specific subdivisions of the MHb and LHb have different activation patterns and astroglial immunoreactivity in good and poor performers. This study could contribute to understanding the neurobiological mechanisms responsible for anxiety disorders.

Multisensory Stimulation Reverses Memory Impairment in Adrß3KO Male Mice.

Norepinephrine plays an important role in modulating memory through its beta-adrenergic receptors (Adrß: ß1, ß2 and ß3). Here, we hypothesized that multisensory stimulation would reverse memory impairment caused by the inactivation of Adrß3 (Adrß3KO) with consequent inhibition of sustained glial-mediated inflammation. To test this, 21- and 86-day-old Adrß3KO mice were exposed to an 8-week multisensory stimulation (MS) protocol that comprised gustatory and olfactory stimuli of positive and negative valence; intellectual challenges to reach food; the use of hidden objects; and the presentation of food in ways that prompted foraging, which was followed by analysis of GFAP, Iba-1 and EAAT2 protein expression in the hippocampus (HC) and amygdala (AMY). The MS protocol reduced GFAP and Iba-1 expression in the HC of young mice but not in older mice. While this protocol restored memory impairment when applied to Adrß3KO animals immediately after weaning, it had no effect when applied to adult animals. In fact, we observed that aging worsened the memory of Adrß3KO mice. In the AMY of Adrß3KO older mice, we observed an increase in GFAP and EAAT2 expression when compared to wild-type (WT) mice that MS was unable to reduce. These results suggest that a richer and more diverse environment helps to correct memory impairment when applied immediately after weaning in Adrß3KO animals and indicates that the control of neuroinflammation mediates this response.

The pandemic brain: Neuroinflammation in non-infected individuals during the COVID-19 pandemic.

While COVID-19 research has seen an explosion in the literature, the impact of pandemic-related societal and lifestyle disruptions on brain health among the uninfected remains underexplored. However, a global increase in the prevalence of fatigue, brain fog, depression and other "sickness behavior"-like symptoms implicates a possible dysregulation in neuroimmune mechanisms even among those never infected by the virus. We compared fifty-seven 'Pre-Pandemic' and fifteen 'Pandemic' datasets from individuals originally enrolled as control subjects for various completed, or ongoing, research studies available in our records, with a confirmed negative test for SARS-CoV-2 antibodies. We used a combination of multimodal molecular brain imaging (simultaneous positron emission tomography / magnetic resonance spectroscopy), behavioral measurements, imaging transcriptomics and serum testing to uncover links between pandemic-related stressors and neuroinflammation. Healthy individuals examined after the enforcement of 2020 lockdown/stay-at-home measures demonstrated elevated brain levels of two independent neuroinflammatory markers (the 18 kDa translocator protein, TSPO, and myoinositol) compared to pre-lockdown subjects. The serum levels of two inflammatory markers (interleukin-16 and monocyte chemoattractant protein-1) were also elevated, although these effects did not reach statistical significance after correcting for multiple comparisons. Subjects endorsing higher symptom burden showed higher TSPO signal in the hippocampus (mood alteration, mental fatigue), intraparietal sulcus and precuneus (physical fatigue), compared to those reporting little/no symptoms. Post-lockdown TSPO signal changes were spatially aligned with the constitutive expression of several genes involved in immune/neuroimmune functions. This work implicates neuroimmune activation as a possible mechanism underlying the non-virally-mediated symptoms experienced by many during the COVID-19 pandemic. Future studies will be needed to corroborate and further interpret these preliminary findings.

Effects of low-intensity training on the brain and muscle in the congenital muscular dystrophy 1D model.

INTRODUCTION: Congenital Muscular Dystrophy type 1D (MDC1D) is characterized by a hypoglycosylation of α-dystroglycan protein (α-DG), and this may be strongly implicated in increased skeletal muscle tissue degeneration and abnormal brain development, leading to cognitive impairment. However, the pathophysiology of brain involvement is still unclear. Low-intensity exercise training (LIET) is known to contribute to decreased muscle degeneration in animal models of other forms of progressive muscular dystrophies. AIM: The objective of this study was to analyze the effects of LIET on cognitive involvement and oxidative stress in brain tissue and gastrocnemius muscle. METHODS: Male homozygous (Largemyd-/-), heterozygous (Largemyd+/-), and wild-type mice were used. To complete 28 days of life, they were subjected to a low-intensity exercise training (LIET) for 8 weeks. After the last day of training, 24 h were expected when the animals were submitted to inhibitory avoidance and open-field test. The striatum, prefrontal cortex, hippocampus, cortex, and gastrocnemius were collected for evaluation of protein carbonylation, lipid peroxidation, and catalase and superoxide dismutase activity. RESULTS: LIET was observed to reverse the alteration in aversive and habituation memory. Increased protein carbonylation in the striatum, prefrontal cortex, and hippocampus and lipid peroxidation in the prefrontal cortex and hippocampus were also reversed by LIET. In the evaluation of the antioxidant activity, LIET increased catalase activity in the hippocampus and cortex. In the gastrocnemius, LIET decreased the protein carbonylation and lipid peroxidation and increased catalase and superoxide dismutase activity. CONCLUSION: In conclusion, it can be inferred that LIET for 8 weeks was able to reverse the cognitive damage and oxidative stress in brain tissue and gastrocnemius muscle in MDC1D animals.

The herbicide paraquat alters growth and melanin production on the Cryptococcus neoformans/Cryptococcus gattii species complex.

Paraquat (1,10-dimethyl-4,4-bipyridinium dichloride; PQ) is a free-radical producing herbicide that affects cell membranes and can upset the environmental balance of microorganisms present in soil, such as Cryptococcus spp. This study aimed to evaluate the in vitro activity of PQ against Cryptococcus spp. in planktonic and biofilm forms, as well as the protective effect of antioxidant agents against the antifungal effect of PQ and the kinetics of melanin production in response to PQ. Susceptibility to PQ was evaluated by microdilution. Cryptococcus sp. strains exposed to PQ were grown in media with ascorbic acid (AA) and glutathione (GSH). Melanin production was assessed in the presence of l-3,4-dihydroxyphenylalanine (l-DOPA) + PQ. The minimum inhibitory concentration of PQ against Cryptococcus spp. ranged from 8 to 256 µg/mL. Furthermore, PQ reduced biofilm formation. AA and GSH restored the fungal growth of Cryptococcus spp. exposed to PQ. In addition, l-DOPA + PQ delayed melanin production by 24 and 48 h for C. deuterogattii and C. neoformans sensu lato, respectively, suggesting that PQ induces a fitness trade-off in melanin production. Taken together, our data suggest that the antifungal effect of PQ against Cryptococcus spp. possibly exerts selective pressures interfering with biofilm formation and melanin production by these yeasts.

Sensorimotor development of male and female rats subjected to neonatal anoxia.

Neonatal hypoxic-ischemic encephalopathy (HIE) is one of the most important reasons for morbidity and mortality in term-born infants. HIE impacts early somatic, neurological, and motor development including social. To illustrate the damages in the sensorimotor system, an adapted and validated model of neonatal anoxia is used. This study evaluated the sex differences in Wistar rats, neurological reflex, and motor development at the suckling period. Short- and long-term impairments associated with sex differences were observed. In general, anoxic males were more affected in comparison to their control group and to anoxic females. Long-lasting effects of the injury in adolescent rats predominately affected males. Similar to previous studies, we also found a decrease in the number of the substantia nigra cells in both sexes, compared to their control. So far, the results indicate that HIE caused neurobehavioral alterations and asymmetrical motor behavior with brain damage, possibly related to cognitive impairments previously observed at adolescence. These alterations may represent a useful endpoint for studying the efficacy of potential strategies that may improve the developmental consequences of a perinatal asphyxia insult in humans.

A comprehensive program of cognitive stimulation with digital inclusion, physical activity and social interaction can modify BDNF levels and improve cognition in adults over 50: a randomized controlled pilot study.

OBJECTIVES: To analyze the effect of a comprehensive program of cognitive stimulation with digital inclusion, physical activity and social interaction, called "Oficina da Lembrança" (OL), on the cognitive status and concentration of biomarkers of neuroplasticity, neurodegeneration in adults aged 50 years and over attending a Memory Clinic. METHODS: In this pilot randomized controlled study, 64 patients without dementia aged 45 to 79 years, seen at a University Memory Clinic in Southern Brazil, were randomly allocated to the intervention and control groups. The intervention consisted of participation in OL for 12 weeks. Serum biomarkers (brain-derived neurotrophic factor [BDNF], S100ß, and neuron-specific enolase [NSE]) and cognitive status were analyzed as primary and secondary outcomes. The Wilcoxon test and Generalized Estimating Equations (GEE) were applied. RESULTS: Of the 64 patients invited to participate in the study, 33 (intervention: 17, control: 16) completed the study with all data. Improvement of cognitive status was significant in the intervention group (22.6 to 24.5) but not in the control group (20.1 to 21.1). There was a significant reduction of BDNF in OL participants, but no significant change was observed in the neurodegenerative biomarkers S100ß or NSE. The concentration of BDNF decreased significantly post-OL in the intervention group (-288.1, 95%CI -362.1 to -94.1), even after adjusting for sex, age, and educational level. Cognitive status was significantly improved in OL participants. CONCLUSION: The OL program improved cognitive status, reduced serum BDNF levels, and empowered digitally excluded older adults. There was no effect of this intervention on S100ß or NSE. CLINICAL TRIAL REGISTRATION: This study has a Universal Trial Number (UTN) U1111-1195-2642 and was registered in the Brazilian Clinical Trials Registry (ReBEC), number RBR-38X665.