Hide-and-sick: How bacteria manipulate a neural circuit that makes you sick.

Infections frequently cause behavioral changes, known as sickness behavior. In a recent study,1 Yipp and collaborators discovered a sensory circuit that is activated by a bacterial lipopolysaccharide during lung infection and drives sickness behaviors independent of inflammation. Biofilm-producing bacteria, however, avoid activating this lung-brain circuit, resulting in infection without sickness behavior.

Modulation of host immunity by sensory neurons.

Recent studies have uncovered a new role for sensory neurons in influencing mammalian host immunity, challenging conventional notions of the nervous and immune systems as separate entities. In this review we delve into this groundbreaking paradigm of neuroimmunology and discuss recent scientific evidence for the impact of sensory neurons on host responses against a wide range of pathogens and diseases, encompassing microbial infections and cancers. These valuable insights enhance our understanding of the interactions between the nervous and immune systems, and also pave the way for developing candidate innovative therapeutic interventions in immune-mediated diseases highlighting the importance of this interdisciplinary research field.

Monitoring autonomic responses in Parkinson's disease individuals: non-linear and chaotic global metrics of heart rate variability.

AIM: To examine and compare the autonomic responses, as assessed through the non-linear and chaotic global metrics of heart rate variability in two groups: the Parkinson's Disease Group (PDG) and the Control Group (CG), both at rest and during an active tilt test. METHODS: The study encompassed 46 participants (PDG: n = 23; 73.73 ± 7.28 years old; CG: n = 23; 70.17 ± 8.20 years old). Initial data collection involved the acquisition of participant's characteristics. The autonomic modulation was estimated both at rest and during the active tilt test. For this assessment, we computed non-linear indices derived from five entropies (Approximate, Sample, Shannon, Renyi, Tsallis), Detrended Fluctuation Analysis and the seven chaotic global metrics (hsCFP1-hsCFP7). RESULTS: At rest, the PDG exhibited lower values of hsCFP3 (0.818 ± 0.116 vs. 0.904 ± 0.065; p < 0.05) and Sample Entropy (0.720 ± 0.149 vs. 0.799 ± 0.171; p < 0.05). During the test, the PDG demonstrated lower values of ApEn, while the CG presented lower values of SampEn, hsCFP1, hsCFP3, hsCFP7, and higher values of hsCFP5. An interaction was observed, indicating that hsCFP1 and hsCFP3 exhibit differential behavior for the CG and PDG in response to the test. CONCLUSION: subjects with PD exhibited reduced complexity of the RR interval series at rest, and a diminished autonomic response to the active tilt test when compared with the CG. The test, together with non-linear indices, may serve for assessing the Autonomic Nervous System in individuals with PD in a clinical setting. The interpretation of these data should be approached with caution, given the possible influences of pharmacotherapies and the inclusion of diabetic participants.

Effects of relative humidity on dry-aged beef quality.

This study was conducted to evaluate the effects of relative humidity (RH) on moisture loss and flavor in dry-aged beef. Sixteen strip loins were assigned to one of the four aging treatments: vacuum (WET), dry-aging at 50% RH, dry-aging at 70% RH, or dry-aging at 85% RH and aged for 42 days at 2 °C. Loins were evaluated for evaporation loss, trim loss, tenderness, sensory, and microbiological characteristics. Results show that lower RH results in accelerated moisture loss during the first 3 days of the aging process without significantly affecting the total amount of moisture loss. Pseudomonadales dominated the aerobically dry-aged loins while Enterobacteriales was the most abundant in the wet-aged samples. Dry-aged samples had increased content of free amino acids in the cooked meat juice compared to the wet-aged counterpart. Dry aging at 50% RH tended to associate with more desirable flavor notes.

Acute physiological responses to "recovery intermittent hypoxia" in hiit / Respuestas agudas a la "hipoxia intermitente de recuperación" en el hiit / Respostas fisiológicas agudas à "hipóxia intermitente de recuperação" no hiit

ABSTRACT Introduction: Traditional intermittent hypoxia training improves sport performance after short periods of exposure, but acute exposure to intermittent hypoxia leads to decreased training intensity and technical quality. The solution to overcome these negative effects may be to perform efforts in normoxia and the intervals between efforts in hypoxia, maintaining the quality of training and the benefits of hypoxia. Objective: This study aimed to evaluate the acute physiological responses to hypoxia exposure during recovery between high intensity efforts. Materials and methods: Randomized, one-blind, placebo-controlled study. Sixteen men performed a graded exercise test to determine their maximal intensity and two sessions of high-intensity interval training. The training intervals could be in hypoxia (HRT), FIO2: 0.136 or normoxia (NRT), FIO2: 0.209. During the two-minute interval between the ten one-minute efforts, peripheral oxygen saturation (SpO2), heart rate (HR), blood lactate ([La]), blood glucose ([Glu]) were constantly measured. Results: There were differences in HR (TRN = 120 ± 14 bpm; TRH = 129 ± 13 bpm, p < 0.01) and SpO2 (TRN = 96.9 ± 1.0%; TRH = 86.2 ± 3.5%, p < 0.01). No differences in [La] and [Glu] TRN (4.4 ± 1.7 mmol.l-1; 3.9 ± 0.5 mmol.l-1) and TRH (5.2 ± 2.0 mmol.l-1; 4.0 ± 0.8 mmol.l-1, p = 0.17). Conclusion: The possibility of including hypoxia only in the recovery intervals as an additional stimulus to the training, without decreasing the quality of the training, was evidenced. Level of Evidence II; Randomized Clinical Trial of Minor Quality.

RESUMEN Introducción: El entrenamiento tradicional en hipoxia intermitente mejora el rendimiento deportivo tras cortos periodos de exposición, sin embargo, la exposición aguda a la hipoxia intermitente conduce a una disminución de la intensidad del entrenamiento y de la calidad técnica. La solución para superar estos efectos negativos puede ser realizar los esfuerzos en normoxia y los intervalos entre esfuerzos en hipoxia, manteniendo la calidad del entrenamiento y los beneficios de la hipoxia. Objetivo: Este estudio pretendía evaluar las respuestas fisiológicas agudas a la exposición a la hipoxia durante la recuperación entre esfuerzos de alta intensidad. Materiales y métodos: Estudio aleatorizado, a ciegas y controlado con placebo. Dieciséis hombres realizaron una prueba de ejercicio graduado para determinar su intensidad máxima y dos sesiones de entrenamiento por intervalos de alta intensidad. Los intervalos de entrenamiento podían ser en hipoxia (HRT), FIO2: 0,136 o normoxia (NRT), FIO2: 0,209. Durante el intervalo de dos minutos entre los diez esfuerzos de un minuto, se midieron constantemente la saturación periférica de oxígeno (SpO2), la frecuencia cardiaca (FC), el lactato en sangre ([La]) y la glucemia ([Glu]). Resultados: Hubo diferencias en la FC (TRN = 120 ± 14 lpm; TRH = 129 ± 13 lpm, p < 0,01) y la SpO2 (TRN = 96,9 ± 1,0%; TRH = 86,2 ± 3,5%, p < 0,01). No hubo diferencias en [La] y [Glu] TRN (4,4 ± 1,7 mmol.l-1; 3,9 ± 0,5 mmol.l-1) y TRH (5,2 ± 2,0 mmol.l-1; 4,0 ± 0,8 mmol.l-1, p = 0,17). Conclusión: Se evidenció la posibilidad de incluir hipoxia sólo en los intervalos de recuperación como estímulo adicional al entrenamiento sin disminuir la calidad del mismo. Nivel de Evidencia II; Ensayo Clínico Aleatorizado de Baja Calidad.

RESUMO Introdução: O treinamento de hipóxia intermitente tradicional melhora o desempenho esportivo após curtos períodos de exposição, porém a exposição aguda à hipóxia intermitente leva à diminuição da intensidade do treinamento e da qualidade técnica. A solução para superar esses efeitos negativos pode ser realizar esforços em normóxia e os intervalos entre os esforços em hipóxia, mantendo a qualidade do treinamento e os benefícios da hipóxia. Objetivo: Este estudo teve como objetivo avaliar as respostas fisiológicas agudas à exposição de hipóxia durante a recuperação entre esforços de alta intensidade. Materiais e métodos: Estudo aleatório e one-blinded, com efeito placebo controlado. Dezesseis homens realizaram um teste de exercício graduado para determinar sua intensidade máxima e duas sessões de treinamento intervalado de alta intensidade. Os intervalos de treinamento podem ser em hipóxia (TRH), FIO2: 0,136 ou normóxia (TRN), FIO2: 0,209. Durante os dois minutos de intervalo entre os dez esforços de um minuto, foram medidos constantemente a saturação periférica de oxigênio (SpO2), frequência cardíaca (FC), lactato sanguíneo ([La]), glicemia ([Glu]). Resultados: Houve diferenças na FC (TRN = 120 ± 14 bpm; TRH = 129 ± 13 bpm, p <0,01) e SpO2 (TRN = 96,9 ± 1,0%; TRH = 86,2 ± 3,5%, p <0,01). Sem diferenças em [La] e [Glu] TRN (4,4 ± 1,7 mmol.l-1; 3,9 ± 0,5 mmol.l-1) e TRH (5,2 ± 2,0 mmol.l-1; 4,0 ± 0,8 mmol.l-1, p = 0,17). Conclusão: Evidenciou-se a possibilidade de incluir a hipóxia apenas nos intervalos de recuperação como um estímulo adicional ao treinamento, sem diminuir a qualidade do treinamento. Nível de Evidência II; Estudo Clínico Randomizado de Menor Qualidade.

Polyurethane Adhesives for Wood Based on a Simple Mixture of Castor Oil and Crude Glycerin.

Developing a new type of polyurethane is essential because conventional options often exhibit shortcomings in terms of environmental sustainability, cost-effectiveness, and performance in specialized applications. A novel polyurethane adhesive derived from a simple mixture of castor oil (CO) and crude glycerin (CG) holds promise as it reduces reliance on fossil fuels and harnesses renewable resources, making it environmentally friendly. Simple CO/CG mixtures, adjusted at three different weight fractions, were used as bio-based polyester polyols to produce polyurethane adhesive for wood bonding. The resulting products are yellowish liquids with moderate-to-high viscosity, measuring 19,800-21,000 cP at 25 °C. The chemical structure of the polyester polyols was characterized using infrared spectroscopy (FTIR), thermogravimetry (TG), and differential scanning calorimetry (DSC). These polyols reacted with polymeric 4,4-methylene diphenyl diisocyanate (p-MDI) at a consistent isocyanate index of 1.3, resulting in the formation of polyurethane adhesives. Crucially, all final adhesives met the adhesive strength requirements specified by ASTM D-5751 standards, underscoring their suitability for wood bonding applications. The addition of CG enhanced the surface and volumetric hydrophobicity of the cured adhesives, resulting in adhesive properties that are not only stronger but also more weather-resistant. Although the thermal stability of the adhesives decreased with the inclusion of CG, FTIR analysis confirmed proper polyurethane polymer formation. The adhesive adjusted for a 2:1 CO:CG weight ratio promoted wood-wood bonding with the highest shear strength, likely due to a higher formation of urethane linkages between hydroxyl groups from the blend of polyols and isocyanate groups from the p-MDI.

Synaptic proteasome is inhibited in Alzheimer's disease models and associates with memory impairment in mice.

The proteasome plays key roles in synaptic plasticity and memory by regulating protein turnover, quality control, and elimination of oxidized/misfolded proteins. Here, we investigate proteasome function and localization at synapses in Alzheimer's disease (AD) post-mortem brain tissue and in experimental models. We found a marked increase in ubiquitinylated proteins in post-mortem AD hippocampi compared to controls. Using several experimental models, we show that amyloid-ß oligomers (AßOs) inhibit synaptic proteasome activity and trigger a reduction in synaptic proteasome content. We further show proteasome inhibition specifically in hippocampal synaptic fractions derived from APPswePS1ΔE9 mice. Reduced synaptic proteasome activity instigated by AßOs is corrected by treatment with rolipram, a phosphodiesterase-4 inhibitor, in mice. Results further show that dynein inhibition blocks AßO-induced reduction in dendritic proteasome content in hippocampal neurons. Finally, proteasome inhibition induces AD-like pathological features, including reactive oxygen species and dendritic spine loss in hippocampal neurons, inhibition of hippocampal mRNA translation, and memory impairment in mice. Results suggest that proteasome inhibition may contribute to synaptic and memory deficits in AD.

Association between clinical, serological, functional and radiological findings and ventilatory distribution heterogeneity in patients with rheumatoid arthritis.

BACKGROUND: In rheumatoid arthritis (RA), the involvement of the pulmonary interstitium can lead to structural changes in the small airways and alveoli, leading to reduced airflow and maldistribution of ventilation. The single-breath nitrogen washout (SBN2W) test is a measure of the ventilatory distribution heterogeneity and evaluates the small airways. This study aimed to find out which clinical, serological, functional and radiological findings are useful to identify RA patients with pathological values of the phase III slope (SIII) measured by the SBN2W test. METHODS: This was a cross-sectional study in which RA patients were assessed using the Health Assessment Questionnaire-Disability Index (HAQ-DI) and the Clinical Disease Activity Index (CDAI) and underwent serological analysis of autoantibodies and inflammatory markers. In addition, they underwent pulmonary function tests (including the SBN2W test) and chest computed tomography (CT). RESULTS: Of the 60 RA patients evaluated, 39 (65%) had an SIII >120% of the predicted value. There were significant correlations between SIII and age (r = 0.56, p<0.0001), HAQ-DI (r = 0.34, p = 0.008), forced vital capacity (FVC, r = -0.67, p<0.0001), total lung capacity (r = -0.46, p = 0.0002), residual volume/total lung capacity (TLC) (r = 0.44, p = 0.0004), and diffusing capacity of the lungs for carbon monoxide (r = -0.45, p = 0.0003). On CT scans, the subgroup with moderate/severe disease had a significantly higher SIII than the normal/minimal/mild subgroup (662 (267-970) vs. 152 (88-283)% predicted, p = 0.0004). In the final multiple regression model, FVC, extent of moderate/severe involvement and age were associated with SIII, explaining 59% of its variability. CONCLUSIONS: In patients with RA, FVC, extent of lung involvement and age, all of which are easily obtained variables in clinical practice, identify poorly distributed ventilation. In addition, the presence of respiratory symptoms and deteriorated physical function are closely related to the distribution of ventilation in these patients.

Emergence of cryptic species and clades of Meyerozyma guilliermondii species complex exhibiting limited in vitro susceptibility to antifungals in patients with candidemia.

Members of the Meyerozyma guilliermondii species complex are able to cause superficial and life-threatening systemic infections with low susceptibility to azoles and echinocandins. We tested 130 bloodstream M. guilliermondii complex isolates collected from eight Latin American medical centers over 18 years (period 1 = 2000-2008 and period 2 = 2009-2018) to investigate trends in species distribution and antifungal resistance. The isolates were identified by rDNA ITS region sequencing, and antifungal susceptibility tests were performed against fluconazole, voriconazole, anidulafungin, and amphotericin B using the CLSI microbroth method. M. guilliermondii sensu stricto (s.s.; n = 116) was the most prevalent species, followed by Meyerozyma caribbica (n = 12) and Meyerozyma carpophila (n = 2). Based on rDNA ITS identification, three clades within M. guilliermondii sensu stricto were characterized (clade 1 n = 94; clade 2 n = 19; and clade 3 n = 3). In the second period of study, we found a substantial increment in the isolation of M. caribbica (3.4% versus 13.8%; P = 0.06) and clade 2 M. guilliermondii s.s. exhibiting lower susceptibility to one or more triazoles. IMPORTANCE Yeast-invasive infections play a relevant role in human health, and there is a concern with the emergence of non-Candida pathogens causing disease worldwide. There is a lack of studies addressing the prevalence and antifungal susceptibility of different species within the M. guilliermondii complex that cause invasive infections. We evaluated 130 episodes of M. guilliermondii species complex candidemia documented in eight medical centers over 18 years. We detected the emergence of less common species within the Meyerozyma complex causing candidemia and described a new clade of M. guilliermondii with limited susceptibility to triazoles. These results support the relevance of continued global surveillance efforts to early detect, characterize, and report emergent fungal pathogens exhibiting limited susceptibility to antifungals.

Assessment of methionine plus cystine requirement of tambaqui (Colossoma macropomum) based on zootechnical performance, body composition, erythrogram, and plasmatic and hepatic metabolites.

Tambaqui (Colossoma macropomum) is a species of great cultural and economic importance in aquaculture in the Amazon region. Methionine is considered the first limiting sulfur amino acid in practical fish diets, which encourages investigating its use in diets for tambaqui. This study aimed to verify the digestible methionine plus cystine (Met + Cys) requirement in diets for tambaqui (89.52 ± 0.53 g) for 60 days. The treatments investigated were: 6.50, 7.80, 9.10, 10.40, 11.70, and 13.00 g Met + Cys kg diet-1. The estimated requirement based on final weight, weight gain, feed conversion ratio, and specific growth rate was 9.04, 8.92, 8.91, and 8.58 g Met + Cys kg diet-1, respectively, while on body protein deposition, body fat deposition, body ash deposition, and nitrogen retention efficiency was 9.29, 9.20, 9.19, and 8.72 g Met + Cys kg diet-1, respectively. Linear regression demonstrated that increased digestible Met + Cys in the diet decreased plasma total protein, globulin, and liver total protein levels. Quadratic regression showed that the highest value for liver glycogen was found with a 10.40 g Met + Cys kg diet-1. Another quadratic regression demonstrated a lower hepatic aspartate aminotransferase (AST) enzymatic activity in fish fed between 7.80 and 11.70 g Met + Cys kg diet-1. The different treatments did not influence the erythrogram. In conclusion, when considering an integrative view of the results for growth performance, whole-body deposition, and liver parameters without harming the physiological and metabolic status, we recommended choosing a diet with digestible Met + Cys between 8.58 and 9.29 g kg- 1 for tambaqui.

Obstructive sleep apnea screening in different age groups: performance of the Berlin, STOP-Bang questionnaires and Epworth Sleepiness Scale.

OBJECTIVE: To evaluate the performance of the Berlin Questionnaire, the STOP-Bang Questionnaire, and the Epworth Sleepiness Scale in screening for the disease in adults of different age groups by comparing them with polysomnography. METHODS: Cross-sectional study with prospective patient allocation, in which individuals underwent a medical interview, completion of the three screening instruments, and polysomnography. Individuals were categorized into three age groups: 18-39, 40-59, and ≥60 years. The results of the screening instruments were compared to the diagnostic criteria of the International Classification of Sleep Disorders-third edition. Performance was assessed using 2×2 contingency tables, estimating sensitivity, specificity, predictive value, likelihood ratio, and accuracy. Receiver Operating Characteristic curves were also constructed and the area under the curve was estimated for each instrument by age group. RESULTS: We obtained a sample with 321 individuals suitable for analysis. The mean age was 50 years, with a predominance of females (56%). The prevalence of the disease in the overall sample was 79%, more prevalent in males in any age group and more frequent in the middle age group. The analyzes revealed that STOP-Bang performed better, both for the overall sample and for all age groups, followed by Berlin Questionnaire and Epworth Sleepiness Scale. CONCLUSION: In an outpatient setting with individuals with characteristics similar to those in this study, it seems sensible to choose the STOP-Bang as a screening tool for the disease, regardless of age group. LEVEL OF EVIDENCE ACCORDING THE GUIDE FOR AUTHORS: level 2.

Therapeutic activity of lipoxin A4 in TiO2-induced arthritis in mice: NF-κB and Nrf2 in synovial fluid leukocytes and neuronal TRPV1 mechanisms.

Background: Lipoxin A4 (LXA4) has anti-inflammatory and pro-resolutive roles in inflammation. We evaluated the effects and mechanisms of action of LXA4 in titanium dioxide (TiO2) arthritis, a model of prosthesis-induced joint inflammation and pain. Methods: Mice were stimulated with TiO2 (3mg) in the knee joint followed by LXA4 (0.1, 1, or 10ng/animal) or vehicle (ethanol 3.2% in saline) administration. Pain-like behavior, inflammation, and dosages were performed to assess the effects of LXA4 in vivo. Results: LXA4 reduced mechanical and thermal hyperalgesia, histopathological damage, edema, and recruitment of leukocytes without liver, kidney, or stomach toxicity. LXA4 reduced leukocyte migration and modulated cytokine production. These effects were explained by reduced nuclear factor kappa B (NFκB) activation in recruited macrophages. LXA4 improved antioxidant parameters [reduced glutathione (GSH) and 2,2-azino-bis 3-ethylbenzothiazoline-6-sulfonate (ABTS) levels, nuclear factor erythroid 2-related factor 2 (Nrf2) mRNA and Nrf2 protein expression], reducing reactive oxygen species (ROS) fluorescent detection induced by TiO2 in synovial fluid leukocytes. We observed an increase of lipoxin receptor (ALX/FPR2) in transient receptor potential cation channel subfamily V member 1 (TRPV1)+ DRG nociceptive neurons upon TiO2 inflammation. LXA4 reduced TiO2-induced TRPV1 mRNA expression and protein detection, as well TRPV1 co-staining with p-NFκB, indicating reduction of neuronal activation. LXA4 down-modulated neuronal activation and response to capsaicin (a TRPV1 agonist) and AITC [a transient receptor potential ankyrin 1 (TRPA1) agonist] of DRG neurons. Conclusion: LXA4 might target recruited leukocytes and primary afferent nociceptive neurons to exert analgesic and anti-inflammatory activities in a model resembling what is observed in patients with prosthesis inflammation.

The unfolded protein response transcription factor XBP1s ameliorates Alzheimer's disease by improving synaptic function and proteostasis.

Alteration in the buffering capacity of the proteostasis network is an emerging feature of Alzheimer's disease (AD), highlighting the occurrence of endoplasmic reticulum (ER) stress. The unfolded protein response (UPR) is the main adaptive pathway to cope with protein folding stress at the ER. Inositol-requiring enzyme-1 (IRE1) operates as a central ER stress sensor, enabling the establishment of adaptive and repair programs through the control of the expression of the transcription factor X-box binding protein 1 (XBP1). To artificially enforce the adaptive capacity of the UPR in the AD brain, we developed strategies to express the active form of XBP1 in the brain. Overexpression of XBP1 in the nervous system using transgenic mice reduced the load of amyloid deposits and preserved synaptic and cognitive function. Moreover, local delivery of XBP1 into the hippocampus of an 5xFAD mice using adeno-associated vectors improved different AD features. XBP1 expression corrected a large proportion of the proteomic alterations observed in the AD model, restoring the levels of several synaptic proteins and factors involved in actin cytoskeleton regulation and axonal growth. Our results illustrate the therapeutic potential of targeting UPR-dependent gene expression programs as a strategy to ameliorate AD features and sustain synaptic function.

Bacteria hijack a meningeal neuroimmune axis to facilitate brain invasion.

The meninges are densely innervated by nociceptive sensory neurons that mediate pain and headache1,2. Bacterial meningitis causes life-threatening infections of the meninges and central nervous system, affecting more than 2.5 million people a year3-5. How pain and neuroimmune interactions impact meningeal antibacterial host defences are unclear. Here we show that Nav1.8+ nociceptors signal to immune cells in the meninges through the neuropeptide calcitonin gene-related peptide (CGRP) during infection. This neuroimmune axis inhibits host defences and exacerbates bacterial meningitis. Nociceptor neuron ablation reduced meningeal and brain invasion by two bacterial pathogens: Streptococcus pneumoniae and Streptococcus agalactiae. S. pneumoniae activated nociceptors through its pore-forming toxin pneumolysin to release CGRP from nerve terminals. CGRP acted through receptor activity modifying protein 1 (RAMP1) on meningeal macrophages to polarize their transcriptional responses, suppressing macrophage chemokine expression, neutrophil recruitment and dural antimicrobial defences. Macrophage-specific RAMP1 deficiency or pharmacological blockade of RAMP1 enhanced immune responses and bacterial clearance in the meninges and brain. Therefore, bacteria hijack CGRP-RAMP1 signalling in meningeal macrophages to facilitate brain invasion. Targeting this neuroimmune axis in the meninges can enhance host defences and potentially produce treatments for bacterial meningitis.

Kaurenoic Acid Reduces Ongoing Chronic Constriction Injury-Induced Neuropathic Pain: Nitric Oxide Silencing of Dorsal Root Ganglia Neurons.

Kaurenoic acid (KA) is a diterpene extracted from Sphagneticola trilobata (L.) Pruski. KA presents analgesic properties. However, the analgesic activity and mechanisms of action of KA in neuropathic pain have not been investigated so far; thus, we addressed these points in the present study. A mouse model of neuropathic pain was induced by chronic constriction injury (CCI) of the sciatic nerve. Acute (at the 7th-day post-CCI surgery) and prolonged (from 7-14th days post-CCI surgery) KA post-treatment inhibited CCI-induced mechanical hyperalgesia at all evaluated time points, as per the electronic version of von Frey filaments. The underlying mechanism of KA was dependent on activating the NO/cGMP/PKG/ATP-sensitive potassium channel signaling pathway since L-NAME, ODQ, KT5823, and glibenclamide abolished KA analgesia. KA reduced the activation of primary afferent sensory neurons, as observed by a reduction in CCI-triggered colocalization of pNF-κB and NeuN in DRG neurons. KA treatment also increased the expression of neuronal nitric oxide synthase (nNOS) at the protein level as well as the intracellular levels of NO in DRG neurons. Therefore, our results provide evidence that KA inhibits CCI neuropathic pain by activating a neuronal analgesic mechanism that depends on nNOS production of NO to silence the nociceptive signaling that generates analgesia.

Chikungunya Virus and Its Envelope Protein E2 Induce Hyperalgesia in Mice: Inhibition by Anti-E2 Monoclonal Antibodies and by Targeting TRPV1.

Chikungunya virus is an arthropod-borne infectious agent that causes Chikungunya fever disease. About 90% of the infected patients experience intense polyarthralgia, affecting mainly the extremities but also the large joints such as the knees. Chronic disease symptoms persist for months, even after clearance of the virus from the blood. Envelope proteins stimulate the immune response against the Chikungunya virus, becoming an important therapeutic target. We inactivated the Chikungunya virus (iCHIKV) and produced recombinant E2 (rE2) protein and three different types of anti-rE2 monoclonal antibodies. Using these tools, we observed that iCHIKV and rE2 protein induced mechanical hyperalgesia (electronic aesthesiometer test) and thermal hyperalgesia (Hargreaves test) in mice. These behavioral results were accompanied by the activation of dorsal root ganglia (DRG) neurons in mice, as observed by calcium influx. Treatment with three different types of anti-rE2 monoclonal antibodies and absence or blockade (AMG-9810 treatment) of transient receptor potential vanilloid 1 (TRPV1) channel diminished mechanical and thermal hyperalgesia in mice. iCHIKV and rE2 activated TRPV1+ mouse DRG neurons in vitro, demonstrating their ability to activate nociceptor sensory neurons directly. Therefore, our mouse data demonstrate that targeting E2 CHIKV protein with monoclonal antibodies and inhibiting TRPV1 channels are reasonable strategies to control CHIKV pain.

Defective proteostasis in Alzheimer's disease.

The homeostasis of cellular proteins, or proteostasis, is critical for neuronal function and for brain processes, including learning and memory. Increasing evidence indicates that defective proteostasis contributes to the progression of neurodegenerative disorders, including Alzheimer's disease (AD), the most prevalent form of dementia in the elderly. Proteostasis comprises a set of cellular mechanisms that control protein synthesis, folding, post-translational modification and degradation, all of which are deregulated in AD. Importantly, deregulation of proteostasis plays a key role in synapse dysfunction and in memory impairment, the major clinical manifestation of AD. Here, we discuss molecular pathways involved in protein synthesis and degradation that are altered in AD, and possible pharmacological approaches to correct these defects.

Cerebrospinal fluid irisin and lipoxin A4 are reduced in elderly Brazilian individuals with depression: Insight into shared mechanisms between depression and dementia.

INTRODUCTION: Depression is frequent among older adults and is a risk factor for dementia. Identifying molecular links between depression and dementia is necessary to shed light on shared disease mechanisms. Reduced brain-derived neurotrophic factor (BDNF) and neuroinflammation are implicated in the pathophysiology of depression and dementia. The exercise-induced hormone, irisin, increases BDNF and improves cognition in animal models of Alzheimer's disease. Lipoxin A4 is a lipid mediator with anti-inflammatory activity. However, the roles of irisin and lipoxin A4 in depression remain to be determined. METHODS: In the present study, blood and CSF were collected from 61 elderly subjects, including individuals with and without cognitive impairment. Screening for symptoms of depression was performed using the 15-item Geriatric Depression Scale (GDS-15). RESULTS: CSF irisin and lipoxin A4 were positively correlated and reduced, along with a trend of BDNF reduction, in elderly individuals with depression, similar to previous observations in patients with dementia. DISCUSSION: Our findings provide novel insight into shared molecular signatures connecting depression and dementia.