Publications

High mobility group box 1 protein (HMGB1) has been suggested to be involved in the immune dysfunction and inflammation reported in autism spectrum disorder (ASD). We aimed to assess HMGB1 serum concentrations (SCs) in high-functioning ASD children compared to typically developing (TD) controls and to explore their associations with the autism spectrum quotient (AQ), the empathy quotient (EQ), and the systemizing quotient (SQ). The study involved 42 ASD children and 38 TD children, all-male, aged between 6.1 and 13.3 years old. HMGB1 SCs were measured by enzyme-linked immunosorbent assay (ELISA). Groups were comparable regarding age, general IQ, birth weight, and maternal age at birth. ASD children showed significantly higher HMGB1 SCs compared to TD children (1.25 ± 0.84 ng/mL versus 1.13 ± 0.79 ng/mL, respectively, p = 0.039). The Spearman’s rho revealed that HMGB1 SCs were positively correlated with the AQ attention to detail subscale (rs = 0.46, p = 0.045) and with the SQ total score (rs = 0.42, p = 0.04) in the ASD group. These results show that HMGB1 serum concentrations are altered in ASD children, and suggest that inflammatory processes mediated by HMGB1 may be associated with specific cognitive features observed in ASD.

<b>Background:</b> In contrast to studies in adults with emphysema, application of fixed thresholds to determine low- and high-attenuation areas (air-trapping and parenchymal lung disease, respectively) in pediatric quantitative chest CT is problematic. <b>Objective:</b> To assess the effects of age on: (i) mean lung attenuation at full inspiration; (ii) low- and high-attenuation thresholds (LAT and HAT) defined as mean and one standard deviation below and above the mean attenuation, respectively. We hypothesized that significant associations exist between age or total lung capacity measured by CT (TLC_CT), and %TLC_CT with low or high attenuation. <b>Methods:</b> Chest CTs from children aged 6-17 years without abnormal findings were retrieved from hospital database and histograms of attenuation coefficients were analyzed. <b>Results:</b> Examinations from 80 children were included. Inverse functions described relationships between age and mean lung attenuation, LAT or HAT (P&lt;.0001). Predicted value for LAT decreased from -846 HU in 6-year-old children to approximately -950 HU in 13- to 17-year-old subjects, which is the cut-off value used to assess emphysema severity in adults. %TLC_CT with low attenuation correlated weakly with age (r_s = -0.31; P =.005) and was &lt;5% for subjects 9-17 years old. Inverse associations were found between: (i) %TLC_CT with low attenuation and TLC_CT (r²=0.47; P&lt;.0001); (ii) %TLC_CT with high attenuation and age (r²=0.49; P&lt;.0001); (iii) %TLC_CT with high attenuation and TLC_CT (r²=0.76; P&lt;.0001). <b>Conclusion:</b> Quantitative analysis of chest CTs from children without lung disease can be applied to define age-specific LAT and HAT for the evaluation of severity of pediatric lung disease.

Amyotrophic lateral sclerosis (ALS) belongs to the ALS-frontotemporal dementia (FTD) spectrum and is hallmarked by upper and lower motor neuron degeneration. Here, we present a patient with a cytoplasmic dynein 1 heavy chain 1 (DYNC1H1) pathogenic variant who fulfilled the ALS El Escorial criteria, and we review relevant literature. Using whole-exome sequencing, we identified a deleterious point variant in DYNC1H1 [c.4106A&gt;G (p. Q1369R))] as a likely contributor to the ALS phenotype. In silico structural analysis, molecular dynamics simulation, and protein stability analysis predicted that this variant may increase DYNC1H1 protein stability. Moreover, this variant may disrupt binding of the transcription factor TFAP4, thus potentially acting as duon. Since a) DYNC1H1 forms part of a ubiquitous eukaryotic motor protein complex, and b) disruption of dynein function by perturbation of the dynein-dynactin protein complex is implicated in other motor neuron degenerative conditions, this variant could disrupt processes like retrograde axonal transport, neuronal migration, and protein recycling. Our findings expand the heterogenous spectrum of DYNC1H1 pathogenic variants−associated phenotype and prompt further investigations of the role of this gene in ALS.

Spondweni virus (SPONV), a possible emerging virus, is a member of the <em>Flaviviridae</em> virus family, of the genus <em>Flavivirus</em> and belongs to a serogroup with the Zika virus. The latest epidemic of Zika fever, which broke out in the Western Hemisphere, warns about the risk of the corresponding urban epidemic potential of SPONV and calls for the design of anti‑SPONV therapies. Previous studies have demonstrated that viral RNA helicases represent promising pharmacological targets for antiviral drugs/inhibitors, as they are implicated in viral replication and proliferation. Therefore, the present study proposes the three‑dimensional structure of the helicase/protease enzyme of SPONV through homology modeling, using the crystal structure of the Dengue virus‑4 helicase/protease of the same viral family as a template. For the evaluation of the accuracy and reliability of the model in structure‑based drug design strategies, the crystal structure of the hepatitis C virus (HCV) helicase was used, complexed with a single‑stranded RNA, a key molecule for the establishment of interactions with a future inhibitor of the SPONV helicase. Following the evaluation of the model and the identification of motifs characteristic of the <em>Flaviviridae</em> family, data from previous publications on the treatment of HCV were incorporated, with the aim of detecting the ideal residues in the Spondweni model, which are similar to those of the HCV structure and are inhibitor targets. The existing pharmacophoric model was tested for its application to the Spondweni helicase model as a potential inhibitor of its functionality and potential future use in design experiments of novel anti‑SPONV agents.

Glucocorticoids have been used in the treatment of inflammatory and autoimmune diseases and to prevent graft rejection for over 50 years. These hormones exert their effects through cytoplasmic, heat shock protein-bound glucocorticoid receptors that translocate into the nucleus, where they regulate the transcriptional activity of responsive genes by binding to specific promoter DNA sequences (transactivation) or by interacting with transcription factors (transrepression). By interacting with different signaling pathways, newly characterized nuclear receptor coregulators enhance or diminish the actions of glucocorticoids, thus explaining the gene-, cell-, tissue- and context-dependent actions of glucocorticoids. Glucocorticoids modulate genes involved in the priming of the innate immune response, while their actions on the adaptive immune response are to suppress cellular [T helper (Th)1-directed] immunity and promote humoral (Th2-directed) immunity and tolerance. The past decade has produced new insights into the mechanisms of glucocorticoid sensitivity and resistance of inflammatory, autoimmune and allergic diseases. Both the quality and severity of the inflammatory stimulus, as well as the genetics and constitution of the patient, play key roles in the glucocorticoid sensitivity, dependency and resistance of these diseases. Although glucocorticoids increase susceptibility to opportunistic infections, they are also highly beneficial in the presence of serious systemic inflammation, such as that observed in septic shock and acute respiratory distress syndrome, when administered in a sustained fashion throughout the course of the disease. Glucocorticoids produce their cardiovascular, metabolic and antigrowth side effects through molecular mechanisms distinct from those involved in immunomodulation. Fortunately, the first generation of tissue- and immune- versus cardiovascular/metabolic effect-selective glucocorticoids is available for study and further improvement. ‘Designer’ glucocorticoids promise to be a great new advance in the therapy of inflammatory diseases.

To examine the joint effect of insomnia and objective short sleep duration on hypertension risk. Representative cross-sectional study. Sleep laboratory. 1,741 men and women randomly selected from central Pennsylvania. None. Insomniawas defined by a complaint of insomnia with a duration ≥ 1 year, while poor sleepwas defined as a complaint of difficulty falling asleep, staying asleep, or early final awakening. Polysomnographic sleep duration was classified into 3 categories: ≥ 6 h sleep (top 50% of the sample); 5-6 h (approximately the third quartile of the sample); and ≤ 5 h (approximately the bottom quartile of the sample). Hypertension was defined based either on blood pressure measures or treatment. We controlled for age, race, sex, body mass index, diabetes, smoking, alcohol use, depression, sleep disordered breathing (SDB), and sampling weight. Compared to the normal sleeping and >6 h sleep duration group, the highest risk of hypertension was in insomnia with <5 h sleep duration group (OR [95% CI] 5.1 [2.2, 11.8]), and the second highest in insomnia who slept 5-6 hours (OR 3.5 [1.6, 7.9] P < 0.01). The risk for hypertension was significantly higher, but of lesser magnitude, in poor sleepers with short sleep duration. Insomnia with short sleep duration is associated with increased risk of hypertension, to a degree comparable to that of other common sleep disorders, e.g., SDB. Objective sleep duration may predict the severity of chronic insomnia a prevalent condition whose medical impact has been apparently underestimated.

Classic congenital hyperplasia (CAH) is characterized by impaired adrenocortical function with a decrease in cortisol and aldosterone secretion and an increase in androgen secretion. Adrenomedullary function is also compromised due to developmental defects in the formation of the adrenal medulla, leading to decreased production of epinephrine. To examine the response to a natural stressful stimulus in patients with classic CAH, we studied hormonal, metabolic, and cardiorespiratory parameters in response to a standardized high-intensity exercise protocol in nine adolescent patients with CAH and nine healthy controls matched for gender, age, and percent body fat. The same relative workload was applied, based on individual maximal aerobic capacity, and all patients received their usual glucocorticoid and mineralocorticoid replacement. When compared with their normal counterparts, patients with CAH had significantly lower epinephrine levels both at baseline and at peak exercise (P < 0.01), whereas norepinephrine levels did not differ. Blood glucose concentrations were similar at baseline, but the normal exercise-induced rise observed in the healthy controls was significantly blunted in the CAH patients (P < 0.01). Peak heart rate was also lower in CAH patients than healthy controls (P < 0.05). As expected, the normal exercise-induced increase in cortisol was not observed in patients with CAH. No significant differences were found in serum levels of insulin, glucagon, GH, lactate and free fatty acids, blood pressure, or ability to sustain exercise between the two groups. Patients with CAH replaced with glucocorticoids have decreased adrenomedullary reserve and impaired exercise-induced changes in glucose but normal short-term high-intensity exercise performance. Whether the combination of epinephrine and cortisol deficiency poses a risk for hypoglycemia and/or decreased endurance during long-term physical stress has to be determined.

The aim of this study was to evaluate the effect of a novel cognitive-behavioral stress management intervention, termed "Pythagorean Self-Awareness Intervention" (PSAI). Materials and Methods: The PSAI was applied to a community sample for eight weeks. Measurements included demographic characteristics, daily habits, sleep quality, fatigue, perceived stress levels and depressive symptoms. Cognitive function was measured by the Symbol Digits Modality Test (SDMT), the California Verbal Learning Test (CVLT) and the Brief Visuospatial Memory Test-Revised (BVMT-R).The high-compliance group showed statistically significant differences in healthy lifestyle and personal control choices (HLPCQ; p=0.006), sleep quality (PSQI; p=0.007), self-regulation eating behavior (SREBQ; p=0.009), perceived stress (PSS; p=0.001) and depressive symptoms (p=0.003). Conclusions: Frequent practice of the PSAI had a positive effect on the psychological, lifestyle, and cognitive measures of the community sample. Larger studies are needed to establish the PSAI as an effective stress management method.

Royal jelly (RJ) excreted by honeybees and used as a nutritional and medicinal agent has estrogen-like effects, yet the compounds mediating these effects remain unidentified. The possible effects of three RJ fatty acids (FAs) (10-hydroxy-2-decenoic-10H2DA, 3,10-dihydroxydecanoic-3,10DDA, sebacic acid-SA) on estrogen signaling was investigated in various cellular systems. In MCF-7 cells, FAs, in absence of estradiol (E(2)), modulated the estrogen receptor (ER) recruitment to the pS2 promoter and pS2 mRNA levels via only ERβ but not ERα, while in presence of E(2) FAs modulated both ERβ and ERα. Moreover, in presence of FAs, the E(2)-induced recruitment of the EAB1 co-activator peptide to ERα is masked and the E(2)-induced estrogen response element (ERE)-mediated transactivation is inhibited. In HeLa cells, in absence of E(2), FAs inhibited the ERE-mediated transactivation by ERβ but not ERα, while in presence of E(2), FAs inhibited ERE-activity by both ERβ and ERα. Molecular modeling revealed favorable binding of FAs to ERα at the co-activator-binding site, while binding assays showed that FAs did not bind to the ligand-binding pocket of ERα or ERβ. In KS483 osteoblasts, FAs, like E(2), induced mineralization via an ER-dependent way. Our data propose a possible molecular mechanism for the estrogenic activities of RJ's components which, although structurally entirely different from E(2), mediate estrogen signaling, at least in part, by modulating the recruitment of ERα, ERβ and co-activators to target genes.