Discovery of New Dual-Target Agents Against PPAR-γ and α-Glucosidase Enzymes with Molecular Modeling Methods: Molecular Docking, Molecular Dynamic Simulations, and MM/PBSA Analysis.

Type 2 diabetes mellitus (T2DM) has become a serious public health problem both in our country and worldwide, being the most prevalent type of diabetes. The combined use of drugs in the treatment of T2DM leads to serious side effects, including gastrointestinal problems, liver toxicity, hypoglycemia, and treatment costs. Hence, there has been a growing emphasis on drugs that demonstrate dual interactions. Several studies have suggested that dual-target agents for peroxisome proliferator-activated receptor-γ (PPAR-γ) and alpha-glucosidase (α-glucosidase) could be a potent approach for treating patients with diabetes. We aim to develop new antidiabetic agents that target PPAR-γ and α-glucosidase enzymes using molecular modeling techniques. These compounds show dual interactions, are more effective, and have fewer side effects. The molecular docking method was employed to investigate the enzyme-ligand interaction mechanisms of 159 newly designed compounds with target enzymes. Additionally, we evaluated the ADME properties and pharmacokinetic suitability of these compounds based on Lipinski and Veber's rules. Compound 70, which exhibited favorable ADME properties, demonstrated more effective binding energy with both PPAR-γ and α-glucosidase enzymes (-12,16 kcal/mol, -10.07 kcal/mol) compared to the reference compounds of Acetohexamide (-9.31 kcal/mol, -7.48 kcal/mol) and Glibenclamide (-11.12 kcal/mol, -8.66 kcal/mol). Further, analyses of MM/PBSA binding free energy and molecular dynamics (MD) simulations were conducted for target enzymes with compound 70, which exhibited the most favorable binding affinities with both enzymes. Based on this information, our study aims to contribute to the development of new dual-target antidiabetic agents with improved efficacy, reduced side effects, and enhanced reliability for diabetes treatment.

Synthesis, Antimicrobial Activities, and Molecular Modeling Studies of Agents for the Sortase A Enzyme.

Sortase A (SrtA) is an attractive target for developing new anti-infective drugs that aim to interfere with essential virulence mechanisms, such as adhesion to host cells and biofilm formation. Herein, twenty hydroxy, nitro, bromo, fluoro, and methoxy substituted chalcone compounds were synthesized, antimicrobial activities and molecular modeling strategies against the SrtA enzyme were investigated. The most active compounds were found to be T2, T4, and T19 against Streptococcus mutans (S. mutans) with MIC values of 1.93, 3.8, 3.94 µg/mL, and docking scores of -6.46, -6.63, -6.73 kcal/mol, respectively. Also, these three active compounds showed better activity than the chlorohexidine (CHX) (MIC value: 4.88 µg/mL, docking score: -6.29 kcal/mol) in both in vitro and in silico. Structural stability and binding free energy analysis of S.mutans SrtA with active compounds were measured by molecular dynamic (MD) simulations throughout 100 nanoseconds (ns) time. It was observed that the stability of the critical interactions between these compounds and the target enzyme was preserved. To prove further, in vivo biological evaluation studies could be conducted for the most promising precursor compounds T2, T4, and T19, and it might open new avenues to the discovery of more potent SrtA inhibitors.

Long-term neurodevelopmental effects of exclusively high cord lactate levels in term newborn.

INTRODUCTION: Cord arterial blood gas analysis (ABGA) results are used as diagnostic criteria for hypoxic-ischemic encephalopathy in newborns with suspected perinatal asphyxia. This study evaluated the effect of cord ABGA lactate level on the long-term neurodevelopment of newborns without any clinical signs of perinatal asphyxia. METHODS: This clinical observation study was designed among term babies born between 2018 and 2019 in our unit. Cases with a 5-min Apgar score <7 and signs of fetal distress in their antenatal follow-up were excluded. The cases (n = 1438) were divided into two groups those with high cord lactate levels (above 5 mmol/L, n = 92) and those with low lactate levels (below 2 mmol/L, n = 255). An Ages and Stages Questionnaire, Third Edition (ASQ-3) developmental screening questionnaire was sent to all parents. Patients with a chronological age between 24 and 42 months and for whom the parents fulfilled the questionnaire (low lactate group, n = 29, and high lactate group, n = 45) were evaluated. RESULTS: No difference was observed between the two groups in terms of demographic characteristics such as age (p = .1669), male gender (p = .906), mother's working situation (p = .948), mother's education level (p = .828), father's education level (p = .507), and family's total income (p = .642). Mean ACQ-3 developmental screening test scores were significantly lower in the high lactate group compared to the low lactate group concerning; fine motor (40 vs. 60, p = .001), problem-solving (50 vs. 60, p = .002), and personal social development (45 vs. 60, p = .003). No difference was observed in terms of communication and gross motor total scores. DISCUSSION: In general practice, routine cord ABGA is not generally recommended for patients with normal Apgar scores and no suspected hypoxia. However, in this study, we observed that cases with a normal 5-min Apgar score, no suspected perinatal asphyxia, and a cord lactate value of ≥5 fell behind their peers when evaluated with the ACQ-3 developmental screening questionnaire.

Design, Synthesis, Pharmacological Activities, Structure-Activity Relationship, and In Silico Studies of Novel 5-Substituted-2-(morpholinoimino)-thiazolidin-4-ones.

This study is aimed to synthesize morpholine- and thiazolidine-based novel 5-(substituted)benzylidene)-2-(morpholinoimino)-3-phenylthiazolidin-4-ones (3-26) and characterized by molecular spectroscopy. The synthesized compounds were subjected to antioxidant activity with anticholinesterase, tyrosinase, and urease inhibition activities and evaluated the structure-activity relationship (SAR) of enzyme inhibition activities. Compound 11 was found to be the most active antioxidant. In anticholinesterase inhibition, compound 12 (IC50: 17.41 ± 0.22 µM) was the most active against AChE, while compounds 3-26 ( except 3, 8, and 17) showed notable activity against BChE. Compounds 17 (IC50: 3.22 ± 0.70 mM), 15 (IC50: 5.19 ± 0.03 mM), 24 (IC50: 7.21 ± 0.27 mM), 23 (IC50: 8.05 ± 0.11 mM), 14 (IC50: 8.10 ± 0.22 mM), 25 (IC50: 8.40 ± 0.64 mM), 26 (IC50: 8.76 ± 0.90 mM), and 22 (IC50: 9.13 ± 0.55 mM) produced higher tyrosinase inhibition activity. In urease inhibition activity, compounds 20 (IC50: 16.79 ± 0.19 µM), 19 (IC50: 18.25 ± 0.50 µM), 18 (IC50: 20.24 ± 0.77 µM), 26 (IC50: 21.51 ± 0.44 µM), 25 (IC50: 21.70 ± 0.06 µM), and 24 (IC50: 22.49 ± 0.11 µM) demonstrated excellent activities. Besides, the molecular docking study was applied to better understand the inhibitory mechanism between (1-26) compounds and enzymes at the molecular level. According to the results of this study, the synthesized compounds exhibited a better binding affinity toward these enzymes compared to the positive control. Further, molecular mechanics Poisson-Boltzmann surface area (MM/PBSA) binding free energy and molecular dynamics (MD) simulation analyses were performed for AChE with compound 26, which showed high inhibitory activity in silico and in vitro studies. In conclusion, novel morpholine and thiazolidine-based derivative compounds may be pharmacologically effective agents for AChE, BChE, tyrosinase, and urease enzymes.

Nocturnal Blood Pressure Estimation from Sleep Plethysmography Using Machine Learning.

BACKGROUND: Elevated nocturnal blood pressure (BP) is a risk factor for cardiovascular disease (CVD) and mortality. Cuffless BP assessment aided by machine learning could be a desirable alternative to traditional cuff-based methods for monitoring BP during sleep. We describe a machine-learning-based algorithm for predicting nocturnal BP using single-channel fingertip plethysmography (PPG) in healthy adults. METHODS: Sixty-eight healthy adults with no apparent sleep or CVD (53% male), with a median (IQR) age of 29 (23-46 years), underwent overnight polysomnography (PSG) with fingertip PPG and ambulatory blood pressure monitoring (ABPM). Features based on pulse morphology were extracted from the PPG waveforms. Random forest models were used to predict night-time systolic blood pressure (SBP) and diastolic blood pressure (DBP). RESULTS: Our model achieved the highest out-of-sample performance with a window length of 7 s across window lengths explored (60 s, 30 s, 15 s, 7 s, and 3 s). The mean absolute error (MAE ± STD) was 5.72 ± 4.51 mmHg for SBP and 4.52 ± 3.60 mmHg for DBP. Similarly, the root mean square error (RMSE ± STD) was 6.47 ± 1.88 mmHg for SBP and 4.62 ± 1.17 mmHg for DBP. The mean correlation coefficient between measured and predicted values was 0.87 for SBP and 0.86 for DBP. Based on Shapley additive explanation (SHAP) values, the most important PPG waveform feature was the stiffness index, a marker that reflects the change in arterial stiffness. CONCLUSION: Our results highlight the potential of machine learning-based nocturnal BP prediction using single-channel fingertip PPG in healthy adults. The accuracy of the predictions demonstrated that our cuffless method was able to capture the dynamic and complex relationship between PPG waveform characteristics and BP during sleep, which may provide a scalable, convenient, economical, and non-invasive means to continuously monitor blood pressure.

Urinary neopterin and biopterin indicate that inflammation has a role in autism spectrum disorder.

Inflammation is thought to be involved in the pathogenesis of autism spectrum disorder (ASD). Pteridine metabolites are biomarkers of inflammation that increase on immune system activation. In this study, we investigated the urinary pteridine metabolites in ASD patients as a possible biomarker for immune activation and inflammation. This observational, cross-sectional, prospective study collected urine samples from 212 patients with ASD and 68 age- and sex-matched healthy individuals. Urine neopterin (NE) and biopterin (BIO) levels were measured. Patients who had chronic disorders, active infection at the time of sampling, or high C-reactive protein levels were excluded. The urine NE and BIO concentrations were determined by high-performance liquid chromatography. The ratios of both NE and BIO to creatinine (CRE) were used to standardise the measurements. The NE/CRE and NE/BIO levels were significantly higher in ASD patients than controls. Univariate and multivariate models revealed a significant increase in NE/CRE and NE/BIO in ASD patients. There was a significant relationship between the NE/BIO [average area under the curve (AUC) = 0.717; range: 0.637-0.797] and NE/CRE (average AUC = 0.756; range: 0.684-0.828) ratios, which distinguished individuals with ASD from controls. The elevated NE/CRE and NE/BIO ratios suggest that inflammation and T cell-mediated immunity are involved in the pathophysiology of autism. NE/BIO could serve as a diagnostic inflammatory marker in the pathogenesis of ASD.

Design, synthesis, and enzyme inhibition evaluation of some novel Mono- and Di-O-ß-D-Glycopyranosyl Chalcone analogues with molecular docking studies.

In this study, some novel mono- and di-O-ß-D-glycopyranosyl chalcone analogs were designed, synthesized, and characterized. The chalcone derivatives were synthesized with good yields by base-catalyzed Claisen-Schmidt condensation in EtOH solution. Then these chalcones were reacted with TAGBr (2,3,4,6-tetra-O-acetyl-α-D-glucopyranosylbromide) in dry acetone under the anhydrous condition at 0-5 °C. Deacylated was carried out by the Zemplen's method with NaOCH3 in dry methanol results in substituted chalcone-O-glycosides (mono- and di-O-ß-D-glycopyranosyl chalcone analogs). The chemical structures of all synthesized compounds were elucidated based on IR, NMR spectral data, and mass spectrometry. Further, the compounds (7a-c, 8a-c, 12a-c, 16a-c, and 17a-c) were tested for their enzyme inhibition activity against α-glycosidase, tyrosinase, and AChE with in vitro and in silico analysis. Amongst them, compounds 12a-c, 16a-c, and 17a-c displayed moderate or less enzyme inhibition activity against α-glycosidase while other compounds 7a-c and 8a-c) were not active. Remarkably interesting enzyme inhibition effects, with IC50 values below 30.59 ± 0.30 µM were recorded with 7c (IC50=11.07 ± 0.55 µM) against tyrosinase.

Investigation of α-glucosidase and α-amylase inhibitory effects of phenoxy chalcones and molecular modeling studies.

Diabetes mellitus is one of the most critical health problems affecting the quality of life of people worldwide, especially in developing countries. According to the World Health Organization reports, the number of patients with diabetes is approximately 420 million, and this number is estimated to be 642 million in 2040. There are 2 main types of diabetes: Type 1 (T1DM), where the body cannot produce enough insulin, and Type 2 (T2DM), where the body cannot use insulin properly. Patients with T1DM are treated with insulin injections while oral glucose-lowering drugs are used for patients with T2DM. Oral antihyperglycemic drugs used in the treatment of type 2 diabetes mellitus have different mechanisms. Among these, α-Glucosidase and α-amylase inhibitors are one of the most important inhibitors. The antidiabetic effect of the chalcones, which show rich activity, draws attention. This research aims to synthesize chalcone derivatives that could show potential antidiabetic activity. In this study, the inhibitory activity of the chalcone compounds (4a-4g, 5a-5g) was tested against α-glucosidase and α-amylase enzymes. Besides, molecular modeling was utilized to predict potential interactions of the synthesized compounds that exhibit inhibitory effects. In both in vitro and in silico studies, the analyses revealed that compound 5e exhibits strong inhibitory effects against α-glucosidase enzymes (Binding energy: -7.75 kcal/mol, IC50 : 28.88 µM). Additionally, compound 4f demonstrates encouraging inhibitory effects against α-Amylase (Binding energy: -11.08 kcal/mol, IC50 : 46. 21 µM).

Design, in Silico Studies and Biological Evaluation of New Chiral Thiourea and 1,3-Thiazolidine-4,5-dione Derivatives.

In this study, new chiral thiourea and 1,3-thiazolidine-4,5-dione derivatives were synthesized, it was aimed to evaluate the various biological activities and molecular docking of these compounds. Firstly, the new thioureas (1-16) were obtained by reacting 1-naphthylisothiocyanate with different chiral amines. Then, the chiral thioureas were cyclized with oxalyl chloride to obtain 1,3-thiazolidine-4,5-dione derivatives (17-32). All compounds were evaluated with several in vitro antioxidant and enzyme inhibition activities. Compound 30 was the most active compound against AChE, with a value of IC50 =8.09±0.58 µM. On the other hand, all compounds were tested in silico absorption, distribution, metabolism, and excretion (ADME) assays to better understand their bioavailability. These physicochemical properties, pharmacokinetics, and drug-likeness of all compounds were calculated using SwissADME. Furthermore, according to molecular docking analyses compound 30 exhibited significant binding affinities for all enzymes. Based on our overall observations, compound 30 could be recommended as a potential lead for the therapuetic of Alzheimer's.

Insights into vascular physiology from sleep photoplethysmography.

STUDY OBJECTIVES: Photoplethysmography (PPG) in consumer sleep trackers is now widely available and used to assess heart rate variability (HRV) for sleep staging. However, PPG waveform changes during sleep can also inform about vascular elasticity in healthy persons who constitute a majority of users. To assess its potential value, we traced the evolution of PPG pulse waveform during sleep alongside measurements of HRV and blood pressure (BP). METHODS: Seventy-eight healthy adults (50% male, median [IQR range] age: 29.5 [23.0, 43.8]) underwent overnight polysomnography (PSG) with fingertip PPG, ambulatory blood pressure monitoring, and electrocardiography (ECG). Selected PPG features that reflect arterial stiffness: systolic to diastolic distance (∆T_norm), normalized rising slope (Rslope) and normalized reflection index (RI) were derived using a custom-built algorithm. Pulse arrival time (PAT) was calculated using ECG and PPG signals. The effect of sleep stage on these measures of arterial elasticity and how this pattern of sleep stage evolution differed with participant age were investigated. RESULTS: BP, heart rate (HR) and PAT were reduced with deeper non-REM sleep but these changes were unaffected by the age range tested. After adjusting for lowered HR, ∆T_norm, Rslope, and RI showed significant effects of sleep stage, whereby deeper sleep was associated with lower arterial stiffness. Age was significantly correlated with the amount of sleep-related change in ∆T_norm, Rslope, and RI, and remained a significant predictor of RI after adjustment for sex, body mass index, office BP, and sleep efficiency. CONCLUSIONS: The current findings indicate that the magnitude of sleep-related change in PPG waveform can provide useful information about vascular elasticity and age effects on this in healthy adults.

A Rare Case of Laryngeal Osteosarcoma Causing Diagnostic Challenges.

Laryngeal osteosarcomas are extremely rare. They cause diagnostic difficulty for the otolaryngologist and pathologist. Differentiation from sarcomatoid carcinoma is challenging but important, as clinical features and treatment strategies are different. Total laryngectomy is generally the preferred surgical approach for laryngeal osteosarcomas. Since lymph node metastasis is not expected, neck dissection is not needed. In this report, we present a case diagnosed with laryngeal osteosarcoma post the examination of the total laryngectomy specimen of a laryngeal tumor that could not be histopathologically differentiated by punch biopsy.

Synthesis and evaluation of the antioxidant and anti-tyrosinase activities of thiazolyl hydrazone derivatives and their application in the anti-browning of fresh-cut potato.

Tyrosinase is a key enzyme in the biosynthesis of melanin, which is responsible for the browning of foods as well as many skin disorders. In order to develop new anti-browning agents with dual antioxidant and anti-tyrosinase capacities, a series of 30 thiazolyl hydrazone derivatives were synthesized. Among the molecules prepared, 6 and 30 were found to be the most potent tyrosinase inhibitors with IC50 values ​​comparable to that of kojic acid. Interestingly, 6 also has the highest radical scavenging activity among the prepared molecules. The inhibition kinetics study indicated that 6 is a non-competitive inhibitor while 30 inhibits tyrosinase competitively. The anti-browning assay of fresh-cut potato slices revealed that 6 and 30 are potent anti-browning agents with a capacity as high as kojic acid. The mechanisms of free radical scavenging and tyrosinase inhibition have been fully investigated in silico using computational kinetics, molecular docking, and molecular dynamics simulations.

Exosomes released from cisplatin-resistant ovarian cancer cells modulate the reprogramming of cells in tumor microenvironments toward the cancerous cells.

Exosomes released from cancer cells are involved in the reorganization of the tumor microenvironment which is the essential aspect of cancer pathogenesis. The intercommunications between cancer cells and diverse cell types in the microenvironment are accomplished by exosomes in ovarian cancer. Internalization pathway, intracellular fate, and biological functions in recipient cells mediated by exosomes released from cisplatin-resistant A2780cis have been studied. Also, histopathological evaluation of tumor, ovary, liver tissues and lymph nodes in vivo studies have been performed. The recipient cells internalized the exosomes via active uptake mechanisms, as shown by confocal microscopy. However, inhibitor studies and flow cytometry analysis showed that each recipient cell line used different uptake pathways. Also, confocal microscopy imaging indicated that the internalized exosomes trapped in the endosomes or phagosomes were distributed to the different cellular compartments including ER, Golgi, and lysosome. The transfer of exosomal oncogenic cargo into the cells modified the intracellular signaling of recipient cells including invasion and metastasis by Boyden-Chamber assay, proliferation by ATP analysis, epithelial-mesenchymal transition (EMT) markers at protein and mRNA levels by western blotting and real-time PCR, and protein kinases in the phospho-kinase array. This remodeling contributed to the initiation of carcinogenesis in ovarian epithelial and peritoneal mesothelial cells, and the progression of carcinogenesis in ovarian cancer cells. In addition, intraperitoneal tumor model studies show that exosomes released from cisplatin-resistant A2780cis cells may play role in the enlargement of lymph nodes, and tumor formations integrated with the liver, attached to the stomach and in the ovarian tissues.

Safety of COVID-19 vaccines in children with inborn errors of metabolism in terms of developing metabolic decompensation.

AIM: There are no recommended guidelines or clinical studies on safety of COVID-19 vaccines in patients with inborn errors of metabolism (IEMs). Here, we aimed to examine the relationship between COVID-19 vaccination and metabolic outcome in paediatric IEM patients. METHODS: Patients with IEM between the ages of 12 and 18 were enrolled. Term metabolic decompensation was defined as acute disruption in metabolic homeostasis due to vaccination. Clinical and biochemical markers were compared between pre- and post-vaccination periods. RESULTS: Data from a total of 36 vaccination episodes in 18 patients were included. Thirteen patients had intoxication-type metabolic disorders including organic acidemia (OA), urea cycle disorders (UCDs), maple syrup urine disease (MSUD) and phenylketonuria (PKU); 4 patients had energy metabolism disorders including fatty acid metabolism disorders and LIPIN 1 deficiency; and 1 patient had glycogen storage disorder (GSD) type 5. Seventeen patients received BNT162b2, and 1 received CoronaVac because of an underlying long QT syndrome. Fatty acid metabolism disorders, LIPIN 1 deficiency and GSD type 5 were included in the same group named 'metabolic myopathies'. In two PKU patients, plasma phenylalanine level increased significantly within 24 h following the second dose of vaccination. None of the OA, UCD, MSUD and metabolic myopathy patients experienced acute metabolic attack and had emergency department admission due to metabolic decompensation within 1 month after vaccination. CONCLUSIONS: COVID-19 vaccines did not cause acute metabolic decompensation in a cohort of 18 children with IEM.

An automated heart rate-based algorithm for sleep stage classification: Validation using conventional polysomnography and an innovative wearable electrocardiogram device.

Background: The rapid advancement in wearable solutions to monitor and score sleep staging has enabled monitoring outside of the conventional clinical settings. However, most of the devices and algorithms lack extensive and independent validation, a fundamental step to ensure robustness, stability, and replicability of the results beyond the training and testing phases. These systems are thought not to be feasible and reliable alternatives to the gold standard, polysomnography (PSG). Materials and methods: This validation study highlights the accuracy and precision of the proposed heart rate (HR)-based deep-learning algorithm for sleep staging. The illustrated solution can perform classification at 2-levels (Wake; Sleep), 3-levels (Wake; NREM; REM) or 4- levels (Wake; Light; Deep; REM) in 30-s epochs. The algorithm was validated using an open-source dataset of PSG recordings (Physionet CinC dataset, n = 994 participants, 994 recordings) and a proprietary dataset of ECG recordings (Z3Pulse, n = 52 participants, 112 recordings) collected with a chest-worn, wireless sensor and simultaneous PSG collection using SOMNOtouch. Results: We evaluated the performance of the models in both datasets in terms of Accuracy (A), Cohen's kappa (K), Sensitivity (SE), Specificity (SP), Positive Predictive Value (PPV), and Negative Predicted Value (NPV). In the CinC dataset, the highest value of accuracy was achieved by the 2-levels model (0.8797), while the 3-levels model obtained the best value of K (0.6025). The 4-levels model obtained the lowest SE (0.3812) and the highest SP (0.9744) for the classification of Deep sleep segments. AHI and biological sex did not affect scoring, while a significant decrease of performance by age was reported across the models. In the Z3Pulse dataset, the highest value of accuracy was achieved by the 2-levels model (0.8812), whereas the 3-levels model obtained the best value of K (0.611). For classification of the sleep states, the lowest SE (0.6163) and the highest SP (0.9606) were obtained for the classification of Deep sleep segment. Conclusion: The results of the validation procedure demonstrated the feasibility of accurate HR-based sleep staging. The combination of the proposed sleep staging algorithm with an inexpensive HR device, provides a cost-effective and non-invasive solution deployable in the home environment and robust across age, sex, and AHI scores.

Primitive neuroectodermal tumor in a child with Currarino syndrome.

BACKGROUND: Curarino syndrome is a rare and complex anomaly with the triad of anorectal malformation, presacral mass and sacral bone deformation. The most common cause of the presacral mass is meningioma, but teratoma is the diagnosis in about one-third of the cases. Malignant transformation of teratoma in the form of carcinoma, rhabdomyosarcoma and leukemia have previously been reported on rare occasions. CASE: A 19 month-old-girl was referred with a presacral mass of 29mm x 23mm x 24mm. She was diagnosed as Currarino syndrome. The presacral mass was surgically resected and pathological examination revealed a foci of primitive neurectodermal tumor. CONCLUSIONS: This is the first case of Currarino syndrome with a primitive neuroectodermal tumor (PNET) foci in the presacral mass. Considering the risk of malignant transformation, the accurate pathological examination is important for complete systemic evaluation and treatment plan in these children.

Multi-Night at-Home Evaluation of Improved Sleep Detection and Classification with a Memory-Enhanced Consumer Sleep Tracker.

Purpose: To evaluate the benefits of applying an improved sleep detection and staging algorithm on minimally processed multi-sensor wearable data collected from older generation hardware. Patients and Methods: 58 healthy, East Asian adults aged 23-69 years (M = 37.10, SD = 13.03, 32 males), each underwent 3 nights of PSG at home, wearing 2nd Generation Oura Rings equipped with additional memory to store raw data from accelerometer, infra-red photoplethysmography and temperature sensors. 2-stage and 4-stage sleep classifications using a new machine-learning algorithm (Gen3) trained on a diverse and independent dataset were compared to the existing consumer algorithm (Gen2) for whole-night and epoch-by-epoch metrics. Results: Gen 3 outperformed its predecessor with a mean (SD) accuracy of 92.6% (0.04), sensitivity of 94.9% (0.03), and specificity of 78.5% (0.11); corresponding to a 3%, 2.8% and 6.2% improvement from Gen2 across the three nights, with Cohen's d values >0.39, t values >2.69, and p values <0.01. Notably, Gen 3 showed robust performance comparable to PSG in its assessment of sleep latency, light sleep, rapid eye movement (REM), and wake after sleep onset (WASO) duration. Participants <40 years of age benefited more from the upgrade with less measurement bias for total sleep time (TST), WASO, light sleep and sleep efficiency compared to those ≥40 years. Males showed greater improvements on TST and REM sleep measurement bias compared to females, while females benefitted more for deep sleep measures compared to males. Conclusion: These results affirm the benefits of applying machine learning and a diverse training dataset to improve sleep measurement of a consumer wearable device. Importantly, collecting raw data with appropriate hardware allows for future advancements in algorithm development or sleep physiology to be retrospectively applied to enhance the value of longitudinal sleep studies.

BNT162b2 COVID-19 vaccination elicited protective robust immune responses in pediatric patients with inborn errors of metabolism.

Introduction: SARS-CoV-2 infection can lead to a life-threatening acute metabolic decompensation in children with inborn errors of metabolism (IEM), so vaccination is mandatory. However, IEMs can also impair innate or adaptive immunity, and the impact of these immune system alterations on immunogenicity and vaccine efficacy is still unknown. Here, we investigated humoral immune responses to the BNT162b2 mRNA COVID-19 vaccine and clinical outcomes in pediatric IEM patients. Methods: Fifteen patients between 12-18 years of age with a confirmed diagnosis of IEM, and received BNT162b2 were enrolled to the study. Patients with an anti-SARS-CoV-2 IgG concentration >50 AU/mL before vaccination were defined as "COVID-19 recovered" whereas patients with undetectable anti-SARS-CoV-2 IgG concentration were defined as "COVID-19 naïve". Anti-SARS-CoV-2 Immunoglobulin G (IgG) and SARS-CoV-2 neutralizing antibody (nAb) titers were measured to assess humoral immune response. Results: Anti-SARS-CoV-2 IgG titers and nAb IH% increased significantly after the first dose. The increase in antibody titers after first and second vaccination remained significant in COVID-19 naïve patients. Complete anti-SARS-CoV-2 IgG seropositivity and nAb IH% positivity was observed in all patients after the second dose. Vaccination appears to be clinically effective in IEM patients, as none of the patients had COVID-19 infection within six months of the last vaccination. Discussion: Humoral immune response after two doses of BNT162b2 in pediatric IEM patients was adequate and the immune response was not different from that of healthy individuals.

Investigation of the antimicrobial activities of various antimicrobial agents on Streptococcus Mutans Sortase A through computer-aided drug design (CADD) approaches.

BACKGROUND AND OBJECTIVE: Tooth decay is a common chronic disease that causes pain, tooth loss, malnutrition, anxiety and significantly affects half of the world's population. Streptococcus mutans (S.mutans), is considered the main pathogen causing tooth decay. Sortase A (SrtA), one of the surface proteins of S. mutans, is a potential target in the development of antimicrobial and caries prevention agents for preventing infections associated with biofilm formation. Recently, various SrtA inhibitors, including small molecules and natural product, especially, trans-chalcone, chlorhexidine (CHX) and flavonoid compounds, which exhibit effective inhibition against SrtA, have been identified. However, due to the limited number of inhibitors, multi-drug resistance and side-effects the discovery of new inhibitors for SrtA is essential. METHODS: In this case, various compounds aimed at the target enzyme underwent high-throughput screening with small molecule libraries. For this screening of a total of 178 compounds, 163 were found to be pharmacokinetically suitable by performing an absorption, distribution, metabolism, and excretion (ADME) analysis. Molecular docking was then applied to investigate the interaction mechanism among these suitable compounds and the target enzyme structure at the molecular level. RESULTS: According to the results of the study, six compounds (CHEMBL243796 (kurarinone), CHEMBL2180472, CHEMBL3335591, CHEMBL373249, CHEMBL1395334, CHEMBL253467 (Isobavachalcone)) exhibited lower docking scores (-7.18, -6.59, -6.53, -6.47, -6.43, and -6.39 kcal/mol, respectively) against S. mutans SrtA than the positive control CHX (-6.29 kcal/mol). Finally, the 100 ns molecular dynamic simulations and binding free energy calculations were performed for the structure stability analysis of the enzyme with CHEMBL243796 (kurarinone), which showed the lowest docking score. As a result of these studies, the stability of the critical interactions between kurarinone and the target enzyme was preserved during the simulation time. CONCLUSIONS: These results indicate that flavonoid and chalcone scaffold compounds are clinically more reliable and potent than CHX as novel inhibitory agents for inhibiting oral biofilm formation. These finding can provide important contribution to the future clinical trials in the development of therapeutically useful inhibitors of SrtA by virtually screening several chemical compounds more rapidly to select suitable compounds for the prevention and treatment of dental caries.

Crosstalk between beta-adrenergic and insulin signaling mediates mechanistic target of rapamycin hyperactivation in liver of high-fat diet-fed male mice.

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease. While increased nutrient intake and sympathetic activity have been associated with the disease, the pathogenesis of NAFLD remains incompletely understood. We investigated the impact of the interaction of high dietary fat and sugar intake with increased beta-adrenergic receptor (ß-AR) signaling on the activity of nutrient-sensing pathways and fuel storage in the liver. C57BL/6J mice were fed a standard rodent diet (STD), a high-fat diet (HFD), a high-fat/high-sugar Western diet (WD), a high-sugar diet with mixed carbohydrates (HCD), or a high-sucrose diet (HSD). After 6 week on diets, mice were treated with isoproterenol (ISO) and the activity of liver mTOR complex 1 (mTORC1)-related signaling analyzed by immunoblotting and correlated with tissue triglyceride and glycogen contents. ISO-stimulated AKT- and ERK-mediated activation of mTORC1 in STD-fed mice. Consumption of all four high-calorie diets exacerbated downstream activation of ribosomal protein S6 kinase beta-1 (S6K1) in response to ISO. S6K1 activity was greater with the fat-enriched HFD and WD and correlated with the presence of metabolic syndrome and a stronger activation of AKT and ERK1/2 pathways. Fat-enriched diets also increased triglyceride accumulation and inhibited glycogen mobilization under ß-AR stimulation. In conclusion, crosstalk between ß-AR and insulin signaling may contribute to HFD-induced hepatic steatosis through ERK1/2- and AKT-mediated hyperactivation of the mTORC1/S6K1 axis. The findings provide further rationale for the development of therapies aimed at targeting augmented ß-AR signaling in the pathogenesis of NAFLD.