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Background and aimVascular dementia (VD) is a common type of dementia. This study aimed to evaluate the effects of low and high doses of lutein administration in bilateral-carotid vessel occlusion (2VO) rats.Experimental procedureThe rats were divided into the following groups: the control, sham-, vehicle (2VO+V) groups, and two groups after 2VO were treated with lutein 0.5 (2VO+LUT-o.5) and 5mg/kg (2VO+LUT-5). The passive-avoidance and Morris water maze were performed to examine fear and spatial memory. The field-potential recording was used to investigate the properties of basal synaptic transmission (BST), paired-pulse ratio (PPR), as an index for measurement of neurotransmitter release, and long-term potentiation (LTP). The hippocampus was removed to evaluate hippocampal cells, volume, and MDA level.ResultTreatment with low and high doses improves spatial memory and LTP impairment in VD rats, but only the high dose restores the fear memory, hippocampal cell loss, and volume and MDA level. Interestingly, low-dose, but not high-dose, increased PPR. However, BST recovered only in the high-dose treated group.ConclusionsTreatment with a low dose might affect neurotransmitter release probability, but a high dose affects postsynaptic processes. It seems likely that low and high doses improve memory and LTP through different mechanisms.

BackgroundThe favorable health-promoting adaptations to exercise result from cumulative responses to individual bouts of physical activity. Older adults often exhibit anabolic resistance; a phenomenon whereby the anabolic responses to exercise and nutrition are attenuated in skeletal muscle. The mechanisms contributing to age-related anabolic resistance are emerging, but our understanding of how chronological age influences responsiveness to exercise is incomplete. The objective was to determine the effects of healthy aging on peripheral blood metabolomic response to a single bout of resistance exercise and whether any metabolites in circulation are predictive of anabolic response in skeletal muscle.MethodsThirty young (20-35 years) and 49 older (65-85 years) men and women were studied in a cross-sectional manner. Participants completed a single bout of resistance exercise consisting of eight sets of 10 repetitions of unilateral knee extension at 70% of one-repetition maximum. Blood samples were collected before exercise, immediately post exercise, and 30-, 90-, and 180-minutes into recovery. Proton nuclear magnetic resonance spectroscopy was used to profile circulating metabolites at all timepoints. Serial muscle biopsies were collected for measuring muscle protein synthesis rates.ResultsOur analysis revealed that one bout of resistance exercise elicits significant changes in 26 of 33 measured plasma metabolites, reflecting alterations in several biological processes. Furthermore, 12 metabolites demonstrated significant interactions between exercise and age, including organic acids, amino acids, ketones, and keto-acids, which exhibited distinct responses to exercise in young and older adults. Pre-exercise histidine and sarcosine were negatively associated with muscle protein synthesis, as was the pre/post-exercise fold change in plasma histidine.ConclusionsThis study demonstrates that while many exercise-responsive metabolites change similarly in young and older adults, several demonstrate age-dependent changes even in the absence of evidence of sarcopenia or frailty.Trial registrationClinical trial registry: ClinicalTrials.gov NCT03350906.

Visible and near-infrared (Vis-NIR) reflectance spectroscopy has recently emerged as an efficient and cost-effective tool for monitoring soil parameters and provides an extensive array of measurements swiftly. This study sought to predict fundamental biological attributes of calcareous soils using spectral reflectance data in the Vis-NIR range through the application of partial least square regression (PLSR) and stepwise multiple linear regression (SMLR) techniques. The objective was to derive spectrotransfer functions (STFs) to predict selected soil biological attributes. A total of 97 composite samples were collected from three distinct agricultural land uses, i.e., sugarcane, wheat, and date palm, in the Khuzestan Province, Iran. The samples were analyzed using both standard laboratory analysis and proximal sensing approach within the Vis-NIR range (400–2500 nm). Biological status was evaluated by determining soil enzyme activities linked to nutrient cycling including acid phosphatase (ACP), alkaline phosphatase (ALP), dehydrogenase (DEH), soil microbial respiration (SMR), microbial biomass phosphorus (Pmic), and microbial biomass carbon (Cmic). The results indicated that the developed PLSR models exhibited superior predictive performance in most biological parameters compared to the STFs, although the differences were not significant. Specifically, the STFs acceptably accurately predicted ACP, ALP, DEH, SMR, Pmic, and Cmic with R2val (val = validation dataset) values of 0.68, 0.67, 0.65, 0.65, 0.76, and 0.72, respectively. These findings confirm the potential of Vis-NIR spectroscopy and the effectiveness of the associated STFs as a rapid and reliable technique for assessing biological soil quality. Overall, in the context of predicting soil properties using spectroscopy-based approaches, emphasis must be placed on developing straightforward, easily deployable, and pragmatic STFs. [ABSTRACT FROM AUTHOR]

Type 2 diabetes mellitus (T2DM) is a challenging and progressive metabolic disease caused by insulin resistance. Skeletal muscle is the major insulin-sensitive tissue that plays a pivotal role in blood sugar homeostasis. Dysfunction of muscle metabolism is implicated in the disturbance of glucose homeostasis, the development of insulin resistance, and T2DM. Understanding metabolism reprogramming in newly diagnosed patients provides opportunities for early diagnosis and treatment of T2DM as a challenging disease to manage. Here, we applied a system biology approach to investigate metabolic dysregulations associated with the early stage of T2DM. We first reconstructed a human muscle-specific metabolic model. The model was applied for personalized metabolic modeling and analyses in newly diagnosed patients. We found that several pathways and metabolites, mainly implicating in amino acids and lipids metabolisms, were dysregulated. Our results indicated the significance of perturbation of pathways implicated in building membrane and extracellular matrix (ECM). Dysfunctional metabolism in these pathways possibly interrupts the signaling process and develops insulin resistance. We also applied a machine learning method to predict potential metabolite markers of insulin resistance in skeletal muscle. 13 exchange metabolites were predicted as the potential markers. The efficiency of these markers in discriminating insulin-resistant muscle was successfully validated.

IntroductionEnd-stage renal disease (ESRD) treatment includes dialysis and kidney transplantation. Transplant rejection is a major barrier to transplant success. One of the markers mentioned in previous studies on renal function in patients with renal failure for various reasons is periostin (POSTN). The expression of POSTN correlates with interstitial fibrosis and reduced renal function. One of the limitations in this regard is the effect of oral lesions on the POSTN level. This study was conducted aimed to measure the relationship between salivary and serum POSTN and renal function in patients with a history of a kidney transplant, taking into account all the conditions affecting POSTN.MethodsIn this study, serum and saliva samples were taken from 23 transplant patients with normal function (NF) and 29 transplant patients with graft failure (GF). At least one year had passed since the transplant. Before sampling, a complete oral examination was performed. Salivary and serum POSTN was examined by ELISA. The results were analyzed by SPSS software.ResultsThe POSTN level in the serum of the NF group (191.00 ± 33.42) was higher than GF patients (178.71 ± 25.68), but the difference was not significant (P = 0.30). Salivary POSTN in NF patients (2.76 ± 0.35) was significantly higher than GF patients (2.44 ± 0.60) (P = 0.01).ConclusionsThe superiority of saliva as a diagnostic fluid includes ease of collection and storage, and non-invasiveness, all of which can lead to the replacement of blood with this bio-fluid. The significant results of salivary POSTN may be due to the lack of serum disturbing factors. Saliva is an ultra-filtered fluid from serum and therefore there are fewer proteins and polysaccharides attached to biomarkers in saliva and the accuracy of measuring these biomarkers in the saliva is more valuable than serum.

Nowadays, a small number of incretin mimics are used to treat type 2 diabetes mellitus (T2DM) due to their longer half-life. The present study aimed to introduce a novel method for producing the liraglutide precursor peptide (LPP) and developing a potentially new incretin mimic. Here, human αB-crystallin (αB-Cry) was ligated to the LPP at the gene level, and the gene construct was expressed in Escherichia coli with a relatively good efficiency. The hybrid protein (αB-lir) was then purified by a precipitation method followed by anion exchange chromatography. After that, the peptide was released from the carrier protein by a chemical cleavage method yielding about 70%. The LPP was then purified by gel filtration chromatography, and HPLC estimated its purity to be about 98%. Also, the molecular mass of the purified peptide was finally confirmed by mass spectroscopy analysis. Assessment of the secondary structures suggested a dominant α-helical structure for the LPP and a β-sheet rich structure for the hybrid protein. The subcutaneous injection of the LPP and the αB-lir hybrid protein significantly reduced the blood sugar levels in healthy and diabetic mice and stimulated insulin secretion. Also, the hybrid protein exerts its bioactivities more effectively than the LPP over a relatively longer period of time. The results of this study suggested a novel method for the easy and cost-effective production of the LPP and introduced a new long-acting incretin mimic that can be potentially used for the treatment of T2DM patients.

Background: The favorable health-promoting adaptations to exercise result from cumulative responses to individual bouts of physical activity. Older adults often exhibit anabolic resistance; a phenomenon whereby the anabolic responses to exercise and nutrition are attenuated in skeletal muscle. The mechanisms contributing to age-related anabolic resistance are emerging, but our understanding of how chronological age influences responsiveness to exercise is incomplete. The objective was to determine the effects of healthy aging on peripheral blood metabolomic response to a single bout of resistance exercise and whether any metabolites in circulation are predictive of anabolic response in skeletal muscle. Methods: Thirty young (20–35 years) and 49 older (65–85 years) men and women were studied in a cross-sectional manner. Participants completed a single bout of resistance exercise consisting of eight sets of 10 repetitions of unilateral knee extension at 70% of one-repetition maximum. Blood samples were collected before exercise, immediately post exercise, and 30-, 90-, and 180-minutes into recovery. Proton nuclear magnetic resonance spectroscopy was used to profile circulating metabolites at all timepoints. Serial muscle biopsies were collected for measuring muscle protein synthesis rates. Results: Our analysis revealed that one bout of resistance exercise elicits significant changes in 26 of 33 measured plasma metabolites, reflecting alterations in several biological processes. Furthermore, 12 metabolites demonstrated significant interactions between exercise and age, including organic acids, amino acids, ketones, and keto-acids, which exhibited distinct responses to exercise in young and older adults. Pre-exercise histidine and sarcosine were negatively associated with muscle protein synthesis, as was the pre/post-exercise fold change in plasma histidine. Conclusions: This study demonstrates that while many exercise-responsive metabolites change similarly in young and older adults, several demonstrate age-dependent changes even in the absence of evidence of sarcopenia or frailty. Trial registration: Clinical trial registry: ClinicalTrials.gov NCT03350906. [ABSTRACT FROM AUTHOR]

Bus services naturally tend to be unstable and are not always capable of adhering to schedules without control strategies. Therefore, bus users and bus service providers face travel time variation and irregularity. After a comprehensive review of the literature, a significant gap was recognized in the field of public transportation reliability. According to literature, there is no consistency in reliability definition and indicators. Companies have their own definition of bus service reliability, and they mostly neglect the passengers' perspective of reliability. Therefore, four reliability indicators were selected in this study to fill the gap in the literature and cover both passengers' and operators' perceptions of reliability: waiting time and on-board crowding level from passengers' perspective, and headway regularity index at stops (HRIS) and bus bunching/big gap percentage from operators' perspective. The primary objective of this research is to improve the reliability of high frequency of bus service and simulation tools currently being used by the public transportation companies. Therefore, a simulation model of bus service was developed to study the strategies to alleviate it. Four different types of strategies were selected and implemented according to Route U32 (Kuala Lumpur) specifications. Model out-put showed that control strategies such as headway-based dispatching could significantly improve headway regularity by almost 62% and the waiting time by 51% on average. Both holding strategies at key stops (previous and Prefol holding) have shown an almost similar impact on reliability indicators. Waiting time was reduced by 44% and 43% after the previous and Prefol Headway strategies were adopted, respectively. However, the implementation of the component of headway-based strategies at the terminal and key stops showed the best impact on reliability, in terms of passenger waiting time. Waiting time and excess waiting time were both significantly reduced by 52.86% and 81.44%, respectively. Nevertheless, the strategies did not show any significant positive effect on the level of crowding during morning peak hours.

Increasing availability and quality of actual, as opposed to scheduled, open transport data offers new possibilities for capturing the spatiotemporal dynamics of railway and other networks of social infrastructure. One way to describe such complex phenomena is in terms of stochastic processes. At its core, a stochastic model is domain-agnostic and algorithms discussed here have been successfully used in other applications, including Google's PageRank citation ranking. Our key assumption is that train routes constitute meaningful sequences analogous to sentences of literary text. A corpus of routes is thus susceptible to the same analytic tool-set as a corpus of sentences. With our experiment in Switzerland, we introduce a method for building Markov Chains from aggregated daily streams of railway traffic data. The stationary distributions under normal and perturbed conditions are used to define systemic risk measures with non-evident, valuable information about railway infrastructure.

In this study we compared the pharmacokinetic profile of four unrelated antibodies, which do not bind to mammalian antigens, in IgG1 and IgG2 frameworks in both rats and non-human primates (NHP). This allowed for extensive cross comparison of the impact of antibody isotype, complementarity determining regions (CDR) and model species on pharmacokinetics without the confounding influence of antigen binding in the hosts. While antibody isotype had no significant impact on the pharmacokinetics, the CDRs do alter the profile, and there is an inverse correlation between the neonatal Fc receptor (FcRn) affinity and pharmacokinetic performance. Faster clearance rates were also associated with higher isoelectric points; however, although this panel of antibodies all possess basic isoelectric points, ranging from 8.44 to 9.18, they also have exceptional in vivo half-lives, averaging 369 hours, and low clearance rates, averaging 0.18 ml/h/kg in NHPs. This pattern of pharmacokinetic characteristics was conserved between rats and NHPs.

Diabetic hyperglycemia provokes glycation of haemoglobin (Hb), an abundant protein in red blood cells (RBCs), by increasing its exposure to carbohydrates. Acetylsalicylic acid (ASA; Aspirin) is one of the first agents, which its antiglycation effect was witnessed. Although the precise molecular mechanism of action of ASA on protein glycation is not indisputably perceived, acetylation as its main molecular mechanism has been proposed. This report aims to unravel the meticulous mechanism of action of ASA by using two ASA analogues; benzoic acid (BA) and para-nitrobenzoic acid (NBA), despite their lack of acetyl group. In this regard, the inhibitory effect of these two chemicals in comparison with ASA on Hb fructation is reported. UV-visible spectroscopy, intrinsic advanced glycation end products (AGE) fluorescence spectroscopy, extrinsic thioflavin T (ThT) binding fluorescence spectroscopy, 2,4,6-trinitrobenzenesulfonic acid (TNBSA) assay, and single cell gel electrophoresis (SCGE) were used to explore the effects of BA and NBA in comparison with aforementioned chemicals in the context of protein glycation. In spite of the lack of acetyl substitution, NBA is reported as a novel agent with prominent inhibitory efficacy than ASA on the protein glycation. This fact brings up a possible new mechanism of action of ASA and reconsiders acetylation as the sole mechanism of inhibition of protein glycation.

Type 2 diabetes mellitus (T2DM) is a challenging and progressive metabolic disease caused by insulin resistance. Skeletal muscle is the major insulin-sensitive tissue that plays a pivotal role in blood sugar homeostasis. Dysfunction of muscle metabolism is implicated in the disturbance of glucose homeostasis, the development of insulin resistance, and T2DM. Understanding metabolism reprogramming in newly diagnosed patients provides opportunities for early diagnosis and treatment of T2DM as a challenging disease to manage. Here, we applied a system biology approach to investigate metabolic dysregulations associated with the early stage of T2DM. We first reconstructed a human muscle-specific metabolic model. The model was applied for personalized metabolic modeling and analyses in newly diagnosed patients. We found that several pathways and metabolites, mainly implicating in amino acids and lipids metabolisms, were dysregulated. Our results indicated the significance of perturbation of pathways implicated in building membrane and extracellular matrix (ECM). Dysfunctional metabolism in these pathways possibly interrupts the signaling process and develops insulin resistance. We also applied a machine learning method to predict potential metabolite markers of insulin resistance in skeletal muscle. 13 exchange metabolites were predicted as the potential markers. The efficiency of these markers in discriminating insulin-resistant muscle was successfully validated. [ABSTRACT FROM AUTHOR]

Focal epileptic seizures can remain localized or, alternatively, spread across brain areas, often resulting in impairment of cognitive function and loss of consciousness. Understanding the factors that promote spread is important for developing better therapeutic approaches. Here, we show that: (1) seizure spread undergoes "critical" phase transitions in models (epileptor-networks) that capture the neural dynamics of spontaneous seizures while incorporating patient-specific brain network connectivity, axonal delays and identified epileptogenic zones (EZs). We define a collective variable for the spreading dynamics as the spread size, i.e. the number of areas or nodes in the network to which a seizure has spread. Global connectivity strength and excitability in the surrounding non-epileptic areas work as phase-transition control parameters for this collective variable. (2) Phase diagrams are predicted by stability analysis of the network dynamics. (3) In addition, the components of the Jacobian's leading eigenvector, which tend to reflect the connectivity strength and path lengths from the EZ to surrounding areas, predict the temporal order of network-node recruitment into seizure. (4) However, stochastic fluctuations in spread size in a near-criticality region make predictability more challenging. Overall, our findings support the view that within-patient seizure-spread variability can be characterized by phase-transition dynamics under transient variations in network connectivity strength and excitability across brain areas. Furthermore, they point to the potential use and limitations of model-based prediction of seizure spread in closed-loop interventions for seizure control.

αB-crystallin (heat shock protein β5/HSPB5) is a member of the family of small heat shock proteins that is expressed in various organs of the human body including eye lenses and muscles. Therefore, mutations in the gene of this protein (CRYAB) might have many pathological consequences. A new mutation has recently been discovered in the α-crystallin domain of this chaperone protein which replaces aspartate 109 with alanine (D109A). This mutation can cause myofibrillar myopathy (MFM), cataracts, and cardiomyopathy. In the current study, several spectroscopic and microscopic analyses, as well as gel electrophoresis assessment were applied to elucidate the pathogenic contribution of human αB-crystallin bearing D109A mutation in development of eye lens cataract and myopathies. The protein oligomerization, chaperone-like activity and chemical/thermal stabilities of the mutant and wild-type protein were also investigated in the comparative assessments. Our results suggested that the D109A mutation has a significant impact on the important features of human αB-crystallin, including its structure, size of the protein oligomers, tendency to form amyloid fibrils, stability, and chaperone-like activity. Given the importance of aspartate 109 in maintaining the proper structure of the α-crystallin domain, its role in the dimerization and chaperone-like activity, as well as preserving protein stability through the formation of salt bridges; mutation at this important site might have critical consequences and can explain the genesis of myopathy and cataract disorders. Also, the formation of large light-scattering aggregates and disruption of the chaperone-like activity by D109A mutation might be considered as important contributing factors in development of the eye lens opacity.