Searching for a partially absorbing target by a run-and-tumble particle in a confined space.

A random search of a partially absorbing target by a run-and-tumble particle in a confined one-dimensional space is investigated. We analytically obtain the mean searching time, which shows a nonmonotonic behavior as a function of the self-propulsion speed of the active particle, indicating the existence of an optimal speed, when the absorption strength of the target is finite. In the limit of large and small absorption strengths, respectively, asymptotes of the mean searching time and the optimal speed are found. We also demonstrate that the first-passage problem of a diffusive run-and-tumble particle in high dimensions can be mapped into a one-dimensional problem with a partially absorbing target. Finally, as a practical application exploiting the existence of the optimal speed, we propose a filtering device to extract active particles with a desired speed and evaluate how the resolution of the filtering device depends on the absorption strength.

Active search for a reactive target in thermal environments.

We study a stochastic process where an active particle, modeled by a one-dimensional run-and-tumble particle, searches for a target with a finite absorption strength in thermal environments. Solving the Fokker-Planck equation for a uniform initial distribution, we analytically calculate the mean searching time (MST), the time for the active particle to be finally absorbed, and show that there exists an optimal self-propulsion velocity of the active particle at which MST is minimized. As the diffusion constant increases, the optimal velocity changes from a finite value to zero, which implies that a purely diffusive Brownian motion outperforms an active motion in terms of searching time. Depending on the absorption strength of the target, the transition of the optimal velocity becomes either continuous or discontinuous, which can be understood based on the Landau approach. In addition, we obtain the phase diagram indicating the passive-efficient and the active-efficient regions. Finally, the initial condition dependence of MST is presented in limiting cases.

Lupenone attenuates thapsigargin-induced endoplasmic reticulum stress and apoptosis in pancreatic beta cells possibly through inhibition of protein tyrosine kinase 2 activity.

AIMS: Prolonged high levels of cytokines, glucose, or free fatty acids are associated with diabetes, elevation of cytosolic Ca2+ concentration ([Ca2+]C), and depletion of Ca2+ concentration in the endoplasmic reticulum (ER) of pancreatic beta cells. This Ca2+ imbalance induces ER stress and apoptosis. Lupenone, a lupan-type triterpenoid, is beneficial in diabetes; however, its mechanism of action is yet to be clarified. This study evaluated the protective mechanism of lupenone against thapsigargin-induced ER stress and apoptosis in pancreatic beta cells. MATERIALS AND METHODS: MIN6, INS-1, and native mouse islet cells were used. Western blot for protein expressions, measurement of [Ca2+]C, and in vivo glucose tolerance test were mainly performed. KEY FINDINGS: Thapsigargin increased the protein levels of cleaved caspase 3, cleaved PARP, and the phosphorylated form of JNK, ATF4, and CHOP. Thapsigargin increased the interaction between stromal interaction molecule1 (Stim1) and Orai1, enhancing store-operated calcium entry (SOCE). SOCE is further activated by protein tyrosine kinase 2 (Pyk2), which is Ca2+-dependent and phosphorylates the tyrosine residue at Y361 in Stim1. Lupenone inhibited thapsigargin-mediated Pyk2 activation, suppressed [Ca2+]C, ER stress, and apoptosis. Lupenone restored impaired glucose-stimulated insulin secretion effectuated by thapsigargin and glucose intolerance in a low-dose streptozotocin-induced diabetic mouse model. SIGNIFICANCE: These results suggested that lupenone attenuated thapsigargin-induced ER stress and apoptosis by inhibiting SOCE; this may be due to the hindrance of Pyk2-mediated Stim1 tyrosine phosphorylation. In beta cells that are inevitably exposed to frequent [Ca2+]C elevation, the attenuation of abnormally high SOCE would be beneficial for their survival.

Whole body mass estimates and error propagation in countermovement jump: a simulated error study.

High-velocity actions are central to clinical and athletic performance, with jumping used to assess outcomes in sports medicine. Ground reaction force (GRF)-based methods are the standard for computing jump characteristics, but require mass estimation and GRF integration, potentially resulting in mass errors which influence outcomes. This study investigated how simulated mass errors influenced the centre of mass (CoM) trajectory during a countermovement jump. The mass was estimated from the static GRF, and simulated errors were added or subtracted to the mass. The CoM trajectory with simulated mass errors was computed using the GRF-based method to investigate mass mis-estimation's influence on jump height. A regression model indicated that, for a 1 kg mass change, there was a 7.7 cm jump height change, and the jump height differed by 11.5 ± 0.4 cm from the maximum to minimum error. A 2-way ANOVA identified significant height differences between the starting position, and landing, or final position with mass errors of ± 0.2 or ± 0.4 kg. These results reveal that small mass errors may produce inaccurate conclusions regarding performance changes, and that errors may propagate throughout the jump trajectory. Caution may be necessary when using GRF-based methods to compute jump height as a power proxy.

Target searches of interacting Brownian particles in dilute systems.

We study the target searches of interacting Brownian particles in a finite domain, focusing on the effect of interparticle interactions on the search time. We derive the integral equation for the mean first-passage time and acquire its solution as a series expansion in the orders of the Mayer function. We analytically obtain the leading order correction to the search time for dilute systems, which are most relevant to target search problems and prove a universal relation given by the particle density and the second virial coefficient. Finally, we validate our theoretical prediction by Langevin dynamics simulations for the various types of the interaction potential.

Beneficial effects of intermittent fasting: a narrative review.

Caloric restriction is a popular approach to treat obesity and its associated chronic illnesses but is difficult to maintain for a long time. Intermittent fasting is an alternative and easily applicable dietary intervention for caloric restriction. Moreover, intermittent fasting has beneficial effects equivalent to those of caloric restriction in terms of body weight control, improvements in glucose homeostasis and lipid profiles, and anti-inflammatory effects. In this review, the beneficial effects of intermittent fasting are discussed.

Optimal searcher distribution for parallel random target searches.

We consider a problem of finding a target located in a finite d-dimensional domain, using N independent random walkers, when partial information about the target location is given as a probability distribution. When N is large, the first-passage time sensitively depends on the initial searcher distribution, which invokes the question of the optimal searcher distribution that minimizes the first-passage time. Here, we analytically derive the equation for the optimal distribution and explore its limiting expressions. If the target volume can be ignored, the optimal distribution is proportional to the target distribution to the power of one third. If we consider a target of a finite volume and the probability of the initial overlapping of searchers with the target cannot be ignored in the large N limit, the optimal distribution has a weak dependence on the target distribution, with its variation being proportional to the logarithm of the target distribution. Using Langevin dynamics simulations, we numerically demonstrate our predictions in one and two dimensions.

Peroxiredoxin 2 deficiency does not affect insulin resistance and oxidative stress in high-fat diet-fed obese mice.

OBJECTIVE: To examine if peroxiredoxin 2 (Prx2) deficiency aggravates high-fat diet-induced insulin resistance. MATERIAL AND METHODS: Insulin sensitivity was measured in Prx2 knockout (KO) and wild-type (WT) littermates using the hyperinsulinemic-euglycemic clamp. RESULTS: Whole body glucose turnover, glucose uptake, and levels of glucose transporter 4 (Glut4) protein in the skeletal muscle were found to be lower. This was followed by increased expression of oxidative stress markers in Prx2 KO mice than that in WT mice in the control diet group. Although, a 12-week high-fat diet induced insulin resistance and enhanced oxidative stress in both genotypes, there was no difference between WT and Prx2 KO mice with respect to insulin sensitivity and the level of oxidative stress markers. Accordingly, the levels of phosphorylated Akt and Glut4 were similar between the two genotypes. CONCLUSION: These results suggest that Prx2 does not affect high-fat diet-induced oxidative stress and insulin resistance in mice.

Mitochondrial TFAM as a Signaling Regulator between Cellular Organelles: A Perspective on Metabolic Diseases.

Tissues actively involved in energy metabolism are more likely to face metabolic challenges from bioenergetic substrates and are susceptible to mitochondrial dysfunction, leading to metabolic diseases. The mitochondria receive signals regarding the metabolic states in cells and transmit them to the nucleus or endoplasmic reticulum (ER) using calcium (Ca2+) for appropriate responses. Overflux of Ca2+ in the mitochondria or dysregulation of the signaling to the nucleus and ER could increase the incidence of metabolic diseases including insulin resistance and type 2 diabetes mellitus. Mitochondrial transcription factor A (Tfam) may regulate Ca2+ flux via changing the mitochondrial membrane potential and signals to other organelles such as the nucleus and ER. Since Tfam is involved in metabolic function in the mitochondria, here, we discuss the contribution of Tfam in coordinating mitochondria-ER activities for Ca2+ flux and describe the mechanisms by which Tfam affects mitochondrial Ca2+ flux in response to metabolic challenges.

Portrait Segmentation Using Ensemble of Heterogeneous Deep-Learning Models.

Image segmentation plays a central role in a broad range of applications, such as medical image analysis, autonomous vehicles, video surveillance and augmented reality. Portrait segmentation, which is a subset of semantic image segmentation, is widely used as a preprocessing step in multiple applications such as security systems, entertainment applications, video conferences, etc. A substantial amount of deep learning-based portrait segmentation approaches have been developed, since the performance and accuracy of semantic image segmentation have improved significantly due to the recent introduction of deep learning technology. However, these approaches are limited to a single portrait segmentation model. In this paper, we propose a novel approach using an ensemble method by combining multiple heterogeneous deep-learning based portrait segmentation models to improve the segmentation performance. The Two-Models ensemble and Three-Models ensemble, using a simple soft voting method and weighted soft voting method, were experimented. Intersection over Union (IoU) metric, IoU standard deviation and false prediction rate were used to evaluate the performance. Cost efficiency was calculated to analyze the efficiency of segmentation. The experiment results show that the proposed ensemble approach can perform with higher accuracy and lower errors than single deep-learning-based portrait segmentation models. The results also show that the ensemble of deep-learning models typically increases the use of memory and computing power, although it also shows that the ensemble of deep-learning models can perform more efficiently than a single model with higher accuracy using less memory and less computing power.

PPARδ Attenuates Alcohol-Mediated Insulin Resistance by Enhancing Fatty Acid-Induced Mitochondrial Uncoupling and Antioxidant Defense in Skeletal Muscle.

Alcohol consumption leads to the dysfunction of multiple organs including liver, heart, and skeletal muscle. Alcohol effects on insulin resistance in liver are well evidenced, whereas its effects in skeletal muscle remain controversial. Emerging evidence indicates that alcohol promotes adipose tissue dysfunction, which may induce organ dysregulation. We show that consumption of ethanol (EtOH) reduces the activation of 5'AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) as well as the protein of carnitine palmitoyltransferase 1 (CPT1) and glucose transporter type 4 (GLUT4) in C2C12 myotube. We observed that chronic EtOH consumption increases free fatty acid levels in plasma and triglyceride (TG) accumulation in skeletal muscle and that these increases induce insulin resistance and decrease glucose uptake. Hence, ethanol dysregulates metabolic factors and induces TG accumulation. We found peroxisome proliferator-activated receptor ß/δ (PPARδ) activation recovers AMPK activation and increases carnitine-acylcarnitine translocase (CACT) protein. These effects may contribute to enhance mitochondrial activation via uncoupling protein 3 (UCP3) when fatty acids are used as a substrate, thus reduces EtOH-induced increases in TG levels in skeletal muscle. In addition, PPARδ activation recovered EtOH-induced loss of protein kinase B (AKT) phosphorylation at serine 473 via rapamycin-insensitive companion of mammalian target of rapamycin (Rictor) activation. Importantly, PPARδ activation enhanced mitochondrial uncoupling via UCP3. Taken together, the study shows PPARδ enhances fatty acid utilization and uncoupled respiration via UCP3 and protects against EtOH-induced lipotoxicity and insulin resistance in skeletal muscle.

Alginate-Derived Elicitors Enhance ß-Glucan Content and Antioxidant Activities in Culinary and Medicinal Mushroom, Sparassis latifolia.

This study aimed to investigate the elicitation effects of alginate oligosaccharides extracted from brown algae (Sargassum species) on ß-glucan production in cauliflower mushroom (Sparassis latifolia). Sodium alginate was refined from Sargassum fulvellum, S. fusiforme, and S. horneri, and characterized by proton nuclear magnetic resonance spectroscopy (1H NMR), resulting mannuronic acid to guluronic acid (M/G) rationes from 0.64 to 1.38. Three oligosaccharide fractions, ethanol fraction (EF), solid fraction (SF), and liquid fraction (LF), were prepared by acid hydrolysis and analyzed by Fourier transform infrared (FT-IR) spectra and high-performance anion-exchange chromatography with a pulsed amperometric detector (HPAEC-PAD). The samples of S. fusiforme resulted in the highest hydrolysate in SF and the lowest in LF, which was consistent with its highest M/G ratio. The SF of S. fusiforme and LF of S. horneri were chosen for elicitation on S. latifolia, yielding the highest ß-glucan contents of 56.01 ± 3.45% and 59.74 ± 4.49% in the stalk, respectively. Total polyphenol content (TPC) and antioxidant activities (2,2'-Azino-bis(3-ethylbenzthiazoline-6-sulfonic acid) (ABTS) radical scavenging and Superoxide dismutase (SOD)-like activity) of aqueous extracts of S. latifolia were greatly stimulated by alginate elicitation. These results demonstrate that alginate oligosaccharides extracted from brown algae may be useful as an elicitor to enhance the nutritional value of mushrooms.

Transthyretin Maintains Muscle Homeostasis Through the Novel Shuttle Pathway of Thyroid Hormones During Myoblast Differentiation.

Skeletal muscle, the largest part of the total body mass, influences energy and protein metabolism as well as maintaining homeostasis. Herein, we demonstrate that during murine muscle satellite cell and myoblast differentiation, transthyretin (TTR) can exocytose via exosomes and enter cells as TTR- thyroxine (T4) complex, which consecutively induces the intracellular triiodothyronine (T3) level, followed by T3 secretion out of the cell through the exosomes. The decrease in T3 with the TTR level in 26-week-old mouse muscle, compared to that in 16-week-old muscle, suggests an association of TTR with old muscle. Subsequent studies, including microarray analysis, demonstrated that T3-regulated genes, such as FNDC5 (Fibronectin type III domain containing 5, irisin) and RXRγ (Retinoid X receptor gamma), are influenced by TTR knockdown, implying that thyroid hormones and TTR coordinate with each other with respect to muscle growth and development. These results suggest that, in addition to utilizing T4, skeletal muscle also distributes generated T3 to other tissues and has a vital role in sensing the intracellular T4 level. Furthermore, the results of TTR function with T4 in differentiation will be highly useful in the strategic development of novel therapeutics related to muscle homeostasis and regeneration.

Selenoprotein W deficiency does not affect oxidative stress and insulin sensitivity in the skeletal muscle of high-fat diet-fed obese mice.

Selenoprotein W (SelW) is a selenium-containing protein with a redox motif found abundantly in the skeletal muscle of rodents. Previous in vitro studies suggest that SelW plays an antioxidant role; however, relatively few in vivo studies have addressed the antioxidant role of SelW. Since oxidative stress is a causative factor for the development of insulin resistance in obese subjects, we hypothesized that if SelW plays a role as an antioxidant, SelW deficiency could aggravate the oxidative stress and insulin resistance caused by a high-fat diet. SelW deficiency did not affect insulin sensitivity and H2O2 levels in the skeletal muscle of control diet-fed mice. SelW levels in the skeletal muscle were decreased by high-fat diet feeding for 12 wk. High-fat diet induced obesity and insulin resistance and increased the levels of H2O2 and oxidative stress makers, which were not affected by SelW deficiency. High-fat diet feeding increased the expression of antioxidant enzymes; however, SelW deficiency did not affect the expression levels of antioxidants. These results suggest that SelW does not play a protective role against oxidative stress and insulin resistance in the skeletal muscle of high-fat diet-fed obese mice.

Prognostic value of adjacent organ resection in patients with left-sided pancreatic ductal adenocarcinoma following distal pancreatectomy.

BACKGROUND: We evaluated whether distal pancreatectomy (DP) with adjacent organ resection (AOR) affected perioperative outcomes and survival in patients with left-sided pancreatic ductal adenocarcinoma (PDAC). METHODS: Retrospective cohort study was conducted at single large volume academic medical center from January 2000 to December 2016. RESULTS: Five hundred and twenty-three patients had undergone standard DP (without additional vessel/organ resection) and 40 had undergone DP with AOR due to adjacent organ infiltration. There were no differences of postoperative morbidity and hospital stay between the two groups. In the patients with AJCC 8th stage I and II PDAC, there were significant differences of median disease-specific and progression-free survivals between the standard and AOR groups (37.9 vs. 20.2 months; P = 0.05, 20 vs. 10 months; P = 0.028, respectively). DP with AOR was identified as independent prognostic factor of stage I and II PDAC by multivariate Cox regression analysis. CONCLUSIONS: Distal pancreatectomy with AOR could be an acceptable surgical treatment for left-sided PDAC. However, AOR group shows poor prognosis than that of the standard group in patients with AJCC 8th stage I and II PDAC. AOR should be considered indicative of a more aggressive tumor in AJCC 8th stage I and II PDAC.

Obesity and Erectile Dysfunction: From Bench to Clinical Implication.

Obesity is a major public health issue worldwide and is frequently associated with erectile dysfunction (ED). Both conditions may share an internal pathologic environment, also known as common soil. Their main pathophysiologic processes are oxidative stress, inflammation, and resultant insulin and leptin resistance. Moreover, the severity of ED is correlated with comorbid medical conditions, including obesity. Therefore, amelioration of these comorbidities may increase the efficacy of ED treatment with phosphodiesterase 5 inhibitors, the first-line medication for patients with ED. Although metformin was originally developed as an insulin sensitizer six decades ago, it has also been shown to improve leptin resistance. In addition, metformin has been reported to reduce oxidative stress, inflammatory response, and body weight, as well as improve ED, in animal and human studies. Moreover, administration of a combination of metformin and phosphodiesterase 5 inhibitors improves erectile function in patients with ED who have a poor response to sildenafil and are insulin resistant. Thus, concomitant treatment of metabolic derangements associated with obesity in patients with ED who are obese would improve the efficacy and reduce the refractory response to penile vasodilators. In this review, we discuss the connecting factors between obesity and ED and the possible combined treatment modalities.

Rodlike Counterions near Charged Cylinders: Counterion Condensation and Intercylinder Interaction.

We study a system composed of like-charged cylinders and dumbbell-like counterions, with the focus laid on the role of the internal structure of counterions, using Monte Carlo simulations. The dumbbell ions are found to exhibit novel counterion condensation behavior governed by their length. Effective electrostatic interactions mediated between charged parallel cylinders also turn out significantly different from the case of pointlike ions, as a result of the complex interplay between the spatially separated charge distribution in the dumbbell counterions, their orientation, and the curvature of the charged cylinder. We show that at a weak-to-moderate electrostatic coupling strength, where effective like-charge interactions are usually found to be repulsive, the intercylinder interaction can become attractive and display a distinctive sensitivity to the cylinder curvature and dumbbell size, proving the significant effect of ion structure.

Interactions between a fluctuating polymer barrier and transport factors together with enzyme action are sufficient for selective and rapid transport through the nuclear pore complex.

The nuclear pore complex, the only pathway for transport between the nucleus and cytoplasm, functions as a highly selective gate that blocks nonspecific macromolecules while allowing the rapid transport of tagged [transport factor (TF) bound] cargo up to an order of magnitude larger. The mechanism of this gate's operation is not yet fully understood and progress has been primarily hindered by the inherent complexity and multiscale nature of the problem. One needs to consider the hundreds of disordered proteins (phenylalanine glycine nucleoporins or FG nups) lining the pore, as well as their overall architecture and dynamics at the microsecond scale, while also accounting for transport at the millisecond scale across the entire pore. Here we formulate an approach that addresses transport properties over a large range of length and time scales. We do this by incorporating microscopic biophysical details, such as charge and specific TF-FG nup interactions, to compute the free energy landscape encountered by the cargo. We connect this to macroscopic transport by treating cargo translocation as a stochastic barrier crossing process and computing the current and the translocation time. We then identify distinct transport regimes (fast permeable, slow permeable, and impermeable) determined by the cargo size, TF affinity for FG nups, and the activity of the enzymes that cleave TFs from cargo. Our results, therefore provide an integrated picture of transport through the NPC, while highlighting how FG nup interactions with TFs and enzyme activity cooperate to produce selectivity and efficiency.

Transduodenal ampullectomy for ampullary tumors - single center experience of consecutive 26 patients.

PURPOSE: Transduodenal ampullectomy (TDA) has been reported in a limited number of cases and in a small number of case series. The aim of this study was to analyze perioperative and long-term oncological outcomes of patients with ampullary tumors who underwent TDA in a single large-volume center. METHODS: Through a retrospective review of data from 2004 to 2016, we identified 26 patients who underwent TDA at Asan Medical Center. RESULTS: Eleven of 26 patients underwent TDA for T1 and carcinoma in situ (high-grade dysplasia) cancer; these patients are still alive without recurrence. A major in-hospital complication (3.8%) occurred in 1 case, but there was no case of 90-day mortality. In addition, none of the patients was diagnosed as having newly developed diabetes mellitus after TDA. No significant differences were found between open and laparoscopic-TDA in terms of operation time, painkiller use, and hospital stay. CONCLUSION: TDA is a feasible and effective surgical procedure for the treatment of selected patients with ampullary tumors. It is an alternative treatment option in cases of ampullary tumors not amenable to endoscopic papillectomy or pancreaticoduodenectomy.

Clusterin deficiency induces lipid accumulation and tissue damage in kidney.

Clusterin is a secretory glycoprotein that is involved in multiple physiopathological processes, including lipid metabolism. Previous studies have shown that clusterin prevents hepatic lipid accumulation via suppression of sterol regulatory element-binding protein (SREBP) 1. In this study, we examined the role of clusterin in renal lipid accumulation in clusterin-knockout mice and NRK52e tubular epithelial cells. Clusterin deficiency increased the expression of SREBP1 and its target genes and decreased malonyl-CoA decarboxylase protein levels in the kidney. Expression of the endocytic receptor, megalin, and scavenger receptor class A was increased in clusterin-deficient mice. Functional analysis of lipid metabolism also revealed that lipid uptake and triglyceride synthesis were increased and fatty acid oxidation was reduced, leading to increased lipid accumulation in clusterin-deficient mice. These phenomena were accompanied by mesangial expansion, fibrosis and increased urinary protein-to-creatinine ratio. High-fat feeding aggravated these clusterin deficiency-induced pathological changes. Clusterin knockdown in NRK52e cells increased lipogenic gene expression and lipid levels, whereas overexpression of clusterin by treatment with adenovirus or recombinant clusterin protein suppressed lipogenic gene expression and lipid levels. Transforming growth factor-beta 1 (TGFB1) expression increased in the kidney of clusterin-deficient mice and suppression of TGFB1 in NRK52e cells suppressed lipid accumulation. These results suggest that clusterin deficiency induces renal lipid accumulation by dysregulating the expression of lipid metabolism-related factors and TGFB1, thereby leading to chronic kidney disease. Hence, clusterin may serve as a therapeutic target for lipid-induced chronic kidney disease.