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Adherens junctions (AJs) create spatially and mechanically discrete microdomains at the interfaces of cells. Using a mechanogenetic platform that generates artificial AJs with controlled protein localization, clustering, and mechanical loading, we report that AJs also organize proteolytic hotspots for γ-secretase with a spatially-regulated substrate selectivity that is critical in the processing of Notch and other transmembrane proteins. Membrane microdomains outside of AJs exclusively organize Notch ligand-receptor engagement (LRE-µdomain) to initialize receptor activation. Conversely, membrane microdomains within AJs exclusively serve to coordinate regulated intramembrane proteolysis (RIP-µdomain). They do so by concentrating γ-secretase and primed receptors while excluding full-length Notch. AJs induce these functionally distinct microdomains by means of cholesterol-dependent γ-secretase recruitment and size-dependent protein segregation. By excluding full-length Notch from RIP-µdomains, AJs prevents inappropriate enzyme-substrate interactions and suppresses spurious Notch activation. Ligand-induced ectodomain shedding eliminates size-dependent segregation, releasing Notch to translocate into AJs for processing by γ-secretase. This mechanism directs radial differentiative expansion of ventricular zone-neural progenitor cells in vivo and more broadly regulates the proteolysis of large cell-surface receptors like amyloid precursor protein. These findings suggest an unprecedented role of AJs in creating size-selective spatial switches that choreograph γ-secretase processing of multiple transmembrane proteins regulating development, homeostasis, and disease.

Dry eye disease (DED) is one of the major ophthalmological healthcare challenges worldwide. DED is a multifactorial disease characterized by a loss of homeostasis of the tear film, and its main pathogenesis is chronic ocular surface inflammation related with various cellular and molecular signaling cascades. The animal model is a reliable and effective tool for understanding the various pathological mechanisms and molecular cascades in DED. Considerable experimental research has focused on developing new strategies for the prevention and treatment of DED. Several experimental models of DED have been developed, and different animal species such as rats, mice, rabbits, dogs, and primates have been used for these models. Although the basic mechanisms of DED in animals are nearly identical to those in humans, proper knowledge about the induction of animal models is necessary to obtain better and more reliable results. Various experimental models (in vitro and in vivo DED models) were briefly discussed in this review, along with pathologic features, analytical approaches, and common measurements, which will help investigators to use the appropriate cell lines, animal, methods, and evaluation parameters depending on their study design.

Adherens junctions (AJs) create spatially, chemically and mechanically discrete microdomains at cellular interfaces. Here, using a mechanogenetic platform that generates artificial AJs with controlled protein localization, clustering and mechanical loading, we find that AJs also organize proteolytic hotspots for γ-secretase with a spatially regulated substrate selectivity that is critical in the processing of Notch and other transmembrane proteins. Membrane microdomains outside of AJs exclusively organize Notch ligand-receptor engagement (LRE microdomains) to initiate receptor activation. Conversely, membrane microdomains within AJs exclusively serve to coordinate regulated intramembrane proteolysis (RIP microdomains). They do so by concentrating γ-secretase and primed receptors while excluding full-length Notch. AJs induce these functionally distinct microdomains by means of lipid-dependent γ-secretase recruitment and size-dependent protein segregation. By excluding full-length Notch from RIP microdomains, AJs prevent inappropriate enzyme-substrate interactions and suppress spurious Notch activation. Ligand-induced ectodomain shedding eliminates size-dependent segregation, releasing Notch to translocate into AJs for processing by γ-secretase. This mechanism directs radial differentiation of ventricular zone-neural progenitor cells in vivo and more broadly regulates the proteolysis of other large cell-surface receptors such as amyloid precursor protein. These findings suggest an unprecedented role of AJs in creating size-selective spatial switches that choreograph γ-secretase processing of multiple transmembrane proteins regulating development, homeostasis and disease.

Amyloid proteins, which aggregate to form highly ordered structures, play a crucial role in various disease pathologies. Despite many previous studies on amyloid fibrils, which are an end product of protein aggregation, the structural characteristics of amyloid proteins in the early stage of aggregation and their related aggregation mechanism still remain elusive. The role of the amino acid sequence in the aggregation-prone structures of amyloid proteins at such a stage is not understood. Here, we have studied the sequence-dependent structural characteristics of islet amyloid polypeptide based on atomistic simulations and spectroscopic experiments. We show that the amino acid sequence determines non-bonded interactions that play a leading role in the formation of aggregation-prone conformations. Specifically, a single point mutation critically changes the population of aggregation-prone conformations, resulting in a change of the aggregation mechanism. Our simulation results were supported by experimental results suggesting that mutation affects the kinetics of aggregation and the structural characteristics of amyloid aggregates. Our study provides an insight into the role of sequence-dependent aggregation-prone conformations in the underlying mechanisms of amyloid aggregation.

Pain afflicts more than 1.5 billion people worldwide, with hundreds of millions suffering from unrelieved chronic pain. Despite widespread recognition of the importance of developing better interventions for the relief of chronic pain, little is known about the mechanisms underlying this condition. However, transient receptor potential (TRP) ion channels in nociceptors have been shown to be essential players in the generation and progression of pain and have attracted the attention of several pharmaceutical companies as therapeutic targets. Unfortunately, TRP channel inhibitors have failed in clinical trials, at least in part due to their thermoregulatory function. Botulinum neurotoxins (BoNTs) have emerged as novel and safe pain therapeutics because of their regulation of exocytosis and pro-nociceptive neurotransmitters. However, it is becoming evident that BoNTs also regulate the expression and function of TRP channels, which may explain their analgesic effects. Here, we summarize the roles of TRP channels in pain, with a particular focus on TRPV1 and TRPA1, their regulation by BoNTs, and briefly discuss the use of BoNTs for the treatment of chronic pain.

Failure to translate promising potential therapeutics for intracerebral hemorrhage (ICH) partially results from limited understanding of cellular mechanisms underlying brain injury and repair. Understanding neural repair mechanisms after brain injury requires intricate comprehension of microglial behavior; however, studying individual microglial cell behavior is challenging. Further single cell isolation techniques may be an excellent means to expand known differences in male and female microglial cell response to ICH. In this study, 24 h after intrastriatal collagenase injection, one male and one female CX3CR1-GFP mouse underwent ex vivo microglial cell isolation via micropipette from perihematomal regions and equivalent location of contralateral striata. After cell collection, individual and grouped cell samples underwent reverse transcription and analyses for gene expression using Fluidigm RT-PCR technology. Data were analyzed by t-tests and visualized as a heatmap of the log2 Ct values. Gene expression assays were chosen for target-specific amplification, including markers of M1 pro-inflammatory microglial phenotype (i.e., Tnf, Il6, Fcgr3/CD16), M2 anti-inflammatory markers (i.e., Mrc1/CD206, Arg1, Tgfb1), and genes involved in the toll-like receptor pathway (i.e., Tlr2, Tlr4 and Myd88). Greater number of individual microglia cells expressed Mcr1, Tlr2, and Arg1 in perihematomal tissue than in contralateral hemispheres. Additionally, more male microglia expressed Myd88, Tlr2, Il6, and Arg1 than did female microglia. Single cell microglial isolation is feasible after in vivo rodent ICH. Differential gene expression can be detected between individual cells from different brain regions and experimental conditions. Cell-specific analyses will contribute to improved understanding of microglial roles in both post-ICH pathogenesis and recovery.

The $R$-matrix analysis of $A=5$ nuclear systems has been partially validated by applying the technique to the $^{5}\mathrm{Li}$ system and comparing the predicted $\ensuremath{\gamma}$-ray spectrum with historical data. $R$-matrix analysis of the similar $^{5}\mathrm{He}$ system was then used to predict the $\ensuremath{\gamma}$-ray spectral shape for the deuterium-tritium (DT) reaction. The resulting spectra have been used in the analysis of DT implosions on the Omega laser where the $\ensuremath{\gamma}$-ray interaction rate was measured by a gas Cherenkov detector. Comparison of predictions to experiment confirmed the presence of both 16.75 and $\ensuremath{\approx}13$ MeV $\ensuremath{\gamma}$-ray contributions; analysis, using $R$-matrix spectra, yielded a ratio of $\ensuremath{\gamma}$-ray emission from a transition to the intermediate excited state to that from a transition to the ground state of $(2.1\ifmmode\pm\else\textpm\fi{}0.4):1$, substantiating the first spectral measurement of the DT fusion $\ensuremath{\gamma}$ ray in an inertial fusion environment.

LED or LD are commonly used for personal or portable micro dust detectors. Photon scattering method is measuring the change of pulse thickness in certain time interval and convert to the particle size and numbers of particles. The advantage of applying photon scattering method is the real time measurement. However, while converting the numbers of scattered photons, accuracy is sacrificed. Especially, for very small micro dust this issue will lead to critical uncertainty. Five different output signals were used to compare and develop accurate system. The efficient software method to transfer data to server is discussed as well.

Riboflavin, also known as vitamin B2, isfound in foods and is used as a dietary supplement. Its deficiency (also called ariboflavinosis) results in some skin lesions and inflammations, such as stomatitis, cheilosis, oily scaly skin rashes, and itchy, watery eyes. Various therapeutic effects of riboflavin, such as anticancer, antioxidant, anti-inflammatory, and anti-nociceptive effects, are well known. Although some studies have identified the clinical effect of riboflavin on skin problems, including itch and inflammation, its underlying mechanism of action remains unknown. In this study, we investigated the molecular mechanism of the effects of riboflavin on histamine-dependent itch based on behavioral tests and electrophysiological experiments. Riboflavin significantly reduced histamine-induced scratching behaviors in mice and histamine-induced discharges in single-nerve fiber recordings, while it did not alter motor function in the rotarod test. In cultured dorsal root ganglion (DRG) neurons, riboflavin showed a dose-dependent inhibitory effect on the histamine- and capsaicin-induced inward current. Further tests wereconducted to determine whether two endogenous metabolites of riboflavin, flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD), have similar effects to those of riboflavin. Here, FMN, but not FAD, significantly inhibited capsaicin-induced currents and itching responses caused by histamine. In addition, in transient receptor potential vanilloid 1 (TRPV1)-transfected HEK293 cells, both riboflavin and FMN blocked capsaicin-induced currents, whereas FAD did not. These results revealed that riboflavin inhibits histamine-dependent itch by modulating TRPV1 activity. This study will be helpful in understanding how riboflavin exerts antipruritic effects and suggests that it might be a useful drug for the treatment of histamine-dependent itch.

$\ensuremath{\gamma}$-ray emission from $^{12}\mathrm{C}$ and $^{13}\mathrm{C}$ samples irradiated with deuterium-tritium fusion neutrons was experimentally measured at the Omega Laser Facility and at the Ohio University Edwards Accelerator Laboratory. The intent of these measurements was to determine the feasibility of using $^{13}\mathrm{C}$-based plastic ablators with embedded $^{12}\mathrm{C}$ layers for ``dark mix'' diagnosis of inertial confinement fusion implosions. Spectrally resolved measurements at Ohio University identified significant 4.44-MeV $\ensuremath{\gamma}$-ray emission from the $^{13}\mathrm{C}(n,2n\ensuremath{\gamma})^{12}\mathrm{C}$-L1 reaction channel. The recorded 4.44-MeV $^{13}\mathrm{C}$ signal was compared against emission from an identically irradiated $^{12}\mathrm{C}$ target with known $^{12}\mathrm{C}$($n,{n}^{\ensuremath{'}}\ensuremath{\gamma})^{12}\mathrm{C}$-L1 cross section, which resulted in an average $^{13}\mathrm{C}(n,2n\ensuremath{\gamma})^{12}\mathrm{C}$-L1 cross section of 117 $\ifmmode\pm\else\textpm\fi{}$ 17 mb over the incident neutron energy distribution range from 14.4 to 15.8 MeV. Integrated $^{13}\mathrm{C}$ $\ensuremath{\gamma}$-ray signals above 2.9 MeV recorded with the Gas Cherenkov Detector at Omega exceeded MCNP6.1 predictions by a factor of 3. The additional signal was attributed to 4.44-MeV $\ensuremath{\gamma}\mathrm{s}$ resulting in an inferred $^{13}\mathrm{C}(n,2n\ensuremath{\gamma})^{12}\mathrm{C}$-L1 cross section of $95\ifmmode\pm\else\textpm\fi{}11$ mb at 14.1-MeV average incident neutron energy. As a result, the $^{13}\mathrm{C}$-based ``dark mix'' diagnostic concept was deemed infeasible.

Here we report the complete genome sequence of Bacillus amyloliquefaciens ATC6, which produces acidic cellulase, isolated from pig feces. The genome is 4,062,817 bp in length and has a guanine-cytosine (GC) content of 46.27%. Among the predicted 3,913 protein-coding genes, two glucanase genes, which are involved in lichenan and cellulose degradation, were found. This genome analysis helps clarify the mechanism involved in cellulose biodegradation and support its application for efficient use of livestock feeds.

Pore-filling ion exchange membranes are fabricated by complicated and energy-inefficient processes, use of large amounts of polar organic solvents, and optionally post-modification using acid or base. For green fabrication of pore-filling anion exchange membranes (PAEMs), we optimized the process parameters such as pretreatment time, impregnation time, water amount, and photo-polymerization rate of each step using roll to roll (R2R) equipment. Based on these optimized process parameters, a PAEM of 57.5 cm width and 39 μm thickness completely filled with a photo-cured electrolyte polymer was fabricated by aqueous pretreatment and by using an impregnation solution without toxic organic solvents. The impregnation step was conducted along with photo-polymerization at a line speed of 0.3 m/min without repeated impregnation with R2R equipment. The IEC, resistance, and permselectivity of this PAEM were similar to those of handmade PAEMs. The PAEM exhibited chemical stability in the pH range of 0–12. In addition, the reverse electrodialysis stack assembled with these PAEMs exhibited a higher power density than a stack of commercial ion exchange membranes. These results demonstrate that industrial-scale PAEM can be fabricated through a rapid, simple, environmentally friendly, and energy-efficient R2R process.

Cancer is one of the leading causes of death in human beings. Therefore, it is important to detect specific target tumors earlier enough in the formative stages of cancer without causing negative side effects and damages to the body. In this study, we proposed bio-engineered short mussel adhesive proteins (MAPs)-carbon nanotubes (CNTs) as specific tumor-targeted carriers for biomedical imaging. Short CNT near-infrared fluorophore (NIRF) hybrid carriers that were developed accumulated in the tumors with exceptional clearance and specific targeting in less time, and these results indicated that bioengineered short CNT-based carriers have great potential for real time tumor imaging.

Multifunctional magnetic nanoparticles have shown great promise as next-generation imaging and perturbation probes for deciphering molecular and cellular processes. As a consequence of multicomponent integration into a single nanosystem, pre-existing nanoprobes are typically large and show limited access to biological targets present in a crowded microenvironment. Here, we apply organic-phase surface PEGylation, click chemistry, and charge-based valency discrimination principles to develop compact, modular, and monovalent magnetofluorescent nanoparticles (MFNs). We show that MFNs exhibit highly efficient labeling to target receptors present in cells with a dense and thick glycocalyx layer. We use these MFNs to interrogate the E-cadherin-mediated adherens junction formation and F-actin polymerization in a three-dimensional space, demonstrating the utility as modular and versatile mechanogenetic probes in the most demanding single-cell perturbation applications.

In this work, Al-0.15Si-0.2Fe-0.3Cu-0.9Mn alloys with different Zn addition (0, 0.15 and 0.3 wt%) were melted and extruded at 200 °C. The effect of Zn on the microstructure, texture evolution and mechanical properties of Al-0.15Si-0.2Fe-0.3Cu-0.9Mn alloys was investigated using scanning electron microscope (SEM), equipped with energy-dispersive X-ray spectrometry (EDS) and electron backscatter diffraction (EBSD) and in the present study. In order to evaluate the mechanical properties, we implemented the tensile tests by a universal material test machine. Al-0.15Si-0.2Fe- 0.3Cu-0.9Mn-xZ resulted in the formation of Al-(Fe, Mn)-Si and Al-(Fe, Mn) intermetallic compounds. The formation of the intermetallic compound and this phase was broken in to small particles during extrusion. The ultimate strength and elongation of the as-extruded Al-0.15Si-0.2Fe-0.3Cu- 0.9Mn alloy were 96.51 MPa and 34.01%, while those of the Al-0.15Si-0.2Fe-0.3Cu-0.9Mn-0.3Zn alloy were 99.08 MPa and 36.21%, respectively. Al-0.15Si-0.2Fe-0.3Cu-0.9Mn alloys with Zn addition resulted in improving the strength with no reduction in elongation.

Microstructure and texture of P-type 75%Sb₂Te₃-25%Bi₂Te₃ alloy fabricated by using gas-atomization and extrusion processes was investigated. The microstructure of the gas-atomized powders exhibited fine grains with needle shape. After hot extrusion, grain size was characterized by fine and equiaxed grains due to dynamic recrystallization by severe deformation. (0001) basal planes of the extruded specimens were preferentially orientated parallel to extrusion direction. As extrusion temperature, fraction of the basal planes was increased.

The utilization of large amounts of volatile organic solvents and the complicated process required for industrial manufacturing of ion-exchange membranes necessitate the development of simple, rapid, and environmentally friendly fabrication methods such as those based on photopolymerization. We employed hydrolytic sol–gel reactions between ammonium- and acrylamide-functionalized silane coupling agents to synthesize water-soluble siloxane resins that exhibit high condensation levels (>80%) and comprise oligomers with molecular weights below 2000 Da. These resins were then mixed with a hydrophilic monomer bearing ammonium and acrylamide groups, and porous polyethylene substrates were impregnated with the resulting mixtures and then irradiated with ultraviolet light. The hydrophilicity, mechanical strength, and other properties of the resulting membranes depended on the resin composition, indicating that the substrate pores were efficiently filled with the prepared resins and further suggesting that the membrane performance could be effectively altered by varying the resin composition. Moreover, the obtained membranes exhibited chemical stability in the pH range between 0 and 11 and in hot water at 60 °C. The reverse electrodialysis stack consisting of these membranes showed higher power density than a stack of commercial membranes. Therefore, it can be concluded that without employing volatile organic solvents for reverse electrodialysis, the developed technique is well-suited for the fabrication of ion-exchange membranes.

A typical aircraft engine consists of fans, compressors, turbines, and so on, and each is made of multiple layers of blades. Discovering the site of damages among the large number of blades during aircraft engine maintenance is quite important. However, it is impossible to look directly into the engine unless it is disassembled. For this reason, optical equipment such as a videoscope is used to visually inspect the blades of an engine through inspection holes. The videoscope inspection method has some obvious drawbacks such as the long-time attention on microscopic video feed and high labor intensity. In this research, we developed a damage recognition algorithm using convolutional neural networks and some image-processing techniques related to feature point extraction and matching in order to improve the videoscope inspection method. The image-processing techniques were mainly used for the preprocessing of the videoscope images, from which a suspected damaged region is selected after the preprocessing. The suspected region is finally classified as damaged or normal by the pre-trained convolutional neural networks. We trained the convolutional neural networks 2000 times by using data from 380 images and calculated the classification accuracy using data from 40 images. After repeating the above procedure 50 times with the data randomly divided into training and test groups, an average classification accuracy of 95.2% for each image and a damage detectability of 100% in video were obtained. For verification of the proposed approach, the convolutional neural network part was compared with the traditional neural network, and the preprocessing was compared with the region proposal network of the faster region–based convolutional neural networks. In addition, we developed a platform based on the developed damage recognition algorithm and conducted field tests with a videoscope for a real engine. The damage detection AI platform was successfully applied to the inspection video probed in an in-service engine.

This paper shows that just taking a picture of the carbon preform can be a powerful detection method of missing rod. The poor quality of the carbon preforms including missing rods cannot provide ta...

Purpose This study aimed to compare the oncologic and short-term outcomes of laparoscopic distal gastrectomy (LDG) and open distal gastrectomy (ODG) for advanced gastric cancer (AGC). Materials and methods From July 2006 to November 2016, 384 patients underwent distal gastrectomy for AGC. Data on short- and long-term outcomes were prospectively collected and reviewed. Propensity score matching was applied at a ratio of 1:1 to compare the LDG and ODG groups. Results The operative times were longer for the LDG group than for the ODG group. However, the time to resumption of diet and the length of hospital stay were shorter in the LDG group than in the ODG group (4.7 vs. 5.6 days, P=0.049 and 9.6 vs. 11.5 days, P=0.035, respectively). The extent of lymph node dissection in the LDG group was more limited than in the ODG group (P=0.002), although there was no difference in the number of retrieved lymph nodes between the 2 groups. The 3-year overall survival rates were 98% and 86.9% (P=0.018), and the 3-year recurrence-free survival rates were 86.3% and 75.3% (P=0.259), respectively, in the LDG and ODG groups. Conclusions LDG is safe and feasible for AGC, with earlier recovery after surgery and long-term oncologic outcomes comparable to those of ODG.

Wearable displays are considered as a bilateral communication tool in the hyperconnected era. Although several electronic clothing display was demonstrated, high power consumption issue still remained. Here, we present wireless powered wearable μLEDs (WμLEDs) with excellent stability. A custom-designed wireless power supply system operated a 30 × 30 WμLED array on a fabric. The WμLED stability was intensively investigated under bending, stretching, 85 °C/85% relative humidity and artificial sunlight conditions, showing the suitability of WμLED outdoor usage. Finally, a passive-matrix WμLED display successfully emitted a brilliant red glow on a fabric.

Wildland fire emissions cause adverse cardiopulmonary outcomes, yet controlled exposure studies to characterize health impacts of specific biomass sources have been complicated by the often latent effects of air pollution. The aim of this study was to determine if postprandial responses after a high fat challenge, long used clinically to predict cardiovascular risk, would unmask latent cardiometabolic responses in rats exposed to peat smoke, a key wildland fire air pollution source. Male Wistar Kyoto rats were exposed once (1 h) to filtered air (FA), or low (0.36 mg/m3 particulate matter) or high concentrations (3.30 mg/m3) of peat smoke, generated by burning peat from an Irish bog. Rats were then fasted overnight, and then administered an oral gavage of a HF suspension (60 kcal% from fat), mimicking a HF meal, 24 h post-exposure. In one cohort, cardiac and superior mesenteric artery function were assessed using high frequency ultrasound 2 h post gavage. In a second cohort, circulating lipids and hormones, pulmonary and systemic inflammatory markers, and circulating monocyte phenotype using flow cytometry were assessed before or 2 or 6 h after gavage. HF gavage alone elicited increases in circulating lipids characteristic of postprandial responses to a HF meal. Few effects were evident after peat exposure in un-gavaged rats. By contrast, exposure to low or high peat caused several changes relative to FA-exposed rats 2 and 6 h post HF gavage including increased heart isovolumic relaxation time, decreased serum glucose and insulin, increased CD11 b/c-expressing blood monocytes, increased serum total cholesterol, alpha-1 acid glycoprotein, and alpha-2 macroglobulin (p = 0.063), decreased serum corticosterone, and increased lung gamma-glutamyl transferase. In summary, these findings demonstrate that a HF challenge reveals effects of air pollution that may otherwise be imperceptible, particularly at low exposure levels, and suggest exposure may sensitize the body to mild inflammatory triggers.

Human exposure to wildfire-derived particulate matter (PM) is linked to adverse health outcomes; however, little is known regarding the influence of biomass fuel type and burn conditions on toxicity. The aim of this study was to assess the irritant potential of extractable organic material (EOM) of biomass smoke condensates from 5 fuels (Eucalyptus, Pine, Pine Needle, Peat, or Red Oak), representing various fire-prone regions of the USA, burned at two temperatures each [flaming ( approximately 640° C) or (smoldering approximately 500° C)] using a locomotor assay in zebrafish (Danio rerio) larvae. It was postulated that locomotor responses as measures of irritant effects, might be dependent up on fuel type and burn conditions and that these differences relate to combustion byproduct chemistry. To test this, locomotor activity was tracked for 60 min in 6-day old zebrafish larvae (25–32/group) immediately after exposure to 0.4% dimethyl sulfoxide (DMSO) vehicle or EOM from the biomass smoke condensates (0.3–30 μg EOM/ml; half-log intervals). All EOM samples produced concentration-dependent irritant responses. Linear regression analysis to derive rank-order potency indicated that on a μg PM basis, flaming Pine and Eucalyptus were the most irritating. In contrast, on an emission-factor basis, which normalizes responses to the amount of PM produced/kg of fuel burned, smoldering smoke condensates induced greater irritant responses (>100-fold) than flaming smoke condensates, with smoldering Pine being the most potent. Importantly, irritant responses significantly correlated with polycyclic aromatic hydrocarbons (PAH) content, but not with organic carbon or methoxyphenols. Data indicate that fuel type and burn condition influence the quantity and chemical composition of PM as well as toxicity.

Background/aim To present the variations in the target delineation and the planning results of intensity-modulated radiation therapy (IMRT) for breast cancers. Patients and methods We requested the target volumes and organs at risk delineation for two cases of left breast cancers, and evaluated the IMRT plans including the supraclavicular and internal mammary node irradiation. Results Twenty-one institutions participated in this study. Differences in the planning target volume among institutions reached up to three-times for breast-conserving surgery (BCS) case and five-times for mastectomy case. Mean heart doses ranged from 3.3 to 24.1 Gy for BCS case and from 5.0 to 26.5 Gy for mastectomy case. Ipsilateral lung volumes receiving more than 20 Gy ranged from 4.7 to 57.4% for BCS case and from 16.4 to 55.5% for mastectomy case. Conclusion There were large variations in the target delineation and planning results of IMRT for breast cancers among institutions. Considering the increased use of breast IMRT, more standardized protocols are needed.

Primary rat alveolar epithelial cell monolayers (RAECM) were grown without (type I cell-like phenotype, RAECM-I) or with (type II cell-like phenotype, RAECM-II) keratinocyte growth factor to assess passive transport of 11 hydrophilic solutes. We estimated apparent permeability (Papp) in the absence/presence of calcium chelator EGTA to determine the effects of perturbing tight junctions on “equivalent” pores. Papp across RAECM-I and -II in the absence of EGTA are similar and decrease as solute size increases. We modeled Papp of the hydrophilic solutes across RAECM-I/-II as taking place via heterogeneous populations of equivalent pores comprised of small (0.41/0.32 nm radius) and large (9.88/11.56 nm radius) pores, respectively. Total equivalent pore area is dominated by small equivalent pores (99.92–99.97%). The number of small and large equivalent pores in RAECM-I was 8.55 and 1.29 times greater, respectively, than those in RAECM-II. With EGTA, the large pore radius in RAECM-I/-II increased by 1.58/4.34 times and the small equivalent pore radius increased by 1.84/1.90 times, respectively. These results indicate that passive diffusion of hydrophilic solutes across an alveolar epithelium occurs via small and large equivalent pores, reflecting interactions of transmembrane proteins expressed in intercellular tight junctions of alveolar epithelial cells.

In this study, microstructure and sintering behaviors of the gas-atomized Al-(25 or 30) Cr-xSi alloy (

BACKGROUND: Growing evidence suggests that metastasis-directed therapy and/or prostate-directed therapy may benefit patients with oligometastatic prostate cancer (OMPC). Stereotactic body radiotherapy (SBRT) is increasingly used to treat oligometastases in various cancers. The purpose of this study was to investigate the current patterns of curative-intent SBRT for OMPC in Korea. METHODS: A 20-item questionnaire was sent to 326 radiation oncologists in 93 institutions in Korea. Only 1 physician per institution was required to complete the survey. Subsequently, the second survey consisting of 3 clinical scenarios was sent to 64 physicians with clinical experience in SBRT: case 1, cT4N0M1 (direct invasion to two pelvic bones); case 2, cT2N0M1 (three bone metastases); and case 3, solitary spine metastasis after radical prostatectomy. RESULTS: Seventy-six physicians from 93 institutions (82%) answered the first survey. The multidisciplinary team approach was practiced in 16 institutions (21%). Most physicians (75%) agreed on the definition of oligometastases as limited lesions and/or organs ≤5: 25% agreed with low-volume disease according to CHAARTED trial. During the last year, 49 physicians (64%) treated OMPC patients with curative intent. Sixty four physicians (84%) had a clinical experience with SBRT: 48 (75%) stated that both dose and fraction number should be considered when defining SBRT, whereas others (25%) stated that only fraction size should be considered. Fifty-five faculties (86%) answered the second survey. Physicians agreed with oligometastases in 89% for case 1, in 80% for case 2, and in 100% for case 3. The rate of SBRT application was the highest in case 3 (70%). CONCLUSIONS: There was diversity in the patterns of SBRT for OMPC in Korea. Additional prospective studies are necessary to strengthen evidence regarding role of SBRT in OMPC.

Chemotherapy-induced neuropathic pain (CINP) is a severe adverse effect of platinum- and taxane-derived anticancer drugs. The pathophysiology of CINP includes damage to neuronal networks and dysregulation of signal transduction due to abnormal Ca2+ levels. Therefore, methods that aid the recovery of neuronal networks could represent a potential treatment for CINP. We developed a mouse model of paclitaxel-induced peripheral neuropathy, representing CINP, to examine whether intrathecal injection of decursin could be effective in treating CINP. We found that decursin reduced capsaicin-induced intracellular Ca2+ levels in F11 cells and stimulated neurite outgrowth in a concentration-dependent manner. Decursin directly reduced mechanical allodynia, and this improvement was even greater with a higher frequency of injections. Subsequently, we investigated whether decursin interacts with the transient receptor potential vanilloid 1 (TRPV1). The web server SwissTargetPrediction predicted that TRPV1 is one of the target proteins that may enable the effective treatment of CINP. Furthermore, we discovered that decursin acts as a TRPV1 antagonist. Therefore, we demonstrated that decursin may be an important compound for the treatment of paclitaxel-induced neuropathic pain that functions via TRPV1 inhibition and recovery of damaged neuronal networks.

Transient receptor potential (TRP) channels are transmembrane protein complexes that play important roles in the physiology and pathophysiology of both the central nervous system (CNS) and the peripheral nerve system (PNS). TRP channels function as non-selective cation channels that are activated by several chemical, mechanical, and thermal stimuli as well as by pH, osmolarity, and several endogenous or exogenous ligands, second messengers, and signaling molecules. On the pathophysiological side, these channels have been shown to play essential roles in the reproductive system, kidney, pancreas, lung, bone, intestine, as well as in neuropathic pain in both the CNS and PNS. In this context, TRP channels have been implicated in several neurological disorders, including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, and epilepsy. Herein, we focus on the latest involvement of TRP channels, with a special emphasis on the recently identified functional roles of TRP channels in neurological disorders related to the disruption in calcium ion homeostasis.

Microstructure and properties of Al–2 wt.%Zn–1 wt.%Cu–xMg (x = 0.1, 0.3, 0.5, 0.7 wt.%) alloy extrusion materials were investigated. The lattice constants for the (311) plane increased to 4.046858, 4.048483, 4.050114 and 4.051149 Å with the addition of 0.1, 0.3, 0.5, and 0.7 wt.% of elemental Mg. The average grain size of the as-extruded Al alloys was found to be 328.7, 297.7, 187.0 and 159.3 μm for the alloys with 0.1, 0.3, 0.5, and 0.7 wt.% Mg content, respectively. The changes in the electrical conductivity by the addition of elemental Mg in Al–2 wt.%Zn–1 wt.%Cu alloy was determined, and it was found that for the addition of 0.1, 0.3, 0.5, and 0.7 wt.% Mg, the conductivity decreased to 51.62, 49.74, 48.26 and 46.80 %IACS. The ultimate tensile strength of Al–2 wt.%Zn–1 wt.%Cu–0.7 wt.%Mg alloy extrusion was increased to 203.55 MPa. Thus, this study demonstrated the correlation between the electrical conductivity and strength for the Al–2 wt.%Zn–1 wt.%Cu–xMg alloys.

The effect of addition of Mischmetal (MM) on the microstructure, electrical and thermal conductivity, and mechanical properties of the as-extruded Al-MM based alloys were investigated. The studied Al

Exposure to wildfire smoke continues to be a growing threat to public health, yet the chemical components in wildfire smoke that primarily drive toxicity and associated disease are largely unknown. This study utilized a suite of computational approaches to identify groups of chemicals induced by variable biomass burn conditions that were associated with biological responses in the mouse lung, including pulmonary immune response and injury markers. Smoke condensate samples were collected and characterized, resulting in chemical distribution information for 86 constituents across ten different exposures. Mixtures-relevant statistical methods included (i) a chemical clustering and data-reduction method, weighted chemical co-expression network analysis (WCCNA), (ii) a quantile g-computation approach to address the joint effect of multiple chemicals in different groupings, and (iii) a correlation analysis to compare mixtures modeling results against individual chemical relationships. Seven chemical groups were identified using WCCNA based on co-occurrence showing both positive and negative relationships with biological responses. A group containing methoxyphenols (e.g., coniferyl aldehyde, eugenol, guaiacol, and vanillin) displayed highly significant, negative relationships with several biological esponses, including cytokines and lung injury markers. This group was further shown through quantile g-computation methods to associate with reduced biological responses. Specifically, mixtures modeling based on all chemicals excluding those in the methoxyphenol group demonstrated more significant, positive relationships with several biological responses; whereas mixtures modeling based on just those in the methoxyphenol group demonstrated significant negative relationships with several biological responses, suggesting potential protective effects. Mixtures-based analyses also identified other groups consisting of inorganic elements and ionic constituents showing positive relationships with several biological responses, including markers of inflammation. Many of the effects identified through mixtures modeling in this analysis were not captured through individual chemical analyses. Together, this study demonstrates the utility of mixtures-based approaches to identify potential drivers and inhibitors of toxicity relevant to wildfire exposures., Graphical Abstract

Chronic pain is a serious condition that occurs in the peripheral nervous system (PNS) and the central nervous system (CNS). It is caused by inflammation or nerve damage that induces the release of inflammatory mediators from immune cells and/or protein kinase activation in neuronal cells. Both nervous systems are closely linked; therefore, inflammation or nerve damage in the PNS can affect the CNS (central sensitization). In this process, nociceptive transient receptor potential (TRP) channel activation and expression are increased. As a result, nociceptive neurons are activated, and pain signals to the brain are amplified and prolonged. In other words, suppressing the onset of pain signals in the PNS can suppress pain signals to the CNS. Resolvins, endogenous lipid mediators generated during the resolution phase of acute inflammation, inhibit nociceptive TRP ion channels and alleviate chronic pain. This paper summarizes the effect of resolvins in chronic pain control and discusses future scientific perspectives. Further study on the effect of resolvins on neuropathic pain will expand the scope of pain research.

Dysregulation of calcium ion homeostasis and abnormal protein aggregation have been proposed as major pathogenic hallmarks underpinning selective degeneration of motor neurons in amyotrophic lateral sclerosis (ALS). Recently, mutations in annexin A11 (ANXA11), a gene encoding a Ca2+-dependent phospholipid-binding protein, have been identified in familial and sporadic ALS. However, the physiological and pathophysiological roles of ANXA11 remain unknown. Here, we report functions of ANXA11 related to intracellular Ca2+ homeostasis and stress granule dynamics. We analyzed the exome sequences of 500 Korean patients with sALS and identified nine ANXA11 variants in 13 patients. The amino-terminal variants p.G38R and p.D40G within the low-complexity domain of ANXA11 enhanced aggregation propensity, whereas the carboxyl-terminal ANX domain variants p.H390P and p.R456H altered Ca2+ responses. Furthermore, all four variants in ANXA11 underwent abnormal phase separation to form droplets with aggregates and led to the alteration of the biophysical properties of ANXA11. These functional defects caused by ALS-linked variants induced alterations in both intracellular Ca2+ homeostasis and stress granule disassembly. We also revealed that p.G228Lfs*29 reduced ANXA11 expression and impaired Ca2+ homeostasis, as caused by missense variants. Ca2+-dependent interaction and coaggregation between ANXA11 and ALS-causative RNA-binding proteins, FUS and hnRNPA1, were observed in motor neuron cells and brain from a patient with ALS-FUS. The expression of ALS-linked ANXA11 variants in motor neuron cells caused cytoplasmic sequestration of endogenous FUS and triggered neuronal apoptosis. Together, our findings suggest that disease-associated ANXA11 mutations can contribute to ALS pathogenesis through toxic gain-of-function mechanisms involving abnormal protein aggregation.

Wildland fires (WF) are linked to adverse health impacts related to poor air quality. The cardiovascular impacts of emissions from specific biomass sources, however, are unknown. The purpose of this study was to assess the cardiovascular impacts of a single exposure to peat smoke, a key regional WF air pollution source, and relate these to baroreceptor sensitivity and inflammation. Three-month-old male Wistar-Kyoto rats, implanted with radiotelemeters for continuous monitoring of heart rate (HR), blood pressure (BP), and spontaneous baroreflex sensitivity (BRS), were exposed once, for 1-hr, to filtered air or low (0.38 mg/m(3) PM) or high (4.04 mg/m(3)) concentrations of peat smoke. Systemic markers of inflammation and sensitivity to aconitine-induced cardiac arrhythmia, a measure of latent myocardial vulnerability, were assessed in separate cohorts of rats 24 hr after exposure. PM size (low peat = 0.4 – 0.5 microns vs. high peat = 0.8 – 1.2 microns) and proportion of organic carbon (low peat = 77% vs. high peat = 65%) varied with exposure level. Exposure to high peat and to a lesser extent low peat increased systolic and diastolic BP relative to filtered air. By contrast, only exposure to low peat elevated BRS and aconitine-induced arrhythmogenesis relative to filtered air and increased circulating levels of low-density lipoprotein cholesterol, complement components C3 and C4, angiotensin converting enzyme (ACE), and white blood cells. Taken together, exposure to peat smoke produced overt and latent cardiovascular consequences that were likely influenced by physicochemical characteristics of the smoke and associated adaptive homeostatic mechanisms.

Local anesthetics (LAs) can completely block nociception by inhibiting voltage-gated sodium channels (VGSCs), and thus, blocking action potentials (APs) within sensory neurons. As one of the several LAs, eugenol is used for dental pain treatment. It reportedly features multiple functions in regulating diverse ion channels. This study aimed to investigate the long-lasting analgesic effect of eugenol alone, as well as that of the combination of eugenol as a noxious-heat-sensitive transient receptor potential vanilloid 1 (TRPV1) channel agonist and a permanently charged sodium channel blocker (QX-314), on neuronal excitability in trigeminal ganglion (TG) neurons. Eugenol alone increased inward current in a dose-dependent manner in capsaicin-sensitive TG neurons. Eugenol also inhibited the VGSC current and AP. These effects were reversed through wash-out. The combination of eugenol and QX-314 was evaluated in the same manner. The combination completely inhibited the VGSC current and AP. However, these effects were not reversed and were continuously blocked even after wash-out. Taken together, our results suggest that, in contrast to the effect of eugenol alone, the combination of eugenol and QX-314 irreversibly and selectively blocked VGSCs in TG neurons expressing TRPV1.

Neuropathic pain caused by lesions or nervous system dysfunction is a neuroimmune disease with limited therapeutic options. Adipose tissue-derived stem cells (ASCs) are multipotent mesenchymal stem cells with potent immunosuppressive properties, and their use as novel cell-based therapeutics have been proposed in many immune diseases. However, the analgesic effect and efficacy of ASCs to treat neuropathic pain remain unclear. This study, thus, investigated whether ASCs or ASC-derived culture medium can relieve neuropathic pain behaviors (i.e., mechanical and cold allodynia) in a rat model with L5 spinal nerve ligation. Intrathecal injection of ASCs significantly reduced cold allodynia, but not mechanical allodynia. Importantly, cold allodynia was completely reversed in rats with repeated injections of ASCs. In contrast, intrathecal injection of ASC-derived culture medium or retro-orbital injection of ASCs had no effect on neuropathic pain behaviors. These results suggest a novel and alternative therapeutic application of ASCs to target specific neuropathic pain behaviors.

Since the global outbreak of SARS-CoV-2 (COVID-19), infections of diverse human organs along with multiple symptoms continue to be reported. However, the susceptibility of the brain to SARS-CoV-2, and the mechanisms underlying neurological infection are still elusive. Here, we utilized human embryonic stem cell-derived brain organoids and monolayer cortical neurons to investigate infection of brain with pseudotyped SARS-CoV-2 viral particles. Spike-containing SARS-CoV-2 pseudovirus infected neural layers within brain organoids. The expression of ACE2, a host cell receptor for SARS-CoV-2, was sustained during the development of brain organoids, especially in the somas of mature neurons, while remaining rare in neural stem cells. However, pseudotyped SARS-CoV-2 was observed in the axon of neurons, which lack ACE2. Neural infectivity of SARS-CoV-2 pseudovirus did not increase in proportion to viral load, but only 10% of neurons were infected. Our findings demonstrate that brain organoids provide a useful model for investigating SARS-CoV-2 entry into the human brain and elucidating the susceptibility of the brain to SARS-CoV-2.

OBJECTIVE: Previous studies have shown that air pollution exposure primes the body to heightened responses to everyday stressors of the cardiovascular system. The purpose of this study was to examine the utility of postprandial responses to a high carbohydrate oral load, a cardiometabolic stressor long used to predict cardiovascular risk, in assessing the impacts of exposure to eucalyptus smoke (ES), a contributor to wildland fire air pollution in the Western coast of the United States. MATERIALS AND METHODS: Three-month-old male Sprague Dawley rats were exposed once (1 hr) to filtered air (FA) or ES (700 μg/m(3) fine particulate matter), generated by burning eucalyptus in a tube furnace. Rats were then fasted for six hours the following morning, and subsequently administered an oral gavage of either water or a HC suspension (70 kcal% from carbohydrate), mimicking a HC meal. Two hours post gavage, cardiovascular ultrasound, cardiac pressure-volume (PV), and baroreceptor sensitivity assessments were made, and pulmonary and systemic markers assessed. RESULTS: ES inhalation alone increased serum interleukin (IL)-4 and nasal airway levels of gamma glutamyl transferase. HC gavage alone increased blood glucose, blood pressure, and serum IL-6 and IL-13 compared to water vehicle. By contrast, only ES-exposed and HC-challenged animals had increased PV loop measures of cardiac output, stroke volume, ejection fraction %, dP/dt(max), dP/dt(min), and stroke work compared to ES exposure alone and/or HC challenge alone. DISCUSSION AND CONCLUSIONS: Exposure to model wildfire air pollution modifies cardiovascular responses to HC challenge, suggesting air pollution sensitizes the body to systemic triggers.

Brain disorders include neurodegenerative diseases (NDs) with different conditions that primarily affect the neurons and glia in the brain. However, the risk factors and pathophysiological mechanisms of NDs have not been fully elucidated. Homeostasis of intracellular Ca2+ concentration and intracellular pH (pHi) is crucial for cell function. The regulatory processes of these ionic mechanisms may be absent or excessive in pathological conditions, leading to a loss of cell death in distinct regions of ND patients. Herein, we review the potential involvement of transient receptor potential (TRP) channels in NDs, where disrupted Ca2+ homeostasis leads to cell death. The capability of TRP channels to restore or excite the cell through Ca2+ regulation depending on the level of plasma membrane Ca2+ ATPase (PMCA) activity is discussed in detail. As PMCA simultaneously affects intracellular Ca2+ regulation as well as pHi, TRP channels and PMCA thus play vital roles in modulating ionic homeostasis in various cell types or specific regions of the brain where the TRP channels and PMCA are expressed. For this reason, the dysfunction of TRP channels and/or PMCA under pathological conditions disrupts neuronal homeostasis due to abnormal Ca2+ and pH levels in the brain, resulting in various NDs. This review addresses the function of TRP channels and PMCA in controlling intracellular Ca2+ and pH, which may provide novel targets for treating NDs.