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The authors find that the insulin receptor forms dynamic clusters during insulin signaling and that these clusters become dysfunctional in insulin resistance. This dysfunction is partially rescued by metformin, a drug used to treat type 2 diabetes.

Elie Zouein,1 Robert Wetz,1 Neville Mobarakai,1 Samer Hassan,1 Iris Tong21Department of Medicine, Staten Island University Hospital, New York, NY USA; 2Department of Medicine, Warren Alpert Medical School of Brown University, Providence, RI, USAAbstract: Primary aortic graft infection early after aortic graft insertion is well described in the literature. Here, we present a unique case of late aortic graft infection 5 years after insertion secondary to mitral valve endocarditis, resulting from cellulitis in a patient with severe venous varicosities. A 63-year-old male presented for severe low back pain, constipation, and low-grade fever. An abdominal computed tomography scan with oral and intravenous contrast showed a normal spine and urinary tract. Blood and urine cultures, done at the same time, grew Staphylococcus aureus. A transesophageal echocardiogram confirmed the diagnosis of endocarditis. Subsequently, a gallium scan showed increased uptake in the vertebral bodies, aortic graft, left patella, and left ankle. After 3 months of antibiotic therapy, the patient's low back pain resolved with normalization of his laboratory values. He remained free of infection at a 2-year follow-up. We reviewed the literature concerning the atypical presentation of infective endocarditis, with a focus on distant metastases at initial presentation, such as osteomyelitis and aortic graft infection, as well as the different treatment modalities. This report describes successful medical treatment with intravenous followed by oral antibiotics for an infected endovascular graft without any surgical intervention.Keywords: endocarditis, osteomyelitis, aortic graft infection, septic emboli, endovascular abdominal aortic aneurysm repair (EVAR)

Insulin receptor (IR) signaling is central to normal metabolic control and is dysregulated in metabolic diseases such as type 2 diabetes. We report here that IR is incorporated into dynamic clusters at the plasma membrane, in the cytoplasm and in the nucleus of human hepatocytes and adipocytes. Insulin stimulation promotes further incorporation of IR into these dynamic clusters in insulin-sensitive cells but not in insulin-resistant cells, where both IR accumulation and dynamic behavior are reduced. Treatment of insulin-resistant cells with metformin, a first-line drug used to treat type 2 diabetes, can rescue IR accumulation and the dynamic behavior of these clusters. This rescue is associated with metformin's role in reducing reactive oxygen species that interfere with normal dynamics. These results indicate that changes in the physico-mechanical features of IR clusters contribute to insulin resistance and have implications for improved therapeutic approaches. The authors find that the insulin receptor forms dynamic clusters during insulin signaling and that these clusters become dysfunctional in insulin resistance. This dysfunction is partially rescued by metformin, a drug used to treat type 2 diabetes. [ABSTRACT FROM AUTHOR]

This study expands the literature on senior tourism in Asia by investigating buying preferences, behaviors and accessibility barriers of seniors visiting integrated resorts (IRs). In-depth interviews were conducted with 17 seniors and 8 companions of seniors who had visited integrated resorts in Macao. Results indicated Chinese seniors usually visited IRs with family, and seniors were price sensitive. Respondents experienced both environmental barriers and poor service quality, which negatively affected their experiences. This study clarifies preferences and difficulties of senior travelers visiting integrated resorts and argues that difficulties are mainly due to IR design. Recommendations are provided to improve facilities and service quality for older visitors in large-scale tourism facilities. [ABSTRACT FROM AUTHOR]

An abnormal structure of the ZnSe nanowheels composed of teethlike extended patterns on nanoring bases has been successfully synthesized by thermal evaporation method. It is interesting to note that the as-synthesized ZnSe nanowheels are metastable wurtzite phase with the dominant exposed surfaces of [formula] while the stable ZnSe is typically zinc blende phase. A full picture of the growth mechanism of the metastable wurtzite phase ZnSe nanostructures will be proposed from the thermodynamic point of view. Meanwhile, the formation of the nanowheels is also explained by a two-stage mechanism. In the first stage, the base of the nanowheel begins to form by vapor-solid mechanism, while in the second stage, the teethlike extended structures grow through the self-catalyzed growth process. The cathodoluminescence spectrum of ZnSe nanowheel exhibited a band edge transition at about 460 nm and a strong self-activated luminescence at 610 nm. It is important to note that the discussions of the nanostructure thermodynamics and stability can be applied to understand the growth mechanism of other nanostructures which are critical for optimization of the nanostructures. [ABSTRACT FROM AUTHOR]

An abnormal structure of the ZnSe nanowheels composed of teethlike extended patterns on nanoring bases is synthesized by thermal evaporation method. The results have shown that the surface energy has played a vital role in the existence of wurtite ZnSe nanostructures, which are applied for the controlled synthesis of stable wurtzite ZnSe nanostructures.

Byline: G. Schultz, I. Tong, K. Kefauver, J. Ishibashi This paper introduces the US Army Roadway Simulator and discusses steering and handling test results from this laboratory-based vehicle dynamics test facility. The basic components and operating principles are briefly described, followed by discussion of steady-state and transient steering test results for two-axle vehicles up to 25,300 pound gross vehicle weight. First, the ability of the Roadway Simulator to measure vehicle understeer gradient and peak cornering capability during skidpad tests is presented. Next, the ability to perform transient steer manoeuvre tests, such as the US National Highway Traffic Safety Administration's (NHTSA's) fishhook test and sine steer tests, is discussed.

Conductivity tensor imaging (CTI) using MRI is an advanced method that can non-invasively measure the electrical properties of living tissues. The contrast of CTI is based on underlying hypothesis about the proportionality between the mobility and diffusivity of ions and water molecules inside tissues. The experimental validation of CTI in both in vitro and in vivo settings is required as a reliable tool to assess tissue conditions. The changes in extracellular space can be indicators for disease progression, such as fibrosis, edema, and cell swelling. In this study, we conducted a phantom imaging experiment to test the feasibility of CTI for measuring the extracellular volume fraction in biological tissue. To mimic tissue conditions with different extracellular volume fractions, four chambers of giant vesicle suspension (GVS) with different vesicle densities were included in the phantom. The reconstructed CTI images of the phantom were compared with the separately-measured conductivity spectra of the four chambers using an impedance analyzer. Moreover, the values of the estimated extracellular volume fraction in each chamber were compared with those measured by a spectrophotometer. As the vesicle density increased, we found that the extracellular volume fraction, extracellular diffusion coefficient, and low-frequency conductivity decreased, while the intracellular diffusion coefficient slightly increased. On the other hand, the high-frequency conductivity could not clearly distinguish the four chambers. The extracellular volume fraction measured by the spectrophotometer and CTI method in each chamber were quite comparable, i.e., (1.00, 0.98 ± 0.01), (0.59, 0.63 ± 0.02), (0.40, 0.40 ± 0.05), and (0.16, 0.18 ± 0.02). The prominent factor influencing the low-frequency conductivity at different GVS densities was the extracellular volume fraction. Further studies are needed to validate the CTI method as a tool to measure the extracellular volume fractions in living tissues with different intracellular and extracellular compartments.

This study aims to find base materials for dry electrode fabrication with high accuracy and without reducing electrode performance for long-term bioelectric potential monitoring after electroless silver plating. Most applications of dry electrodes that have been developed in the past few decades are restricted by low accuracy compared to commercial Ag/AgCl gel electrodes, as in our previous study of PVDF-based dry electrodes. In a recent study, however, nanoweb-based chlorinated polyisoprene (CPI) and poly(styrene-b-butadiene-b-styrene) (SBS) rubber were selected as promising candidates due to their excellent elastic properties, as well as their nanofibril nature, which may improve electrode durability and skin contact. The electroless silver plating technique was employed to coat the nanofiber web with silver, and silver nanoweb(AgNW)-based dry electrodes were fabricated. The key electrode properties (contact impedance, step response, and noise characteristics) for AgNW dry electrodes were investigated thoroughly using agar phantoms. The dry electrodes were subsequently tested on human subjects to establish their realistic performance in terms of ECG, EMG monitoring, and electrical impedance tomography (EIT) measurements. The experimental results demonstrated that the AgNW dry electrodes, particularly the SBS-AgNW dry electrodes, performed similarly to commercial Ag/AgCl gel electrodes and were outperformed in terms of long-term stability.

Abstract The importance of perioperative respiration monitoring is highlighted by high incidences of postoperative respiratory complications unrelated to the original disease. The objectives of this pilot study were to (1) simultaneously acquire respiration rate (RR), tidal volume (TV), minute ventilation (MV), SpO2 and PetCO2 from patients in post-anesthesia care unit (PACU) and (2) identify a practical continuous respiration monitoring method by analyzing the acquired data in terms of their ability and reliability in assessing a patient’s respiratory status. Thirteen non-intubated patients completed this observational study. A portable electrical impedance tomography (EIT) device was used to acquire RREIT, TV and MV, while PetCO2, RRCap and SpO2 were measured by a Capnostream35. Hypoventilation and respiratory events, e.g., apnea and hypopnea, could be detected reliably using RREIT, TV and MV. PetCO2 and SpO2 provided the gas exchange information, but were unable to detect hypoventilation in a timely fashion. Although SpO2 was stable, the sidestream capnography using the oronasal cannula was often unstable and produced fluctuating PetCO2 values. The coefficient of determination (R2) value between RREIT and RRCap was 0.65 with a percentage error of 52.5%. Based on our results, we identified RR, TV, MV and SpO2 as a set of respiratory parameters for robust continuous respiration monitoring of non-intubated patients. Such a respiration monitor with both ventilation and gas exchange parameters would be reliable and could be useful not only for respiration monitoring, but in making PACU discharge decisions and adjusting opioid dosage on general hospital floor. Future studies are needed to evaluate the potential clinical utility of such an integrated respiration monitor.

Electrical impedance tomography (EIT) can monitor the real-time hemodynamic state of a conscious and spontaneously breathing patient noninvasively. However, cardiac volume signal (CVS) extracted from EIT images has a small amplitude and is sensitive to motion artifacts (MAs). This study aimed to develop a new algorithm to reduce MAs from the CVS for more accurate heart rate (HR) and cardiac output (CO) monitoring in patients undergoing hemodialysis based on the source consistency between the electrocardiogram (ECG) and the CVS of heartbeats. Two signals were measured at different locations on the body through independent instruments and electrodes, but the frequency and phase were matched when no MAs occurred. A total of 36 measurements with 113 one-hour sub-datasets were collected from 14 patients. As the number of motions per hour (MI) increased over 30, the proposed algorithm had a correlation of 0.83 and a precision of 1.65 beats per minute (BPM) compared to the conventional statical algorithm of a correlation of 0.56 and a precision of 4.04 BPM. For CO monitoring, the precision and upper limit of the mean ∆CO were 3.41 and 2.82 L per minute (LPM), respectively, compared to 4.05 and 3.82 LPM for the statistical algorithm. The developed algorithm could reduce MAs and improve HR/CO monitoring accuracy and reliability by at least two times, particularly in high-motion environments.

Jingtao Tong III,1,* Yifei Mao,2,* Ziru Yang,1 Quan Xu,1 Zhen Zheng,1 Hui Zhang,1 Jingjing Wang,1 Sandian Zhang,1 Weibo Rong,3 Lu Zheng III1 1Department of Radiation Oncology, Ningbo Medical Treatment Center Li Huili Hospital, Ningbo, 315040, People’s Republic of China; 2Department of Emergency Medicine, Ninghai First Hospital, Ningbo, 315600, People’s Republic of China; 3Department of Pharmacy, Ningbo Medical Treatment Center Li Huili Hospital, Ningbo, 315040, People’s Republic of China*These authors contributed equally to this workCorrespondence: Lu ZhengDepartment of Radiation Oncology, Ningbo Medical Treatment Center Li Huili Hospital, No. 57, Xing Ning Road, Yinzhou District, Ningbo, 315040, People’s Republic of ChinaTel +86 13486688768Fax +86 574 83872180Email zhenglu2008@139.comPurpose: Although predictive markers of immune checkpoint inhibitor (ICI)-based treatments have been extensively studied, with the exception of programmed death ligand 1 (PD-L1), most are not widely used in the clinic due to poor effects or defective practicability. The aim of this study was to identify those patients with high baseline serum cholesterol who benefit from ICI-based treatments.Patients and Methods: Patients with advanced non-small cell lung cancer (NSCLC) treated at Ningbo Medical Center, Li Huili Hospital between August 2017 and December 2019 were enrolled in this retrospective study. The Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1) were used to evaluate the efficacy of the ICI-based treatment. Progression-free survival (PFS) and overall survival (OS) were calculated using the Kaplan–Meier survival curves and compared using the log rank test. Univariate and multivariate analyses were conducted using the logistic regression analysis and Cox proportional hazards model. A receiver operating characteristic curve was created, and the area under the curve (AUC) was calculated to compare the predictive value of baseline serum cholesterol with PD-L1 expression for patient response to ICI-based treatment.Results: In our cohort of 169 NSCLC patients, the objective response rate (ORR) and disease control rate (DCR) of the treatment were significantly higher in patients with hypercholesterolemia (> 5.18 mmol/L) than in those with hypocholesterolemia (ORR: 33.67% vs 14.08%, P=0.004; DCR: 68.37% vs 42.25%, P=0.001). The median PFS was 7.9 months in the hypercholesterolemia group, significantly longer than in the hypocholesterolemia group (4.4 months, 95% CI: 4.620– 7.380, P< 0.001). The median OS in the two groups were 11 months and 8 months, with 95% CIs of 8.980– 10.420 (P< 0.001). The AUC for the baseline level of cholesterol was 0.706 (P< 0.001), while it was 0.643 (P=0.001) for PD-L1 expression.Conclusion: The baseline serum cholesterol level is predictive of a clinical benefit for advanced NSCLC patients who undergo ICI-based treatment, and hence it is a promising prognostic indicator for ICI-based treatment of NSCLC.Keywords: non-small cell lung cancer, NSCLC, serum cholesterol, immune checkpoint inhibitors, ICIs, prognostic marker

Tong III J, Mao Y, Yang Z, et al. Cancer Manag Res. 2021;13:4041–4053. The authors have advised due to an error at the time of figure assembly, Figure 2D on page 4048 is incorrect. The correct Figure 2 is shown in Download Article: The authors apologize for this error and advise it does not affect the results of the paper. Read the original article

Abstract Background Electrical impedance tomography (EIT) has been used for functional lung imaging of regional air distributions during mechanical ventilation in intensive care units (ICU). From numerous clinical and animal studies focusing on specific lung functions, a consensus about how to use the EIT technique has been formed lately. We present an integrated EIT system implementing the functions proposed in the consensus. The integrated EIT system could improve the usefulness when monitoring of mechanical ventilation for lung protection so that it could facilitate the clinical acceptance of this new technique. Methods Using a custom-designed 16-channel EIT system with 50 frames/s temporal resolution, the integrated EIT system software was developed to implement five functional images and six EIT measures that can be observed in real-time screen view and analysis screen view mode, respectively. We evaluated the performance of the integrated EIT system with ten mechanically ventilated porcine subjects in normal and disease models. Results Quantitative and simultaneous imaging of tidal volume (TV), end-expiratory lung volume change ($$\triangle$$ ▵ EELV), compliance, ventilation delay, and overdistension/collapse images were performed. Clinically useful parameters were successfully extracted including anterior/posterior ventilation ratio (A/P ratio), center of ventilation ($${\mathrm{CoV}}_{{x}}$$ CoVx , $${\mathrm{CoV}}_{{y}}$$ CoVy ), global inhomogeneity (GI), coefficient of variation (CV), ventilation delay and percentile of overdistension/collapse. The integrated EIT system was demonstrated to suggest an optimal positive end-expiratory pressure (PEEP) for lung protective ventilation in normal and in the disease model of an acute injury. Optimal PEEP for normal and disease model was 2.3 and $$7.9 \, {\mathrm{cmH}}_{2}\mathrm{O}$$ 7.9cmH2O , respectively. Conclusions The proposed integrated approach for functional lung ventilation imaging could facilitate clinical acceptance of the bedside EIT imaging method in ICU. Future clinical studies of applying the proposed methods to human subjects are needed to show the clinical significance of the method for lung protective mechanical ventilation and mechanical ventilator weaning in ICU.

Summary: Transcriptional dysregulation of the MYC oncogene is among the most frequent events in aggressive tumor cells, and this is generally accomplished by acquisition of a super-enhancer somewhere within the 2.8 Mb TAD where MYC resides. We find that these diverse cancer-specific super-enhancers, differing in size and location, interact with the MYC gene through a common and conserved CTCF binding site located 2 kb upstream of the MYC promoter. Genetic perturbation of this enhancer-docking site in tumor cells reduces CTCF binding, super-enhancer interaction, MYC gene expression, and cell proliferation. CTCF binding is highly sensitive to DNA methylation, and this enhancer-docking site, which is hypomethylated in diverse cancers, can be inactivated through epigenetic editing with dCas9-DNMT. Similar enhancer-docking sites occur at other genes, including genes with prominent roles in multiple cancers, suggesting a mechanism by which tumor cell oncogenes can generally hijack enhancers. These results provide insights into mechanisms that allow a single target gene to be regulated by diverse enhancer elements in different cell types. : Schuijers et al. show that a conserved CTCF site at the promoter of the MYC oncogene plays an important role in enhancer-promoter looping with tumor-specific super-enhancers. Perturbation of this site provides a potential therapeutic vulnerability. Keywords: gene regulation, super-enhancers, chromosome structure, enhancer docking

The successful management of cervical intraepithelial neoplasia (CIN) with proper screening and treatment methods could prevent cervical cancer progression. We propose a bioimpedance spectroscopic measurement device and a multi-electrode probe as an independent screening tool for CIN. To evaluate the performance of this screening method, we enrolled 123 patients, including 69 patients with suspected CIN and 54 control patients without cervical dysplasia who underwent a hysterectomy for benign disease (non-CIN). Following conization, the electrical properties of the excised cervical tissue were characterized using an electrical bioimpedance spectroscopy-based multi-electrode probe. Twenty-eight multifrequency voltages were collected through the two concentric array electrodes via a sensitivity-optimized measurement protocol based on an electrical energy concentration method. The electrical properties of the CIN and non-CIN groups were compared with the results of the pathology reports. Reconstructed resistivity tended to decrease in the CIN and non-CIN groups as frequency increased. Reconstructed resistivity from 625 Hz to 50 kHz differed significantly between the CIN and non-CIN groups (p < 0.001). Using 100 kHz as the reference, the difference between the CIN and non-CIN groups was significant. Based on the difference in reconstructed resistivity between 100 kHz and the other frequencies, this method had a sensitivity of 94.3%, a specificity of 84%, and an accuracy of 90% in CIN screening. The feasibility of noninvasive CIN screening was confirmed through the difference in the frequency spectra evaluated in the excised tissue using the electrical bioimpedance spectroscopy-based multi-electrode screening probe.

Otitis media is mainly caused by upper respiratory tract infection and eustachian tube dysfunction. If external upper respiratory tract infection is not detected early in the middle ear, or an appropriate immune response does not occur, otitis media can become a chronic state or complications may occur. Therefore, given the important role of Toll-like receptors (TLRs) in the early response to external antigens, we surveyed the role of TLRs in otitis media. To summarize the role of TLR in otitis media, we reviewed articles on the expression of TLRs in acute otitis media (AOM), otitis media with effusion (OME), chronic otitis media (COM) with cholesteatoma, and COM without cholesteatoma. Many studies showed that TLRs 1–10 are expressed in AOM, OME, COM with cholesteatoma, and COM without cholesteatoma. TLR expression in the normal middle ear mucosa is absent or weak, but is increased in inflammatory fluid of AOM, effusion of OME, and granulation tissue and cholesteatoma of COM. In addition, TLRs show increased or decreased expression depending on the presence or absence of bacteria, recurrence of disease, tissue type, and repeated surgery. In conclusion, expression of TLRs is associated with otitis media. Inappropriate TLR expression, or delayed or absent induction, are associated with the occurrence, recurrence, chronicization, and complications of otitis media. Therefore, TLRs are very important in otitis media and closely related to its etiology.

Literature in the field of stem cell therapy indicates that, when stem cells in a state of single-cell suspension are injected systemically, they show poor in vivo survival, while such cells show robust cell survival and regeneration activity when transplanted in the state of being attached on a biomaterial surface. Although an attachment-deprived state induces anoikis, when cell-surface engineering technology was adopted for stem cells in a single-cell suspension state, cell survival and regenerative activity dramatically improved. The biochemical signal coming from ECM (extracellular matrix) molecules activates the cell survival signal transduction pathway and prevents anoikis. According to the target disease, various therapeutic cells can be engineered to improve their survival and regenerative activity, and there are several types of biomaterials available for cell-surface engineering. In this review, biomaterial types and application strategies for cell-surface engineering are presented along with their expected efficacy.

In Saccharomyces cerevisiae, glucose depletion causes a profound alteration in metabolism, mediated in part by global transcriptional changes. Many of the transcription factors that regulate these changes act combinatorially. We have analyzed combinatorial regulation by Adr1 and Cat8, two transcription factors that act during glucose depletion, by combining genome-wide expression and genome-wide binding data. We identified 32 genes that are directly activated by Adr1, 28 genes that are directly activated by Cat8, and 14 genes that are directly regulated by both. Our analysis also uncovered promoters that Adr1 binds but does not regulate and promoters that are indirectly regulated by Cat8, stressing the advantage of combining global expression and global localization analysis to find directly regulated targets. At most of the coregulated promoters, the in vivo binding of one factor is independent of the other, but Adr1 is required for optimal Cat8 binding at two promoters with a poor match to the Cat8 binding consensus. In addition, Cat8 is required for Adr1 binding at promoters where Adr1 is not required for transcription. These data provide a comprehensive analysis of the direct, indirect, and combinatorial requirements for these two global transcription factors. [ABSTRACT FROM AUTHOR]

Meningiomas are mostly benign brain tumours with the potential for becoming atypical or malignant. Here, the authors show that primary atypical meningiomas are epigenetically and genetically distinct from benign and progressed tumours, highlighting possible therapeutic targets such as PRC2.

Sequencing initiatives have detected multiple types of mutations in cancer. Here the authors, analysing enhancer-targeting sequence data, show that small insertions in transcriptional enhancers are frequently found near oncogenes, and demonstrate how one mutation deregulates expression of LMO2 in leukemia cells.

Previous imaging studies have shown the morphological malformation and the alterations of ionic mobility, water contents, electrical properties, or metabolites in seizure brains. Magnetic resonance electrical properties tomography (MREPT) is a recently developed technique for the measurement of electrical tissue properties with a high frequency that provides cellular information regardless of the cell membrane. In this study, we examined the possibility of MREPT as an applicable technique to detect seizure-induced functional changes in the brain of rats. Ultra-high field (9.4 T) magnetic resonance imaging (MRI) was performed, 2 h, 2 days, and 1 week after the injection of N-methyl-D-aspartate (NMDA; 75 mg/kg). The conductivity images were reconstructed from B1 phase images using a magnetic resonance conductivity imaging (MRCI) toolbox. The high-frequency conductivity was significantly decreased in the hippocampus among various brain regions of NMDA-treated rats. Nissl staining showed shrunken cell bodies and condensed cytoplasm potently at 2 h after NMDA treatment, and neuronal cell loss at all time points in the hippocampus. These results suggest that the reduced electrical conductivity may be associated with seizure-induced neuronal loss in the hippocampus. Magnetic resonance (MR)-based electrical conductivity imaging may be an applicable technique to non-invasively identify brain damage after a seizure.

Near the bone remodeling compartments (BRC), extracellular calcium concentration (Ca2+o) is locally elevated and bone marrow stromal cells (BMSCs) close to the BRC can be exposed to high calcium concentration. The calcium-sensing receptor (CaSR) is known to play a key role in maintaining extracellular calcium homeostasis by sensing fluctuations in the levels of extracellular calcium (Ca2+o). When human BMSCs (hBMSCs) were exposed to various calcium concentrations (1.8, 3, 5, 10, 30 mM), moderate-high extracellular calcium concentrations (3–5 mM) stimulated proliferation, while a high calcium concentration (30 mM) inhibited the proliferation. Exposure to various calcium concentrations did not induce significant differences in the apoptotic cell fraction. Evaluation of multi-lineage differentiation potential showed no significant difference among various calcium concentration groups, except for the high calcium concentration (30 mM) treated group, which resulted in increased calcification after in vitro osteogenic differentiation. Treatment of NPS2143, a CaSR inhibitor, abolished the stimulatory effect on hBMSCs proliferation and migration indicating that CaSR is involved. These results suggest that the calcium concentration gradient near the BRC may play an important role in bone remodeling by acting as an osteoblast–osteoclast coupling mechanism through CaSR.

Hundreds of transcription factors (TFs) are expressed in each cell type, but cell identity can be induced through the activity of just a small number of core TFs. Systematic identification of these core TFs for a wide variety of cell types is currently lacking and would establish a foundation for understanding the transcriptional control of cell identity in development, disease, and cell-based therapy. Here, we describe a computational approach that generates an atlas of candidate core TFs for a broad spectrum of human cells. The potential impact of the atlas was demonstrated via cellular reprogramming efforts where candidate core TFs proved capable of converting human fibroblasts to retinal pigment epithelial-like cells. These results suggest that candidate core TFs from the atlas will prove a useful starting point for studying transcriptional control of cell identity and reprogramming in many human cell types.

1,3-Propanediol (1,3-PD) is an intermediate in chemical and polymer synthesis. We have previously expressed the genes of a biochemical pathway responsible for 1,3-PD production, the dha regulon of Klebsiella pneumoniae, in Escherichia coli. An analysis of the maximum theoretical yield of 1,3-PD from glycerol indicates that the yield can be improved by the cofermentation of sugars, provided that kinetic constraints are overcome. The yield of 1,3-PD from glycerol was improved from 0.46 mol/mol with glycerol alone to 0.63 mol/mol with glucose cofermentation and 0.55 mol/mol with xylose cofermentation. The engineered E. coli also provides a model system for the study of metabolic pathway engineering. [ABSTRACT FROM AUTHOR]

Purpose To realistically map the electric fields of biological tissues using a diffusion tensor magnetic resonance electrical impedance tomography (DT-MREIT) method to estimate tissue response during electrical stimulation. Methods Imaging experiments were performed using chunks of bovine muscle. Two silver wire electrodes were positioned inside the muscle tissue for electrical stimulation. Electric pulses were applied with a 100-V amplitude and 100-μs width using a voltage stimulator. During electrical stimulation, we collected DT-MREIT data from a 3T magnetic resonance imaging scanner. We adopted the projected current density method to calculate the electric field. Based on the relation between the water diffusion tensor and the conductivity tensor, we computed the position-dependent scale factor using the measured magnetic flux density data. Then, a final conductivity tensor map was reconstructed using the multiplication of the water diffusion tensor and the scale factor. Results The current density images from DT-MREIT data represent the internal current flows that exist not only in the electrodes but also in surrounding regions. The reconstructed electric filed map from our anisotropic conductivity tensor with the projected current density shows coverage that is more than 2 times as wide, and higher signals in both the electrodes and surrounding tissues, than the previous isotropic method owing to the consideration of tissue anisotropy. Conclusions An electric field map obtained by an anisotropic reconstruction method showed different patterns from the results of the previous isotropic reconstruction method. Since accurate electric field mapping is important to correctly estimate the coverage of the electrical treatment, future studies should include more rigorous validations of the new method through in vivo and in situ experiments.

New methods for in vivo mapping of brain responses during deep brain stimulation (DBS) are indispensable to secure clinical applications. Assessment of current density distribution, induced by internally injected currents, may provide an alternative method for understanding the therapeutic effects of electrical stimulation. The current flow and pathway are affected by internal conductivity, and can be imaged using magnetic resonance-based conductivity imaging methods. Magnetic resonance electrical impedance tomography (MREIT) is an imaging method that can enable highly resolved mapping of electromagnetic tissue properties such as current density and conductivity of living tissues. In the current study, we experimentally imaged current density distribution of in vivo canine brains by applying MREIT to electrical stimulation. The current density maps of three canine brains were calculated from the measured magnetic flux density data. The absolute current density values of brain tissues, including gray matter, white matter, and cerebrospinal fluid were compared to assess the active regions during DBS. The resulting current density in different tissue types may provide useful information about current pathways and volume activation for adjusting surgical planning and understanding the therapeutic effects of DBS.

When we use a conductive fabric as a pressure sensor, it is necessary to quantitatively understand its electromechanical property related with the applied pressure. We investigated electromechanical properties of three different conductive fabrics using the electrical impedance spectroscopy (EIS). We found that their electrical impedance spectra depend not only on the electrical properties of the conductive yarns, but also on their weaving structures. When we apply a mechanical tension or compression, there occur structural deformations in the conductive fabrics altering their apparent electrical impedance spectra. For a stretchable conductive fabric, the impedance magnitude increased or decreased under tension or compression, respectively. For an almost non-stretchable conductive fabric, both tension and compression resulted in decreased impedance values since the applied tension failed to elongate the fabric. To measure both tension and compression separately, it is desirable to use a stretchable conductive fabric. For any conductive fabric chosen as a pressure-sensing material, its resistivity under no loading conditions must be carefully chosen since it determines a measurable range of the impedance values subject to different amounts of loadings. We suggest the EIS method to characterize the electromechanical property of a conductive fabric in designing a thin and flexible fabric pressure sensor.

Anisotropy of biological tissues is a low-frequency phenomenon that is associated with the function and structure of cell membranes. Imaging of anisotropic conductivity has potential for the analysis of interactions between electromagnetic fields and biological systems, such as the prediction of current pathways in electrical stimulation therapy. To improve application to the clinical environment, precise approaches are required to understand the exact responses inside the human body subjected to the stimulated currents. In this study, we experimentally evaluate the anisotropic conductivity tensor distribution of canine brain tissues, using a recently developed diffusion tensor-magnetic resonance electrical impedance tomography method. At low frequency, electrical conductivity of the biological tissues can be expressed as a product of the mobility and concentration of ions in the extracellular space. From diffusion tensor images of the brain, we can obtain directional information on diffusive movements of water molecules, which correspond to the mobility of ions. The position dependent scale factor, which provides information on ion concentration, was successfully calculated from the magnetic flux density, to obtain the equivalent conductivity tensor. By combining the information from both techniques, we can finally reconstruct the anisotropic conductivity tensor images of brain tissues. The reconstructed conductivity images better demonstrate the enhanced signal intensity in strongly anisotropic brain regions, compared with those resulting from previous methods using a global scale factor.

Nature Communications 8: Article number: 14433 (2017) Published online 14 February 2017; Updated 20 April 2018 In this Article, a subset of the H3K27ac ChIP-seq data (15 benign meningiomas and 2 dura samples (Sample IDs: MN-297, MN-288, MN-292, MN-163, MN-1037, MN-105, MN-201, MN-249, MN-191, MN-1066, MN-169, MN-291, MN-24, MN-79, MN-1044, CONTROL1, CONTROL2) was reported previously in a publication by the corresponding author1.

Electromagnetic fields provide fundamental data for the imaging of electrical tissue properties, such as conductivity and permittivity, in recent magnetic resonance (MR)-based tissue property mapping. The induced voltage, current density, and magnetic flux density caused by externally injected current are critical factors for determining the image quality of electrical tissue conductivity. As a useful tool to identify bio-electromagnetic phenomena, precise approaches are required to understand the exact responses inside the human body subject to an injected currents. In this study, we provide the numerical simulation results of electromagnetic field mapping of brain tissues using a MR-based conductivity imaging method. First, we implemented a realistic three-dimensional human anisotropic head model using high-resolution anatomical and diffusion tensor MR images. The voltage, current density, and magnetic flux density of brain tissues were imaged by injecting 1 mA of current through pairs of electrodes on the surface of our head model. The current density map of anisotropic brain tissues was calculated from the measured magnetic flux density based on the linear relationship between the water diffusion tensor and the electrical conductivity tensor. Comparing the current density to the previous isotropic model, the anisotropic model clearly showed the differences between the brain tissues. This originates from the enhanced signals by the inherent conductivity contrast as well as the actual tissue condition resulting from the injected currents.

Nature Communications 8: Article number:14385 (2017); Published: 9 February 2017; Updated: 1 June 2017 In the original version of Supplementary Data 1 associated with this Article, the list of predicted enhancer-associated insertions was inadvertently truncated. The HTML has now been updated to include the correct version of the Supplementary Data 1.

A continuous Nondestructive monitoring method is required to apply proper feedback controls during tissue regeneration. Conductivity is one of valuable information to assess the physiological function and structural formation of regenerated tissues or cultured cells. However, conductivity imaging methods suffered from inherited ill-posed characteristics in image reconstruction, unknown boundary geometry, uncertainty in electrode position, and systematic artifacts. In order to overcome the limitation of microscopic electrical impedance tomography (micro-EIT), we applied a 3D-specific container with a fixed boundary geometry and electrode configuration to maximize the performance of Graz consensus reconstruction algorithm for EIT (GREIT). The separation of driving and sensing electrodes allows us to simplify the hardware complexity and obtain higher measurement accuracy from a large number of small sensing electrodes. We investigated the applicability of the GREIT to 3D micro-EIT images via numerical simulations and large-scale phantom experiments. We could reconstruct multiple objects regardless of the location. The resolution was 5 mm3 with 30 dB SNR and the position error was less than 2.54 mm. This shows that the new micro-EIT system integrated with GREIT is robust with the intended resolution. With further refinement and scaling down to a microscale container, it may be a continuous nondestructive monitoring tool for tissue engineering applications.

Abstract: Background: Hepatic ischemia/reperfusion (HI/R) injury is a common pathologic process caused by many clinical settings, such as liver resection, liver transplantation, hypovolemic shock, and trauma. The use of ambroxol, which acts as a mucolytic agent, provides antioxidant and anti-inflammatory effects. Methods: A rat model of HI/R was induced by clamping the hepatic artery, the hepatoportal vein, and the bile duct with a vascular clamp for 30 minutes followed by reperfusion for 6 hours under anesthesia. The sham group underwent laparotomy without hepatic ischemia. The ambroxol group was injected into the tail vein in the ambroxol group 5 minutes before HI/R at one dose of 20 mg/kg, 80 mg/kg, or 140 mg/kg. The control group underwent the same procedure as the ambroxol group but with administration of physiological saline. Liver injury was evaluated by biochemical and histopathological examinations. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were assayed in serum samples. Superoxide dismutase (SOD), catalase (CAT), malondiadehyde (MDA), and glutathione (GSH) were spectrophotometrically measured. Furthermore, caspase-3, Bcl-2 and Bax expression as well as the level of c-Jun N-terminal kinases (JNK) we estimated activation. Results: Wistar rats that received 20, 80 mg or 140 mg of ambroxol displayed reduced HI/R injury compared with controls. Use of ambroxol reduced the histologic injury and significantly decreased serum ALT and AST levels. In addition, ambroxol enhanced the activity of hepatic tissue SOD and CAT, increasing GSH but decreasing MDA tissue contents. In the ambroxol group, Bcl-2 expression was increased and Bax and caspase-3 decreased compared with the controls. Furthermore, ambroxol reduced levels of phosphorylated JNK (P < .05). Conclusion: These results indicated that ambroxol attenuated rat HI/R through upregulation of intracellular antioxidant and anti-apoptotic signaling pathways. [Copyright &y& Elsevier]

The antioxidant and lysosomotropic properties of a fluorescent analogue of propranolol, 9-amino-acridine-propranolol (9-AAP) were compared to those of propranolol. Using isolated microsomal membranes exposed to a superoxide and hydroxyl radical generating system, 9-AAP was found to be at least 10-fold more potent than propranolol (and about 50% as potent as vitamin E) in inhibiting lipid peroxidation. In cultured endothelial cells, 9-AAP afforded moderate protective effect against acute loss of glutathione but potent cytoprotective activity against free radical-mediated loss of viability/survival. Intracellular localization of 9-AAP was examined by fluorescent microscopy and compared with two known fluorescent lysosomal markers: acridine orange and Lysosensor. All three agents appeared to localize to similar peri-nuclear vesicles, presumably lysosomes or pre-lysosomes. Lysosensor fluorescence was not observable in the presence of 9-AAP, foreclosing the possibility of a direct dual labeling experiment. We employed the pH sensitivity of acridine orange to determine if it labels the same vesicles as 9-AAP. When the endothelial cells were preloaded with acridine orange, washed and resuspended in buffer containing 9-AAP, the dark orange-labeled vesicles observed with acridine orange alone became increasingly lighter with time. Since the fluorescence of acridine orange is altered by pH change, this spectral shift in fluorescence emission is consistent with the indication that added propranolol (or the analog) leads to lysosomal alkalization. In conclusion, 9-AAP is both a strong antioxidant and a lysosomotropic agent that is remarkably insensitive to photobleaching . These properties may contribute to the enhanced endothelial cytoprotective effects against free radical-induced injury. [ABSTRACT FROM AUTHOR]

The gene expression programs that define the identity of each cell are controlled by master transcription factors (TFs) that bind cell-type-specific enhancers, as well as signaling factors, which bring extracellular stimuli to these enhancers. Recent studies have revealed that master TFs form phase-separated condensates with the Mediator coactivator at super-enhancers. Here, we present evidence that signaling factors for the WNT, TGF-β, and JAK/STAT pathways use their intrinsically disordered regions (IDRs) to enter and concentrate in Mediator condensates at super-enhancers. We show that the WNT coactivator β-catenin interacts both with components of condensates and DNA-binding factors to selectively occupy super-enhancer-associated genes. We propose that the cell-type specificity of the response to signaling is mediated in part by the IDRs of the signaling factors, which cause these factors to partition into condensates established by the master TFs and Mediator at genes with prominent roles in cell identity. • Signaling factors incorporate into Mediator condensates at super-enhancers • β-Catenin IDRs are required for both phase separation and target gene activation • Both condensate interactions and TF interactions contribute to β-catenin localization Zamudio et al. demonstrate that components of the WNT, TGF-β, and JAK/STAT signaling pathways use their intrinsically disordered regions to condense with Mediator and to target specific genes. These findings provide a model for how context-dependent transcriptional responses can be achieved in cell signaling. [ABSTRACT FROM AUTHOR]

Background: Hypertension (HTN) accounts for one in five deaths of American women. Major societies worldwide aim to make evidence-based recommendations for HTN management. Sex- or gender-based differences exist in epidemiology and management of HTN; in this study, we aimed to assess sex- and gender-based language in major society guidelines. Materials and Methods: We reviewed HTN guidelines from four societies: the American College of Cardiology (ACC), the American College of Emergency Physicians (ACEP), the European Society of Cardiology (ESC), and the Eighth Joint National Committee (JNC8). We quantified the sex- and gender-based medicine (SGBM) content by word count in each guideline as well as identified the gender of guideline authors. Results: Two of the four HTN guidelines (ACC, ESC) included SGBM content. Of these two guidelines, there were variations in the quantity and depth of content coverage. Pregnancy had the highest word count found in both guidelines (422 words in ACC and 1,523 words in ESC), which represented 2.45% and 3.04% of the total words in each guideline, respectively. There was minimal coverage, if any, of any other life periods. The number of women authors did not impact the SGBM content within a given guideline. Conclusions: Current HTN management guidelines do not provide optimal guidance on sex- and gender-based differences. Inclusion of sex, gender identity, hormone therapy, pregnancy and lactation status, menopause, and advanced age in future research will be critical to bridge the current evidence gap. Guideline writing committees should include diverse perspectives, including cisgender and transgender persons from diverse racial and ethnic backgrounds.