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Force Prediction of Composite-coated Needle Moving Inside TissuesThis research investigates the effectiveness of a composite coating consisting of Polydopamine (PDA), Polytetrafluoroethylene (PTFE), and Activated Carbon (C) to mitigate the potentially harmful effects of needle insertion forces. By evaluating the forces at the interface between the needle and tissue, this study aims to develop a model incorporating experimental and numerical approaches to better understand the mechanics of interfacial forces during coated needle insertion. The proposed model is divided into two components: frictional forces on the needle shaft, modeled using a modified Karnopp model with an elastic force component and cutting forces on the needle tip, modeled using a constant cutting coefficient for a given tissue and insertion speed. Upon testing the model on bovine kidney tissue with a 35mm insertion depth, the results demonstrate that the difference between experimental and modeled insertion forces is in the range of 6.5-17.1% for bare and coated needle. Notably, this difference in the insertion force model is expected when working with real tissues, which possess highly complex structures.
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Predicting Needle Deflection in Soft Tissue: An Investigation of Interfacial Mechanics and Tissue DeformationPercutaneous needle insertion has become a standard procedure in the region of open surgery, notably for biopsies of abdominal tumors, breast cancer, and prostate cancer [1]. In many cases, achieving high needle targeting accuracy is difficult due to the complexity of the human body tissues. Therefore, it is essential to study and model the steering behavior of a needle inserted into multi-layered tissues to plan for the optimal path of the needle during the insertion. The procedure during which the needle must pass through multi-layer tissues requires professional skills due to complex deflections. Therefore, it is essential to create realistic simulators for surgeons and nurses, to practice their clinical skills [2].A model based on a Euler-Bernoulli beam deflecting under static force distribution profiles was developed to simulate needle insertion [3]. A needle was modeled as a cantilever beam supported by a series of nonlinear springs [4].
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Finite Element Simulation of Active Steerable Needle Insertion in Soft TissuesA finite element (FE) simulation of an active needle actuated by a nitinol shape memory alloy (SMA) actuator designed in our previous studies [1,2] has been performed for application in needle-based procedures like biopsy, brachytherapy, and tissue ablation. The simulation predicts the active needle deflection in liver and prostate tissue by applying a thermomechanical material model for the SMA actuator and needle tissue interaction forces using commercial FE software.
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Insertion Mechanics of Curved Bio-inspired NeedlesNeedle insertion is an essential process during minimally invasive surgery (MIS), which has been used for biopsies, blood sampling, and brachytherapy. The minimally invasive procedure involves less intrusive and fewer post operations than traditional open surgeries, so this leads to fast recovery times, and decreased risk infection. For successful diagnosis and treatment, accuracy of needle insertion is vital, and previous studies are shown that insertion force, tissue deformation, and tissue damage can affect needle insertion precision. Insertion force, which is composed of stiffness, cutting, and friction force can be affected by the geometry and materials of the needle, mechanical properties of tissue, and insertion velocity. The traditional biopsy needles can cause harm to the patient, including tissue damage, bleeding, and pain. An essential aspect of the study is the mechanics and geometry of the needle, which plays a crucial role in its performance. This study focuses on decreasing insertion force, which is the total applied force of the needle that is coming from the tissue or organ. The study incorporates structures such as curved insect’s stinger to achieve a balance between penetration and minimal insertion force.
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Global DNA methylation levels are altered by modifiable clinical manipulations in assisted reproductive technologiesBackground: We analyzed placental DNA methylation levels at repeated sequences (LINE1 elements) and all CCGG sites (the LUMA assay) to study the effect of modifiable clinical or laboratory procedures involved in in vitro fertilization. We included four potential modifiable factors: oxygen tension during embryo culture, fresh embryo transfer vs frozen embryo transfer, intracytoplasmic sperm injection (ICSI) vs conventional insemination or day 3 embryo transfer vs day 5 embryo transfer. Results: Global methylation levels differed between placentas from natural conceptions compared to placentas conceived by IVF. Placentas from embryos cultured at 20% oxygen showed significant differences in LINE1 methylation compared to in vivo conceptions, while those from embryos cultured at 5% oxygen, did not have significant differences. In addition, placentas from fresh embryo transfer had significantly different LINE1 methylation compared to placentas from in vivo conceptions, while embryos resulting from frozen embryos were not significantly different from controls. On sex-stratified analysis, only males had significant methylation differences at LINE1 elements stratified for the modifiable factors. As expected, LINE1 methylation was significantly different between males and females in the control population. However, we did not observe sex-specific differences in the IVF group. We validated this sex-specific observation in an additional cohort and in opposite sex IVF twins. Conclusion: We show that two clinically modifiable factors (embryo culture in 5 vs 20% oxygen tension and fresh vs frozen embryo transfer) are associated with global placental methylation differences. Interestingly, males appear more vulnerable to such treatment-related global changes in DNA methylation than do females.
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Acute aerobic exercise increases exogenously infused bone marrow cell retention in the heartStem cell therapy for myocardial infarction (MI) has been shown to improve cardiac function and reduce infarct size. Exercise training, in the form of cardiac rehabilitation, is an essential part of patient care post-MI. Hence, we tested the effects of acute and chronic aerobic exercise on stem cell retention and cardiac remodeling post-MI. Small epicardial MI's were induced in 12-month-old C57BL/6 mice via cryoinjury. Two weeks post-MI, vehicle infusion (N = 4) or GFP+ bone marrow-derived cells (BMC) were injected (tail vein I.V.) immediately after acute exercise (N = 14) or sedentary conditions (N = 14). A subset of mice continued a 5-week intervention of chronic treadmill exercise (10–13 m/min; 45 min/day; 4 days/week; N = 7) or remained sedentary (N = 6). Exercise tolerance was assessed using a graded exercise test, and cardiac function was assessed with echocardiography. Acute exercise increased GFP+ BMC retention in the infarcted zone of the heart by 30% versus sedentary (P < 0.05). This was not associated with alterations in myocardial function or gene expression of key cell adhesion molecules. Animals treated with chronic exercise increased exercise capacity (P < 0.05) and cardiac mass (P < 0.05) without change in left ventricular ejection fraction (LVEF), infarct size, or regional wall thickness (P = NS) compared with sedentary. While BMC's alone did not affect exercise capacity, they increased LVEF (P < 0.05) and Ki67+ nuclei number in the border zone of the heart (P < 0.05), which was potentiated with chronic exercise training (P < 0.05). We conclude that acute exercise increases BMC retention in infarcted hearts and chronic training increases exogenous BMC-mediated effects on stimulating the cardiomyocyte cell cycle. These preclinical results suggest that exercise may help to optimize stem cell therapeutics following MI.
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Achieving Secure and Efficient Data Access Control for Cloud-Integrated Body Sensor NetworksBody sensor network has emerged as one of the most promising technologies for e-healthcare, which makes remote health monitoring and treatment to patients possible. With the support of mobile cloud computing, large number of health-related data collected from various body sensor networks can be managed efficiently. However, how to keep data security and data privacy in cloud-integrated body sensor network (C-BSN) is an important and challenging issue since the patients’ health-related data are quite sensitive. In this paper, we present a novel secure access control mechanism MC-ABE (Mask-Certificate Attribute-Based Encryption) for cloud-integrated body sensor networks. A specific signature is designed to mask the plaintext, and then the masked data can be securely outsourced to cloud severs. An authorization certificate composed of the signature and related privilege items is constructed which is used to grant privileges to data receivers. To ensure security, a unique value is chosen to mask the certificate for each data receiver. Thus, the certificate is unique for each user and user revocation can be easily completed by removing the mask value. The analysis shows that proposed scheme can meet the security requirement of C-BSN, and it also has less computation cost and storage cost compared with other popular models.
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Glycosylation and Cross-linking in Bone Type I CollagenFibrillar type I collagen is the major organic component in bone, providing a stable template for mineralization. During collagen biosynthesis, specific hydroxylysine residues become glycosylated in the form of galactosyl- and glucosylgalactosyl-hydroxylysine. Furthermore, key glycosylated hydroxylysine residues, α1/2-87, are involved in covalent intermolecular cross-linking. Although cross-linking is crucial for the stability and mineralization of collagen, the biological function of glycosylation in cross-linking is not well understood. In this study, we quantitatively characterized glycosylation of non-cross-linked and cross-linked peptides by biochemical and nanoscale liquid chromatography-high resolution tandem mass spectrometric analyses. The results showed that glycosylation of non-cross-linked hydroxylysine is different from that involved in cross-linking. Among the cross-linked species involving α1/2-87, divalent cross-links were glycosylated with both mono- and disaccharides, whereas the mature, trivalent cross-links were primarily monoglycosylated. Markedly diminished diglycosylation in trivalent cross-links at this locus was also confirmed in type II collagen. The data, together with our recent report (Sricholpech, M., Perdivara, I., Yokoyama, M., Nagaoka, H., Terajima, M., Tomer, K. B., and Yamauchi, M. (2012) Lysyl hydroxylase 3-mediated glucosylation in type I collagen: molecular loci and biological significance. J. Biol. Chem. 287, 22998–23009), indicate that the extent and pattern of glycosylation may regulate cross-link maturation in fibrillar collagen.
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A Splice Variant of the Human Ion Channel TRPM2 Modulates Neuroblastoma Tumor Growth through Hypoxia-inducible Factor (HIF)-1/2α*The calcium-permeable ion channel TRPM2 is highly expressed in a number of cancers. In neuroblastoma, full-length TRPM2 (TRPM2-L) protected cells from moderate oxidative stress through increased levels of forkhead box transcription factor 3a (FOXO3a) and superoxide dismutase 2. Cells expressing the dominant negative short isoform (TRPM2-S) had reduced FOXO3a and superoxide dismutase 2 levels, reduced calcium influx in response to oxidative stress, and enhanced reactive oxygen species, leading to decreased cell viability. Here, in xenografts generated with SH-SY5Y neuroblastoma cells stably expressing TRPM2 isoforms, growth of tumors expressing TRPM2-S was significantly reduced compared with tumors expressing TRPM2-L. Expression of hypoxia-inducible factor (HIF)-1/2α was significantly reduced in TRPM2-S-expressing tumor cells as was expression of target proteins regulated by HIF-1/2α including those involved in glycolysis (lactate dehydrogenase A and enolase 2), oxidant stress (FOXO3a), angiogenesis (VEGF), mitophagy and mitochondrial function (BNIP3 and NDUFA4L2), and mitochondrial electron transport chain activity (cytochrome oxidase 4.1/4.2 in complex IV). The reduction in HIF-1/2α was mediated through both significantly reduced HIF-1/2α mRNA levels and increased levels of von Hippel-Lindau E3 ligase in TRPM2-S-expressing cells. Inhibition of TRPM2-L by pretreatment with clotrimazole or expression of TRPM2-S significantly increased sensitivity of cells to doxorubicin. Reduced survival of TRPM2-S-expressing cells after doxorubicin treatment was rescued by gain of HIF-1 or -2α function. These data suggest that TRPM2 activity is important for tumor growth and for cell viability and survival following doxorubicin treatment and that interference with TRPM2-L function may be a novel approach to reduce tumor growth through modulation of HIF-1/2α, mitochondrial function, and mitophagy.TRPM2 channels play an essential role in cell death following oxidative stress. Results: Dominant negative TRPM2-S decreases growth of neuroblastoma xenografts and increases doxorubicin sensitivity through modulation of HIF-1/2α expression, mitophagy, and mitochondrial function. Conclusion: TRPM2 is important for neuroblastoma growth and viability through modulation of HIF-1/2α. Significance: Modulation of TRPM2 may be a novel approach in cancer therapeutics.
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Health behavior practice among understudied Chinese and Filipino Americans with cardiometabolic diseasesLifestyle modification and health behavior practice among the individuals with cardiometabolic diseases (CMD) are important for secondary prevention and disease control. This study was designed to investigate and compare health behavior practices among Chinese and Filipino Americans with CMD. Three hundred seventy-four Asian Americans (211 Chinese and 163 Filipino) who reside in the greater Philadelphia region and had either CMD or no identified disease were included in the study. Information on smoking, alcohol intake, physical activity, and salt and sweets consumption was collected, as well as demographic and acculturative characteristics. Of the 374 participants, 241 (64.4%) had CMD and 133 (35.6%) had no identified disease. The majority of Chinese and Filipino Americans with CMD failed to meet the dietary and physical activity guidelines, and only a small percentage of them restricted their amount of salt added to food and amount of sweets consumption. Compared to participants with no disease, Chinese participants with CMD were more likely to “never” add salt to food (AOR 4.42 compared to “frequently”). Filipino Americans with CMD were less likely to be those who “never” consume sweets than those who frequently consume sweets (AOR = 0.12). Among the participants with CMD, Chinese participants with CMD were less likely to restrict drinking (AOR 0.11) than Filipinos with CMD. The findings suggest that tailored interventions for Chinese and Filipino Americans with CMD should be developed to enhance their compliance to behavioral guidelines to prevent further disease progression and complications.
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HIV-Associated Neurocognitive Disorders: The Relationship of HIV Infection with Physical and Social ComorbiditiesThe prevalence of HIV (human immunodeficiency virus) associated neurocognitive disorders (HAND) will undoubtedly increase with the improved longevity of HIV-infected persons. HIV infection, itself, as well as multiple physiologic and psychosocial factors can contribute to cognitive impairment and neurologic complications. These comorbidities confound the diagnosis, assessment, and interventions for neurocognitive disorders. In this review, we discuss the role of several key comorbid factors that may contribute significantly to the development and progression of HIV-related neurocognitive impairment, as well as the current status of diagnostic strategies aimed at identifying HIV-infected individuals with impaired cognition and future research priorities and challenges.
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Accurate lattice geometrical parameters and bulk moduli from a semilocal density functionalAccurate prediction of lattice constants is very important in applications of density functional theory. In this work, we assess the efficacy of a non-empirical meta-generalized gradient approximation proposed by Tao and Mo (TM) by calculating the lattice constants as well as bulk moduli of 33 crystalline semiconductors within the TM scheme. We find that the TM functional is able to produce very accurate lattice constants, with a mean absolute error of 0.038 Å, and bulk moduli with a mean absolute error of 3.2 GPa, improving upon commonly-used semilocal density functionals, such as the LSDA, PBE, SOGGA, PBEsol, TPSS, M06L, and SCAN. The high computational efficiency and remarkable agreements with the corresponding experimental values suggest that the TM functional can be a very competitive candidate in electronic structure theory. We attribute the accuracy of the TM functional to be the result of its satisfaction of many exact or nearly-exact conditions related to the exchange-correlation energy and the associated hole, leading to an improved description of the short- as well as intermediate-range van der Waals interactions.
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Homocysteine modulates 5-lipoxygenase expression level via DNA methylationElevated levels of homocysteinemia (Hcy), a risk factor for late-onset Alzheimer's disease (AD), have been associated with changes in cell methylation. Alzheimer's disease is characterized by an upregulation of the 5-lipoxygenase (5LO), whose promoter is regulated by methylation. However, whether Hcy activates 5LO enzymatic pathway by influencing the methylation status of its promoter remains unknown. Brains from mice with high Hcy were assessed for the 5LO pathway and neuronal cells exposed to Hcy implemented to study the mechanism(s) regulating 5LO expression levels and the effect on amyloid β formation. Diet- and genetically induced high Hcy resulted in 5LO protein and mRNA upregulation, which was associated with a significant increase of the S-adenosylhomocysteine (SAH)/S-adenosylmethionine ratio, and reduced DNA methyltrasferases and hypomethylation of 5-lipoxygenase DNA. In vitro studies confirmed these results and demonstrated that the mechanism involved in the Hcy-dependent 5LO activation and amyloid β formation is DNA hypomethylation secondary to the elevated levels of SAH. Taken together these findings represent the first demonstration that Hcy directly influences 5LO expression levels and establish a previously unknown cross talk between these two pathways, which is highly relevant for AD pathogenesis. The discovery of such a novel link not only provides new mechanistic insights in the neurobiology of Hcy, but most importantly new therapeutic opportunities for the individuals bearing this risk factor for the disease.
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HIV RNA Suppression during and after Pregnancy among Women in the HIV Outpatient Study, 1996 to 2015Objective: To examine HIV viral suppression during/after pregnancy. Design: Prospective observational cohort. Methods: We identified pregnancies from 1996 to 2015. We examined HIV RNA viral load (VL), VL suppression (≤500 copies/mL), and antiretroviral therapy (ART) status at pregnancy start, end, and 6 months postpartum. We estimated risk ratios (RRs) and 95% confidence intervals (CIs) for VL nonsuppression. Results: Among 253 pregnancies analyzed, 34.8% of women exhibited VL suppression at pregnancy start, 60.1% at pregnancy end, and 42.7% at 6 months postpartum. Median VL (log10 copies/mL) was 2.80 (interquartile range [IQR]: 1.40-3.85) at pregnancy start, 1.70 (IQR: 1.40-2.82) at pregnancy end, and 2.30 (IQR: 1.40-3.86) at postpartum. Risk of postpartum VL nonsuppression was also lower among women on ART and with VL suppression at pregnancy end (versus those not; adjusted RR = 0.30, 95% CI: 0.17-0.53). Conclusions: Maintaining VL suppression among US women remains a challenge, particularly during postpartum. Achieving VL suppression earlier during pregnancy benefits women subsequently.
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Identification of Novel Inhibitors of DLK Palmitoylation and Signaling by High Content ScreeningAfter axonal insult and injury, Dual leucine-zipper kinase (DLK) conveys retrograde pro-degenerative signals to neuronal cell bodies via its downstream target c-Jun N-terminal kinase (JNK). We recently reported that such signals critically require modification of DLK by the fatty acid palmitate, via a process called palmitoylation. Compounds that inhibit DLK palmitoylation could thus reduce neurodegeneration, but identifying such inhibitors requires a suitable assay. Here we report that DLK subcellular localization in non-neuronal cells is highly palmitoylation-dependent and can thus serve as a proxy readout to identify inhibitors of DLK palmitoylation by High Content Screening (HCS). We optimized an HCS assay based on this readout, which showed highly robust performance in a 96-well format. Using this assay we screened a library of 1200 FDA-approved compounds and found that ketoconazole, the compound that most dramatically affected DLK localization in our primary screen, dose-dependently inhibited DLK palmitoylation in follow-up biochemical assays. Moreover, ketoconazole significantly blunted phosphorylation of c-Jun in primary sensory neurons subjected to trophic deprivation, a well known model of DLK-dependent pro-degenerative signaling. Our HCS platform is thus capable of identifying novel inhibitors of DLK palmitoylation and signalling that may have considerable therapeutic potential.
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Activation and polarization of circulating monocytes in severe chronic obstructive pulmonary diseaseBackground: The ability of circulating monocytes to develop into lung macrophages and promote lung tissue damage depends upon their phenotypic pattern of differentiation and activation. Whether this phenotypic pattern varies with COPD severity is unknown. Here we characterize the activation and differentiation status of circulating monocytes in patients with moderate vs. severe COPD. Methods: Blood monocytes were isolated from normal non-smokers (14), current smokers (13), patients with moderate (9), and severe COPD (11). These cells were subjected to analysis by flow cytometry to characterize the expression of activation markers, chemoattractant receptors, and surface markers characteristic of either M1- or M2-type macrophages. Results: Patients with severe COPD had increased numbers of total circulating monocytes and non-classical patrolling monocytes, compared to normal subjects and patients with moderate COPD. In addition, while the percentage of circulating monocytes that expressed an M2-like phenotype was reduced in patients with either moderate or severe disease, the levels of expression of M2 markers on this subpopulation of monocytes in severe COPD was significantly elevated. This was particularly evident for the expression of the chemoattractant receptor CCR5. Conclusions: Blood monocytes in severe COPD patients undergo unexpected pre-differentiation that is largely characteristic of M2-macrophage polarization, leading to the emergence of an unusual M2-like monocyte population with very high levels of CCR5. These results show that circulating monocytes in patients with severe COPD possess a cellular phenotype which may permit greater mobilization to the lung, with a pre-existing bias toward a potentially destructive inflammatory phenotype.
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A novel application of the Staudinger ligation to access neutral cyclic di-nucleotide analog precursors via a divergent methodOur efforts to develop a scalable and divergent synthesis of cyclic di-nucleotide analog precursors have resulted in (1) an orthogonally protected di-amino carbohydrate as well as (2) the novel application of the Staudinger ligation to provide medium-sized macrocycles featuring carbamate or urea linkages.
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An exploration of some magnetic fundamentals in EuSe using μSREuSe is a simple magnetic system that appears to show many complicated features. Under applied pressure it undergoes a transition from an antiferromagnet (AF) to a ferromagnet (FM). This transition provides a means of testing certain basic fundamentals of magnetic theory and an opportunity to explore the complexities of EuSe. Using the muon-spin rotation and relaxation technique (μSR), EuSe was measured at pressures ranging from ambient to 11 kbar. In ambient-pressure EuSe, muon data reveal two local fields, but show only a single field in the FM state formed under pressure. The μSR measurements appear to show a continuous transition at Tc, contrary to previous Mössbauer results that were interpreted as being evidence of a first-order transition. Values determined for the critical exponent, β, in AF and FM EuSe, differ and therefore appear to be a clear counterexample to the Universality Hypothesis. The values of β also are indicative of EuSe’s being a 2D magnet for pressures up to 11 kbar. The nature and values of the local fields seen by the muons is discussed and analyzed.
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Investigating undergraduate students’ ideas about the fate of the UniverseAs astronomers further develop an understanding of the fate of the Universe, it is essential to study students’ ideas on the fate of the Universe so that instructors can communicate the field’s current status more effectively. In this study, we examine undergraduate students’ preinstruction ideas of the fate of the Universe in ten semester-long introductory astronomy course sections (ASTRO 101) at three institutions. We also examine students’ postinstruction ideas about the fate of the Universe in ASTRO 101 over five semester-long course sections at one institution. The data include precourse surveys given during the first week of instruction (N=264), postinstruction exam questions (N=59), and interviews. We find that, preinstruction, more than a quarter of ASTRO 101 students either do not respond or respond with “I don’t know” when asked what the long-term fate of the Universe is. We also find that, though the term was not necessarily used, students tend to describe a “big chill” scenario in the preinstruction surveys, among a wide variety of other scenarios. A fraction of students describe the fate of smaller-scale systems, possibly due to confusion of the hierarchical nature of structure in the Universe. Preinstruction, students mention the Universe’s expansion when describing how astronomers know the fate of the Universe but do not discuss how we know the Universe is expanding or the relationship between expansion and the fate of the Universe. Postinstruction, students’ responses shift toward greater degrees of completeness and correctness.
