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关键词： Conformable   Neutral type stochastic functional differential equations   Exponential stability   Ulam's type stability  

摘要： This paper studies conformable stochastic functional differential equations of neutral type. Firstly, the existence and uniqueness theorem of a solution is established. Secondly, the moment estimation and exponential stability results are given. Thirdly, the Ulam type stability in mean square is discussed. Finally, two examples are given to illustrate our results.

关键词： cognitive impairment   differential misclassification   hip fracture   sex   under-recognized  

摘要： Background Males have worse outcomes after hip fracture than female counterparts. Cognitive impairment (CI) also increases the risk of poor recovery from hip fracture;however, CI is under-recognized. Patient sex may contribute to this under-recognition through differential misclassification. The objective of this study was to measure under-recognition and differential misclassification of CI by patient sex. Methods A cross-sectional analysis of baseline data from an observational cohort study of community-dwelling hip fracture patients aged 65 and older (n = 339;females = 171, males = 168) recruited from eight hospitals in the greater Baltimore, MD area within 15 days of hospitalization for surgical repair with cognitive testing within 22 days of admission. Indication of Alzheimer's disease or related dementias and/or delirium as a postoperative complication in the medical record was considered evidence of documented CI. Observed CI was measured with the Modified Mini-Mental State Examination (3MS, <= 78). Source of cognitive impairment identification (SCI) was defined as: "3MS Only," "Hospital Record Only," "Both," "No CI" was compared between males and females using logistic regression. Results Males had more comorbidities and worse physical status upon admission, but otherwise had similar hospital experiences. SCI distribution was 12.7% "3MS Only" (n = 42), 11.5% "Hospital Record Only" (n = 38), 9.4% "Both" (n = 31), and "No CI" (n = 219). Males were more likely to be identified with CI using the "3MS Only" and "Both," and females were more likely to have no indication of CI. Conclusion There were sex differences in the documentation of CI versus observed impairment. Males had more CI using direct testing. This may be contributing to sex differences in recovery outcomes after hip fracture. Results support the implementation of cognitive testing in hip fracture patients to reduce the impact of differential misclassification by patient sex.

关键词： ErbB3   HER3   Cancer therapy   Hybridoma   Monoclonal antibodies  

摘要： Purpose The therapeutic potential of targeting the human epidermal growth factor receptor-3 (ErbB3/HER3) has long been ignored due to impaired tyrosine kinase function and low expression level in tumor cells compared with EGFR and HER2. Although recent investigations have explored the potential benefit of HER3 targeting and several anti-HER3 agents have been developed, there is still a critical need to design and produce more efficient therapeutics. This study was designed to develop tumor inhibitory monoclonal antibodies (MAbs) against different extracellular subdomains of HER3. Methods Distinct extracellular subdomains of HER3 (DI+II and DIII+IV) were utilized to produce MAbs by hybridoma technology. Biochemical and functional characteristics of these MAbs were then investigated by various methodologies, including immunoblotting, flow cytometry, cell proliferation, cell signaling, and enzyme-linked immunosorbent assays. Results Four anti-DI+II and six anti-DIII+IV MAbs were obtained, selected based on their ability to bind recombinant full HER3 extracellular domain (ECD). Our data showed that only one anti-DI+II and four anti-DIII+IV MAbs recognized the native form of HER3 by immunoblotting. Four MAbs recognized the membranous HER3 by flow cytometry leading to induction of different levels of receptor internalization and subsequent degradation. Results of cell proliferation assays using these MAbs indicated that they differentially inhibited proliferation of HER3-expressing cancer cells and showed considerable synergistic effects in combination with trastuzumab. Selected MAb with the highest inhibitory effect significantly inhibited the phosphorylation of AKT and ERK1/2 molecules. Conclusion Some of the anti-HER3 MAbs produced in this study displayed tumor inhibitory function and may be considered promising candidates for future HER3-targeted cancer therapy.

关键词： high salt diet and hypertension   sex differences   small resistance arteries   vascular elasticity   vascular structure and function  

摘要： Background: Increase in vascular stiffness is associated with a higher risk of cardiovascular morbidity and mortality and is likely sex-specific. Method: Our objectives were to compare structural and functional alterations in small resistance arteries as related to vascular stiffness from Dahl salt-sensitive male and female rats (n = 8, mean +/- s.e.m.). Results: Arterial blood pressure and pulse wave velocity were significantly (P < 0.05) elevated in males (161 +/- 3 mmHg;6.4 +/- 0.2 m/s) and females (147 +/- 2 mmHg;5.5 +/- 0.1 m/s) on a high (H) salt compared with regular (R) diets but were significantly higher in males (H) than in all others. Significant increases in collagen and smooth muscle cell areas were evident in ultrastructure of mesenteric arteries of hypertensive males compared to normotensive or corresponding females. There were no significant differences in composite Young's modulus (CYM) between groups. Vasoconstriction resulted in significantly higher CYM in male (H: 8.6 +/- 1 KPa) than R (4.5 +/- 0.8 KPa), and the corresponding females (H: 5.6 +/- 0.6 KPa and R: 5 +/- 0.9 KPa). In contrast, vasodilation significantly reduced CYM in the male groups (H: 2.5 +/- 0.4 KPa and R: 2.7 +/- 0.5 KPa) compared with the corresponding values in females (H: 4.2 +/- 0.6 KPa and R: 5 +/- 0.5 KPa). Moreover, the slope of pressure-volume curves revealed significantly greater distended vascular compliance in male H than R, and the corresponding females. Conclusion: Our findings are supportive of a link between high salt intake and elevated blood pressure as being sex specific, likely involving sex-dependent changes in ultrastructure of the vessels, which ultimately may alter the biomechanics, and thus, the haemodynamic functions of both macro-circulation and micro-circulations.

关键词： circulator   differential   magnetless   nonreciprocity   spatiotemporal modulation bias  

摘要： This article presents a magnetless differential microstrip circulator for high frequency operation. The differential design is obtained by pairing two single-ended (SE) circulators, each based on three resonators connected in a wye topology with spatiotemporal modulation (STM). What is more, the STM biases of the two SE circulators are kept a fixed 180 degrees phase difference. The resonance of the circuit is realized by varactor-loaded microstrip line sections rather than conventional series of inductor and varactor. The design method of the proposed microstrip circulator has been presented by analyzing its equivalent circuit, which indicates the microstrip line sections cannot be simply equivalent to inductors with the conventional method. The analysis of the time-varying circuit is verified by the simulated results of both the microstrip circulator and its equivalent circuit. A magnetless microstrip circulator was designed, fabricated and measured at center frequency of 1.99 GHz, showing maximum isolation (IX) of more than 50 dB, minimum insertion loss of 4.8 dB, and 1.4% 20 dB IX bandwidth.

关键词： Transplant rejection   Nr4A1   CD4+T cells   Apoptosis   Regulatory T cells  

摘要： CD4+T cell-mediated acute rejection remains a major factor that affects the early survival of transplanted organs post-transplantation. Here, we reveal that nuclear receptor subfamily 4 Group A member 1 (Nr4A1) was upregulated during cardiac allograft rejection and that the increased Nr4A1 was primarily localized in intragraftinfiltrating CD4+T cells. Nr4A1 acts as a transcription factor with an important role in CD4+T cell apoptosis, differentiation and T cell dysfunction, which indicates that Nr4A1 may play a critical role in transplant rejection. Cytosporone B (Csn-B) is a naturally occurring agonist of Nr4A1, and the role of Csn-B in the physiological process of cardiac rejection is poorly defined. This study constructed an acute rejection model of abdominal heterotopic cardiac transplantation in mice and investigated whether Csn-B could attenuate acute transplant rejection by modulating the CD4+T lymphocyte response. The results showed that Csn-B prolonged murine cardiac allograft survival and reduced inflammation in allografts. Subsequently, it was confirmed that Csn-B functions by inducing non-Treg apoptosis and promoting Treg cell differentiation. Finally, we also confirmed that Csn-B attenuates acute rejection by directly targeting Nr4A1 in CD4+T cells. Our data suggest that Csn-B is a promising novel therapeutic approach for acute cardiac allograft rejection.

关键词： Vascular endothelium   VCAM1 promoter haplotypes   TNF-alpha   Heme   Hydroxyurea   Sickle cell anemia  

摘要： Endothelial dysfunction plays a major role in sickle cell anemia (SCA) systemic vasculopathy, with upregulation of adhesion molecules (e.g., VCAM-1), decreased nitric oxide bioavailability, and oxidative stress. We aimed to assess the modulation role of pro-inflammatory and pro-oxidative stimuli on endothelial VCAM1, NOS3, and HMOX1 expression. We also evaluated the effect of the main SCA therapeutic agent, hydroxyurea, on that modulation. Our results showed that two VCAM1 promoter haplotypes, we previously associated with pediatric cerebral vasculopathy and severe hemolysis in SCA, increased promoter activity in TNF-alpha-stimulated transfected EA. hy926 and HBEC cell lines, consistent with a higher VCAM1 expression in macro and microvascular settings. In non-transfected cells, we also observed TNF-alpha-induced VCAM1 overexpression as well as heme-induced overexpression of HMOX1 in both cell models. Heme did not affect VCAM1 nor NOS3 expression and the latter was also not affected by TNF-alpha stimulus. Hydroxyurea treatment lowered TNF-induced VCAM1 and NOS3 expression but did not affect heme-induced HMOX1 expression. These data further indicate that VCAM1 haplotypes we studied lead to higher VCAM1 expression affecting not only cerebral but also systemic vasculopathy risk. The differential endothelial expression of VCAM1, NOS3, and HMOX1 also confirms their genetic modulation role in SCA systemic vasculopathy.

摘要： Multiomic analysis of transcriptional and metabolic responses from the predatory myxobacteria Myxococcus xanthus and Cystobacter ferrugineus exposed to prey signalling molecules of the acylhomoserine lactone and quinolone quorum signalling classes provided insight into predatory specialization. Acylhomoserine lactone quorum signals elicited a general response from both myxobacteria. We suggest that this is likely due to the generalist predator lifestyles of myxobacteria and ubiquity of acylhomoserine lactone signals. We also provide data that indicates the core homoserine lactone moiety included in all acylhomoserine lactone scaffolds to be sufficient to induce this general response. Comparing both myxobacteria, unique transcriptional and metabolic responses were observed from Cystobacter ferrugineus exposed to the quinolone signal 2-heptylquinolin-4(1H)-one (HHQ) natively produced by Pseudomonas aeruginosa. We suggest that this unique response and ability to metabolize quinolone signals contribute to the superior predation of P. aeruginosa observed from C. ferrugineus. These results further demonstrate myxobacterial eavesdropping on prey signalling molecules and provide insight into how responses to exogenous signals might correlate with prey range of myxobacteria.

关键词： Delay differential equations   Multi-segment boundary-value problems   Implicitly defined manifolds   Problem regularization   Constrained optimization   Lagrange multipliers   Adjoint equations   Graph representations   Phase response curves  

摘要： This paper treats comprehensively the construction of problems from nonlinear dynamics and constrained optimization amenable to parameter continuation techniques and with particular emphasis on multi-segment boundary-value problems with delay. The discussion is grounded in the context of the coco software package and its explicit support for community-driven development. To this end, the paper first formalizes the coco construction paradigm for augmented continuation problems compatible with simultaneous analysis of implicitly defined manifolds of solutions to nonlinear equations and the corresponding adjoint variables associated with optimization of scalar objective functions along such manifolds. The paper uses applications to data assimilation from finite time histories and phase response analysis of periodic orbits to identify a universal paradigm of construction that permits abstraction and generalization. It then details the theoretical framework for a coco-compatible toolbox able to support the analysis of a large family of delay-coupled multi-segment boundary-value problems, including periodic orbits, quasiperiodic orbits, connecting orbits, initial-value problems, and optimal control problems, as illustrated in a suite of numerical examples. The paper aims to present a pedagogical treatment that is accessible to the novice and inspiring to the expert by appealing to the many senses of the applied nonlinear dynamicist. Sprinkled among a systematic discussion of problem construction, graph representations of delay-coupled problems, and vectorized formulas for problem discretization, the paper includes an original derivation using Lagrangian sensitivity analysis of phase response functionals for periodic-orbit problems in abstract Banach spaces, as well as a demonstration of the regularizing benefits of multi-dimensional manifold continuation for near-singular problems analyzed using real-time experimental data.

关键词： Atmospheric pressure  

摘要： Differential ion mobility (DMS) is a versatile ion separation method that is often integrated with mass spectrometry (MS). In DMS, extremely high electric fields are used such that ion mobility depends non-linearly on electric field and thus, ion separations can be more orthogonal to MS than lower field ion mobility-based methods. DMS can have sufficiently high resolution to be used for enantiomer analysis of small molecules and to separate protein ions with peak widths comparable to those obtained for peptides. However, the performance of high resolution DMS-MS can be limited owing to the substantial loss of ions (>10-fold) that can occur upon their transfer from atmospheric pressure (where DMS separation typically occurs) to vacuum through a narrow conductance limited inlet (e.g. capillary) to the MS. Here, results from simulated ion trajectory simulations suggest that in high resolution DMS most ions can be lost by 'crashing' onto the narrow capillary inlet after exiting the DMS separation channel. To enhance DMS sensitivity and resolving power, an integrated DMS-MS interface concept is reported that consists of a slit electrode and a 12-electrode atmospheric pressure ion funnel (APIF). By using an APIF with slit entrance, the simulated ion transmission efficiencies increase by up to 257% for singly charged ions ([DMMP + H](+), [tryptophan + H](+), and [(2-dodecanone)(2) + H](+)) and by 209% for [ubiquitin + 12H](12+), without compromising resolving power. The use of APIF improves the ion focussing from the DMS exit to the MS capillary to improve sensitivity, and the slit ensures that ion dispersion in the analytically relevant direction perpendicular to the DMS electrodes is restricted to enhance resolution. By narrowing the slit of the DMS-Slit-APIF interface, the DMS resolving power can be increased further by at least 20%. Overall, these results indicate that the integrated DMS-Slit-APIF interface is promising for improving the sensitivity and resolution for