Although photodynamic therapy (PDT) is an effective, minimally-invasive therapeutic modality with advantages in highly localized and specific tumor treatments, large and deep-seated cancers within the body cannot be successfully treated due to low transparency to visible light. To improve the therapeutic efficiency of tumor treatment in deep tissue and reduce the side effects in normal tissue, this study developed a near-infrared (NIR)-triggered upconversion nanoparticle (UCNP)-based photosensitizer (PS) carrier as a novel theranostics system. The NaYF4:Yb/Er UCNPs were synthesized by a hydrothermal method, producing uniformly small size (≈20 nm) nanoparticles and crystalline morphology of the hexagonal phase. These UCNPs were modified with folic acid-conjugated biocompatible block copolymers through a bidentate dihydrolipoic acid linker. The polymer modified hexagonal phase UCNPs (FA-PEAH-UCNPs) showed an improved dispersibility in the aqueous solution and strong NIR-to-vis upconversion fluorescence. The hydrophobic PS, pheophorbide a (Pha), was then conjugated to the stable vectors through a pH-sensitive linkage. Moreover, these UCNP-based Pha carriers containing tumor targeting folic acid ligands exhibited the significantly enhanced cellular uptake efficiency as well as PDT treatment efficiency. These results suggested that this system could extend the excitation wavelength of PDT to the NIR region and effectively improve therapeutic efficiency of PSs.
The biodiverse Neotropical ecoregion remains insufficiently assessed, poorly managed, and threatened by unregulated human activities. Novel, rapid and cost-effective DNA-based approaches are valuable to improve understanding of the biological communities and for biomonitoring in remote areas. Here, we evaluate the potential of environmental DNA (eDNA) metabarcoding for assessing the structure and distribution of fish communities by analysing sediments and water from 11 locations along the Jequitinhonha River catchment (Brazil). Each site was sampled twice, before and after a major rain event in a five-week period and fish diversity was estimated using high-through-put sequencing of 12S rRNA amplicons. In total, 252 Molecular Operational Taxonomic Units (MOTUs) and 34 fish species were recovered, including endemic, introduced, and previously unrecorded species for this basin. Spatio-temporal variation of fish assemblages was detected, richness during the first campaign was nearly twice as high as in the second sampling round; though peaks of diversity were primarily associated with only four locations. No correlation between β-diversity and longitudinal distance or presence of dams was detected, but low species richness observed at sites located near dams indicates that these anthropogenic barriers might have an impact on local fish diversity. Unexpectedly high α-diversity levels recorded at the river mouth suggest that these sections should be further evaluated as putative “eDNA reservoirs” for rapid monitoring. By uncovering spatio-temporal changes, unrecorded biodiversity components, and putative anthropogenic impacts on fish assemblages, we further strengthen the potential of eDNA metabarcoding as a biomonitoring tool, especially in regions often neglected or difficult to access.
Acquired drug resistance syndrom (ADR) is one of the most important features associated with tumor treatment and it is therefore a~topic of intensive studies. We present two simple mathematical models reflecting different mechanisms of ADR with some Darwinian effects included. These effects allow resistant cells to become sensitive again. Basing on this mathematical approach we conclude that for constant continuous treatment, if no Darwinian effects are present then once resistant cells appear, sensitive cells are eliminated after a long time, independently of the mechanism of acquiring the resistance. However, with Darwinian effects the situation is a little better as the sensitive cells are not completely eliminated but they are still outcompeted by the resistant ones. Moreover, if the therapy is stopped resistant cells become dominated by sensitive cells and the situation changes completely in comparison to the case without Darwinian effects. We discuss these mechanisms on the example of gliomas.
The formulation and analysis of two operator Boundary-Domain Integral Equation systems for variable coefficient mixed BVP with in two dimensional domain is discussed. To analyse the two-operator approach, we applied one of its linear versions to the mixed (Dirichlet-Neumann) BVP for a linear second-order scalar elliptic variable-coefficient PDE and reduced it to four different BDIE systems. %The two-operator BDIE systems are nonstandard systems of equations containing integral operators defined on the domain under consideration and potential type and pseudo-differential operators defined on open sub-manifolds of the boundary. Using the results as in CMN09 andAM11, a rigorous analysis of the two-operator BDIE systems is given and it is shown that they are equivalent to the mixed BVP and thus are uniquely solvable, while the corresponding boundary domain integral operators are invertible in the appropriate Sobolev-Slobodetski (Bessel potential) spaces.
Primary biliary cholangitis (PBC) is an immune-mediated chronic cholestasis. The disruption of T cell homeostasis plays an important role in PBC pathogenesis. Lysosomal associated membrane protein 2 isoform A (LAMP-2A) has been implicated in the regulation of CD4+ T cell responses, therefore we aim to evaluate the activation state of CD4+ T cells in PBC, and to investigate the role of LAMP-2A in it. The peripheral blood of PBC patients (PBC, n=42) and healthy controls (HC, n=20) were phenotypically analyzed, and LAMP-2A expression in CD4+ T cells was assessed by flow cytometry. Naïve CD4+ T cells of PBC patients were isolated and activated in vitro to estimate their activation responses. Additionally, we assessed the changes induced by silencing LAMP-2A expression. We found that CD4+ T cells of PBC patients exhibited significant hyperactivity, and naïve CD4+ T cells showed high LAMP-2A expression, which could be a novel biomarker for PBC activity. Moreover, by interfering with LAMP-2A expression in vitro, the overreactions of PBC naïve CD4+ T cells were reversed. Our study will help to clarify that increased LAMP-2A expression in the naïve CD4+ T cells of PBC patients may lead to a tendency for increased activation responses, which may be involved in the development and progression of PBC. To reverse the hyperactivity of CD4+ T cells and reduce the resulting biliary injury, LAMP-2A could be a novel therapeutic target for the treatment of PBC.
Mycorrhizal fungi alter their host plant’s resistance to herbivores and their competitive ability. However, most studies on how mycorrhizae alter resistance have been conducted in single plant studies, and so the interacting effects of mycorrhizae and competition on constitutive and induced plant resistance is largely unexplored. We tested whether mycorrhizal colonization with Rhizophagus intraradice would alter herbivore performance and the expression of chemical resistance traits in tomato plants with and without intraspecific competition. We treated the plants with jasmonic acid to measure their induced chemical resistance traits which we evaluated by measuring leaf consumption by Trichoplusia ni caterpillars and two traits that affect herbivore performance: protease inhibitors, an antinutritive protein, and carbon/nitrogen ratio, a metric of plant nutritional quality. Mycorrhizae decreased resistance (increased leaf consumption) to herbivores when the plants were not in competition but had no effect in competition. While mycorrhizae reduced protease inhibitors, independent of competition or treatment with jasmonic acid, this did not increase caterpillar feeding. However, mycorrhizae, competition and induction with jasmonic acid interacted to decrease plant nutrition, measured as C/N ratio, which was correlated with caterpillar feeding. Here, we show that mycorrhizae induced decreases in plant nutritional quality; a novel mechanism by which mycorrhizae affect resistance to herbivores. Mycorrhizae and competition interact to decrease plant nutritional quality and alter resistance to herbivores.
A combined experimental work and molecular electron density theory (MEDT) analysis was performed to reveal the strict click of 1,2,3-triazole derivatives by Ag(I)-catalyzed azide-alkyne cycloaddition (AgAAC) reaction and its corresponding mechanistic pathway. Such straightforward protocol for the click formation of 1,4-disubstituted-1,2,3-triazoles makes use of AgCl as catalyst in water as solvent under ambient conditions., with excellent yields and simple experimental work-up. MEDT study was performed by using DFT calculations at the B3LYP/6-31G(d,p) (LANL2DZ for Ag) level in order to understand the observed regioselectivity in AgAAC reactions, and to delineate the number of silver(I) species and their roles in this clickable 1,2,3-triazole formation. The comparison of the mononuclear Ag(I)-acetylide and binuclear Ag(I)-acetylide in the AgAAC reaction paths concerning the AgAAC reactions, shows that the values of the energy barriers for the binuclear processes are smaller than that of the mononuclear one. The intramolecular nature of these AgAAC reactions accounts for the regioselective formation of the 1,4-regiosisomeric triazole derivatives. The ionic nature of the starting metallated species is revealed for the first time, ruling out any covalent interaction involving the silver(I) complexes throughout the reaction as supported by the ELF topological analysis of the electronic structure of the stationary points, reaffirming the zw-type mechanism of the AgAAC reactions.
In this paper I focus on the FDA regulation of medical treatments. As a matter of fact, since the advent of drug regulation in 1962, we have a variety of standards for testing the safety and the efficacy of treatments and products. I want to make explicit the reasons for explaining that variety. Here I argue that medical regulatory schemes are grounded on an implicit socio-political consensus on the risks involved by different medical interventions: the bigger the threat, the stricter the testing standards. Finally, by analysing the concept of risk, I claim that, from the point of view of regulators, innovative drugs might be not very different from medical devices or even surgical procedures, therefore lower testing standards are more defensible than what critics usually think.
1. Wild animal populations typically harbour multiple parasite species, which can interact in various ways depending on the species involved and the state of the host upon infection. While many pairwise parasite interactions and within-guild parasite communities have been characterised, understanding how an interaction network spanning multiple parasite groups might be mediated has been less commonly explored. 2. We aimed to characterise parasites associations across guilds in a wild population of a model species, allowing for comparisons with existing laboratory-based research, and better understanding of how any observed associations might manifest within the host. 3. We used cross-sectional data from an island population of the house mouse, Mus musculus domesticus, to identify associations between a broad range of parasite species, including blood-borne microparasites, arthropod ectoparasites, and gastrointestinal and hepatic helminths. 4. Every recorded species was found to exist within a framework of positive and negative associations, involving multiple between-guild associations, and with the under-studied helminth species Calodium hepaticum playing a central role. 5. This study highlights the need to account for as many infections as possible when studying naturally infected populations, due to the prevalence of inter-species associations. Various potential mechanisms, including immunological and ecological, are suggested to explain how these associations might occur. Comparisons with analogous laboratory research from the same species are explored. A need for longitudinal study to determine causality of interactions is highlighted.
In this paper, the Dirichlet and Neumann boundary value problems for the steady-state Stokes system of partial differential equations for a compressible viscous fluid with variable viscosity coefficient is considered in two-dimensional bounded domain. Using an appropriate parametrix, this problem is reduced to a system of direct segregated boundary-domain integral equations (BDIEs). The BDIEs in the two-dimensional case have special properties in comparison with the three dimension because of the logarithmic term in the parametrix for the associated partial differential equations. Consequently, we need to set conditions on the function spaces or on the domain to ensure the invertibility of corresponding parametrix-based hydrodaynamic single layer and hypersingular potentials and hence the unique solvability of BDIEs. Equivalence of the BDIE systems to the Dirichlet and Neumann BVPs and the invertibility of the corresponding boundary-domain integral operators in appropriate Sobolev spaces are shown.
In this paper, we deal with the wave equation with acoustic boundary conditions. The exponential stabilization is obtained by Lyapunov approach and Riemannian geometry method. We then apply our main theorem to the wave equations with memory type acoustic boundary conditions, which is not available in the literature and give an example in the end.
In this paper, the Boundary-Domain Integral Equations (BDIEs) for the mixed boundary value problem(BVP) for a compressible Stokes system of partial differential equation(PDE) with variable coefficient in 2D is considered . An appropriate parametrix is used to reduce this BVP to the BDIEs. Although the theory of BDIEs in 3D is well developed, the BDIEs in 2D need a special consideration due to their different equivalence properties. As a result, we need to set conditions on the domain or on the spaces to ensure the invertibility of corresponding parametrix-based integral layer potentials and hence the unique solvability of BDIEs. The properties of corresponding potential operators are investigated. Equivalence of the BDIE systems to the mixed BVP and invertibility of the matrix operators associated with the BDIE systems in appropriate Sobolev spaces are proved.
The main prospect of this proposed work is to confer an algebraic theory for analyzing fractional singular systems. A modern class of linear fractional singular delay systems with two orders are proposed. The key notion used in the enlargement is the decomposition form for matrix regular pencils. As crucial issue, a procedure for computation of reachable set, and control input of addressed system is acquainted. The considerations are illustrated by suitable examples.
Vulnerability assessment has become a critical issue and an important approach for regional sustainable development. The Qinghai Province, located in the northeastern part of the Qinghai-Tibet Plateau, suffers a severe grassland degradation caused by climate change and human activities. The degradation constrains the development of local animal husbandry and further affects the vulnerability of social system. In this study, based on the vulnerability assessment framework of exposure-sensitivity-adaptability, two index systems were established including ecological and social aspects. The entropy weight method was used to determine the index weight. The dynamic changes of the ecological vulnerability and social vulnerability of Qinghai province were assessed from 1995 to 2015. Results indicated that ecological vulnerability in Qinghai province increased from eastern part to the west, and decreased from northern to southern part, while social vulnerability showed an opposite trend. Key ecologically fragile areas were mainly located in the Qaidam Basin and western Three-River Headwaters Region (TRHR), while key social vulnerability areas were mainly distributed in the Qilian Mountains and eastern Qinghai province. The overall ecological vulnerability showed a decreasing trend through time, but increased in several local areas. Social vulnerability dropped significantly, especially in the eastern part of Qinghai province. The results will help to identify key vulnerable areas of Qinghai province and provide references for the ecological protection and restoration and the formulation of ecosystem management policies.
Turtles have been prominent subjects of analyses of sexual size dimorphism (SSD) owing to their mating system and habitat diversity. In prior studies, marine turtles were grouped with non-marine aquatic turtles (NMAT). This is odd because it is well-established that the marine environment imposes a distinct selective milieu on body form of vagile vertebrates, driven by convergent adaptations for energy-efficient propulsion and drag reduction. We generated a comprehensive database of adult marine turtle body size (38,569 observations across all species), which we then used to evaluate both the magnitude of SSD in marine turtles and how it compares to SSD in NMAT. We find that marine turtles are not sexually size dimorphic, whereas NMAT typically exhibit female-biased SSD. We argue that the reason for this difference is the sustained long-distance swimming that characterises marine turtle ecology, which entails significant energetic costs incurred by both sexes. Hence, the ability of either sex to allocate proportionately more to growth than the other is likely constrained, meaning that sexual differences in growth and resultant body size are not possible. Consequently, lumping marine turtles with NMAT dilutes the statistical signature of different kinds of selection on SSD and should be avoided in future studies.
Rationale, aims and objectives: Little is known about the effect of electronic audit and feedback (A&F) in primary care and its features affecting intervention effectiveness. The aim of this systematic review is: 1) to assess electronic A&F’s effectiveness in primary care and 2) to investigate facilitating factors of electronic A&F in primary care, as proposed in previous research. These factors are the use of benchmarks, frequency, cognitive load and evidence-based aspect of the feedback. Methods: The authors searched MEDLINE, Embase, CINAHL and CENTRAL from 2010 onwards by replicating the search strategy provided in the last Cochrane review on A&F. Two independent reviewers assessed the records for their eligibility, performed the data extraction and evaluated the risk of bias of the included studies using a tool provided by Cochrane. Results: Our search resulted in 8,744 records, including the 140 RCTs from the last Cochrane Review, of which 431 full-text articles were assessed for their eligibility. Twenty-nine articles were included, of which 22 studies (76%) showed an effect of the electronic A&F intervention. Of these, only 3 studies (10.5%), targeting the quality of diabetes care and the prescription of antibiotics by dentist & physicians, met all the investigated feedback features and were effective. There was a high heterogeneity in the results and the design of the A&F interventions, causing a meta-analysis to be unreliable. Conclusion: This systematic review included 29 articles describing an electronic A&F intervention in primary care, of which 22 studies (76%) showed an effect of the intervention. It was not feasible to compare the different electronic A&F interventions and their facilitating factors because they were designed and implemented very diversely. Developing a framework or methodology for automated A&F interventions in primary care could be useful for investigating future interventions although further research is necessary.
Objectives: Older adults living in long-term care facilities (LTCFs) are particularly at risk during transitions in care, most notably from acute care back to their LCTF. Issues surrounding miscommunication of information or medications are often mentioned as important challenges. Transitional care interventions (TCi) have emerged as solutions to improve outcomes. The objective of this review was therefore to determine the effects of TCi on several indicators of quality of care, clinical outcomes, healthcare services use and satisfaction among older patients discharged from acute care to LTCFs. Methods: Medline, CINAHL, EMBASE, Cochrane Central and Social Work Abstracts were searched. Study selection (title/abstract, full-text), data extraction and assessment of study quality were conducted by two independent reviewers. A narrative synthesis of the data was performed. Results: From the 5,506 references identified, 11 were included. Eight studies reported on quality of care: six on medication problems, and two on advance directives. Four studies reported on clinical outcomes: three on mortality, two on mobility/function and one on confusion/behavioral symptoms. Seven studies reported on healthcare services use: six on hospital readmissions/ED visits, and five on hospital days. Three studies reported on satisfaction with TCi. While satisfaction levels were high with TCi, other outcomes were inconclusive. Medications problems appeared to be the outcome most likely to benefit from TCi. Discussion: TCi targeting the acute to long-term care transition have obtained inconclusive results so far. More studies investigating the outcomes of quality of care, clinical outcomes, healthcare services use are needed.
Due to the Doppler effect in waves, one can't efficiently transmit signals underwater. This paper takes you to novel approaches that utilize sonar conversion techniques as well as different UART communication methods and software defined networking mechanisms, in order to build underwater wireless networks. The case for UWNs being utilized for oceanic colonization is also presented, as well as how this applies to the creation of "Aquatic IOT type technologies" and new forms of telemetry. Presented in this paper are concepts that were deployed by the Stark Drones Corporation in competing for various challenges such as "The Internet of H2O Challenge" and GigabitDCx. Also presented, is a proposal to apply these technologies for monitoring lake contamination and various forms of e-coli buildup as well as phosphorus run-ons. These networks allow for a cleaner, more sustainable and observable ocean.