Hyperpolarization induces a rise in intracellular sodium concentration in dopamine cells of the substantia nigra pars compacta

We investigated the effect of changes in membrane-voltage on intracellular sodium concentration ([Na+]i) of dopamine-sensitive neurons of the substantia nigra pars compacta in a slice preparation of rat mesencephalon. Whole-cell patch-clamp techniques were combined with microfluorometric measurements of [Na+]i using the Na+-sensitive probe, sodium-binding benzofuran isophthalate (SBFI). Hyperpolarization of spontaneously active dopamine neurons (recorded in current-clamp mode) caused the cessation of action potential firing accompanied by an elevation in [Na+]i. In dopamine neurons voltage-clamped at a holding potential of -60 mV elevations of [Na+]i were induced by long-lasting (45-60 s) voltage jumps to more negative membrane potentials (-90 to -120 mV) but not by corresponding voltage jumps to -30 mV. These hyperpolarization-induced elevations of [Na+]i were depressed during inhibition of I(h), a hyperpolarization-activated inward current, by Cs+. Hyperpolarization-induced elevations in [Na+]i might occur also in other cell types which express a powerful I(h) and might signal lack of postsynaptic activity.     

Adenovirus-Mediated Inducible Expression of a PD-L1 Blocking Antibody in Combination with Macrophage Depletion Improves Survival in a Mouse Model of Peritoneal Carcinomatosis

Immune checkpoint inhibitors (ICIs) have demonstrated remarkable efficacy in a growing number of malignancies. However, overcoming primary or secondary resistances is difficult due to pharmacokinetics issues and side effects associated with high systemic exposure. Local or regional expression of monoclonal antibodies (mAbs) using gene therapy vectors can alleviate this problem. In this work, we describe a high-capacity adenoviral vector (HCA-EFZP-aPDL1) equipped with a mifepristone-inducible system for the controlled expression of an anti-programmed death ligand 1 (PD-L1) blocking antibody. The vector was tested in an immune-competent mouse model of colorectal cancer based on implantation of MC38 cells. A single local administration of HCA-EFZP-aPDL1 in subcutaneous lesions led to a significant reduction in tumor growth with minimal release of the antibody in the circulation. When the vector was tested in a more stringent setting (rapidly progressing peritoneal carcinomatosis), the antitumor effect was marginal even in combination with other immune-stimulatory agents such as polyinosinic-polycytidylic acid (pI:C), blocking mAbs for T cell immunoglobulin, mucin-domain containing-3 (TIM-3) or agonistic mAbs for 4-1BB (CD137). In contrast, macrophage depletion by clodronate liposomes enhanced the efficacy of HCA-EFZP-aPDL1. These results highlight the importance of addressing macrophage-associated immunoregulatory mechanisms to overcome resistance to ICIs in the context of colorectal cancer.     

A universal design resource for rich Internet applications based on design patterns

Rich Internet applications have removed most of the constraints of Web 1.0 while giving users more responsiveness and advanced browsing and interaction experiences. These new horizons, however, raise many challenges for people with disabilities or using limited hardware and software technologies, whose risk to be excluded from the benefits deriving from advanced web applications. To address this problem, WCAG 2.0 guidelines have been released as the newest World Wide Web Consortium recommendation for accessible web content, and WAI-ARIA is a candidate recommendation which provides reference specifications for accessible rich Internet applications. However, both specifications contain a huge amount of information that often discourages most web designers from dealing with accessibility issues. Moreover, guidelines are suitable and usually adopted to judge a design solution a posteriori, but they do not suggest how to face a design problem constructively. This paper proposes a design pattern language for accessibility. The language can be regarded as a universal design resource for helping web designers create accessible rich Internet applications compliant with the most recent standards. Knowledge representation through design patterns reflects the problem-solving approach usually followed by software and web designers, while pattern organization in a structured language aims to guide web designers throughout the design process. The language has been implemented as an accessible rich Internet application itself, thus allowing designers with disabilities to participate in web design. In order to evaluate the design pattern language, a three-step process was carried out including: (1) a heuristic analysis with a group of human–computer interaction experts, (2) a survey study with a group of web designers, and (3) a validation on the field with two designers who have been requested to apply the language in real design cases.     

Disjunctive databases for representing repairs

This paper addresses the problem of representing the set of repairs of a possibly inconsistent database by means of a disjunctive database. Specifically, the class of denial constraints is considered. We show that, given a database and a set of denial constraints, there exists a (unique) disjunctive database, called canonical, which represents the repairs of the database w.r.t. the constraints and is contained in any other disjunctive database with the same set of minimal models. We propose an algorithm for computing the canonical disjunctive database. Finally, we study the size of the canonical disjunctive database in the presence of functional dependencies for both subset-based repairs and cardinality-based repairs.     

Approximation processes for resolvent operators

We introduce general sequences of linear operators obtained from classical approximation processes which are useful in the approximation of the resolvent operators of the generators of suitable C ₀-semigroups. The main aim is the representation of the resolvent operators in terms of classical approximation operators. Work performed under the auspices of PRIN 2006–07 “Kolmogorov equations” (coordinator G. Da Prato)     

Highly Conductive MXene/PEDOT:PSS-Integrated Poly(N-Isopropylacrylamide) Hydrogels for Bioinspired Somatosensory Soft Actuators

Sophisticated sensing and actuation capabilities of many living organisms in nature have inspired scientists to develop biomimetic somatosensory soft robots. Herein, the design and fabrication of homogeneous and highly conductive hydrogels for bioinspired somatosensory soft actuators are reported. The conductive hydrogels are synthesized by in situ copolymerization of conductive surface-functionalized MXene/Poly(3,4-ethylenedioxythiophene)/poly(styrenesulfonate) ink with thermoresponsive poly(N-isopropylacrylamide) hydrogels. The resulting hydrogels are found to exhibit high conductivity (11.76 S m⁻¹), strain sensitivity (GF of 9.93), broad working strain range (≈560% strain), and high stability after over 300 loading–unloading cycles at 100% strain. Importantly, shape-programmable somatosensory hydrogel actuators with rapid response, light-driven remote control, and self-sensing capability are developed by chemically integrating the conductive hydrogels with a structurally colored polymer. As the proof-of-concept illustration, structurally colored hydrogel actuators are applied for devising light-driven programmable shape-morphing of an artificial octopus, an artificial fish, and a soft gripper that can simultaneously monitor their own motions via real-time resistance variation. This work is expected to offer new insights into the design of advanced somatosensory materials with self-sensing and actuation capabilities, and pave an avenue for the development of soft-matter-based self-regulatory intelligence via built-in feedback control that is of paramount significance for intelligent soft robotics and automated machines.     

Integrating cognitive load theory and concepts of human–computer interaction

With the continually increasing complexity of e-learning environments, there is a need for integrating concepts of cognitive load theory (CLT) with concepts of human–computer interaction (HCI). Basic concepts of both fields were reviewed and contrasted. A literature review was conducted within the literature database “The Guide to Computing Literature,” searching for “cognitive load theory” and “Sweller.” Sixty-five publications contained “cognitive load” in their titles or abstracts. Each publication was checked to see whether it contained the concepts of intrinsic, extraneous, or germane cognitive load. The review showed that CLT concepts have been adopted in HCI. However, the concept of germane cognitive load has attracted less attention up to the present time. Two conceptual models are proposed. The first model divides extraneous cognitive load into load induced by the instructional design and load caused by software usage. The model clarifies the focus of traditional usability principles and of existing instructional design principles derived from CLT. The second model fits CLT concepts into the basic components of user-centered design. The concept of germane cognitive load illustrates that an increase of cognitive load can be desirable when designing e-learning environments. Areas for future interdisciplinary research are sketched.     

Sensitivity analysis in fuzzy systems: Integration of SimLab and DANA

This work addresses the sensitivity analysis on the settings of fuzzy inference systems where multiple, yet dissimilar inputs are aggregated and resolved into a single output. The JAVA platform-independent development environment DANA (Data Analysis aNd Assessment) includes components for computation of fuzzy-logic based rules guiding the fuzzification–aggregation–defuzzification process by alternative membership functions (of an input to belong to fuzzy sets) and weighing systems, and unlimited aggregation levels. The integration of the library for sensitivity analysis SimLab within DANA is illustrated using the Morris screening method to determine the relative importance ranking of fuzzy settings (lower and upper limits, weights) on the final defuzzified output. The assumptions about the settings of the analysis are also discussed using an illustrative example where sensitivity analysis is applied to the fuzzy inference system designed to evaluate analytical methods in the domain of genetically modified organisms.     

The fractional Fourier transform and quadratic field magnetic resonance imaging

The fractional Fourier transform (FrFT) is revisited in the framework of strongly continuous periodic semigroups to restate known results and to explore new properties of the FrFT. We then show how the FrFT can be used to reconstruct Magnetic Resonance (MR) images acquired under the presence of quadratic field inhomogeneity. Particularly, we prove that the order of the FrFT is a measure of the distortion in the reconstructed signal. Moreover, we give a dynamic interpretation to the order as time evolution of a function. We also introduce the notion of ρ-α space as an extension of the Fourier or k-space in MR, and we use it to study the distortions introduced in two common MR acquisition strategies. We formulate the reconstruction problem in the context of the FrFT and show how the semigroup theory allows us to find new reconstruction formulas for discrete sampled signals. Finally, the results are supplemented with numerical examples that show how it performs in a standard 1D MR signal reconstruction.