EFFECT OF POTASSIUM CHANNEL MODULATORS IN MOUSE FORCED SWIMMING TEST

1. The effect of intracerebroventricular (i.c.v.) administration of different potassium channel blockers (tetraethylammonium, apamin, charybdotoxin, gliquidone), potassium channel openers (pinacidil, minoxidil, cromakalim) and aODN to mKv1.1 on immobility time was evaluated in the mouse forced swimming test, an animal model of depression. 2. Tetraethylammonium (TEA; 5 μg per mouse i.c.v.), apamin (3 ng per mouse i.c.v.), charybdotoxin (1 μg per mouse i.c.v.) and gliquidone (6 μg per mouse i.c.v.) administered 20 min before the test produced anti-immobility comparable to that induced by the tricyclic antidepressants amitriptyline (15 mg kg(−1) s.c.) and imipramine (30 mg kg(−1) s.c.). 3. By contrast pinacidil (10–20 μg per mouse i.c.v.), minoxidil (10–20 μg per mouse i.c.v.) and cromakalim (20–30 μg per mouse i.c.v.) increased immobility time when administered in the same experimental conditions. 4. Repeated administration of an antisense oligonucleotide (aODN) to the mKv1.1 gene (1 and 3 nmol per single i.c.v. injection) produced a dose-dependent increase in immobility time of mice 72 h after the last injection. At day 7, the increasing effect produced by aODN disappeared. A degenerate mKv1.1 oligonucleotide (dODN), used as control, did not produce any effect in comparison with saline- and vector-treated mice. 5. At the highest effective dose, potassium channels modulators and the mKv1.1 aODN did not impair motor coordination, as revealed by the rota rod test, nor did they modify spontaneous motility as revealed by the Animex apparatus. 6. These results suggest that modulation of potassium channels plays an important role in the regulation of immobility time in the mouse forced swimming test

A General Framework for Accelerator Management Based on ISA Extension

Thanks to the promised improvements in performance and energy efficiency, hardware accelerators are taking momentum in many computing contexts, both in terms of variety and relative weight in the silicon area of many chips. Commonly, the way an application interacts with these hardware modules has many accelerator-specific traits and requires ad-hoc drivers that usually rely on potentially expensive system calls to manage accelerator resources and access orchestration. As a consequence, driver-based interfacing is far from uniform and can expose high latency, limiting the set of tasks suitable for acceleration. In this paper, we propose a uniform and low-latency interface based on Instruction Set Architecture (ISA) extension. All the previous studies that proposed extensions, were deeply tailored to address a single accelerator. One of the biggest disadvantages of those methods is their inability to scale. Adding more of these accelerators to one System-on-Chip (SoC) would result in ISA bloat, increasing power consumption and complexifying the decoding phase proportionally. Our proposed framework consists of a six-instruction ISA extension and the corresponding architectural support that implements the interface abstraction and the reservation logic at the hardware level. Our proposal allows controlling a broad class of integrated accelerators directly from the CPU. The proposed framework is ISA-independent, which means that it is applicable to all the existing ISAs. We implement it on the gem5 simulator by extending the RISC-V ISA. We evaluate it by simulating three compute-intensive accelerators and comparing our interfacing with a conventional driver-based one. The benchmarks highlight the performance benefits brought by our framework, with up to 10.38x speed up, as well as the ability to seamlessly support different accelerators with the same interface. The speed up advantage of our technique diminishes as the granularity of the workloads increases and the overhead for driver-based accelerators becomes less important. We also show that the impact of its hardware components on chip area and power consumption is limited

IXIAM: ISA EXtension for Integrated Accelerator Management

During the last few years, hardware accelerators have been gaining popularity thanks to their ability to achieve higher performance and efficiency than classic general-purpose solutions. They are fundamentally shaping the current generations of Systems-on-Chip (SoCs), which are becoming increasingly heterogeneous. However, despite their widespread use, a standard, general solution to manage them while providing speed and consistency has not yet been found. Common methodologies rely on OS mediation and a mix of user-space and kernel-space drivers, which can be inefficient, especially for fine-grained tasks. This paper addresses these sources of inefficiencies by proposing an ISA eXtension for Integrated Accelerator Management (IXIAM), a cost-effective HW-SW framework to control a wide variety of accelerators in a standard way, and directly from the cores. The proposed instructions include reservation, work offloading, data transfer, and synchronization. They can be wrapped in a high-level software API or even integrated into a compiler. IXIAM features also a user-space interrupt mechanism to signal events directly to the user process. We implement it as a RISC-V extension in the gem5 simulator and demonstrate detailed support for complex accelerators, as well as the ability to specify sequences of memory transfers and computations directly from the ISA and with significantly lower overhead than driver-based schemes. IXIAM provides a performance advantage that is more evident for small and medium workloads, reaching around 90x in the best case. This way, we enlarge the set of workloads that would benefit from hardware acceleration

Frequency Scaling as a Security Threat on Multicore Systems

Most modern processors use Dynamic Voltage and Frequency Scaling (DVFS) for power management. DVFS allows to optimize power consumption by scaling voltage and frequency depending on performance demand. Previous research has indicated that this frequency scaling might pose a security threat in the form of a covert channel, which could leak sensitive information. However, an analysis able to determine whether DVFS is a serious security issue is still missing. In this paper, we conduct a detailed analysis of the threat potential of a DVFS-based covert channel. We investigate two multicore platforms representative of modern laptops and hand-held devices. Furthermore, we develop a channel model to determine an upper bound to the channel capacity, which is in the order of 1 bit per channel use. Last, we perform an experimental analysis using a novel transceiver implementation. The neural network based receiver yields packet error rates between 1% and 8% at average throughputs of up to 1.83 and 1.20 bits per second for platforms representative of laptops and hand-held devices, respectively. Considering the well-known small message criterion, our results show that a relevant covert channel can be established by exploiting the behaviour of computing systems with DVFS.ISSN:0278-0070ISSN:1937-415

Exopolysaccharides from vaginal lactobacilli modulate microbial biofilms

Background: Exopolysaccharides (EPS) secreted by beneficial lactobacilli exert a plethora of positive activities, but little is known about their effects on biofilms of opportunistic vaginal pathogens and especially on biofilms of lactobacilli themselves. Here, the EPS produced by six vaginal lactobacilli, belonging to Lactobacillus crispatus (BC1, BC4, BC5) and Lactobacillus gasseri (BC9, BC12, BC14) species were isolated from cultural supernatants and lyophilized. Results: Lactobacillus EPS were chemically characterized in terms of monosaccharide composition by liquid chromatography (LC) analysis coupled to UV and mass spectrometry (MS) detection. Moreover, the ability of EPS (0.1, 0.5, 1 mg/mL) to stimulate the biofilm formation of lactobacilli and to inhibit the formation of pathogens’ biofilms was evaluated by crystal violet (CV) staining and 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. Isolated EPS (yields 133–426 mg/L) were heteropolysaccharides mainly composed of d-mannose (40–52%) and d-glucose (11–30%). For the first time we demonstrated that Lactobacillus EPS were able to stimulate in a dose-dependent manner (p < 0.05) the formation of biofilms of ten strains belonging to L. crispatus, L. gasseri and Limosilactobacillus vaginalis species, in terms of cell viability (84–282% increase at 1 mg/mL) and especially biofilm biomass (40–195% increase at 1 mg/mL), quantified with MTT assay and CV staining, respectively. EPS released from L. crispatus and L. gasseri were found to better stimulate the biofilms of the same producer species rather than that of other species, including producing strains themselves and other strains. Conversely, the biofilm formation of bacterial (Escherichia coli, Staphylococcus spp., Enterococcus spp. and Streptococcus agalactiae) and fungal (Candida spp.) pathogens was inhibited. The anti-biofilm activity was dose-dependent and was more marked for L. gasseri-derived EPS (inhibition up to 86%, 70%, and 58% at 1 mg/mL, 0.5 mg/mL, and 0.1 mg/mL, respectively), whilst L. crispatus-derived EPS resulted overall less efficient (inhibition up to 58% at 1 mg/mL and 40% at 0.5 mg/mL) (p < 0.05). Conclusions: Lactobacilli-derived EPS favour the biofilm formation of lactobacilli preventing, at the same time, that of opportunistic pathogens. These results support the possible employment of EPS as postbiotics in medicine as a therapeutic/preventive strategy to counteract vaginal infections

Retinoids and cancer: antitumoral effects of ATRA, 9-cis RA and the new retinoid IIF on the HL-60 leukemic cell line.

Objective: To compare the antitumoral effects of all-trans retinoic acid (ATRA) and 9-cis retinoic acid (9-cis RA) with those of 5-OH,11-O-hydrophenanthrene (IIF), a new derivative of retinoic acid. Materials and Methods: The effect of retinoids was tested on cell line HL-60. Cell differentiation and apoptosis were evaluated by morphological and biochemical analysis as bcl-2 protein and by DNA fragmentation assay. The ability to activate retinoic acid receptors (RAR) and/or retinoid X receptors (RXR) and to modulate gene expression was determined by transactivation assay. Results: With cell line HL-60, the antiproliferative effect of IIF was stronger than that of ATRA and 9-cis RA. Following retinoid treatment, cells appeared to differentiate and apoptotic cells were observed. The appearance of DNA laddering and a decrease in the amount of bcl-2 protein confirmed apoptosis. IIF transcriptionally activated RXR-γ more than RAR-α. Conclusion: The findings indicate that IIF transcriptionally activates RXR-γ preferentially, induces apoptosis and has a more antiproliferative activity than ATRA and 9-cis RA on cell line HL-60

Effects of endogenous morphine deprivation on memory retention of passive avoidance learning in mice

Memory and the processes of learning in mammals are well known to be affected by opioid agonists such as morphine, which has been proven to interfere and cause amnesia. The presence of endogenous morphine has been demonstrated in various tissues from mammals to invertebrates. In this study, we have investigated the effects caused by in-vivo immunodepletion of endogenous morphine on working memory under different experimental conditions. When mice were submitted to fasting, a stress condition, acquisition and consolidation of memory were significantly impaired compared to controls. This was demonstrated by a decrease in entry latency into the dark room in the retention session of the passive avoidance test. This effect was significantly reversed to baseline values when endogenous morphine was depleted from the extracellular brain space. These findings support a role for endogenous morphine in weakening memory processes under stress conditions

From combinations to single-molecule polypharmacology—cromolyn-ibuprofen conjugates for alzheimer’s disease

Despite Alzheimer’s disease (AD) incidence being projected to increase worldwide, the drugs currently on the market can only mitigate symptoms. Considering the failures of the classical paradigm “one target-one drug-one disease” in delivering effective medications for AD, polypharmacology appears to be a most viable therapeutic strategy. Polypharmacology can involve combinations of multiple drugs and/or single chemical entities modulating multiple targets. Taking inspiration from an ongoing clinical trial, this work aims to convert a promising cromolyn–ibuprofen drug combination into single-molecule “codrugs.” Such codrugs should be able to similarly modulate neuroinflammatory and amyloid pathways, while showing peculiar pros and cons. By exploiting a linking strategy, we designed and synthesized a small set of cromolyn–ibuprofen conjugates (4–6). Preliminary plasma stability and neurotoxicity assays allowed us to select diamide 5 and ethanolamide 6 as promising compounds for further studies. We investigated their immunomodulatory profile in immortalized microglia cells, in vitro anti-aggregating activity towards Aβ42-amyloid self-aggregation, and their cellular neuroprotective effect against Aβ42-induced neurotoxicity. The fact that 6 effectively reduced Aβ-induced neuronal death, prompted its investigation into an in vivo model. Notably, 6 was demonstrated to significantly increase the longevity of Aβ42-expressing Drosophila and to improve fly locomotor performance