Microglia are the resident immune cells of the central nervous system that guarantee immune surveillance and exert also a modulating role on neuronal synaptic development and function. Upon injury, ...microglia get activated and modify their morphology acquiring an ameboid phenotype and pro- or anti-inflammatory features. The active role of microglia in blood-brain barrier (BBB) function and their interaction with different cellular components of the BBB-endothelial cells, astrocytes and pericytes-are described. Here, we report the specific crosstalk of microglia with all the BBB cell types focusing in particular on the involvement of microglia in the modulation of BBB function in neuroinflammatory conditions that occur in conjunction with an acute event, such as a stroke, or in a slow neurodegenerative disease, such as Alzheimer's disease. The potential of microglia to exert a dual role, either protective or detrimental, depending on disease stages and environmental conditioning factors is also discussed.
This work proposes a comparison among GaN and SiC device main parameters measured with a dedicated and low-cost embedded system, employing an STM32 microcontroller designed to the purpose. The system ...has the advantage to avoid the use of expensive laboratory measurement equipment to test the devices, allowing to obtain their behavior in operating conditions. The following KPIs (Key Performance Indicators) are measured and critically compared: threshold voltage, on-resistance and input capacitance. All the measurements are carried out in a short time interval and on a wide range of switching frequencies, ranging from 10 kHz to 1 MHz. This investigation is focused on the deviation of the figures of merit when the switching frequency changes, since it is crucial for wide-bandgap devices. The devised, low-cost, microcontroller unit allows high flexibility and system portability, while the employed equivalent-time sampling technique overcomes some issues related to the need of high sampling frequency. It allows good performances with common microcontroller embedded AD converters. To validate the proposed system, the obtained results have been compared with the time-domain waveforms acquired with a traditional laboratory oscilloscope and a study of the system’s measurement errors has been carried out. Results show that GaN devices achieve a higher efficiency with respect to SiC devices in the considered range of switching frequencies. The on-resistance exhibited by GaN devices shows, as expected, an increase with frequency, which happens to switching losses, too. On the other hand, GaN devices are more sensitive to parasitic effects and the high dV/dt, due to the reduced switching times, can excite unwanted ringing phenomena.
We performed a systematic review and meta-analysis of all the available evidence comparing efficacy and safety of oral prolonged released beclomethasone dipropionate (BDP) to active oral controls in ...patients with mild-to-moderate ulcerative colitis (UC). A subgroup-analysis compared the effectiveness of BDP and 5-ASA.
Literature research was performed in different databases, as well as manual search to identify abstracts from international meetings with data not included in extensive publications. Experts in the field and companies involved in BDP development and manufacture were contacted to identify unpublished studies used for registration purposes. Dichotomous data were pooled to obtain odds ratio meta-analysis.
Five randomized controlled trials that compared oral BDP 5mg/day vs. all oral active controls in treating UC were identified as eligible. Efficacy and safety have been addressed after 4-week treatment period. One study evaluated efficacy and safety of BDP vs. prednisone and 4 of BDP vs. 5-ASA. Treatment with oral BDP 5 mg/day induces a significant better clinical response compared to oral 5-ASA (OR 1.86, 95% CI = 1.23-2.82, P = 0.003). The effect is detectable even when the comparison to prednisone is added (OR 1.41, 95% CI = 1.03-1.93, P = 0.03). Data on remission indicate that the potential clinical efficacy of BDP may be better than 5-ASA (OR 1.55, 95% CI = 1.00-2.40, P = 0.05). This difference is lost when the comparison with prednisone is added (OR 1.30, 95% CI = 0.76-2.23, P = 0.34). The safety analysis showed no differences between BDP and 5-ASA (OR 0.55, 95% CI = 0.24-1.27, P = 0.16). The lack of difference is maintained even when the study with prednisone is added (OR 0.67, 95% CI = 0.44-1.01, P = 0.06). However, the trend of difference is clear and indicates a more favourable safety profile of BDP compared to 5-ASA and PD.
Oral prolonged release BDP showed a superior efficacy vs. oral 5-ASA in inducing clinical improvement of mild-to-moderate UC with a similar safety profile.
Portable neuroimaging technologies can be employed for long-term monitoring of neurophysiological and neuropathological states. Functional Near-Infrared Spectroscopy (fNIRS) and ...Electroencephalography (EEG) are highly suited for such a purpose. Their multimodal integration allows the evaluation of hemodynamic and electrical brain activity together with neurovascular coupling. An innovative fNIRS-EEG system is here presented. The system integrated a novel continuous-wave fNIRS component and a modified commercial EEG device. fNIRS probing relied on fiberless technology based on light emitting diodes and silicon photomultipliers (SiPMs). SiPMs are sensitive semiconductor detectors, whose large detection area maximizes photon harvesting from the scalp and overcomes limitations of fiberless technology. To optimize the signal-to-noise ratio and avoid fNIRS-EEG interference, a digital lock-in was implemented for fNIRS signal acquisition. A benchtop characterization of the fNIRS component showed its high performances with a noise equivalent power below 1 pW. Moreover, the fNIRS-EEG device was tested in vivo during tasks stimulating visual, motor and pre-frontal cortices. Finally, the capabilities to perform ecological recordings were assessed in clinical settings on one Alzheimer's Disease patient during long-lasting cognitive tests. The system can pave the way to portable technologies for accurate evaluation of multimodal brain activity, allowing their extensive employment in ecological environments and clinical practice.
The paper deals with the control of a quadratic boost converter supplied by low-voltage energy sources, such as photovoltaic panels, fuel cells, or batteries. The control scheme consists of two ...control loops. A min-type controller governs the inner loop to force the current state of the nominal model to converge in a neighborhood of the equilibrium state. The external loop processes the output tracking error using an integrator, and it allows reconfiguring the converter's working point by changing the equilibrium state given in the input to the internal loop. This configuration assures both zero tracking error of the output voltage and robustness against load and input voltage variations and converter parameter uncertainties. The stability of the whole system is investigated using the hybrid system framework. The proposed control technique has been tested experimentally in a suitably developed (low-cost) setup, and the results show the effectiveness of the proposed approach.
This study aimed to highlight the distinctive features of four Traditional Agri-food Products (TAP), namely, Caprino, Pecorino, Vaccino, and Cacioricotta cheeses produced at the same dairy plant to ...reveal any possible relationships between their microbiological and biochemical characteristics. Two distinct natural whey starter (NWS) cultures were used during Caprino and Vaccino cheesemaking, whereas no starter was used for the other cheeses. Cacioricotta retained the highest concentrations of salt and residual carbohydrates. Lactic acid bacteria dominated the microbiota of the cheeses. Furthermore, staphylococci represented an additional dominant microbial population in Cacioricotta. Although culture-dependent analysis showed that the use of NWS cultures only slightly affected the microbial community of cheeses, 16S metagenetic analysis showed that
dominated both the NWS cultures and the corresponding Caprino and Vaccino cheeses. This analysis indicated that
and
dominated Cacioricotta and Pecorino cheeses, respectively. The highest peptidase activities were found in either Caprino or Vaccino. Enzymes involved in the catabolism of free amino acids and esterase showed the highest activity in Pecorino cheese. Each cheese showed a distinct profile of volatile organic compounds, with Pecorino being the richest cheese in carboxylic acids, ketones, and esters, related to lipolysis. The results of this study contribute to valorizing and safeguarding these TAP cheeses, sustaining local farming.
Microglia, together with astrocytes and pericytes, cooperate to ensure blood–brain barrier (BBB) stability, modulating endothelial responses to inflammatory insults. Agonists of the sphingosine 1 ...phosphate (S1P) receptors, such as siponimod (BAF-312), are important pharmacological tools in multiple sclerosis and other inflammatory diseases. Modulation of S1P receptors may result in a reduced inflammatory response and increased BBB stability. An in vitro BBB model was reproduced using human-derived endothelial cells, astrocytes and microglia. Co-cultures were exposed to inflammatory cytokines (TNFα, 10 UI and IFNγ, 5 UI) in the presence of BAF-312 (100 nM), and the BBB properties and microglia role were evaluated. The drug facilitated microglial migration towards endothelial/astrocyte co-cultures, involving the activity of the metalloprotease 2 (MMP2). Microglia actively cooperated with astrocytes in the maintenance of endothelial barrier stability: in the triple co-culture, selective treatment of microglial cells with BAF-312 significantly prevented cytokines’ effects on the endothelial barrier. In conclusion, BAF-312, modulating S1P receptors in microglia, may contribute to the reinforcement of the endothelial barrier at the BBB, suggesting an additional effect of the drug in the treatment of multiple sclerosis.
With the introduction of more and more monoclonal antibodies selectively targeting various mediators of the immune system, together with Janus-Kinase (JAK)-inhibitors with variable affinities towards ...different JAK subtypes, the available therapeutic options for the treatment of inflammatory bowel diseases (IBD) have undergone an acceleration in the last five years. On the other hand, the prevalence of IBD patients over 65-years-old is steadily increasing, and, with this, there is a large population of patients that presents more comorbidities, polypharmacy, and, more frequently, frailty compared to younger patients, exposing them to potentially major risks for adverse events deriving from newer therapies, e.g., infections, cardiovascular risks, and malignancies. Unfortunately, pivotal trials for the commercialization of new therapies rarely include older IBD patients, and those with serious comorbidities are virtually excluded. In the present review, we focus on existing literature from pivotal trials and real-world studies, analyzing data on efficacy/effectiveness and safety of newer therapies in older IBD patients with special emphasis on comorbidities and frailty, two distinct but intercorrelated aspects of the older population since age by itself seems to be of minor importance.
Raw cow milk is one of the most complex and unpredictable food matrices shaped by the interaction between biotic and abiotic factors. Changes in dairy farming conditions impact the quality and safety ...of milk, which largely depend on seasonality. Changes in microbiome composition and relative metabolic pathways are derived from microbial interactions, as well as from seasonality, mammary, and extramammary conditions (e.g., farm management and outdoor environment). Breeding data from >600 Apulian farms were examined, and the associated physicochemical parameters were processed by a reductionist approach to obtain a raw cow milk sample subset. We investigated the microbiological variability in cultivable and 16S rRNA sequencing microbiota as affected by seasonal fluctuations at two time points (winter and summer seasons). We identified families (Xanthomonadaceae, Enterobacteriaceae, and Pseudomonadaceae) whose increased abundance during winter may cause a shift toward a pathobiont microbial niche that leads to lower milk quality. Apulian summer season conditions were advantageous to the presence of specific taxa, i.e., Streptococcaceae (i.e., Lactococcus) and Limosilactobacillus fermentum, which in turn may favor better milk preservation. IMPORTANCE The strength of this study lies in the microbiological characterization of a wide range of farm management data to achieve a more comprehensive framework of Apulian milk. Specific regional pedoclimatic and management conditions impact the taxa present and their abundances within this ecological food niche. The obtained results lay the groundwork for comparison with other worldwide extensive farming areas.
Microglia represent a first-line defense in the brain. However, in pathological conditions such as Alzheimer's disease (AD), a pro-inflammatory switch may occur, leading to loss of protective ...functions. Using the human microglial cell line HMC3, we showed that exposure to low concentrations of β-amyloid peptide 1-42 (Aβ42; 0.2 μM) initially (6 h) upregulated anti-inflammatory markers interleukin (IL)-4, IL-13, and brain-derived neurotrophic factor (BDNF). BDNF increase was prevented by selective inhibition of SIRT1 with EX527 (2 μM). Accordingly, these early effects were accompanied by a significant Aβ42-induced increase of SIRT1 expression, nuclear localization, and activity. SIRT1 modulation involved adenosine monophosphate-regulated kinase (AMPK), which was promptly (30 min) phosphorylated by Aβ42, while the AMPK inhibitor BML-275 (2 μM) attenuated Aβ42-induced SIRT1 increase. Initially observed microglial responses appeared transient, as microglial features changed when exposure to Aβ42 was prolonged (0.2 μM for 72 h). While SIRT1 and BDNF levels were reduced, the expression of inflammatory markers IL-1β and tumor necrosis factor (TNF)-α increased. This coincided with a rise in NF-kB nuclear localization. The effects of melatonin (1 μM) on prolonged microglial exposure to Aβ42 were analyzed for their protective potential. Melatonin was able to prolong SIRT1 and BDNF upregulation, as well as to prevent NF-kB nuclear translocation and acetylation. These effects were sensitive to the melatonin receptor antagonist, luzindole (25 μM). In conclusion, our data define an early microglial defensive response to Aβ42, featuring SIRT1-mediated BDNF upregulation that can be exogenously modulated by melatonin, thus identifying an important target for neuroprotection.
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