Novel [1,3,4]Thiadiazole[3,2-a]pyrimidin-5-ones as Promising Biofilm Dispersal Agents against Relevant Gram-Positive and Gram-Negative Pathogens

Biofilm-associated infections pose significant challenges in healthcare settings due to their resistance to conventional antimicrobial therapies. In the last decade, the marine environment has been a precious source of bioactive molecules, including numerous derivatives with antibiofilm activity. In this study, we reported the synthesis and the biological evaluation of a new series of twenty-two thiadiazopyrimidinone derivatives obtained by using a hybridization approach combining relevant chemical features of two important classes of marine compounds: nortopsentin analogues and Essramycin derivatives. The synthesized compounds were in vitro tested for their ability to inhibit biofilm formation and to disrupt mature biofilm in various bacterial strains. Among the tested compounds, derivative 8j exhibited remarkable dispersal activity against preformed biofilms of relevant Gram-positive and Gram-negative pathogens, as well as towards the fungus Candida albicans, showing BIC50 values ranging from 17 to 40 mu g/mL. Furthermore, compound 8j was in vivo assayed for its toxicity and the anti-infective effect in a Galleria mellonella model. The results revealed a promising combination of anti-infective properties and a favorable toxicity profile for the treatment of severe chronic biofilm-mediated infections

The prevalence and topography of spinal cord demyelination in multiple sclerosis: a retrospective study

Spinal cord pathology is a major determinant of irreversible disability in progressive multiple sclerosis. The demyelinated lesion is a cardinal feature. The well-characterised anatomy of the spinal cord and new analytic approaches allows the systematic study of lesion topography and its extent of inflammatory activity unveiling new insights into disease pathogenesis. We studied cervical, thoracic, and lumbar spinal cord tissue from 119 pathologically confirmed multiple sclerosis cases. Immunohistochemistry was used to detect demyelination (PLP) and classify lesional inflammatory activity (CD68). Prevalence and distribution of demyelination, staged by lesion activity, was determined and topographical maps were created to identify patterns of lesion prevalence and distribution using mixed models and permutation-based voxelwise analysis. 460 lesions were observed throughout the spinal cord with 76.5% of cases demonstrating at least 1 lesion. The cervical level was preferentially affected by lesions. 58.3% of lesions were inflammatory with 87.9% of cases harbouring at least 1 inflammatory lesion. Topographically, lesions consistently affected the dorsal and lateral columns with relative sparing of subpial areas in a distribution mirroring the vascular network. The presence of spinal cord lesions and the proportion of active lesions related strongly with clinical disease milestones, including time from onset to wheelchair and onset to death. We demonstrate that spinal cord demyelination is common, highly inflammatory, has a predilection for the cervical level, and relates to clinical disability. The topography of lesions in the dorsal and lateral columns and relative sparing of subpial areas points to a role of the vasculature in lesion pathogenesis, suggesting short-range cell infiltration from the blood and signaling molecules circulating in the perivascular space incite lesion development. These findings challenge the notion that end-stage progressive multiple sclerosis is ‘burnt out’ and an outside-in lesional gradient predominates in the spinal cord. Taken together, this study provides support for long-term targeting of inflammatory demyelination in the spinal cord and nominates vascular dysfunction as a potential target for new therapeutic approaches to limit irreversible disability

Functional Living Skills: A Non-Immersive Virtual Reality Training for Individuals with Major Neurocognitive Disorders

The loss of functional living skills (FLS) is an essential feature of major neurocognitive disorders (M-NCD); virtual reality training (VRT) offers many possibilities for improving FLS in people with M-NCD. The aim of our study was to verify the effectiveness of a non-immersive VRT on FLS for patients with M-NCD. VRT was carried out for 10 to 20 sessions, by means of four 3D apps developed in our institute and installed on a large touch screen. The experimental group (EG) and the control group (CG) included 24 and 18 patients with M-NCD, respectively. They were administered the in vivo test (in specific hospital places reproducing the natural environments) at T1 (pre-training) and T3 (post-training); at T2, only EG was administered VRT. Statistically significant differences between EG and CG in all the in vivo tests were found in the number of correct responses; during VRT, the number of correct responses increased, while the execution times and the number of clues decreased. The improvement in the in vivo tests appeared to be related to the specific VRT applied. The satisfaction of participants with the VRT was moderate to high

Corticosteroid status influences the volume of the rat cingulate cortex: a magnetic resonance imaging study

Imbalances in the corticosteroid milieu result in reductions in hippocampal volume in humans and experimental rodents. The functional correlates of these changes include deficits in cognitive performance and regulation of the hypothalamic–pituitary–adrenal axis. Since other limbic structures which are intricately connected with the hippocampal formation, also play an important role in behavioural and neuroendocrine functions, we here used magnetic resonance imaging (MRI) to analyse how two of these areas, the anterior cingulate and retrosplenial cortex, respond to chronic alterations of adrenocortical status: hypocortisolism (induced by adrenalectomy, ADX), normocortisolism (ADX with low-dose corticosterone replacement), and hypercortisolism (ADX with high-dose dexamethasone supplementation). Hypercortisolism was associated with a significant reduction in the volume (absolute and normalized) of the left anterior cingulate gyrus as measured by MRI and confirmed using classical histological methods; a similar trend was observed in the right anterior cingulate region. In contrast, hypercortisolism did not influence the volume of the adjacent retrosplenial cortex. The volumes of the anterior cingulate gyrus and retrosplenial cortex were unaffected by the absence of adrenocortical hormones. These findings are the first to suggest that corticosteroid influences on the structure of the limbic system extend beyond the hippocampal formation, i.e., to fronto-limbic areas also

Equinins as Novel Broad-Spectrum Antimicrobial Peptides Isolated from the Cnidarian Actinia equina (Linnaeus, 1758)

Sea anemones are valuable for therapeutic research as a diversified source of bioactive molecules, due to their diverse bioactive molecules linked to predation and defence mechanisms involving toxins and antimicrobial peptides. Acid extracts from Actinia equina tentacles and body were examined for antibacterial activity against Gram-positive, Gram-negative bacteria, and fungi. The peptide fractions showed interesting minimum inhibitory concentration (MIC) values (up to 0.125 μg/mL) against the tested pathogens. Further investigation and characterization of tentacle acid extracts with significant antimicrobial activity led to the purification of peptides through reverse phase chromatography on solid phase and HPLC. Broad-spectrum antimicrobial peptide activity was found in 40% acetonitrile fractions. The resulting peptides had a molecular mass of 2612.91 and 3934.827 Da and MIC ranging from 0.06 to 0.20 mg/mL. Sequencing revealed similarities to AMPs found in amphibians, fish, and Cnidaria, with anti-Gram+, Gram-, antifungal, candidacidal, anti-methicillin-resistant Staphylococcus aureus, carbapenemase-producing, vancomycin-resistant bacteria, and multi-drug resistant activity. Peptides 6.2 and 7.3, named Equinin A and B, respectively, were synthesized and evaluated in vitro towards the above-mentioned bacterial pathogens. Equinin B exerted interesting antibacterial activity (MIC and bactericidal concentrations of 1 mg/mL and 0.25 mg/mL, respectively) and gene organization supporting its potential in applied research

Genetically altered AMPA-type glutamate receptor kinetics in interneurons disrupt long-range synchrony of gamma oscillation

Gamma oscillations synchronized between distant neuronal populations may be critical for binding together brain regions devoted to common processing tasks. Network modeling predicts that such synchrony depends in part on the fast time course of excitatory postsynaptic potentials (EPSPs) in interneurons, and that even moderate slowing of this time course will disrupt synchrony. We generated mice with slowed interneuron EPSPs by gene targeting, in which the gene encoding the 67-kDa form of glutamic acid decarboxylase (GAD67) was altered to drive expression of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptor subunit GluR-B. GluR-B is a determinant of the relatively slow EPSPs in excitatory neurons and is normally expressed at low levels in γ-aminobutyric acid (GABA)ergic interneurons, but at high levels in the GAD-GluR-B mice. In both wild-type and GAD-GluR-B mice, tetanic stimuli evoked gamma oscillations that were indistinguishable in local field potential recordings. Remarkably, however, oscillation synchrony between spatially separated sites was severely disrupted in the mutant, in association with changes in interneuron firing patterns. The congruence between mouse and model suggests that the rapid time course of AMPA receptor-mediated EPSPs in interneurons might serve to allow gamma oscillations to synchronize over distance

Distributed subglacial discharge drives significant submarine melt at a Greenland tidewater glacier

Submarine melt can account for substantial mass loss at tidewater glacier termini. However, the processes controlling submarine melt are poorly understood due to limited observations of submarine termini. Here at a tidewater glacier in central West Greenland, we identify subglacial discharge outlets and infer submarine melt across the terminus using direct observations of the submarine terminus face. We find extensive melting associated with small discharge outlets. While the majority of discharge is routed to a single, large channel, outlets not fed by large tributaries drive submarine melt rates in excess of 3.0 m d−1 and account for 85% of total estimated melt across the terminus. Nearly the entire terminus is undercut, which may intersect surface crevasses and promote calving. Severe undercutting constricts buoyant outflow plumes and may amplify melt. The observed morphology and melt distribution motivate more realistic treatments of terminus shape and subglacial discharge in submarine melt models

progression free survival pfs benefit from first line endocrine based therapies in postmenopausal women with hr her2 metastatic breast cancer mbc according to different prognostic subgroups a combined analysis of data from paloma 2 monaleesa 2 monarch 3 falcon swog and fact trials

n/