The CYFIP1/SRA1 gene is located in a chromosomal region linked to various neurological disorders, including intellectual disability, autism, and schizophrenia. CYFIP1 plays a dual role in two ...apparently unrelated processes, inhibiting local protein synthesis and favoring actin remodeling. Here, we show that brain-derived neurotrophic factor (BDNF)-driven synaptic signaling releases CYFIP1 from the translational inhibitory complex, triggering translation of target mRNAs and shifting CYFIP1 into the WAVE regulatory complex. Active Rac1 alters the CYFIP1 conformation, as demonstrated by intramolecular FRET, and is key in changing the equilibrium of the two complexes. CYFIP1 thus orchestrates the two molecular cascades, protein translation and actin polymerization, each of which is necessary for correct spine morphology in neurons. The CYFIP1 interactome reveals many interactors associated with brain disorders, opening new perspectives to define regulatory pathways shared by neurological disabilities characterized by spine dysmorphogenesis.
•BDNF-Rac1 signaling redistributes CYFIP1 between eIF4E and WRC•FRET demonstrates that BDNF-Rac1 signaling alters CYFIP1 conformation•CYFIP1-eIF4E-WRC regulates ARC synthesis, actin polymerization, and spine morphology•The CYFIP1 interactome is enriched in genes implicated in neurological disorders
CYFIP1 plays a dual role in inhibiting local protein synthesis and favoring actin remodeling. De Rubeis et al. show that BDNF-driven synaptic signaling releases CYFIP1 from the translational inhibitory complex, triggering translation of target mRNAs and shifting CYFIP1 into the WAVE regulatory complex.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
A loss of neurons is observed in the hippocampus of many patients with epilepsies of temporal lobe origin. It has been hypothesized that damage limitation or repair, for example using neurotrophic ...factors (NTFs), may prevent the transformation of a normal tissue into epileptic (epileptogenesis). Here, we used viral vectors to locally supplement two NTFs, fibroblast growth factor-2 (FGF-2) and brain-derived neurotrophic factor (BDNF), when epileptogenic damage was already in place. These vectors were first characterized in vitro, where they increased proliferation of neural progenitors and favored their differentiation into neurons, and they were then tested in a model of status epilepticus-induced neurodegeneration and epileptogenesis. When injected in a lesioned hippocampus, FGF-2/BDNF expressing vectors increased neuronogenesis, embanked neuronal damage, and reduced epileptogenesis. It is concluded that reduction of damage reduces epileptogenesis and that supplementing specific NTFs in lesion areas represents a new approach to the therapy of neuronal damage and of its consequences.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Abstract
A recent paper by Mak et al. grants the opportunity to discuss two different definitions of the frontogenetical function proposed in the literature to study the formation and evolution of ...upper-level fronts. This comment exposes some problems that, in this author’s opinion, are related to the use of the Lagrangian tendency of the 3D (in place of horizontal) gradient of potential temperature, as adopted in the Mak et al. paper.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background: This study aimed to gather data on physical activity (PA), bleeding, health-related quality of life, and health status, using a wearable device and an electronic patient-reported outcome ...(ePRO) app, in individuals with moderate or severe hemophilia A (HA) without inhibitors receiving treatment according to the clinical practice. Methods: This is a 12-month multicenter cohort study conducted in Italy. The primary outcomes included the description of PA by type and intensity, adherence to World Health Organization guidelines, bleeding, and health-related quality of life by EQ-5D questionnaire. PA data were collected continuously through a fitness tracker worn by the patient; all the other variables were collected through ePRO questionnaires. Results: Only 54 of the 103 enrolled subjects (52.4%) used their fitness tracker for the defined valid period; adolescents were the least compliant age group. PA was performed at low rates and intensity. Approximately 52% of the subjects had sedentary behavior. The mean EQ-5D values did not change over time. At least one bleeding was reported in 43.7% of the subjects, mostly with sedentary behavior. The PA in the 2 days preceding the bleeding was comparable to the one observed in the overall observational period. Conclusions: The systematic recording of data through a fitness tracker and ePRO app shows that subjects with HA without inhibitors have lower-than-expected PA and that they still experience issues related to bleeding.
: Double-balloon enteroscopy (DBE) is a well-established procedure for direct visualisation of the entire small bowel mucosa, and, in contrast with other imaging techniques, allows to perform ...biopsies and therapeutic interventions. The aim of this study was to evaluate the indications, diagnostic yield, therapeutic yield, and complications of DBE in a cohort of consecutive patients according to patients' age.
: We conducted a retrospective study of consecutive patients who underwent DBE in our endoscopy unit between January 2006 and December 2021.
: A total of 387 consecutive patients who underwent 460 DBE procedures were included. Mean age of the patients was 63 years. The overall diagnostic yield was 67.6%; vascular lesions were the predominant endoscopic findings (31.5%), followed by polyps or neoplastic masses (17.6%). Older patients (≥65 years) showed statistically higher rates of clinically relevant findings than adult patients (18-65 years) (
= 0.001). Crohn's disease and polyps or neoplastic masses were more frequent in the younger group (
= 0.009 and
= 0.066, respectively), while vascular lesions and non-specific inflammation were the most common findings in the older group (
< 0.001 and
< 0.001, respectively). The therapeutic intervention rate was 31.7%. Rates of endoscopic treatment were significantly higher in the older group (
< 0.001). Total complications occurred in five procedures (1.1%).
: In clinical practice, DBE is an efficient diagnostic and therapeutic tool with a high safety profile, particularly in the elderly population.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Abstract Unverricht–Lundborg disease (ULD) is the most common progressive myoclonic epilepsy. Its etiology has been identified in a defect of a protease inhibitor, cystatin B (CSTB), but the ...mechanism(s) by which this defect translates in the clinical manifestations of the disease are still obscure. We tested the hypothesis that ULD is accompanied by a loss of cortical GABA inhibition in a murine model (the CSTB knockout mouse) and in a human case. Cortical GABA signaling has been investigated measuring VGAT immunohistochemistry (a histological marker of the density of GABA terminals), GABA release from synaptosomes and paired-pulse stimulation. In CSTB knockout mice, a progressive decrease in neocortex thickness was found, associated with a prevalent loss of GABA interneurons. A marked reduction in VGAT labeling was found in the cortex of both CSTB knockout mice and an ULD patient. This implicates a reduction in GABA synaptic transmission, which was confirmed in the mouse model as reduction in GABA release from isolated nerve terminals and as loss of electrophysiologically measured GABA inhibition. The alterations in VGAT immunolabeling progressed in time, paralleling the worsening of myoclonus. These results provide direct evidence that loss of cortical GABA input occurs in a relevant animal model and in a case of human ULD, leading to a condition of latent hyperexcitability that favors myoclonus and seizures. These findings contribute to the understanding of the pathogenic mechanism of ULD and of the neurobiological basis of the effect of currently employed drugs.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
The intense precipitation event that occurred between 3 and 6 November 1994 and caused extensive flooding over Piedmont in northwestern Italy is simulated and tested with respect to various physical ...aspects, using a meteorological mesoscale model (BOLAM). The period when the most intense rain occurred, mainly covering the second half of 4 and all of 5 November, is examined. A control experiment, starting at 1200 UTC 4 November, simulates the two observed precipitation peaks and captures the magnitude and timing of the most intense precipitation well even at relatively low horizontal resolution (about 30 km). The European Centre for Medium-Range Weather Forecasts analyses are used to provide the initial and boundary conditions. Model output diagnostics and comparison with observations indicate that most of the precipitation is associated with a prefrontal low-level jet, ahead of the cold front, impinging upon the orography of the region (Alps and Apennines). The model simulates a multiple rainband and frontal structure whose evolution determines both intensity and location of the prefrontal warm and moist flow. Almost all of the simulated precipitation over the Alps forms in the middle-low troposphere through forced ascent, whereas part of the secondary maximum, observed over the Apennines, is of convective type. Sensitivity experiments have been conducted to investigate the effects of orography, surface fluxes, and latent heat exchange processes in the atmosphere. The role of the orography is crucial in determining distribution and amount of precipitation, whereas sensible and latent heat fluxes from the Mediterranean Sea (over the period considered) enhanced only the convective precipitation. Distinct dynamical effects, important for the amount and the spatial distribution of precipitation, are found to be associated with warming due to condensation and cooling due to evaporation and melting of precipitation. The latter process seems to be responsible for the simulated formation of rainbands and complex evolution of the cold front over the western Mediterranean. The multiple front life cycle and propagation feeds back on the simulated precipitation distribution, affecting the location of the prefrontal moist flow. Condensation affects the atmospheric effective stratification where the flow impinges on the orography, determining the flow regime (orographic lifting vs blocking and flow around), which, in turn, has an important impact on precipitation.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
About 5000 people in Italy suffer from hemophilia, the most common coagulation disorder. As for other chronic diseases, even in the case of hemophilia, the engagement of the patient is essential: the ...patients, in fact, must be empowered and helped to become strong partners of the care team and sensitized with respect to their rights and duties for the successful achievement of the goals set by their healthcare path. Hence the initiative to start a new research-intervention project in the field of hemophilia. The study had different phases of research: a first moment inspired by the principles of narrative medicine, aimed at collecting stories and narratives of patients with hemophilia related to the experience of the disease and therapy and expectations of active involvement in the relationship with the clinician. At the same time, among hematologists and patients has been surveyed the experience of therapeutical relationship and communication, to capture the aspects in which they feel effective and the areas of improvement and unmet needs. Subsequently, a workshop dedicated to patients and hematologists was organized to foster mutual awareness between these two targets and the formation of a better communication and relational skills of clinicians.
The results of the project formed the basis for a policy brief document, aimed at disseminating recommendations to support better relationship and empathic communication between clinicians and patients.
Following the publication of a book of personal memories by one of us (CS1,2), we have attempted to synthesis our joint memories of three ageing men, born in the era preceding universal access to ...treatment, in an attempt to describe our experience, our challenges and our reflections on the development of therapies, which have ensured that our experience of growing up with haemophilia in the 1950s and 1960s has not been mirrored by the current generation of patients. We describe our upbringing in different parts of Europe in health care systems which, while of varying standards, were all unable to offer the kind of care which developed after the development of specific therapies. We assess the effect of the contamination of these therapies by blood‐borne pathogens on our own development, and the development of our communities around us. In addition, we reflect on the lessons learnt, sometimes painfully, by our generation of people with haemophilia and how some of these enabled us to overcome substantial hurdles, survive and build productive lives. Finally, we survey the development of therapies in the past 20 years, and offer some reflections on how our experience can be integrated in a realistic expectation of what the future holds for our community, in our own affluent societies and in countries less advantaged economically. We hope that our thoughts may contribute to continued progress in the field of haemophilia care.
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DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract Unverricht–Lundborg disease (EPM1), the most common progressive myoclonic epilepsy, is associated with a defect of cystatin B (CSTB), a protease inhibitor. We used CSTB knockout mice to test ...the hypothesis that EPM1 onset is related to a latent hyperexcitability and that progression depends on higher susceptibility to seizure-induced cell damage. Hippocampal slices prepared from CSTB-deficient mice were hyperexcitable, as they responded to afferent stimuli in CA1 with multiple population spikes and kainate perfusion provoked the appearance of epileptic-like activity earlier than in WT mice. This hyperexcitability may depend on loss of inhibition, because the density of GABA-immunoreactive cells was reduced in the hippocampus of CSTB knockouts. In vivo , CSTB-deficient mice treated with kainate displayed increased susceptibility to seizures, with shorter latency to seizure onset and increased seizure severity compared with WT littermates. Furthermore, a greater degree of neuronal damage was observed in CSTB-deficient than in WT mice after seizures of identical grade, indicating increased susceptibility to seizure-induced cell death.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
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