Abstract
At Mount Etna volcano, the focus point of persistent tectonic extension is represented by the Summit Craters. A muographic telescope has been installed at the base of the North-East Crater ...from August 2017 to October 2019, with the specific aim to find time related variations in the density of volcanic edifice. The results are significant, since the elaborated images show the opening and evolution of different tectonic elements; in 2017, a cavity was detected months before the collapse of the crater floor and in 2018 a set of underground fractures was identified, at the tip of which, in June 2019, a new eruptive vent started its explosive activity, still going on (February, 2020). Although this is the pilot experiment of the project, the results confirm that muography could be a turning point in the comprehension of the plumbing system of the volcano and a fundamental step forward to do mid-term (weeks/months) predictions of eruptions. We are confident that an increment in the number of telescopes could lead to the realization of a monitoring system, which would keep under control the evolution of the internal dynamic of the uppermost section of the feeding system of an active volcano such as Mount Etna.
The Serotonin Transporter (SERT) regulates extracellular serotonin levels and is the target of most current drugs used to treat depression. The mechanisms by which inhibition of SERT activity ...influences behavior are poorly understood. To address this question in the model organism Drosophila melanogaster, we developed new loss of function mutations in Drosophila SERT (dSERT). Previous studies in both flies and mammals have implicated serotonin as an important neuromodulator of sleep, and our newly generated dSERT mutants show an increase in total sleep and altered sleep architecture that is mimicked by feeding the SSRI citalopram. Differences in daytime versus nighttime sleep architecture as well as genetic rescue experiments unexpectedly suggest that distinct serotonergic circuits may modulate daytime versus nighttime sleep. dSERT mutants also show defects in copulation and food intake, akin to the clinical side effects of SSRIs and consistent with the pleomorphic influence of serotonin on the behavior of D. melanogaster. Starvation did not overcome the sleep drive in the mutants and in male dSERT mutants, the drive to mate also failed to overcome sleep drive. dSERT may be used to further explore the mechanisms by which serotonin regulates sleep and its interplay with other complex behaviors.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Astrocytes are complex bushy cells that serve important functions through close contacts between their processes and synapses. However, the spatial interactions and dynamics of astrocyte processes ...relative to synapses have proven problematic to study in adult living brain tissue. Here, we report a genetically targeted neuron-astrocyte proximity assay (NAPA) to measure astrocyte-synapse spatial interactions within intact brain preparations and at synaptic distance scales. The method exploits resonance energy transfer between extracellularly displayed fluorescent proteins targeted to synapses and astrocyte processes. We validated the method in the striatal microcircuitry following in vivo expression. We determined the proximity of striatal astrocyte processes to distinct neuronal input pathways, to D1 and D2 medium spiny neuron synapses, and we evaluated how astrocyte-to-excitatory synapse proximity changed following cortical afferent stimulation, during ischemia and in a model of Huntington’s disease. NAPA provides a simple approach to measure astrocyte-synapse spatial interactions in a variety of experimental scenarios.
Display omitted
•An imaging method was developed to assess astrocyte-synapse proximity•The method was used to determine the wiring diagram of striatal astrocytes•Dynamics of striatal astrocyte interactions with excitatory inputs were evaluated•Resources to track static and dynamic astrocyte-synapse interactions are provided
The Khakh laboratory and collaborators used state-of-the-art optical and genetic strategies to develop an imaging approach to measure static and dynamic interactions of astrocyte processes with synaptic elements within intact adult brain preparations.
The transcriptional effects of SSRIs and other serotonergic drugs remain unclear, in part due to the heterogeneity of postsynaptic cells, which may respond differently to changes in serotonergic ...signaling. Relatively simple model systems such as Drosophila afford more tractable microcircuits in which to investigate these changes in specific cell types. Here, we focus on the mushroom body, an insect brain structure heavily innervated by serotonin and comprised of multiple different but related subtypes of Kenyon cells. We use fluorescence-activated cell sorting of Kenyon cells, followed by either bulk or single-cell RNA sequencing to explore the transcriptomic response of these cells to SERT inhibition. We compared the effects of two different Drosophila Serotonin Transporter (dSERT) mutant alleles as well as feeding the SSRI citalopram to adult flies. We find that the genetic architecture associated with one of the mutants contributed to significant artefactual changes in expression. Comparison of differential expression caused by loss of SERT during development versus aged, adult flies, suggests that changes in serotonergic signaling may have relatively stronger effects during development, consistent with behavioral studies in mice. Overall, our experiments revealed limited transcriptomic changes in Kenyon cells, but suggest that different subtypes may respond differently to SERT loss-of-function. Further work exploring the effects of SERT loss-of-function in other circuits may be used help to elucidate how SSRIs differentially affect a variety of different neuronal subtypes both during development and in adults.
Sensory systems rely on neuromodulators, such as serotonin, to provide flexibility for information processing as stimuli vary, such as light intensity throughout the day. Serotonergic neurons broadly ...innervate the optic ganglia of Drosophila melanogaster, a widely used model for studying vision. It remains unclear whether serotonin modulates the physiology of interneurons in the optic ganglia. To address this question, we first mapped the expression patterns of serotonin receptors in the visual system, focusing on a subset of cells with processes in the first optic ganglion, the lamina. Serotonin receptor expression was found in several types of columnar cells in the lamina including 5-HT2B in lamina monopolar cell L2, required for spatiotemporal luminance contrast, and both 5-HT1A and 5-HT1B in T1 cells, whose function is unknown. Subcellular mapping with GFP-tagged 5-HT2B and 5-HT1A constructs indicated that these receptors localize to layer M2 of the medulla, proximal to serotonergic boutons, suggesting that the medulla neuropil is the primary site of serotonergic regulation for these neurons. Exogenous serotonin increased basal intracellular calcium in L2 terminals in layer M2 and modestly decreased the duration of visually induced calcium transients in L2 neurons following repeated dark flashes, but otherwise did not alter the calcium transients. Flies without functional 5-HT2B failed to show an increase in basal calcium in response to serotonin. 5-HT2B mutants also failed to show a change in amplitude in their response to repeated light flashes but other calcium transient parameters were relatively unaffected. While we did not detect serotonin receptor expression in L1 neurons, they, like L2, underwent serotonin-induced changes in basal calcium, presumably via interactions with other cells. These data demonstrate that serotonin modulates the physiology of interneurons involved in early visual processing in Drosophila.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Management of small cell lung cancer (SCLC) has not changed over the last decades. In more recent years, alterations of DNA repair machinery and other molecular pathways have been identified in SCLC ...and preclinical data suggest that dysregulation of these pathways might offer new therapeutic opportunities.While immune checkpoint inhibitors (ICIs) have had a major impact on the clinical outcome of several solid tumors, including non-small cell lung cancer, the potential role of ICIs is currently under investigation in SCLC and some promising data are available. However, several clinical and biological hurdles have to be overcome and predictive markers are still eagerly needed. Knowledge of molecular pathways specifically involved in SCLC growth and treatment resistance is essential for a more rational planning of new combinations including ICIs.The present manuscript summarizes the current clinical evidence on immunotherapy in SCLC, describes the molecular bases underlying treatment resistance and discusses the potentialities and the rationale of different therapeutic combinations.
The prognosis of small-cell lung cancer (SCLC) is dismal and new effective therapies are needed. Immunotherapy looks promising, but no molecular predictive markers are currently available, and data ...on immune microenvironment are very limited.
We retrospectively analysed 104 SCLC cases. Immunohistochemistry evaluation of PD-L1 was performed both on tumour cells (TCs) and on tumour-infiltrating immune cells (TIICs) by using anti-PD-L1 22C3 antibody (DAKO) and categorised by using 1% as cut-off point. Tumour-infiltrating lymphocytes (TILs) were characterised by using anti-CD8 and anti-FOXP3 antibodies. Semi-quantitative score was used and categorised as positive versus negative/low. The relation of molecular markers with prognosis and with clinical variables was evaluated.
The analysis included 66 stage I–III patients (48 surgically resected, 18 treated with radical-intent chemoradiotherapy) and 38 metastatic cases. In the overall study population, PD-L1 was expressed on TCs and TIICs in 25% and 40% of cases, respectively. The proportion of PD-L1-positive cases was significantly higher in stage I–III versus metastatic patients (32% versus 13%, p: 0.034 for TCs; 51.5% versus 21% for TIICs, p: 0.002). CD8- and FOXP3-positive TILs were present in 59% and 72% of samples, respectively. The presence of FOXP3-TILs was associated with improved prognosis among non-metastatic patients, with a hazard ratio for survival of 0.32 (95% confidence interval CI: 0.16–0.7, p: 0.006) for univariate analysis, and 0.37 (95% CI: 0.17–0.81, p: 0.013) for multivariate analysis.
Immune contexture of SCLC may differ according to stage. The presence of FOXP3-positive TILs is a potential prognostic marker for stage I–III SCLCs and warrants further investigation.
•The study depicts distribution of PD-L1 expression in small-cell lung cancer (SCLC) according to stage.•The study characterises tumour-infiltrating lymphocytes (TILs) in SCLC.•Independent positive prognostic impact of FOXP3-TILs is shown in stage I–III SCLCs.
Background Stimulation of the immune system by gut microbes might prevent allergy development. Objective The present study examined the hypothesis that sensitization to food allergens and atopic ...eczema are influenced by the infantile intestinal colonization pattern. Methods Infants were recruited perinatally in Göteborg (n = 116), London (n = 108), and Rome (n = 100). Commensal bacteria were identified to the genus or species level in rectal (3 days) and quantitative stool cultures (7, 14, and 28 days and 2, 6, and 12 months of age). At 18 months of age, atopic eczema and total and food-specific IgE levels were assessed. These outcomes were modeled in relation to time to colonization with 11 bacterial groups and to ratios of strict anaerobic to facultative anaerobic bacteria and gram-positive to gram-negative bacteria at certain time points. Study center, mode of delivery, parity, and infant diet were included as covariates. Results Neither atopic eczema nor food-specific IgE by 18 months of age were associated with time of acquisition of any particular bacterial group. Cesarean section delayed colonization by Escherichia coli and Bacteroides and Bifidobacterium species, giving way to, for example, Clostridium species. Lack of older siblings was associated with earlier colonization by Clostridium species and lower strict anaerobic/facultative anaerobic ratio at 12 months. Conclusions This study does not support the hypothesis that sensitization to foods or atopic eczema in European infants in early life is associated with lack of any particular culturable intestinal commensal bacteria. Clinical implications The nature of the microbial stimulus required for protection from allergy remains to be identified.
To conduct focus group interviews with operating room (OR) personnel to determine components of effective teamwork to inform a revision of a teamwork assessment instrument.
Qualitative research study ...targeting OR personnel using semi-structured focus group interviews of interprofessional OR personnel. Responses were digitally recorded and transcribed. Qualitative analysis was undertaken by 2 reviewers who identified major themes related to effective teamwork. Inter-coder agreement was employed to confirm findings and themes.
Major academic medical center and Level 1 Trauma Center in Southeastern United States.
Fifteen OR staff members including surgeons, an anesthesiologist, nurse anesthetists, circulating nurses, and scrub technicians.
Three focus groups involving 15 individuals (2 surgeons, 1 anesthesiologist, 8 nurse anesthetists, 2 circulating nurses, and 2 surgical technologists) were conducted over a 1-month period in 2017. Four major themes related to effective teamwork emerged from analysis: (1) Smooth flow, (2) United effort, (3) Communication, and (4) Positive attitude.
Among the OR team members, agreement regarding effective teamwork centers around the concepts of smooth procedural flow, unified effort, clear communication, and positive attitude of the team. These findings have helped refine a teamwork instrument to increase its utility for formative use in the clinical environment.
Sexually selected male weaponry is widespread in nature. Despite being model systems for the study of male aggression in Western science and for cricket fights in Chinese culture, field crickets ...(Orthoptera, Gryllidae, Gryllinae) are not known to possess sexually dimorphic weaponry. In a wild population of the fall field cricket, Gryllus pennsylvanicus, we report sexual dimorphism in head size as well as the size of mouthparts, both of which are used when aggressive contests between males escalate to physical combat. Male G. pennsylvanicus have larger heads, maxillae and mandibles than females when controlling for pronotum length. We conducted two experiments to test the hypothesis that relatively larger weaponry conveys an advantage to males in aggressive contests. Pairs of males were selected for differences in head size and consequently were different in the size of maxillae and mandibles. In the first experiment, males were closely matched for body size (pronotum length), and in the second, they were matched for body mass. Males with proportionately larger weaponry won more fights and increasing differences in weaponry size between males increased the fighting success of the male with the larger weaponry. This was particularly true when contests escalated to grappling, the most intense level of aggression. However, neither contest duration nor intensity was related to weaponry size as predicted by models of contest settlement. These results are the first evidence that the size of the head capsule and mouthparts are under positive selection via male-male competition in field crickets, and validate 800-year-old Chinese traditional knowledge.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
PDF
