From enhanceropathies to the epigenetic manifold underlying human cognition

A vast portion of intellectual disability and autism spectrum disorders is genetically caused by mutations in chromatin modulators. These proteins play key roles in development and are also highly expressed in the adult brain. Specifically, the pivotal role of chromatin regulation in transcription has placed enhancers at the core of neurodevelopmental disorders (NDDs) studies, ushering in the coining of the term enhanceropathies. The convergence of these disorders is multilayered, spanning from molecular causes to pathophysiological traits, including extensive overlaps between enhanceropathies and neurocristopathies. The reconstruction of epigenetic circuitries wiring development and underlying cognitive functions has gone hand in hand with the development of tools that increase the sensitivity of identifying regulatory regions and linking enhancers to their target genes. The available models, including loop extrusion and phase separation, have been bringing into relief complementary aspects to interpret gene regulation datasets, reinforcing the idea that enhancers are not all the same and that regulatory regions possess shades of enhancer-ness and promoter-ness. The current limits in enhancer definition, within the emerging broader understanding of chromatin dynamics in time and space, are now on the verge of being transformed by the possibility to interrogate developmentally relevant three-dimensional cellular models at single-cell resolution. Here we discuss the contours of how these technological advances, as well as the epistemic limitations they are set to overcome, may well usher in a change of paradigm for NDDs, moving the quest for convergence from enhancers to the four-dimensional (4D) genome

Un criterio di selezione dell’input sismico per l’analisi dinamica non lineare delle strutture

Viene proposto un metodo di selezione di accelerogrammi naturali da impiegare nell’analisi dinamica non lineare al passo. Allo scopo di valutare la capacità dei parametri di intensità sismica di rappresentare il potenziale di danneggiamento del sisma, sono stati analizzati gli spettri delle correlazioni tra i parametri di intensità sismica che caratterizzano le registrazioni accelerometriche ed i parametri cinematici, energetici e di danno rappresentativi della risposta strutturale di un sistema ad un grado di libertà. In tale ambito, è stato definito un nuovo parametro di intensità sismica in forma integrale, l’Accelerazione di Picco Efficace per la Struttura (SEPA - Structure Effective Peak Acceleration), che è risultato fortemente correlato con i parametri di risposta della struttura in tutto il campo dei periodi e per qualsiasi livello di non linearità della risposta. Successivamente è stato proposto un metodo di selezione degli accelerogrammi, in grado di tenere conto delle due componenti di ogni accelerazione sismica, in grado di fornire set di accelerogrammi compatibili con un prefissato spettro di risposta e che singolarmente siano coerenti con l’intensità sismica da esso rappresentato, riducendo la dispersione delle caratteristiche delle registrazioni che caratterizzano i campioni scelti sulla base dei metodi presenti in letteratur

HIV prevalence and characteristics of sex work among female sex workers in Hargeisa, Somaliland, Somalia.

OBJECTIVE: To measure prevalence of HIV and syphilis and describe characteristics of sex work among female sex workers (FSWs) in Hargeisa, Somaliland, Somalia. METHODS: A cross-sectional survey recruited 237 FSWs using respondent-driven sampling (RDS). A face-to-face, structured interview using handheld-assisted personal interviewing (HAPI) on personal digital assistants (PDAs) was completed and blood collected for serological testing. RESULTS: FSWs 15-19 years old accounted for 6.9% of the population; 20-24 year-old constituted an additional 18.0%. The majority (86.6%) never attended school. International (59.0%) and interzonal (10.7%) migration was common. Most (95.7%) reported no other source of income; 13.8% had five or more clients in the last 7 days. A minority (38.4%) had heard of STIs, even fewer (6.9%) held no misconceptions about HIV. Only 24% of FSW reported using a condom at last transactional sex, and 4% reported ever been tested for HIV. HIV prevalence was 5.2% and syphilis prevalence was 3.1%. CONCLUSION: Sex work in Hargeisa, Somaliland, Somalia, is characterized by high numbers of sexual acts and extremely low knowledge of HIV. This study illustrates the need for targeted HIV prevention interventions focusing on HIV testing, risk-reduction awareness raising, and review of condom availability and distribution mechanisms among FSWs and males engaging with FSWs

Clinical use of contrast-enhanced ultrasound beyond the liver: a focus on renal, splenic, and pancreatic applications

Contrast-enhanced ultrasound (CEUS) is a relatively novel, but increasingly used, diagnostic imaging modality. In recent years, due to its safety, quickness, and repeatability, several studies have demonstrated the accuracy, specificity, and sensitivity of CEUS. The European Federation of Societies for Ultrasound in Medicine and Biology has recently updated the previous guidelines from 2012 for the use of CEUS in non-hepatic applications. This review deals with the clinical use and applications of CEUS for the evaluation of non-hepatic abdominal organs, focusing on renal, splenic, and pancreatic applications

Non linear and linearized combination coefficients for modal pushover analysis

Current design practice and seismic codes tend to assess seismic demand of buildings by Non linear Static Analysis (NSA), based on the evaluation of the pushover curve. Earlier non-linear static analysis procedure estimate the response peak value by evaluating the push-over curve adopting a distribution of invariant forces proportional to the fundamental vibration mode. In order to include the effect of higher modes several multimodal push-over analysis procedures were proposed in literature. In In the most famous of these, namely Modal Pushover Analysis (MPA), nodal response peak values are obtained by combination of "modal" responses by the traditional SRSS or CQC methods: the use of the CQC rule is mandatory for irregular plane frames or spatial structures possessing modes with close natural frequencies. In order to take into account the actual characteristics of modal oscillators, the use of pertinent cross correlation coefficients defined for non-linear systems is required. In this paper the accuracy of correlation coefficients for linear systems in predicting the statistical correlation of hysteretic oscillator responses is investigated by a parametric analysis by Monte Carlo simulation. Furthermore, new correlation coefficients, determined through a pertinent statistical linearization are introduced, and the results provided by the classical and the proposed approach for two illustrative irregular plane and spatial frame are compared with non-linear time history analysis results, showing the effectiveness of the new procedure

The chromatin basis of neurodevelopmental disorders: Rethinking dysfunction along the molecular and temporal axes

The complexity of the human brain emerges from a long and finely tuned developmental process orchestrated by the crosstalk between genome and environment. Vis \uc3\ua0 vis other species, the human brain displays unique functional and morphological features that result from this extensive developmental process that is, unsurprisingly, highly vulnerable to both genetically and environmentally induced alterations. One of the most striking outcomes of the recent surge of sequencing-based studies on neurodevelopmental disorders (NDDs) is the emergence of chromatin regulation as one of the two domains most affected by causative mutations or Copy Number Variations besides synaptic function, whose involvement had been largely predicted for obvious reasons. These observations place chromatin dysfunction at the top of the molecular pathways hierarchy that ushers in a sizeable proportion of NDDs and that manifest themselves through synaptic dysfunction and recurrent systemic clinical manifestation. Here we undertake a conceptual investigation of chromatin dysfunction in NDDs with the aim of systematizing the available evidence in a new framework: first, we tease out the developmental vulnerabilities in human corticogenesis as a structuring entry point into the causation of NDDs; second, we provide a much needed clarification of the multiple meanings and explanatory frameworks revolving around "epigenetics", highlighting those that are most relevant for the analysis of these disorders; finally we go in-depth into paradigmatic examples of NDD-causing chromatin dysregulation, with a special focus on human experimental models and datasets

Hypericum scruglii Bacch., Brullo & Salmeri, a Potential Natural Remedy for Fibromyalgia: A Narrative Review

Abstract: Fibromyalgia (FM) is a disorder of central pain processing marked by widespread chronic pain together with fatigue, sleep disturbances, cognitive dysfunction, and depressive episodes. Tested treatments have expressed limited efficacy. Oxidative stress plays a role in the pathology of FM, while multiple neurotransmitters are involved in this syndrome. Antidepressants are used as conventional treatment, especially those with double action on serotonin and norepinephrine that leads to an increased risk of a manic switch. It should be noted that fibromyalgia is high-frequency comorbidity in bipolar disorder. This narrative review, given the limited literature, consisted of animal and in vitro studies, which aims to highlight the positive aspects of Hypericum scruglii as a potential remedy against FM. Many in vitro and clinical studies confirm the Hypericum genus as a natural antidepressant resource. The use of Hypericum derivatives in various acute and chronic diseases has been known for a long time. It is reported that the phloroglucinol derivatives from Hypericum longistylum improve and accelerate the differentiation of neural progenitor cells. The advantage of Hypericum scruglii is that it owns greater antioxidant potential than other species of the Hypericum genus. Suggestions for improving the oral bioavailability of very poor water-soluble molecules of hypericum extracts are also described in this pape

Hunting for intermediate mass black holes in a sample of close dwarf spheroidal galaxies

We analyse archival XMM-Newton and Chandra observations of some dwarf MW satellites and characterized the X-ray source population by cross-correlating with available databases. We also investigate if intermediate-mass black holes are hosted in the center of these galaxies. In the most interesting case of UMI dwarf, we put an upper limit to the central compact object luminosity of ≃ 4 × 1033 erg s-1. As the target correlates in position also with a radio source, we estimated a black hole mass of ≃ 32.0-2.76+2.54 × 106 M☉

Signal-in-Space Range Error Analysis of the Simulated Broadcast Ephemerides for the Kepler System.

Kepler navigation system is a DLR’s proposal for the next generation of GNSS. It comprises a constellation of Galileo-like satellites augmented by Low Earth Orbit (LEO) satellites and exploits optical inter-satellite links (OISLs) for constellation-wide clock synchronization, communication and precise ranging. In our previous works we analyzed extensively precise orbit determination (POD) performance of this system. We simulated various Kepler scenarios, and the POD results were compared to the baseline Galileo scenario. We demonstrated, that Kepler precise orbits can achieve sub-cm Signal in Space Range Errors (SiSREs) compared to few cm for Galileo. However, precise orbits – based on measurement data, are only available with substantial delay and cannot be used for real-time navigation directly. Operational GNSS provides predicted orbits and clock offsets which are distributed in the navigation message for user positioning. Thus, we extended our POD system with prediction and generation of navigation messages. In this contribution, we focus on the analysis of orbit, clock and Earth rotation parameter (ERP) prediction errors for Galileo and selected Kepler scenarios. The Galileo clocks were simulated using a model for Passive Hydrogen Masers with a stability and drift consistent with the precise clocks estimated by the Center for Orbit Determination in Europe (CODE). For the Kepler system, the clocks are assumed to be synchronized and were simulated as null value with a Gaussian noise of 3-10 ps (1-3 mm). The Galileo F/NAV broadcast ephemeris model, which consists of 15 orbital parameters, is used for our analysis. The parameters were fitted to the predicted orbits with a least-squares adjustment and truncated in the navigation message according to the number of bits allocated to each parameter. The clock prediction model consists of a constant and a drift term obtained from linear fit to the clocks estimated in POD. The accuracy of the predicted orbits and clocks found depends on the constellation, POD modelling errors and the propagation interval. In our analysis, we considered scenarios with perfect models and, for more realistic results, with a number of modeling errors introduced in the POD. For all analyzed cases we report global average Signal in Space Range Error (SiSRE) which accounts for orbit and clock errors and is a key performance indicator of a navigation system. Our simulations show, that the Galileo system is capable of providing broadcast data with SiSRE at a dm level, consistent with 1-2 dm SiSRE for the actual broadcast data. For the Kepler system the clocks are synchronized with 1-3 mm precision and there are no additional clock prediction errors. The orbit prediction errors can be well below 1 cm due the exploitation of precise intersatellite ranges. However, the accuracy of predicted Earth rotation parameters (ERPs), which are used in transformation of the orbits from the Earth-Center-Inertial (ECI) to Earth-Centered Earth-Fixed frame (ECEF), have a significant impact on the accuracy of the predicted orbits in ECEF. Currently, we have implemented in our prediction system a simple linear extrapolation of ERPs based on values estimated in POD. We found, that this introduces significant errors in the orbit cross- and along-track direction, increasing the SiSRE by up to a decimeter after 24 h. Therefore, precise modelling and prediction of ERPs is an important factor for achieving sub-cm SiSRE for the Kepler system. We identified two other parameters, GNSS ionosphere-free pseudo-range hardware delays (HDs) and antenna radial phase center offsets (PCOs), that are relevant for SiSRE. For Galileo, they are not critical since HDs and most of the PCO error are absorbed by the estimated satellite clocks and, if assumed stable, do not degrade the accuracy of the clock prediction. For Kepler, where clocks are synchronized in the optical domain and are not estimated in POD, errors of these parameters directly affect SiSRE and must be precisely calibrated. We analyzed also in details the impact of broadcast parameter fit interval length, varying from 10 minutes to 4 h, and parameter truncation on the accuracy of reconstructed orbits and SiSRE. We found, that the maximum orbit fit error for intervals up to 2 h contributes to SiSRE at few mm level, while the fit interval of 4 h can increase SiSRE by a decimeter. The parameter truncation errors are not dependent on the fitting interval and increase SiSRE by an average of 1 cm and maximum of 3 cm. Such errors can be seen as a SiSRE limiting factor for highly accurate Kepler orbits (below 1 cm) and need to be mitigated, e.g. by allocation of more bits to most relevant parameters. Finally, we concluded that SiSRE below 1 cm can be continuously achieved for the Kepler system, which is at least an order of magnitude smaller than for Galileo. However, this requires precisely calibrated GNSS hardware delays and antenna phase center offsets