Impaired Functional Connectivity Underlies Fragile X Syndrome

Fragile X syndrome (FXS), the most common form of inherited intellectual disability, is caused by a developmentally regulated silencing of the FMR1 gene, but its effect on human neuronal network development and function is not fully understood. Here, we isolated isogenic human embryonic stem cell (hESC) subclones-one with a full FX mutation and one that is free of the mutation (control) but shares the same genetic background-differentiated them into induced neurons (iNs) by forced expression of NEUROG-1, and compared the functional properties of the derived neuronal networks. High-throughput image analysis demonstrates that FX-iNs have significantly smaller cell bodies and reduced arborizations than the control. Both FX- and control-neurons can discharge repetitive action potentials, and FX neuronal networks are also able to generate spontaneous excitatory synaptic currents with slight differences from the control, demonstrating that iNs generate more mature neuronal networks than the previously used protocols. MEA analysis demonstrated that FX networks are hyperexcitable with significantly higher spontaneous burst-firing activity compared to the control. Most importantly, cross-correlation analysis enabled quantification of network connectivity to demonstrate that the FX neuronal networks are significantly less synchronous than the control, which can explain the origin of the development of intellectual dysfunction associated with FXS

Relation between 2D/3D chirality and the appearence of chiroptical effects in real nanostructures.

The optical activity of fabricated metallic nanostructures is investigated by complete polarimetry. While lattices decorated with nanoscale gammadia etched in thin metallic films have been described as two dimensional, planar nanostructures, they are better described as quasi-planar structures with some three dimensional character. We find that the optical activity of these structures arises not only from the dissymmetric backing by a substrate but, more importantly, from the selective rounding of the nanostructure edges. A true chiroptical response in the far-field is only allowed when the gammadia contain these non-planar features. This is demonstrated by polarimetric measurements in conjunction with electrodynamical simulations based on the discrete dipole approximation that consider non-ideal gammadia. It is also shown that subtle planar dissymmetries in gammadia are sufficient to generate asymmetric transmission of circular polarized light

Comparative effectiveness of intensity modulated radiation therapy to 3-dimensional conformal radiation in locally advanced lung cancer: pathological and clinical outcomes.

OBJECTIVE: Intensity-modulated radiotherapy (IMRT) has better normal-tissue sparing compared with 3-dimensional conformal radiation (3DCRT). We sought to assess the impact of radiation technique on pathological and clinical outcomes in locally advanced non-small cell lung cancer (LANSCLC) treated with a trimodality strategy. METHODS: Retrospective review of LANSCLC patients treated from August 2012 to August 2018 at Sheba Medical Center, Israel. The trimodality strategy consisted of concomitant chemoradiation to 60 Gray (Gy) followed by completion surgery. The planning target volume (PTV) was defined by co-registered PET/CT. Here we compare the pathological regression, surgical margin status, local control rates (LC), disease free (DFS) and overall survival (OS) between 3DCRT and IMRT. RESULTS: Our cohort consisted of 74 patients with mean age 62.9 years, male in 51/74 (69%), adenocarcinoma in 46/74 (62.1%), stage 3 in 59/74 (79.7%) and chemotherapy in 72/74 (97.3%). Radiation mean dose: 59.2 Gy (SD ± 3.8). Radiation technique : 3DCRT in 51/74 (68.9%), IMRT in 23/74 (31%). Other variables were similar between groups.Major pathological response (including pathological complete response or less than 10% residual tumor cells) was similar: 32/51 (62.7%) in 3DCRT and 15/23 (65.2%) in IMRT, p=0.83. Pathological complete response (pCR) rates were similar: 17/51 (33.3%) in 3DCRT and 8/23 (34.8%) in IMRT, p=0.9. Surgical margins were negative in 46/51 (90.1%) in 3DCRT vs. 17/19 (89.4%) in IMRT (p=1.0).The 2-year LC rates were 81.6% (95% CI 69-89.4%); DFS 58.3% (95% CI 45.5-69%) and 3-year OS 70% (95% CI57-80%). Comparing radiation techniques, there were no significant differences in LC (p=0.94), DFS (p=0.33) and OS (p=0.72). CONCLUSION: When used to treat LANSCLC in the neoadjuvant setting, both IMRT and 3DCRT produce comparable pathological and clinical outcomes. ADVANCES IN KNOWLEDGE: This study validates the real-world effectiveness of IMRT compared to 3DCRT

PTF10iya: A short-lived, luminous flare from the nuclear region of a star-forming galaxy

We present the discovery and characterisation of PTF10iya, a short-lived (dt ~ 10 d, with an optical decay rate of ~ 0.3 mag per d), luminous (M_g ~ -21 mag) transient source found by the Palomar Transient Factory. The ultraviolet/optical spectral energy distribution is reasonably well fit by a blackbody with T ~ 1-2 x 10^4 K and peak bolometric luminosity L_BB ~ 1-5 x 10^44 erg per s (depending on the details of the extinction correction). A comparable amount of energy is radiated in the X-ray band that appears to result from a distinct physical process. The location of PTF10iya is consistent with the nucleus of a star-forming galaxy (z = 0.22405 +/- 0.00006) to within 350 mas (99.7 per cent confidence radius), or a projected distance of less than 1.2 kpc. At first glance, these properties appear reminiscent of the characteristic "big blue bump" seen in the near-ultraviolet spectra of many active galactic nuclei (AGNs). However, emission-line diagnostics of the host galaxy, along with a historical light curve extending back to 2007, show no evidence for AGN-like activity. We therefore consider whether the tidal disruption of a star by an otherwise quiescent supermassive black hole may account for our observations. Though with limited temporal information, PTF10iya appears broadly consistent with the predictions for the early "super-Eddington" phase of a solar-type star disrupted by a ~ 10^7 M_sun black hole. Regardless of the precise physical origin of the accreting material, the large luminosity and short duration suggest that otherwise quiescent galaxies can transition extremely rapidly to radiate near the Eddington limit; many such outbursts may have been missed by previous surveys lacking sufficient cadence.Comment: 18 pages, 8 figures; revised following referee's comment

The Cytosolic Tail of the Golgi Apyrase Ynd1 Mediates E4orf4-Induced Toxicity in Saccharomyces cerevisiae

The adenovirus E4 open reading frame 4 (E4orf4) protein contributes to regulation of the progression of virus infection. When expressed individually, E4orf4 was shown to induce non-classical transformed cell-specific apoptosis in mammalian cells. At least some of the mechanisms underlying E4orf4-induced toxicity are conserved from yeast to mammals, including the requirement for an interaction of E4orf4 with protein phosphatase 2A (PP2A). A genetic screen in yeast revealed that the Golgi apyrase Ynd1 associates with E4orf4 and contributes to E4orf4-induced toxicity, independently of Ynd1 apyrase activity. Ynd1 and PP2A were shown to contribute additively to E4orf4-induced toxicity in yeast, and to interact genetically and physically. A mammalian orthologue of Ynd1 was shown to bind E4orf4 in mammalian cells, confirming the evolutionary conservation of this interaction. Here, we use mutation analysis to identify the cytosolic tail of Ynd1 as the protein domain required for mediation of the E4orf4 toxic signal and for the interaction with E4orf4. We also show that E4orf4 associates with cellular membranes in yeast and is localized at their cytoplasmic face. However, E4orf4 is membrane-associated even in the absence of Ynd1, suggesting that additional membrane proteins may mediate E4orf4 localization. Based on our results and on a previous report describing a collection of Ynd1 protein partners, we propose that the Ynd1 cytoplasmic tail acts as a scaffold, interacting with a multi-protein complex, whose targeting by E4orf4 leads to cell death

Hubble Space Telescope studies of low-redshift Type Ia supernovae: Evolution with redshift and ultraviolet spectral trends

We present an analysis of the maximum light, near ultraviolet (NUV; 2900-5500 A) spectra of 32 low redshift (0.001<z<0.08) Type Ia supernovae (SNe Ia), obtained with the Hubble Space Telescope (HST). We combine this spectroscopic sample with high-quality gri light curves obtained with robotic telescopes to measure photometric parameters, such as stretch, optical colour, and brightness. By comparing our data to a comparable sample of SNe Ia at intermediate-z (0.4<z<0.9), we detect modest spectral evolution (3-sigma), in the sense that our mean low-z NUV spectrum has a depressed flux compared to its intermediate-z counterpart. We also see a strongly increased dispersion about the mean with decreasing wavelength, confirming the results of earlier surveys. These trends are consistent with changes in metallicity as predicted by contemporary SN Ia spectral models. We also examine the properties of various NUV spectral diagnostics in the individual spectra. We find a general correlation between stretch and the velocity (or position) of many NUV spectral features. In particular, we observe that higher stretch SNe have larger Ca II H&K velocities, that also correlate with host galaxy stellar mass. This latter trend is probably driven by the well-established correlation between stretch and stellar mass. We find no trends between UV spectral features and optical colour. Mean spectra constructed according to whether the SN has a positive or negative Hubble residual show very little difference at NUV wavelengths, indicating that the NUV evolution and variation we identify do not directly correlate with Hubble residuals. Our work confirms and strengthens earlier conclusions regarding the complex behaviour of SNe Ia in the NUV spectral region, but suggests the correlations we find are more useful in constraining progenitor models than improving the use of SNe Ia as cosmological probes.Comment: 22 pages, 14 figures, accepted in MNRAS with minor changes - Spectra are available on WISeREP, http://www.weizmann.ac.il/astrophysics/wiserep

The detection rate of early UV emission from supernovae: A dedicated GALEX/PTF survey and calibrated theoretical estimates

The radius and surface composition of an exploding massive star,as well as the explosion energy per unit mass, can be measured using early UV observations of core collapse supernovae (SNe). We present the first results from a simultaneous GALEX/PTF search for early UV emission from SNe. Six Type II SNe and one Type II superluminous SN (SLSN-II) are clearly detected in the GALEX NUV data. We compare our detection rate with theoretical estimates based on early, shock-cooling UV light curves calculated from models that fit existing Swift and GALEX observations well, combined with volumetric SN rates. We find that our observations are in good agreement with calculated rates assuming that red supergiants (RSGs) explode with fiducial radii of 500 solar, explosion energies of 10^51 erg, and ejecta masses of 10 solar masses. Exploding blue supergiants and Wolf-Rayet stars are poorly constrained. We describe how such observations can be used to derive the progenitor radius, surface composition and explosion energy per unit mass of such SN events, and we demonstrate why UV observations are critical for such measurements. We use the fiducial RSG parameters to estimate the detection rate of SNe during the shock-cooling phase (<1d after explosion) for several ground-based surveys (PTF, ZTF, and LSST). We show that the proposed wide-field UV explorer ULTRASAT mission, is expected to find >100 SNe per year (~0.5 SN per deg^2), independent of host galaxy extinction, down to an NUV detection limit of 21.5 mag AB. Our pilot GALEX/PTF project thus convincingly demonstrates that a dedicated, systematic SN survey at the NUV band is a compelling method to study how massive stars end their life.Comment: See additional information including animations on http://www.weizmann.ac.il/astrophysics/ultrasa

A Compact Representation of Drawing Movements with Sequences of Parabolic Primitives

Some studies suggest that complex arm movements in humans and monkeys may optimize several objective functions, while others claim that arm movements satisfy geometric constraints and are composed of elementary components. However, the ability to unify different constraints has remained an open question. The criterion for a maximally smooth (minimizing jerk) motion is satisfied for parabolic trajectories having constant equi-affine speed, which thus comply with the geometric constraint known as the two-thirds power law. Here we empirically test the hypothesis that parabolic segments provide a compact representation of spontaneous drawing movements. Monkey scribblings performed during a period of practice were recorded. Practiced hand paths could be approximated well by relatively long parabolic segments. Following practice, the orientations and spatial locations of the fitted parabolic segments could be drawn from only 2–4 clusters, and there was less discrepancy between the fitted parabolic segments and the executed paths. This enabled us to show that well-practiced spontaneous scribbling movements can be represented as sequences (“words”) of a small number of elementary parabolic primitives (“letters”). A movement primitive can be defined as a movement entity that cannot be intentionally stopped before its completion. We found that in a well-trained monkey a movement was usually decelerated after receiving a reward, but it stopped only after the completion of a sequence composed of several parabolic segments. Piece-wise parabolic segments can be generated by applying affine geometric transformations to a single parabolic template. Thus, complex movements might be constructed by applying sequences of suitable geometric transformations to a few templates. Our findings therefore suggest that the motor system aims at achieving more parsimonious internal representations through practice, that parabolas serve as geometric primitives and that non-Euclidean variables are employed in internal movement representations (due to the special role of parabolas in equi-affine geometry)

Coding “What” and “When” in the Archer Fish Retina

Traditionally, the information content of the neural response is quantified using statistics of the responses relative to stimulus onset time with the assumption that the brain uses onset time to infer stimulus identity. However, stimulus onset time must also be estimated by the brain, making the utility of such an approach questionable. How can stimulus onset be estimated from the neural responses with sufficient accuracy to ensure reliable stimulus identification? We address this question using the framework of colour coding by the archer fish retinal ganglion cell. We found that stimulus identity, “what”, can be estimated from the responses of best single cells with an accuracy comparable to that of the animal's psychophysical estimation. However, to extract this information, an accurate estimation of stimulus onset is essential. We show that stimulus onset time, “when”, can be estimated using a linear-nonlinear readout mechanism that requires the response of a population of 100 cells. Thus, stimulus onset time can be estimated using a relatively simple readout. However, large nerve cell populations are required to achieve sufficient accuracy

Fluorescent Multifunctional Organic Nanoparticles for Drug Delivery and Bioimaging: A Tutorial Review

Fluorescent organic nanoparticles (FONs) are a large family of nanostructures constituted by organic components that emit light in different spectral regions upon excitation, due to the presence of organic fluorophores. FONs are of great interest for numerous biological and medical applications, due to their high tunability in terms of composition, morphology, surface functionalization, and optical properties. Multifunctional FONs combine several functionalities in a single nanostructure (emission of light, carriers for drug-delivery, functionalization with targeting ligands, etc.), opening the possibility of using the same nanoparticle for diagnosis and therapy. The preparation, characterization, and application of these multifunctional FONs require a multidisciplinary approach. In this review, we present FONs following a tutorial approach, with the aim of providing a general overview of the different aspects of the design, preparation, and characterization of FONs. The review encompasses the most common FONs developed to date, the description of the most important features of fluorophores that determine the optical properties of FONs, an overview of the preparation methods and of the optical characterization techniques, and the description of the theoretical approaches that are currently adopted for modeling FONs. The last part of the review is devoted to a non-exhaustive selection of some recent biomedical applications of FONs.This project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowka-Curie grant agreement No. 101007804 (Micro4Nano). M.K., N.V., and I.R. acknowledge financial support from the Spanish Ministry of Science and Innovation through the Severo Ochoa Program for Centers of Excellence in R&D (SEV-2015-0496 and CEX2019-000917-S) and through the grant “MOL4BIO” (PID2019-105622RB-I00). K.D.B acknowledges support from the US National Science Foundation (EFMA-2203704) and the National Institutes of Health (R21AA028340).With funding from the Spanish government through the ‘Severo Ochoa Centre of Excellence’ accreditation (CEX2019-000917-S).Peer reviewe