Immunization of Mice with Anthrax Protective Antigen Limits Cardiotoxicity but Not Hepatotoxicity Following Lethal Toxin Challenge

Protective immunity against anthrax is inferred from measurement of vaccine antigen-specific neutralizing antibody titers in serum samples. In animal models, in vivo challenges with toxin and/or spores can also be performed. However, neither of these approaches considers toxin-induced damage to specific organ systems. It is therefore important to determine to what extent anthrax vaccines and existing or candidate adjuvants can provide organ-specific protection against intoxication. We therefore compared the ability of Alum, CpG DNA and the CD1d ligand alpha-galactosylceramide (alphaGC) to enhance protective antigen-specific antibody titers, to protect mice against challenge with lethal toxin, and to block cardiotoxicity and hepatotoxicity. By measurement of serum cardiac Troponin I (cTnI), and hepatic alanine aminotransferase (ALT), and aspartate aminotransferase (AST), it was apparent that neither vaccine modality prevented hepatic intoxication, despite high Ab titers and ultimate survival of the subject. In contrast, cardiotoxicity was greatly diminished by prior immunization. This shows that a vaccine that confers survival following toxin exposure may still have an associated morbidity. We propose that organ-specific intoxication should be monitored routinely during research into new vaccine modalities

The fate of disk galaxies in IllustrisTNG clusters

We study the stellar morphological evolution of disc galaxies within clusters in the TNG50 and TNG100 runs from the IllustrisTNG simulation suite. We select satellites of masses $10^{9.7} \leq M_{*,z=0}/\text{M}_{\odot} \leq 10^{11.6}$ residing in clusters of masses $10^{14} \lesssim M_{\text{200c,z=0}}/\text{M}_{\odot} \leq 10^{14.6}$ at $z=0$ and that were discs at accretion according to a kinematic morphology indicator (the circularity fraction). These are traced from the time of accretion to $z=0$ and compared to a control sample of central galaxies mass-matched at accretion. Most cluster discs become non-discy by $z=0$, in stark contrast with the control discs, of which a significant fraction remains discy over the same timescales. Cluster discs become non-discy accompanied by gas removal and star formation quenching, loss of dark matter and little growth or a loss of stellar mass. In contrast, control discs transform while also losing gas mass and quenching, but growing significantly in dark matter and stellar mass. Most cluster satellites change morphologies on similar timescales regardless of stellar mass, in $\sim0.5-4$ Gyr after accretion. Cluster discs that experienced more numerous and closer pericentric passages show the largest change in morphology. Morphological change in all cases requires the presence of a gravitational perturbation to drive stellar orbits to non-discy configurations, along with gas removal/heating to prevent replenishment of the disc through continued star-formation. For cluster discs, the perturbation is impulsive tidal shocking at pericentres and not tidal stripping of outer disc stellar material, whereas for control discs, a combination of mergers and AGN feedback appears to be the key driving force behind morphological transformations.Comment: Accepted to MNRA

Quenched fractions in the IllustrisTNG simulations: the roles of AGN feedback, environment, and pre-processing

We use the IllustrisTNG simulations to show how the fractions of quenched galaxies vary across different environments and cosmic time, and to quantify the role AGN feedback and preprocessing play in quenching group and cluster satellites. At $z=0$, we select galaxies with $M_* = 10^{9-12} M_{\odot}$ residing within ($\leq R_{200c}$) groups and clusters of total host mass $M_{200c}=10^{13-15.2} M_{\odot}$. TNG predicts a quenched fraction of $\sim70-90\%$ (on average) for centrals and satellites $\gtrsim 10^{10.5} M_{\odot}$, regardless of host mass, cosmic time ($0\leq z\leq0.5$), clustercentric distance and time since infall in the $z=0$ host. Low-mass centrals ($\lesssim 10^{10} M_{\odot}$), instead, are rarely quenched unless they become members of groups ($10^{13-14} M_{\odot}$) or clusters ($\geq10^{14} M_{\odot}$), where the quenched fraction rises to $\sim80\%$. The fraction of low-mass passive galaxies is higher closer to the host center and for more massive hosts. The population of low-mass satellites accreted $\gtrsim$4-6 Gyr ago in massive hosts is almost entirely passive, thus suggesting an upper limit for the time needed for environmental quenching to occur. In fact, $\sim30\%$ of group and cluster satellites that are quenched at $z=0$ were already quenched before falling into their current host, and the bulk of them quenched as early as 4 to 10 billion years ago. For low-mass galaxies ($\lesssim10^{10-10.5}M_{\odot}$), this is due to preprocessing, whereby current satellites may have been members of other hosts, and hence have undergone environmental processes, before falling into their final host, this mechanism being more common and more effective for the purposes of quenching for satellites found today in more massive hosts. On the other hand, massive galaxies quench on their own and because of AGN feedback, regardless of whether they are centrals or satellites.Comment: 21 Pages, 11 figures, 2 tables, 1 appendix, submitted to MNRA

Topical Application of an Irreversible Small Molecule Inhibitor of Lysyl Oxidases Ameliorates Skin Scarring and Fibrosis

Scarring is a lifelong consequence of skin injury, with scar stiffness and poor appearance presenting physical and psychological barriers to a return to normal life. Lysyl oxidases are a family of enzymes that play a critical role in scar formation and maintenance. Lysyl oxidases stabilize the main component of scar tissue, collagen, and drive scar stiffness and appearance. Here we describe the development and characterisation of an irreversible lysyl oxidase inhibitor, PXS-6302. PXS-6302 is ideally suited for skin treatment, readily penetrating the skin when applied as a cream and abolishing lysyl oxidase activity. In murine models of injury and fibrosis, topical application reduces collagen deposition and cross-linking. Topical application of PXS-6302 after injury also significantly improves scar appearance without reducing tissue strength in porcine injury models. PXS-6302 therefore represents a promising therapeutic to ameliorate scar formation, with potentially broader applications in other fibrotic diseases

On the Location of the Gamma-ray Emission in the 2008 Outburst in the BL Lacertae Object AO 0235+164 through Observations across the Electromagnetic Spectrum

We present observations of a major outburst at centimeter, millimeter, optical, X-ray, and gamma-ray wavelengths of the BL Lacertae object AO 0235+164. We analyze the timing of multi-waveband variations in the flux and linear polarization, as well as changes in Very Long Baseline Array (VLBA) images at 7mm with 0.15 milliarcsecond resolution. The association of the events at different wavebands is confirmed at high statistical significance by probability arguments and Monte-Carlo simulations. A series of sharp peaks in optical linear polarization, as well as a pronounced maximum in the 7 mm polarization of a superluminal jet knot, indicate rapid fluctuations in the degree of ordering of the magnetic field. These results lead us to conclude that the outburst occurred in the jet both in the quasi-stationary "core" and in the superluminal knot, both parsecs downstream of the supermassive black hole. We interpret the outburst as a consequence of the propagation of a disturbance, elongated along the line of sight by light-travel time delays, that passes through a standing recollimation shock in the core and propagates down the jet to create the superluminal knot. The multi-wavelength light curves vary together on long time-scales (months/years), but the correspondence is poorer on shorter time-scales. This, as well as the variability of the polarization and the dual location of the outburst, agrees with the expectations of a multi-zone emission model in which turbulence plays a major role in modulating the synchrotron and inverse Compton fluxes.Comment: Accepted for Publication in the Astrophysical Journal Letters. 7 pages (including 5 figures). Minor corrections with regard to previous version, as proposed by the refere

DNM1 encephalopathy: A new disease of vesicle fission.

ObjectiveTo evaluate the phenotypic spectrum caused by mutations in dynamin 1 (DNM1), encoding the presynaptic protein DNM1, and to investigate possible genotype-phenotype correlations and predicted functional consequences based on structural modeling.MethodsWe reviewed phenotypic data of 21 patients (7 previously published) with DNM1 mutations. We compared mutation data to known functional data and undertook biomolecular modeling to assess the effect of the mutations on protein function.ResultsWe identified 19 patients with de novo mutations in DNM1 and a sibling pair who had an inherited mutation from a mosaic parent. Seven patients (33.3%) carried the recurrent p.Arg237Trp mutation. A common phenotype emerged that included severe to profound intellectual disability and muscular hypotonia in all patients and an epilepsy characterized by infantile spasms in 16 of 21 patients, frequently evolving into Lennox-Gastaut syndrome. Two patients had profound global developmental delay without seizures. In addition, we describe a single patient with normal development before the onset of a catastrophic epilepsy, consistent with febrile infection-related epilepsy syndrome at 4 years. All mutations cluster within the GTPase or middle domains, and structural modeling and existing functional data suggest a dominant-negative effect on DMN1 function.ConclusionsThe phenotypic spectrum of DNM1-related encephalopathy is relatively homogeneous, in contrast to many other genetic epilepsies. Up to one-third of patients carry the recurrent p.Arg237Trp variant, which is now one of the most common recurrent variants in epileptic encephalopathies identified to date. Given the predicted dominant-negative mechanism of this mutation, this variant presents a prime target for therapeutic intervention

s-Process Abundances in Planetary Nebulae

The s-process should occur in all but the lower mass progenitor stars of planetary nebulae, and this should be reflected in the chemical composition of the gas which is expelled to create the current planetary nebula shell. Weak forbidden emission lines are expected from several s-process elements in these shells, and have been searched for and in some cases detected in previous investigations. Here we extend these studies by combining very high signal-to-noise echelle spectra of a sample of PNe with a critical analysis of the identification of the emission lines of Z>30 ions. Emission lines of Br, Kr, Xe, Rb, Ba, and Pb are detected with a reasonable degree of certainty in at least some of the objects studied here, and we also tentatively identify lines from Te and I, each in one object. The strengths of these lines indicate enhancement of s-process elements in the central star progenitors, and we determine the abundances of Br, Kr, and Xe, elements for which atomic data relevant for abundance determination have recently become available. As representative elements of the ``light'' and ``heavy'' s-process peaks Kr and Xe exhibit similar enhancements over solar values, suggesting that PNe progenitors experience substantial neutron exposure.Comment: 56 Pages, 6 figures, accepted for publication in ApJ This version corrects missing captions in Figure 1-3 and minor typo

Disambiguation of biomedical text using diverse sources of information

Background: Like text in other domains, biomedical documents contain a range of terms with more than one possible meaning. These ambiguities form a significant obstacle to the automatic processing of biomedical texts. Previous approaches to resolving this problem have made use of various sources of information including linguistic features of the context in which the ambiguous term is used and domain-specific resources, such as UMLS. Materials and methods: We compare various sources of information including ones which have been previously used and a novel one: MeSH terms. Evaluation is carried out using a standard test set (the NLM-WSD corpus). Results: The best performance is obtained using a combination of linguistic features and MeSH terms. Performance of our system exceeds previously published results for systems evaluated using the same data set. Conclusion: Disambiguation of biomedical terms benefits from the use of information from a variety of sources. In particular, MeSH terms have proved to be useful and should be used if available

Computed Tomography With Intravenous Contrast Alone: The Role of Intra‐abdominal Fat on the Ability to Visualize the Normal Appendix in Children

Background Computed tomography ( CT ) with enteric contrast is frequently used to evaluate children with suspected appendicitis. The use of CT with intravenous ( IV ) contrast alone ( CT IV ) may be sufficient, however, particularly in patients with adequate intra‐abdominal fat ( IAF ). Objectives The authors aimed 1) to determine the ability of radiologists to visualize the normal (nondiseased) appendix with CT IV in children and to assess whether IAF adequacy affects this ability and 2) to assess the association between IAF adequacy and patient characteristics. Methods This was a retrospective 16‐center study using a preexisting database of abdominal CT scans. Children 3 to 18 years who had CT IV scan and measured weights and for whom appendectomy history was known from medical record review were included. The sample was chosen based on age to yield a sample with and without adequate IAF . Radiologists at each center reread their site's CT IV scans to assess appendix visualization and IAF adequacy. IAF was categorized as “adequate” if there was any amount of fat completely surrounding the cecum and “inadequate” if otherwise. Results A total of 280 patients were included, with mean age of 10.6 years (range = 3.1 to 17.9 years). All 280 had no history of prior appendectomy; therefore, each patient had a presumed normal appendix. A total of 102 patients (36.4%) had adequate IAF . The proportion of normal appendices visualized with CT IV was 72.9% (95% confidence interval [ CI ] = 67.2% to 78.0%); the proportions were 89% (95% CI  = 81.5% to 94.5%) and 63% (95% CI  = 56.0% to 70.6%) in those with and without adequate IAF (95% CI for difference of proportions = 16% to 36%). Greater weight and older age were strongly associated with IAF adequacy (p < 0.001), with weight appearing to be a stronger predictor, particularly in females. Although statistically associated, there was noted overlap in the weights and ages of those with and without adequate IAF . Conclusions Protocols using CT with IV contrast alone to visualize the appendix can reasonably include weight, age, or both as considerations for determining when this approach is appropriate. However, although IAF will more frequently be adequate in older, heavier patients, highly accurate prediction of IAF adequacy appears challenging solely based on age and weight. Resumen Tomografía Computarizada Únicamente con Contraste Intravenoso: El Papel de la Grasa Intrabadominal en la Capacidad para Visualizar el Apéndice Normal en los Niños Introduction La tomografía computarizada ( TC ) con contraste entérico es usada frecuentemente para evaluar a los niños con sospecha de apendicitis. El uso de la TC únicamente con contraste intravenoso ( TC IV ) puede ser suficiente, especialmente en pacientes con adecuada grasa intrabdominal ( GIA ). Objetivos 1) Determinar la capacidad de los radiólogos para visualizar el apéndice normal (sin enfermedad) con TC IV en niños, y valorar si la cantidad de GIA afecta a esta capacidad; y 2) valorar la asociación entre la idoneidad de la GIA y las características del paciente. Metodología Estudio retrospectivo de 16 hospitales que utilizó una base de datos prexistente de TC abdominales. Se incluyó a los niños entre 3 y 18 años que tenían una TC IV , una medida del peso e historia de apendectomía conocida por la revisión de la historia clínica. La muestra se eligió en base a la edad con el fin de conseguir una muestra con y sin GIA adecuada. Los radiólogos de cada centro releyeron las TC IV de sus centros para valorar la visualización del apéndice y la adecuación de la GIA . La GIA se clasificó como “adecuada” si había cualquier cantidad de grasa completamente alrededor del ciego e “inadecuada” si era de otra manera. Resultados Se incluyeron 280 pacientes, con una media de edad de 10,6 años (rango 3,1 a 17,9 años). Ninguno tenía historia previa de apendectomía; por lo tanto todos los pacientes tuvieron un apéndice presumiblemente normal. Ciento dos pacientes (36,4%) tuvieron GIA adecuada. El porcentaje de apéndices normales visualizados con TC IV fue de 72,9% ( IC 95% = 67,2% a 78,0%); la proporción fue 89% ( IC 95% = 81,5% a 94,5%), y 63% ( IC 95% = 56,0% a 70,6%) en aquéllos con y sin GIA adecuada ( IC 95% para la diferencia de proporciones = 16% a 36%). El mayor peso y la mayor edad se asociaron fuertemente con la adecuación de la GIA (p < 0,001), y el peso resultó ser el mayor factor predictivo, especialmente en mujeres. Aunque se asoció estadísticamente, se vio un solapamiento en los pesos y edades de aquéllos con y sin GIA adecuada. Conclusiones Los protocolos que usan la TC IV para visualizar el apéndice pueden razonablemente incluir el peso, la edad, o ambas como consideraciones para determinar cuándo esta aproximación es apropiada. Sin embargo, aunque la cantidad de GIA será frecuentemente más apropiada en los pacientes más mayores y de mayor peso, la predicción certera de adecuación de GIA es altamente desafiante si se basa sólo en la edad y el peso.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/99695/1/acem12185.pd