Publisher Correction: An engineered human Fc domain that behaves like a pH-toggle switch for ultra-long circulation persistence.

An amendment to this paper has been published and can be accessed via a link at the top of the paper

Time Dependent Models of Flares from Sagittarius A*

The emission from Sgr A*, the supermassive black hole in the Galactic Center, shows order of magnitude variability ("flares") a few times a day that is particularly prominent in the near-infrared (NIR) and X-rays. We present a time-dependent model for these flares motivated by the hypothesis that dissipation of magnetic energy powers the flares. We show that episodic magnetic reconnection can occur near the last stable circular orbit in time-dependent magnetohydrodynamic simulations of black hole accretion - the timescales and energetics of these events are broadly consistent with the flares from Sgr A*. Motivated by these results, we present a spatially one-zone time-dependent model for the electron distribution function in flares, including energy loss due to synchrotron cooling and adiabatic expansion. Synchrotron emission from transiently accelerated particles can explain the NIR/X-ray lightcurves and spectra of a luminous flare observed 4 April 2007. A significant decrease in the magnetic field strength during the flare (coincident with the electron acceleration) is required to explain the simultaneity and symmetry of the simultaneous lightcurves. Our models predict that the NIR and X-ray spectral indices differ by 0.5 and that there is only modest variation in the spectral index during flares. We also explore implications of this model for longer wavelength (radio-submm) emission seemingly associated with X-ray and NIR flares; we argue that a few hour decrease in the submm emission is a more generic consequence of large-scale magnetic reconnection than delayed radio emission from adiabatic expansion.Comment: 18 pages, 10 figures, ApJ accepte

Interfacial Self-Assembly of Water-Soluble Cationic Porphyrins for the Reduction of Oxygen to Water

AN APPEAL FROM JUDGMENT ENTERED BY THE THIRD JUDICIAL DISTRICT COURT, SALT LAKE COUNTY, STATE OF UTAH, MURRAY DEPARTMENT, The Hon. Michael K. Burton, Judge Presiding (Trial Court Case No. 00-201-0956

Susceptibility to tuberculosis is associated with variants in the ASAP1 gene encoding a regulator of dendritic cell migration

Human genetic factors predispose to tuberculosis (TB). We studied 7.6 million genetic variants in 5,530 people with pulmonary TB and in 5,607 healthy controls. In the combined analysis of these subjects and the follow-up cohort (15,087 TB patients and controls altogether), we found an association between TB and variants located in introns of the ASAP1 gene on chromosome 8q24 (P = 2.6 × 10−11 for rs4733781; P = 1.0 × 10−10 for rs10956514). Dendritic cells (DCs) showed high ASAP1 expression that was reduced after Mycobacterium tuberculosis infection, and rs10956514 was associated with the level of reduction of ASAP1 expression. The ASAP1 protein is involved in actin and membrane remodeling and has been associated with podosomes. The ASAP1-depleted DCs showed impaired matrix degradation and migration. Therefore, genetically determined excessive reduction of ASAP1 expression in M. tuberculosis–infected DCs may lead to their impaired migration, suggesting a potential mechanism of predisposition to TB

An engineered human Fc domain that behaves like a pH-toggle switch for ultra-long circulation persistence.

The pharmacokinetic properties of antibodies are largely dictated by the pH-dependent binding of the IgG fragment crystallizable (Fc) domain to the human neonatal Fc receptor (hFcRn). Engineered Fc domains that confer a longer circulation half-life by virtue of more favorable pH-dependent binding to hFcRn are of great therapeutic interest. Here we developed a pH Toggle switch Fc variant containing the L309D/Q311H/N434S (DHS) substitutions, which exhibits markedly improved pharmacokinetics relative to both native IgG1 and widely used half-life extension variants, both in conventional hFcRn transgenic mice and in new knock-in mouse strains. engineered specifically to recapitulate all the key processes relevant to human antibody persistence in circulation, namely: (i) physiological expression of hFcRn, (ii) the impact of hFcγRs on antibody clearance and (iii) the role of competing endogenous IgG. DHS-IgG retains intact effector functions, which are important for the clearance of target pathogenic cells and also has favorable developability

Sporadic Infantile Epileptic Encephalopathy Caused by Mutations in PCDH19 Resembles Dravet Syndrome but Mainly Affects Females

Dravet syndrome (DS) is a genetically determined epileptic encephalopathy mainly caused by de novo mutations in the SCN1A gene. Since 2003, we have performed molecular analyses in a large series of patients with DS, 27% of whom were negative for mutations or rearrangements in SCN1A. In order to identify new genes responsible for the disorder in the SCN1A-negative patients, 41 probands were screened for micro-rearrangements with Illumina high-density SNP microarrays. A hemizygous deletion on chromosome Xq22.1, encompassing the PCDH19 gene, was found in one male patient. To confirm that PCDH19 is responsible for a Dravet-like syndrome, we sequenced its coding region in 73 additional SCN1A-negative patients. Nine different point mutations (four missense and five truncating mutations) were identified in 11 unrelated female patients. In addition, we demonstrated that the fibroblasts of our male patient were mosaic for the PCDH19 deletion. Patients with PCDH19 and SCN1A mutations had very similar clinical features including the association of early febrile and afebrile seizures, seizures occurring in clusters, developmental and language delays, behavioural disturbances, and cognitive regression. There were, however, slight but constant differences in the evolution of the patients, including fewer polymorphic seizures (in particular rare myoclonic jerks and atypical absences) in those with PCDH19 mutations. These results suggest that PCDH19 plays a major role in epileptic encephalopathies, with a clinical spectrum overlapping that of DS. This disorder mainly affects females. The identification of an affected mosaic male strongly supports the hypothesis that cellular interference is the pathogenic mechanism

Accelerating development of engineered T cell therapies in the EU: current regulatory framework for studying multiple product versions and T2EVOLVE recommendations

To accelerate the development of Advanced Therapy Medicinal Products (ATMPs) for patients suffering from life-threatening cancer with limited therapeutic options, regulatory approaches need to be constantly reviewed, evaluated and adjusted, as necessary. This includes utilizing science and risk-based approaches to mitigate and balance potential risks associated with early clinical research and a more flexible manufacturing paradigm. In this paper, T2EVOLVE an Innovative Medicine Initiative (IMI) consortium explores opportunities to expedite the development of CAR and TCR engineered T cell therapies in the EU by leveraging tools within the existing EU regulatory framework to facilitate an iterative and adaptive learning approach across different product versions with similar design elements or based on the same platform technology. As understanding of the linkage between product quality attributes, manufacturing processes, clinical efficacy and safety evolves through development and post licensure, opportunities are emerging to streamline regulatory submissions, optimize clinical studies and extrapolate data across product versions reducing the need to perform duplicative studies. It is worth noting that this paper is focusing on CAR- and TCR-engineered T cell therapies but the concepts may be applied more broadly to engineered cell therapy products (e.g., CAR NK cell therapy products)

Design and Characterization of an Electrically Powered Single Molecule on Gold

The surface diffusion of individual molecules is of paramount importance in self-assembly processes and catalytic processes. However, the fundamental understanding of molecule diffusion peculiarities considering conformations and adsorption sites remain poorly known at the atomic scale. Here, we probe the 4′-(4-tolyl)-2,2′:6′,2″-terpyridine adsorbed on the Au(111) herringbone structure combining scanning tunneling microscopy and atomic force microscopy. Molecules are controllably translated by electrons excitations over the reconstruction, except at elbows acting as pinning centers. Experimental data supported by theoretical calculations show the formation of coordination bonds between the molecule and Au atoms of the surface. Using force spectroscopy, we quantify local variation of the surface potential and the lateral force required to move the molecule. We found an elevation of the diffusion barrier at elbows of the reconstruction of ∼100 meV compared to the rest of the surface