Exploring structural and electronic effects in three isomers of tris{bis(trifluoromethyl)phenyl}borane: Towards the combined electrochemical-frustrated Lewis pair activation of H2

Three structural isomers of tris{bis(trifluoromethyl)phenyl}borane have been studied as the acidic com- ponent of frustrated Lewis pairs. While the 3,5-substituted isomer is already known to heterolytically cleave H2 to generate a bridging-hydride; ortho-substituents in the 2,4- and 2,5-isomers quench such reactivity through electron donation into the vacant boron pz orbital and steric blocking of the boron centre; as shown by electrochemical, structural and computational studies. Electrochemical studies of the corresponding borohydrides identify that the two-electron oxidation of terminal-hydrides occurs at more positive potentials than observed for [HB(C6F5)3]−, while the bridging-hydride oxidizes at a higher poten- tial still, comparable to that of free H2

Comparing Communication Doctoral Programs, Alumni, and Faculty: The Use of Google Scholar

This paper examines three aspects of doctoral programs in Communication: (a) how doctoral department faculty compare using combined citations to published work using Google Scholar, (b) the contribution in quantity and quality (measured by citations) of alumni teaching in doctoral programs, and (c) identifying the top 25 most cited communication doctoral faculty in Google Scholar. The goal is to provide a series of additional alternatives for faculty and program evaluation beyond simply counting the number of published journal articles

Ultra-Sharp Nanowire Arrays Natively Permeate, Record, and Stimulate Intracellular Activity in Neuronal and Cardiac Networks

Intracellular access with high spatiotemporal resolution can enhance our understanding of how neurons or cardiomyocytes regulate and orchestrate network activity, and how this activity can be affected with pharmacology or other interventional modalities. Nanoscale devices often employ electroporation to transiently permeate the cell membrane and record intracellular potentials, which tend to decrease rapidly to extracellular potential amplitudes with time. Here, we report innovative scalable, vertical, ultra-sharp nanowire arrays that are individually addressable to enable long-term, native recordings of intracellular potentials. We report large action potential amplitudes that are indicative of intracellular access from 3D tissue-like networks of neurons and cardiomyocytes across recording days and that do not decrease to extracellular amplitudes for the duration of the recording of several minutes. Our findings are validated with cross-sectional microscopy, pharmacology, and electrical interventions. Our experiments and simulations demonstrate that individual electrical addressability of nanowires is necessary for high-fidelity intracellular electrophysiological recordings. This study advances our understanding of and control over high-quality multi-channel intracellular recordings, and paves the way toward predictive, high-throughput, and low-cost electrophysiological drug screening platforms.Comment: Main manuscript: 33 pages, 4 figures, Supporting information: 43 pages, 27 figures, Submitted to Advanced Material

Reduced 8-Gray compared to standard 12-Gray Total Body Irradiation for allogeneic transplantation in first remission acute lymphoblastic leukemia: a study of the Acute Leukemia Working Party of the EBMT

In this registry-based study, we compared outcomes of allogeneic hematopoietic cell transplantation (allo-HCT) in adult patients with acute lymphoblastic leukemia (ALL) transplanted in first complete remission (CR-1), following conditioning with total body irradiation (TBI) at a standard 12-Gray or at a lower 8-Gray total dose. Patients received fludarabine (flu) as the sole chemotherapy complementing TBI. Eight-Gray TBI/flu was used in 494 patients and 12-Gray TBI/flu in 145 patients. Eighty-eight (23.1%) and 36 (29%) of the patients had Ph-negative B-ALL, 222 (58.3%) and 53 (42.7%) had Ph-positive B-ALL, 71 (18.6%) and 35 (28.2%) T-ALL, respectively (P = 0.008). Patients treated with 8-Gray were older than ones received 12-Gray (median 55.7 versus 40.3 years, P < 0.0001) and were more frequently administered in vivo T-cell depletion (71% versus 40%, P <0.0001). In a multivariate model adjusted for age, type of ALL, and other prognostic factors, leukemia-free survival (primary endpoint) as well as relapse, nonrelapse mortality, overall survival, and GVHD-free, relapse-free survival were not influenced by the TBI dose. These results were confirmed when we focused on patients <55 years of age (median 47 years). Patients with Ph-positive ALL or T-ALL had significantly better survival outcomes than ones with Ph-negative B-ALL, mainly due to significantly fewer relapses. We conclude that 8-Gray TBI is sufficient for adult patients with ALL transplanted in CR-1 with no additional benefit of augmenting the conditioning intensity to 12-Gray

Drugs and drug-like molecules can modulate the function of mucosal-associated invariant T cells

The major-histocompatibility-complex-(MHC)-class-I-related molecule MR1 can present activating and non-activating vitamin-B-based ligands to mucosal-associated invariant T cells (MAIT cells). Whether MR1 binds other ligands is unknown. Here we identified a range of small organic molecules, drugs, drug metabolites and drug-like molecules, including salicylates and diclofenac, as MR1-binding ligands. Some of these ligands inhibited MAIT cells ex vivo and in vivo, while others, including diclofenac metabolites, were agonists. Crystal structures of a T cell antigen receptor (TCR) from a MAIT cell in complex with MR1 bound to the non-stimulatory and stimulatory compounds showed distinct ligand orientations and contacts within MR1, which highlighted the versatility of the MR1 binding pocket. The findings demonstrated that MR1 was able to capture chemically diverse structures, spanning mono- and bicyclic compounds, that either inhibited or activated MAIT cells. This indicated that drugs and drug-like molecules can modulate MAIT cell function in mammals

Salmonella Typhi-specific multifunctional CD8+ T cells play a dominant role in protection from typhoid fever in humans.

BACKGROUND: Typhoid fever, caused by the human-restricted organism Salmonella Typhi (S. Typhi), is a major public health problem worldwide. Development of novel vaccines remains imperative, but is hampered by an incomplete understanding of the immune responses that correlate with protection. METHODS: Recently, a controlled human infection model was re-established in which volunteers received ~10(3) cfu wild-type S. Typhi (Quailes strain) orally. Twenty-one volunteers were evaluated for their cell-mediated immune (CMI) responses. Ex vivo PBMC isolated before and up to 1 year after challenge were exposed to three S. Typhi-infected targets, i.e., autologous B lymphoblastoid cell-lines (B-LCL), autologous blasts and HLA-E restricted AEH B-LCL cells. CMI responses were evaluated using 14-color multiparametric flow cytometry to detect simultaneously five intracellular cytokines/chemokines (i.e., IL-17A, IL-2, IFN-g, TNF-a and MIP-1b) and a marker of degranulation/cytotoxic activity (CD107a). RESULTS: Herein we provide the first evidence that S. Typhi-specific CD8+ responses correlate with clinical outcome in humans challenged with wild-type S. Typhi. Higher multifunctional S. Typhi-specific CD8+ baseline responses were associated with protection against typhoid and delayed disease onset. Moreover, following challenge, development of typhoid fever was accompanied by decreases in circulating S. Typhi-specific CD8+ T effector/memory (TEM) with gut homing potential, suggesting migration to the site(s) of infection. In contrast, protection against disease was associated with low or no changes in circulating S. Typhi-specific TEM. CONCLUSIONS: These studies provide novel insights into the protective immune responses against typhoid disease that will aid in selection and development of new vaccine candidates

Considerations and recent advances in nanoscale interfaces with neuronal and cardiac networks

Nanoscale interfaces with biological tissue, principally made with nanowires (NWs), are envisioned as minimally destructive to the tissue and as scalable tools to directly transduce the electrochemical activity of a neuron at its finest resolution. This review lays the foundations for understanding the material and device considerations required to interrogate neuronal activity at the nanoscale. We first discuss the electrochemical nanoelectrode-neuron interfaces and then present new results concerning the electrochemical impedance and charge injection capacities of millimeter, micrometer, and nanometer scale wires with Pt, PEDOT:PSS, Si, Ti, ITO, IrOx, Ag, and AgCl materials. Using established circuit models for NW-neuron interfaces, we discuss the impact of having multiple NWs interfacing with a single neuron on the amplitude and temporal characteristics of the recorded potentials. We review state of the art advances in nanoelectrode-neuron interfaces, the standard control experiments to investigate their electrophysiological behavior, and present recent high fidelity recordings of intracellular potentials obtained with ultrasharp NWs developed in our laboratory that naturally permeate neuronal cell bodies. Recordings from arrays and individually addressable electrically shorted NWs are presented, and the long-term stability of intracellular recording is discussed and put in the context of established techniques. Finally, a perspective on future research directions and applications is presented

G(D3) Synthase Expression Enhances Proliferation and Tumor Growth of MDA-MB-231 Breast Cancer Cells through c-Met Activation

International audienceThe disialoganglioside GD3 is over-expressed in about 50 % of invasive ductal breast carcinoma and the GD3 synthase gene (ST8SIA1) displayed higher expression among estrogen receptor negative breast cancer tumors, associated with a decreased overall survival of breast cancer patients. However, no relationship between ganglioside expression and breast cancer development and aggressiveness has been reported. We have previously shown that the over-expression of GD3 synthase induces the accumulation of b- and c-series gangliosides (GD3, GD2 and GT3) at the cell surface of MDA-MB-231 breast cancer cells together with the acquisition of a proliferative phenotype in absence of serum. Here we show that PI3K/Akt and MEK/ERK pathways are constitutively activated in GD3 synthase expressing cells. Analysis of tyrosine kinase receptors phosphorylation shows a specific c-Met constitutive activation in GD3 synthase expressing cells, in absence of its ligand the HGF/SF. In addition, inhibition of c-Met or downstream signaling pathways reverses the proliferative phenotype. We also show that GD3 synthase expression enhances tumor growth in severe combined immunodeficiency (SCID) mice. Finally, a higher expression of ST8SIA1 and MET in the basal subtype of human breast tumors are observed. Altogether, our results demonstrate that GD3 synthase expression is sufficient to enhance the tumorigenicity of MDA-MB-231 breast cancer cells through a ganglioside-dependent activation of c-Met receptor