The basis for limited specificity and MHC restriction in a T cell receptor interface

αβ Tcell receptors (TCRs) recognize peptides presented by major histocompatibility complex (MHC) proteins using multiple complementarity-determining region (CDR) loops. TCRs display an array of poorly understood recognition properties, including specificity, crossreactivity and MHC restriction. Here we report a comprehensive thermodynamic deconstruction of the interaction between the A6 TCR and the Tax peptide presented by the class I MHC HLA-A*0201, uncovering the physical basis for the receptor’s recognition properties. Broadly, our findings are in conflict with widely held generalities regarding TCR recognition, such as the relative contributions of central and peripheral peptide residues and the roles of the hypervariable and germline CDR loops in engaging peptide and MHC. Instead, we find that the recognition properties of the receptor emerge from the need to engage the composite peptide/MHC surface, with the receptor utilizing its CDR loops in a cooperative fashion such that specificity, crossreactivity and MHC restriction are inextricably linked

High-pressure batch reverse osmosis (RO) for zero liquid discharge (ZLD) in a Cr(III) electroplating process

A batch RO system was designed and built for high-pressure (120 bar) operation. The system was developed for a ZLD application involving treatment of metal plating wastewater from a Cr(III) electroplating process at a major industrial plant. Hybrid semi-batch/batch operation enabled a compact design to be achieved. To maximize water recovery without exceeding a set peak pressure, a method for controlling the switch point between semi-batch and batch phases was developed. The system was tested with feed representative of rinse water from the electroplating process. A range of feed concentrations (at 10–20× dilution of the plating bath), feed flows (0.21–0.46 m3/h), water fluxes (6–14 LMH) and water recoveries (87–95.7 %) were investigated. The system successfully recovered Cr(III) and restored its concentration to that of the electrolyte bath, thus meeting the requirements for reuse in the electroplating process. Rejection of most species was >99.8 %, sufficient for reuse of the permeate as rinse. However, rejection of boric acid was only 69–80 % such that a second RO pass may be needed to remove boric acid. Specific Energy Consumption was <2.25 kWh per m3 of treated rinse water, representing a 50-fold saving compared to the current method of treatment and disposal at the industrial plant

Structural diversity in the type IV pili of multidrug-resistant Acinetobacter

Acinetobacter baumannii is a Gram-negative coccobacillus found primarily in hospital settings that has recently emerged as a source of hospital-acquired infections. A. baumannii expresses a variety of virulence factors, including type IV pili, bacterial extracellular appendages often essential for attachment to host cells. Here, we report the high resolution structures of the major pilin subunit, PilA, from three Acinetobacter strains, demonstrating thatA. baumannii subsets produce morphologically distinct type IV pilin glycoproteins. We examine the consequences of this heterogeneity for protein folding and assembly as well as host-cell adhesion by Acinetobacter. Comparisons of genomic and structural data with pilin proteins from other species of soil gammaproteobacteria suggest that these structural differences stem from evolutionary pressure that has resulted in three distinct classes of type IVa pilins, each found in multiple species

Fluorine substitutions in an antigenic peptide selectively modulate T cell receptor binding in a minimally perturbing manner

T cell receptor (TCR) recognition of antigenic peptides bound and presented by major histocompatibility complex (MHC) molecules forms the basis of the cellular immune response to pathogens and cancer. TCRs bind peptide/MHC molecules weakly and with fast kinetics, features which have hindered detailed biophysical studies of these interactions. Modified peptides resulting in enhanced TCR binding could help overcome these challenges. Further, there is considerable interest in using modified peptides with enhanced TCR binding as the basis for clinical vaccines. Here, we studied how fluorine substitutions in an antigenic peptide can selectively impact TCR recognition. Using a structure-guided design approach, we found that fluorination of the HTLV-1 Tax11-19 peptide (Tax) enhanced binding by the Tax-specific TCR A6, yet weakened binding by the Tax-specific TCR B7. The changes in affinity were consistent with crystallographic structures and fluorine chemistry, and with A6, independent of other substitutions in the interface. Peptide fluorination thus provides a means to selectively modulate TCR binding affinity without significantly perturbing peptide composition or structure. Lastly, in probing the mechanism of fluorine’s effect on TCR binding, our data were most consistent with fluorine’s unique “polar hydrophobicity,” a finding which should impact other attempts to alter molecular recognition with fluorine

The JCMT 12CO(3-2) Survey of the Cygnus X Region: I. A Pathfinder

Cygnus X is one of the most complex areas in the sky. This complicates interpretation, but also creates the opportunity to investigate accretion into molecular clouds and many subsequent stages of star formation, all within one small field of view. Understanding large complexes like Cygnus X is the key to understanding the dominant role that massive star complexes play in galaxies across the Universe. The main goal of this study is to establish feasibility of a high-resolution CO survey of the entire Cygnus X region by observing part of it as a Pathfinder, and to evaluate the survey as a tool for investigating the star-formation process. A 2x4 degree area of the Cygnus X region has been mapped in the 12CO(3-2) line at an angular resolution of 15" and a velocity resolution of ~0.4km/s using HARP-B and ACSIS on the James Clerk Maxwell Telescope. The star formation process is heavily connected to the life-cycle of the molecular material in the interstellar medium. The high critical density of the 12CO(3-2) transition reveals clouds in key stages of molecule formation, and shows processes that turn a molecular cloud into a star. We observed ~15% of Cygnus X, and demonstrated that a full survey would be feasible and rewarding. We detected three distinct layers of 12CO(3-2) emission, related to the Cygnus Rift (500-800 pc), to W75N (1-1.8 kpc), and to DR21 (1.5-2.5 kpc). Within the Cygnus Rift, HI self-absorption features are tightly correlated with faint diffuse CO emission, while HISA features in the DR21 layer are mostly unrelated to any CO emission. 47 molecular outflows were detected in the Pathfinder, 27 of them previously unknown. Sequentially triggered star formation is a widespread phenomenon.Comment: 18 pages, 13 figures, accepted for publication in Astronomy & Astrophysic

Submillimeter Observations of The Isolated Massive Dense Clump IRAS 20126+4104

We used the CSO 10.4 meter telescope to image the 350 micron and 450 micron continuum and CO J=6-5 line emission of the IRAS 20126+4104 clump. The continuum and line observations show that the clump is isolated over a 4 pc region and has a radius of ~ 0.5 pc. Our analysis shows that the clump has a radial density profile propto r ^{-1.2} for r <~ 0.1 pc and has propto r^{-2.3} for r >~ 0.1 pc which suggests the inner region is infalling, while the infall wave has not yet reached the outer region. Assuming temperature gradient of r^{-0.35}, the power law indices become propto r ^{-0.9} for r < ~0.1 pc and propto r^{-2.0} for r >~ 0.1 pc. Based on a map of the flux ratio of 350micron/450micron, we identify three distinct regions: a bipolar feature that coincides with the large scale CO bipolar outflow; a cocoon-like region that encases the bipolar feature and has a warm surface; and a cold layer outside of the cocoon region. The complex patterns of the flux ratio map indicates that the clump is no longer uniform in terms of temperature as well as dust properties. The CO emission near the systemic velocity traces the dense clump and the outer layer of the clump shows narrow line widths (< ~3 km/s). The clump has a velocity gradient of ~ 2 km/s pc^{-1}, which we interpret as due to rotation of the clump, as the equilibrium mass (~ 200 Msun) is comparable to the LTE mass obtained from the CO line. Over a scale of ~ 1 pc, the clump rotates in the opposite sense with respect to the >~ 0.03 pc disk associated with the (proto)star. This is one of four objects in high-mass and low-mass star forming regions for which a discrepancy between the rotation sense of the envelope and the core has been found, suggesting that such a complex kinematics may not be unusual in star forming regions.Comment: 34 pages, 13 figures, Accepted for publication in the Ap

From the National to the Local: Issues of Trust and a Model For Community-Academic-Engagement

Inequities in health and health care in the United States have persisted for decades, and the impacts on equity from the COVID-19 pandemic were no exception. In addition to the disproportionate burden of the disease across various populations, the pandemic posed several challenges, which exacerbated these existing inequities. This has undoubtedly contributed to deeply rooted public mistrust in medical research and healthcare delivery, particularly among historically and structurally oppressed populations. In the summer of 2020, given the series of social injustices posed by the pandemic and highly publicized incidents of police brutality, notably the murder of George Floyd, the Association of American Medical Colleges (AAMC) enlisted the help of a national collaborative, the AAMC Collaborative for Health Equity: Act, Research, Generate Evidence (CHARGE) to establish a three-way partnership that would gather and prioritize community perspectives and lived experiences from multiple regions across the US on the role of academic medicals centers (AMCs) in advancing health and social justice. Given physical gathering constraints posed by the pandemic, virtual interviews were conducted with 30 racially and ethnically diverse community members across the country who expressed their views on how medical education, clinical care, and research could or did impact their health experiences. These interviews were framed within the context of the relationship between historically oppressed groups and the COVID-19 vaccine clinical trials underway. From the three-way partnership formed with the AAMC, AAMC CHARGE participants, and 30 community members from racially and ethnically diverse groups, qualitative methods provided lived experiences supporting other literature on the lack of trust between oppressed communities and AMCs. This led to the development of the Principles of Trustworthiness (PoT) toolkit, which features ten principles inspired by community members\u27 insights into how AMCs can demonstrate they are worthy of their community\u27s trust. In the end, the three-way partnership serves as a successful model for other national medical and health organizations to establish community engaged processes that elicit and prioritize lived experiences describing relationships between AMCs and oppressed communities

The Peculiar Nebula Simeis 57: I. Ionized Gas and Dust Extinction

We present high resolution radio continuum maps of the Galactic nebula Simeis 57 (= HS 191 = G 80.3+4.7) made with the WSRT and the DRAObservatory at frequencies of 609, 1412 and 1420 MHz. At optical and at radio wavelengths, the nebula has a peculiar ``S'' shape, crossed by long, thin and straight filaments. The radio maps, combined with other maps from existing databases, show essentially all radio emission from the peculiar and complex nebula to be thermal and optically thin. Although neither the distance nor the source of excitation of Simeis 57 are known, the nebula can only have a moderate electron density of typically n(e) = 100 cm-3. Its mass is also low, not exceeding some tens of solar masses. Peak emission measures are 5000 pc cm-6.Obscuring dust is closely associated with the nebula, but seems to occur mostly in front of it. Extinctions vary from A(V) = 1.0 mag to A(V) = 2.8 mag with a mean of about 2 mag. The extinction and the far-infrared emission at 100 microns are well-correlated.Comment: Accepted for Publication in Astronomy & Astrophysic

Generalized eigenfunctions and spectral theory for strongly local Dirichlet forms

We present an introduction to the framework of strongly local Dirichlet forms and discuss connections between the existence of certain generalized eigenfunctions and spectral properties within this framework. The range of applications is illustrated by a list of examples