An Autonomous CDR3δ is Sufficient for γδ T Cell Recognition of the Nonclassical MHC-I T10/T22

It remains unclear whether γδ T cell receptors (TCRs) detect antigens in a manner similar to antibodies or αβ TCRs. Here we show that reactivity between G8 and KN6 γδ TCRs and the MHC class Ib molecule T22 can be transplanted, with retention of wild-type ligand affinity, after en bloc grafting of G8 and KN6 CDR3δ loops in place onto the CDR3α loop of an αβ TCR. We also find that a shared sequence motif within CDR3δ loops of all T22-reactive γδ TCRs binds T22 in energetically distinct fashions, and that T10d, which binds G8 with weak affinity, is converted into a high-affinity ligand by a single point mutation. These results demonstrate an unprecedented autonomy of a single CDR3 loop in antigen recognition

Short KIR Haplotypes in Pygmy Chimpanzee (Bonobo) Resemble the Conserved Framework of Diverse Human KIR Haplotypes

Some pygmy chimpanzees (also called Bonobos) give much simpler patterns of hybridization on Southern blotting with killer cell immunoglobulin-like receptor (KIR) cDNA probes than do either humans or common chimpanzees. Characterization of KIRs from pygmy chimpanzees having simple and complex banding patterns identified nine different KIRs, representing seven genes. Five of these genes have orthologs in the common chimpanzee, and three of them (KIRCI, KIR2DL4, and KIR2DL5) also have human orthologs. The remaining two genes are KIR3D paralogous to the human and common chimpanzee major histocompatibility complex A– and/or -B–specific KIRs. Within a pygmy chimpanzee family, KIR haplotypes were defined. Simple patterns on Southern blot were due to inheritance of “short” KIR haplotypes containing only three KIR genes, KIRCI, KIR2DL4, and KIR3D, each of which represents one of the three major KIR lineages. These three genes in pygmy chimpanzees or their corresponding genes in humans and common chimpanzees form the conserved “framework” common to all KIR haplotypes in these species and upon which haplotypic diversity is built. The fecundity and health of individual pygmy chimpanzees who are homozygotes for short KIR haplotypes attest to the viability of short KIR haplotypes, indicating that they can provide minimal, essential KIRs for the natural killer and T cells of the hominoid immune system

Mobile devices for the remote acquisition of physiological and behavioral biomarkers in psychiatric clinical research

Psychiatric disorders are linked to a variety of biological, psychological, and contextual causes and consequences. Laboratory studies have elucidated the importance of several key physiological and behavioral biomarkers in the study of psychiatric disorders, but much less is known about the role of these biomarkers in naturalistic settings. These gaps are largely driven by methodological barriers to assessing biomarker data rapidly, reliably, and frequently outside the clinic or laboratory. Mobile health (mHealth) tools offer new opportunities to study relevant biomarkers in concert with other types of data (e.g., self-reports, global positioning system data). This review provides an overview on the state of this emerging field and describes examples from the literature where mHealth tools have been used to measure a wide array of biomarkers in the context of psychiatric functioning (e.g., psychological stress, anxiety, autism, substance use). We also outline advantages and special considerations for incorporating mHealth tools for remote biomarker measurement into studies of psychiatric illness and treatment and identify several specific opportunities for expanding this promising methodology. Integrating mHealth tools into this area may dramatically improve psychiatric science and facilitate highly personalized clinical care of psychiatric disorders

Weight Loss and Illness Severity in Adolescents With Atypical Anorexia Nervosa.

BACKGROUND:Lower weight has historically been equated with more severe illness in anorexia nervosa (AN). Reliance on admission weight to guide clinical concern is challenged by the rise in patients with atypical anorexia nervosa (AAN) requiring hospitalization at normal weight. METHODS:We examined weight history and illness severity in 12- to 24-year-olds with AN (n = 66) and AAN (n = 50) in a randomized clinical trial, the Study of Refeeding to Optimize Inpatient Gains (www.clinicaltrials.gov; NCT02488109). Amount of weight loss was the difference between the highest historical percentage median BMI and admission; rate was the amount divided by duration (months). Unpaired t tests compared AAN and AN; multiple variable regressions examined associations between weight history variables and markers of illness severity at admission. Stepwise regression examined the explanatory value of weight and menstrual history on selected markers. RESULTS:Participants were 16.5 ± 2.6 years old, and 91% were of female sex. Groups did not differ by weight history or admission heart rate (HR). Eating Disorder Examination Questionnaire global scores were higher in AAN (mean 3.80 [SD 1.66] vs mean 3.00 [SD 1.66]; P = .02). Independent of admission weight, lower HR (β = -0.492 [confidence interval (CI) -0.883 to -0.100]; P = .01) was associated with faster loss; lower serum phosphorus was associated with a greater amount (β = -0.005 [CI -0.010 to 0.000]; P = .04) and longer duration (β = -0.011 [CI -0.017 to 0.005]; P = .001). Weight and menstrual history explained 28% of the variance in HR and 36% of the variance in serum phosphorus. CONCLUSIONS:Weight history was independently associated with markers of malnutrition in inpatients with restrictive eating disorders across a range of body weights and should be considered when assessing illness severity on hospital admission

Long-Chain Fatty Acid Combustion Rate Is Associated with Unique Metabolite Profiles in Skeletal Muscle Mitochondria

Incomplete or limited long-chain fatty acid (LCFA) combustion in skeletal muscle has been associated with insulin resistance. Signals that are responsive to shifts in LCFA beta-oxidation rate or degree of intramitochondrial catabolism are hypothesized to regulate second messenger systems downstream of the insulin receptor. Recent evidence supports a causal link between mitochondrial LCFA combustion in skeletal muscle and insulin resistance. We have used unbiased metabolite profiling of mouse muscle mitochondria with the aim of identifying candidate metabolites within or effluxed from mitochondria and that are shifted with LCFA combustion rate.Large-scale unbiased metabolomics analysis was performed using GC/TOF-MS on buffer and mitochondrial matrix fractions obtained prior to and after 20 min of palmitate catabolism (n = 7 mice/condition). Three palmitate concentrations (2, 9 and 19 microM; corresponding to low, intermediate and high oxidation rates) and 9 microM palmitate plus tricarboxylic acid (TCA) cycle and electron transport chain inhibitors were each tested and compared to zero palmitate control incubations. Paired comparisons of the 0 and 20 min samples were made by Student's t-test. False discovery rate were estimated and Type I error rates assigned. Major metabolite groups were organic acids, amines and amino acids, free fatty acids and sugar phosphates. Palmitate oxidation was associated with unique profiles of metabolites, a subset of which correlated to palmitate oxidation rate. In particular, palmitate oxidation rate was associated with distinct changes in the levels of TCA cycle intermediates within and effluxed from mitochondria.This proof-of-principle study establishes that large-scale metabolomics methods can be applied to organelle-level models to discover metabolite patterns reflective of LCFA combustion, which may lead to identification of molecules linking muscle fat metabolism and insulin signaling. Our results suggest that future studies should focus on the fate of effluxed TCA cycle intermediates and on mechanisms ensuring their replenishment during LCFA metabolism in skeletal muscle

The Hypervariable Loops of Free TCRs Sample Multiple Distinct Metastable Conformations in Solution

CD4+ and CD8+ αβ T cell antigen recognition is determined by the interaction between the TCR Complementarity Determining Region (CDR) loops and the peptide-presenting MHC complex. These T cells are known for their ability to recognize multiple pMHC complexes, and for a necessary promiscuity that is required for their selection and function in the periphery. Crystallographic studies have previously elucidated the role of structural interactions in TCR engagement, but our understanding of the dynamic process that occurs during TCR binding is limited. To better understand the dynamic states that exist for TCR CDR loops in solution, and how this relates to their states when in complex with pMHC, we simulated the 2C T cell receptor in solution using all-atom molecular dynamics in explicit water and constructed a Markov State Model for each of the CDR3α and CDR3β loops. These models reveal multiple metastable states for the CDR3 loops in solution. Simulation data and metastable states reproduce known CDR3β crystal conformations, and reveal several novel conformations suggesting that CDR3β bound states are the result of search processes from nearby pre-existing equilibrium conformational states. Similar simulations of the invariant, Type I Natural Killer T cell receptor NKT15, which engages the monomorphic, MHC-like CD1d ligand, demonstrate that iNKT TCRs also have distinct states, but comparatively restricted degrees of motion

Book Reviews

Book reviews of: Grant at Vicksburg: The General and the Siege. By Michael B. Ballard. Carbondale: Southern Illinois University Press, 2013. Illustrations, maps, notes, index. Pp. xiii, 232. $32.95 cloth,$32.95 e-book. ISBN: 9780809332403. A Voice That Could Stir an Army: Fannie Lou Hamer and the Rhetoric of the Black Freedom Movement. By Maegan Parker Brooks (Jackson: University Press of Mississippi, 2014. Index, bibliography. Pp. 314. $60 cloth,$60 e-book. ISBN 978- 1-628646-004-9.) A New Southern Woman: T he Correspondence of Eliza Lucy Irion Neilson, 1871-1883. Edited by Giselle Roberts. (Columbia: University of South Carolina Press, 2013. Acknowledgements, illustrations, notes, index. Pp. viii, 306. $49.95 cloth. ISBN: 9781611171037.) Pageants, Parlors, and Pretty Women: Race and Beauty in the Twentieth-Century South. By Blain Roberts. (Chapel Hill: University of North Carolina Press, 2014). Acknowledgments, illustrations, notes, bibliography, index. Pp. ix, 363.$39.95 hardcover, $29.99 e-book. ISBN: 978-1-4696-1420-5.) Black Freedom, White Resistance, and Red Menace: Civil Rights and Anticommunism in the Jim Crow South. By Yasuhiro Katagiri. (Baton Rouge: Louisiana State University Press, 2014. Acknowledgements, illustrations, notes, index. Pp.xi, 392.$47.50 hardcover. ISBN 9780807153130.) Natchez Country: Indians, Colonists, and the Landscapes of Race in French Louisiana. By George Edward Milne. (Athens: The University of Georgia Press, 2015. List of figures, acknowledgments, notes, bibliography, index. Pp. xi, 293. $84.95 cloth,$26.95 paper. ISBN: 9780820347509.) In Remembrance of Emmett Till: Regional Stories and Media Responses to the Black Freedom Struggle. By Darryl Mace. (Lexington: University Press of Kentucky, 2014. Preface, introduction, illustrations, acknowledgements, notes, bibliography, index. Pp. xi, 212. $40 cloth. ISBN: 978- 0-8131-4536-5.) The Edible South: The Power of Food and the Making of an American Region. By Marcie Cohen Ferris. (Chapel Hill: The University of North Carolina Press, 2014. 496 pp., 7x10, 50 halftones, notes, bibl., index.$35 cloth, $34.99 e-book. ISBN: 978- 1-4696-1768-8.) Down to the Crossroads: Civil Rights, Black Power, and the Meredith March Against Fear. By Aram Goudsouzian. (New York: Farrar, Straus and Giroux, 2014. Map, notes, acknowledgements, index. Pp. ix, 351.$30 cloth, $18 paper. ISBN: 0374192200.) After Slavery: Race, Labor, and Citizenship in the Reconstruction South. Edited by Bruce Baker and Brian Kelly. Afterword by Eric Foner. (Gainesville: University Press of Florida, 2013. Acknowledgments, images, maps, notes, bibliography, index. Pp. vii, 279.$74.95 cloth. $24.95 paper. ISBN 978- 0-8130-4477-4.) George Ohr: Sophisticate and Rube. By Ellen J. Lippert. (Jackson: University Press of Mississippi, 2013. Acknowledgements, illustrations, notes, bibliography, index, Pp. x, 163.$40 cloth. ISBN: 9781617039010.

The emerging field of venom-microbiomics for exploring venom as a microenvironment, and the corresponding Initiative for Venom Associated Microbes and Parasites (iVAMP)

Venom is a known source of novel antimicrobial natural products. The substantial, increasing number of these discoveries have unintentionally culminated in the misconception that venom and venom-producing glands are largely sterile environments. Culture-dependent and -independent studies on the microbial communities in venom microenvironments reveal the presence of archaea, algae, bacteria, endoparasites, fungi, protozoa, and viruses. Venom-centric microbiome studies are relatively sparse to date and the adaptive advantages that venom-associated microbes might offer to their hosts, or that hosts might provide to venom-associated microbes, remain unknown. We highlight the potential for the discovery of venom-microbiomes within the adaptive landscape of venom systems. The considerable number of known, convergently evolved venomous animals juxtaposed with the comparatively few studies to identify microbial communities in venom provides new possibilities for both biodiversity and therapeutic discoveries. We present an evidence-based argument for integrating microbiology as part of venomics to which we refer to as venom-microbiomics. We also introduce iVAMP, the Initiative for Venom Associated Microbes and Parasites (https://ivamp-consortium.github.io/), as a growing consortium for interested parties to contribute and collaborate within this subdiscipline. Our consortium seeks to support diversity, inclusion and scientific collaboration among all researchers interested in this subdiscipline

Spitzer Imaging of the Nearby Rich Young Cluster, Cep OB3b

We map the full extent of a rich massive young cluster in the Cep OB3b association with the IRAC and MIPS instruments aboard the {\it Spitzer} Space Telescope and the ACIS instrument aboard the $\it{Chandra}$ X-Ray Observatory. At 700 pc, it is revealed to be the second nearest large ($>1000$ member), young ($< 5$ Myr) cluster known. In contrast to the nearest large cluster, the Orion Nebula Cluster, Cep OB3b is only lightly obscured and is mostly located in a large cavity carved out of the surrounding molecular cloud. Our infrared and X-ray datasets, as well as visible photometry from the literature, are used to take a census of the young stars in Cep OB3b. We find that the young stars within the cluster are concentrated in two sub-clusters; an eastern sub-cluster, near the Cep B molecular clump, and a western sub-cluster, near the Cep F molecular clump. Using our census of young stars, we examine the fraction of young stars with infrared excesses indicative of circumstellar disks. We create a map of the disk fraction throughout the cluster and find that it is spatially variable. Due to these spatial variations, the two sub-clusters exhibit substantially different average disk fractions from each other: $32$ and $50$. We discuss whether the discrepant disk fractions are due to the photodestruction of disks by the high mass members of the cluster or whether they result from differences in the ages of the sub-clusters. We conclude that the discrepant disk fractions are most likely due to differences in the ages.Comment: 48 Pages, 12 figures, 6 table