Diamino Allose Phosphates: Novel, Potent, and Highly Stable Toll-like Receptor 4 Agonists.

Most known synthetic toll-like receptor 4 (TLR4) agonists are carbohydrate-based lipid-A mimetics containing several fatty acyl chains, including a labile 3-O-acyl chain linked to the C-3 position of the non-reducing sugar known to undergo cleavage impacting stability and resulting in loss of activity. To overcome this inherent instability, we rationally designed a new class of chemically more stable synthetic TLR4 ligands that elicit robust innate and adaptive immune responses. This new class utilized a diamino allose phosphate (DAP) scaffold containing a nonhydrolyzable 3-amide bond instead of the classical 3-ester. Accordingly, the DAPs have significantly improved thermostability in aqueous formulations and potency relative to other known natural and synthetic TLR4 ligands. Furthermore, the DAP analogues function as potent vaccine adjuvants to enhance influenza-specific antibodies in mice and provide protection against lethal influenza virus challenges. This novel set of TLR4 ligands show promise as next-generation vaccine adjuvants and stand-alone immunomodulators.

The Anorexia Nervosa Genetics Initiative (ANGI): Overview and methods.

BACKGROUND: Genetic factors contribute to anorexia nervosa (AN); and the first genome-wide significant locus has been identified. We describe methods and procedures for the Anorexia Nervosa Genetics Initiative (ANGI), an international collaboration designed to rapidly recruit 13,000 individuals with AN and ancestrally matched controls. We present sample characteristics and the utility of an online eating disorder diagnostic questionnaire suitable for large-scale genetic and population research. METHODS: ANGI recruited from the United States (US), Australia/New Zealand (ANZ), Sweden (SE), and Denmark (DK). Recruitment was via national registers (SE, DK); treatment centers (US, ANZ, SE, DK); and social and traditional media (US, ANZ, SE). All cases had a lifetime AN diagnosis based on DSM-IV or ICD-10 criteria (excluding amenorrhea). Recruited controls had no lifetime history of disordered eating behaviors. To assess the positive and negative predictive validity of the online eating disorder questionnaire (ED100K-v1), 109 women also completed the Structured Clinical Interview for DSM-IV (SCID), Module H. RESULTS: Blood samples and clinical information were collected from 13,363 individuals with lifetime AN and from controls. Online diagnostic phenotyping was effective and efficient; the validity of the questionnaire was acceptable. CONCLUSIONS: Our multi-pronged recruitment approach was highly effective for rapid recruitment and can be used as a model for efforts by other groups. High online presence of individuals with AN rendered the Internet/social media a remarkably effective recruitment tool in some countries. ANGI has substantially augmented Psychiatric Genomics Consortium AN sample collection. ANGI is a registered clinical trial: clinicaltrials.govNCT01916538; https://clinicaltrials.gov/ct2/show/NCT01916538?cond=Anorexia+Nervosa&draw=1&rank=3.

The role of leptin, melanocortin, and neurotrophin system genes on body weight in anorexia nervosa and bulimia nervosa.

OBJECTIVE: Although low weight is a key factor contributing to the high mortality in anorexia nervosa (AN), it is unclear how AN patients sustain low weight compared with bulimia nervosa (BN) patients with similar psychopathology. Studies of genes involved in appetite and weight regulation in eating disorders have yielded variable findings, in part due to small sample size and clinical heterogeneity. This study: (1) assessed the role of leptin, melanocortin, and neurotrophin genetic variants in conferring risk for AN and BN; and (2) explored the involvement of these genes in body mass index (BMI) variations within AN and BN. METHOD: Our sample consisted of 745 individuals with AN without a history of BN, 245 individuals with BN without a history of AN, and 321 controls. We genotyped 20 markers with known or putative function among genes selected from leptin, melanocortin, and neurotrophin systems. RESULTS: There were no significant differences in allele frequencies among individuals with AN, BN, and controls. AGRP rs13338499 polymorphism was associated with lowest illness-related BMI in those with AN (p = 0.0013), and NTRK2 rs1042571 was associated with highest BMI in those with BN (p = 0.0018). DISCUSSION: To our knowledge, this is the first study to address the issue of clinical heterogeneity in eating disorder genetic research and to explore the role of known or putatively functional markers in genes regulating appetite and weight in individuals with AN and BN. If replicated, our results may serve as an important first step toward gaining a better understanding of weight regulation in eating disorders.

Thickness-dependent crossover from charge- to strain-mediated magnetoelectric coupling in ferromagnetic/piezoelectric oxide heterostructures.

Magnetoelectric oxide heterostructures are proposed active layers for spintronic memory and logic devices, where information is conveyed through spin transport in the solid state. Incomplete theories of the coupling between local strain, charge, and magnetic order have limited their deployment into new information and communication technologies. In this study, we report direct, local measurements of strain- and charge-mediated magnetization changes in the La0.7Sr0.3MnO3/PbZr0.2Ti0.8O3 system using spatially resolved characterization techniques in both real and reciprocal space. Polarized neutron reflectometry reveals a graded magnetization that results from both local structural distortions and interfacial screening of bound surface charge from the adjacent ferroelectric. Density functional theory calculations support the experimental observation that strain locally suppresses the magnetization through a change in the Mn-eg orbital polarization. We suggest that this local coupling and magnetization suppression may be tuned by controlling the manganite and ferroelectric layer thicknesses, with direct implications for device applications.

Executive function in eating disorders: the role of state anxiety.

OBJECTIVE: We examined the influence of depression and anxiety on executive function in individuals with a DSM-IV diagnosis of anorexia nervosa-restricting type, anorexia nervosa-binge-eating/purging type, bulimia nervosa, or eating disorder not otherwise specified. METHOD: We assessed 106 women after their inpatient treatment in an eating disorders program. All participants were nutritionally stable at the time of testing. RESULTS: Thirty percent of the total sample showed impaired performance on one or more tests of executive function. No differences in executive function were observed among diagnostic groups. Anxiety scores accounted for significant variance in performance for all groups. DISCUSSION: Executive function deficits were found in a minority of our sample, with significant variance in performance accounted for by self-reported anxiety. State anxiety appears to contribute to diminished executive function in women with eating disorders.

An examination of early childhood perfectionism across anorexia nervosa subtypes.

OBJECTIVE: To examine childhood perfectionism in anorexia nervosa (AN) restricting (RAN), purging (PAN), and binge eating with or without purging (BAN) subtypes. METHOD: The EATATE, a retrospective assessment of childhood perfectionism, and the eating disorder inventory (EDI-2) were administered to 728 AN participants. RESULTS: EATATE responses revealed general childhood perfectionism, 22.3% of 333 with RAN, 29.2% of 220 with PAN, and 24.8% of 116 with BAN; school work perfectionism, 31.2% with RAN, 30.4% with PAN, and 24.8% with BAN; childhood order and symmetry, 18.7% with RAN, 21.7% with PAN, and 17.8% with BAN; and global childhood rigidity, 42.6% with RAN, 48.3% with PAN and 48.1% with BAN. Perfectionism preceded the onset of AN in all subtypes. Significant associations between EDI-2 drive for thinness and body dissatisfaction were present with four EATATE subscales. DISCUSSION: Global childhood rigidity was the predominate feature that preceded all AN subtypes. This may be a risk factor for AN.

Habitual starvation and provocative behaviors: two potential routes to extreme suicidal behavior in anorexia nervosa.

Anorexia nervosa (AN) is perhaps the most lethal mental disorder, in part due to starvation-related health problems, but especially because of high suicide rates. One potential reason for high suicide rates in AN may be that those affected face pain and provocation on many fronts, which may in turn reduce their fear of pain and thereby increase risk for death by suicide. The purpose of the following studies was to explore whether repetitive exposure to painful and destructive behaviors such as vomiting, laxative use, and non-suicidal self-injury (NSSI) was a mechanism that linked AN-binge-purging (ANBP) subtype, as opposed to AN-restricting subtype (ANR), to extreme suicidal behavior. Study 1 utilized a sample of 787 individuals diagnosed with one or the other subtype of AN, and structural equation modeling results supported provocative behaviors as a mechanism linking ANBP to suicidal behavior. A second, unexpected mechanism emerged linking ANR to suicidal behavior via restricting. Study 2, which used a sample of 249 AN patients, replicated these findings, including the second mechanism linking ANR to suicide attempts. Two potential routes to suicidal behavior in AN appear to have been identified: one route through repetitive experience with provocative behaviors for ANBP, and a second for exposure to pain through the starvation of restricting in ANR.

Refining behavioral dysregulation in borderline personality disorder using a sample of women with anorexia nervosa.

One of the primary facets of borderline personality disorder (BPD) is behavioral dysregulation, a wide array of behaviors that are difficult to control and harmful to the individual. The purpose of this study was to explore the association between BPD and a variety of dysregulated behaviors, some of which have received little empirical attention. Using a large sample of individuals diagnosed with anorexia nervosa, 41 individuals diagnosed with BPD were compared to the rest of the sample on the presence of dysregulated behaviors using logistic regression analyses. Anorexia nervosa subtypes, age, and other Cluster B personality disorders were used as covariates. Results support an association between BPD and alcohol misuse, hitting someone/breaking things, provoking fights/arguments, self-injury, overdosing, street drug use, binge-eating, impulsive spending, shoplifting/stealing, and risky sexual behaviors. Differences between dichotomous and continuous measures of BPD yielded somewhat different results. Information on co-occurring anorexia nervosa and BPD was generated.

Rate of inpatient weight restoration predicts outcome in anorexia nervosa.

OBJECTIVE: To examine weight restoration parameters during inpatient treatment as predictors of outcome in anorexia nervosa (AN). METHOD: Adolescent and adult females admitted for inpatient eating disorder treatment were recruited for an ongoing longitudinal study. This analysis examined several weight restoration parameters as predictors of clinical deterioration after discharge among participants with AN. RESULTS: Rate of weight gain was the only restoration parameter that predicted year 1 outcome. Clinical deterioration occurred significantly less often among participants who gained >or=0.8 kg/week (12/41, 29%) than those below this threshold (20/38, 53%) (chi(2) = 4.37, df = 1, p = .037) and remained significant after adjustment for potential confounders. DISCUSSION: Weight gain rate during inpatient treatment for AN was a significant predictor of short-term clinical outcome after discharge. It is unclear whether weight gain rate exerts a causal effect or is rather a marker for readiness to tolerate weight restoration and engage in the recovery process.

The 'Ethereal' nature of TLR4 agonism and antagonism in the AGP class of lipid A mimetics.

To overcome the chemical and metabolic instability of the secondary fatty acyl residues in the AGP class of lipid A mimetics, the secondary ether lipid analogs of the potent TLR4 agonist CRX-527 (2) and TLR4 antagonist CRX-526 (3) were synthesized and evaluated along with their ester counterparts for agonist/antagonist activity in both in vitro and in vivo models. Like CRX-527, the secondary ether lipid 4 showed potent agonist activity in both murine and human models. Ether lipid 5, on the other hand, showed potent TLR4 antagonist activity similar to CRX-526 in human cell assays, but did not display any antagonist activity in murine models and, in fact, was weakly agonistic. Glycolipids 2, 4, and 5 were synthesized via a new highly convergent method utilizing a common advanced intermediate strategy. A new method for preparing (R)-3-alkyloxytetradecanoic acids, a key component of ether lipids 4 and 5, is also described.

National athletic trainers' association position statement: preventing, detecting, and managing disordered eating in athletes.

OBJECTIVE: To present recommendations for the prevention, detection, and comprehensive management of disordered eating (DE) in athletes. BACKGROUND: Athletes with DE rarely self-report their symptoms. They tend to deny the condition and are often resistant to referral and treatment. Thus, screenings and interventions must be handled skillfully by knowledgeable professionals to obtain desired outcomes. Certified athletic trainers have the capacity and responsibility to play active roles as integral members of the health care team. Their frequent daily interactions with athletes help to facilitate the level of medical surveillance necessary for early detection, timely referrals, treatment follow-through, and compliance. RECOMMENDATIONS: These recommendations are intended to provide certified athletic trainers and others participating in the health maintenance and performance enhancement of athletes with specific knowledge and problem-solving skills to better prevent, detect, and manage DE. The individual biological, psychological, sociocultural, and familial factors for each athlete with DE result in widely different responses to intervention strategies, challenging the best that athletics programs have to offer in terms of resources and expertise. The complexity, time intensiveness, and expense of managing DE necessitate an interdisciplinary approach representing medicine, nutrition, mental health, athletic training, and athletics administration in order to facilitate early detection and treatment, make it easier for symptomatic athletes to ask for help, enhance the potential for full recovery, and satisfy medicolegal requirements. Of equal importance is establishing educational initiatives for preventing DE.

The genetics of anorexia nervosa collaborative study: methods and sample description.

OBJECTIVE: Supported by National Institute of Mental Health (NIMH), this 12-site international collaboration seeks to identify genetic variants that affect risk for anorexia nervosa (AN). METHOD: Four hundred families will be ascertained with two or more individuals affected with AN. The assessment battery produces a rich set of phenotypes comprising eating disorder diagnoses and psychological and personality features known to be associated with vulnerability to eating disorders. RESULTS: We report attributes of the first 200 families, comprising 200 probands and 232 affected relatives. CONCLUSION: These results provide context for the genotyping of the first 200 families by the Center for Inherited Disease Research. We will analyze our first 200 families for linkage, complete recruitment of roughly 400 families, and then perform final linkage analyses on the complete cohort. DNA, genotypes, and phenotypes will form a national eating disorder repository maintained by NIMH and available to qualified investigators.

Effects of elastic anisotropy on strain distributions in decahedral gold nanoparticles.

Metallic nanoparticles exhibit exceptional optoelectronic properties with applications in plasmonics, biosensing and nanomedicine. Recently, new synthesis techniques have enabled precise control over the sizes and shapes of metal nanoparticles, occasionally leading to morphologies that cannot be properly characterized using standard techniques. An example is five-fold-twinned decahedral Au nanoparticles, which are intrinsically strained as a result of their unique geometry. Various competing models have been proposed to predict the strain states of such nanoparticles. Here, we present a detailed analysis of the internal structure of a decahedral Au nanoparticle using aberration-corrected high-resolution electron microscopy and strain mapping. Our measurements confirm the presence of a disclination, which is consistent with the commonly accepted strain model. However, we also observed shear gradients, which are absent from the models. By comparing our local strain determinations with finite-element calculations, we show the effect of elastic anisotropy on the strain state in these nanoparticles.

Synthetic toll-like receptor 4 agonists stimulate innate resistance to infectious challenge.

A compound family of synthetic lipid A mimetics (termed the aminoalkyl glucosaminide phosphates [AGPs]) was evaluated in murine infectious disease models of protection against challenge with Listeria monocytogenes and influenza virus. For the Listeria model, intravenous administration of AGPs was followed by intravenous bacterial challenge 24 h later. Spleens were harvested 2 days postchallenge for the enumeration of CFU. For the influenza virus model, mice were challenged with virus via the intranasal/intrapulmonary route 48 h after intranasal/intrapulmonary administration of AGPs. The severity of disease was assessed daily for 3 weeks following challenge. Several types of AGPs provided strong protection against influenza virus or Listeria challenge in wild-type mice, but they were inactive in the C3H/HeJ mouse, demonstrating the dependence of the AGPs on toll-like receptor 4 (TLR4) signaling for the protective effect. Structure-activity relationship studies showed that the activation of innate immune effectors by AGPs depends primarily on the lengths of the secondary acyl chains within the three acyl-oxy-acyl residues and also on the nature of the functional group attached to the aglycon component. We conclude that the administration of synthetic TLR4 agonists provides rapid pharmacologic induction of innate resistance to infectious challenge by two different pathogen classes, that this effect is mediated via TLR4, and that structural differences between AGPs can have dramatic effects on agonist activity in vivo.

Nanoscale waviness of low-angle grain boundaries.

Low-angle grain boundaries (LAGBs) are ubiquitous in natural and man-made materials and profoundly affect many of their mechanical, chemical, and electrical properties. The properties of LAGBs are understood in terms of their constituent dislocations that accommodate the small misorientations between grains. Discrete dislocations result in a heterogeneous local structure along the boundary. In this article, we report the lattice rotation across a LAGB in olivine (Mg(1.8)Fe(0.2)SiO(4)) measured at the nanometer scale by using quantitative high-resolution transmission electron microscopy. The analysis reveals a grain boundary that is corrugated. Elastic calculations show that this waviness is independent of the host material and thus a general feature of LAGBs. Based on our observations and analysis, we provide equations for the boundary position, local curvature, and the lattice rotation field for any LAGB. These results provide the basis for a reexamination of grain-boundary properties in materials such as high-temperature superconductors, nanocrystalline materials, and naturally deformed minerals.