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Behavioral and emotional dyscontrol commonly occur following traumatic brain injury (TBI). Neuroimaging and electrophysiological correlates of dyscontrol have not been systematically summarized in the literature to date.To complete a systematic review of the literature examining neuroimaging and electrophysiological findings related to behavioral and emotional dyscontrol due to TBI.A Preferred Reporting Items for Systematic Reviews and Meta-Analyses-compliant literature search was conducted in PubMed (MEDLINE), PsycINFO, EMBASE, and Scopus databases prior to May 2019. The database query yielded 4392 unique articles. These articles were narrowed based on specific inclusion criteria (e.g., clear TBI definition, statistical analysis of the relationship between neuroimaging and dyscontrol).A final cohort of 24 articles resulted, comprising findings from 1552 patients with TBI. Studies included civilian (n = 12), military (n = 10), and sport (n = 2) samples with significant variation in the severity of TBI incorporated. Global and region-based structural imaging was more frequently used to study dyscontrol than functional imaging or diffusion tensor imaging. The prefrontal cortex was the most common neuroanatomical region associated with behavioral and emotional dyscontrol, followed by other frontal and temporal lobe findings.Frontal and temporal lesions are most strongly implicated in the development of postinjury dyscontrol symptoms although they are also the most frequently investigated regions of the brain for these symptom categories. Future studies can make valuable contributions to the field by (1) emphasizing consistent definitions of behavioral and emotional dyscontrol, (2) assessing premorbid dyscontrol symptoms in subjects, (3) utilizing functional or structural connectivity-based imaging techniques, or (4) restricting analyses to more focused brain regions.

Alopecia areata is a chronic hair loss disorder that involves autoimmune disruption of hair follicles by CD8+ T cells. Most patients present with patchy hair loss on the scalp that improves spontaneously or with topical and intralesional steroids, topical minoxidil, or topical immunotherapy. However, recurrence of hair loss is common, and patients with extensive disease may require treatment with oral corticosteroids or oral Janus kinase (JAK) inhibitors, both of which may cause systemic toxicities with long-term use. Itaconate is an endogenous molecule synthesized in macrophages that exerts anti-inflammatory effects. To investigate the use of itaconate derivatives for treating alopecia areata, we designed a prodrug of 4-methyl itaconate (4-MI), termed SCD-153, with increased lipophilicity compared to 4-MI (CLogP 1.159 vs. 0.1442) to enhance skin and cell penetration. Topical SCD-153 formed 4-MI upon penetrating the stratum corneum in C57BL/6 mice and showed low systemic absorption. When added to human epidermal keratinocytes stimulated with polyinosinic-polycytidylic acid (poly I:C) or interferon (IFN)γ, SCD-153 significantly attenuated poly I:C-induced interleukin (IL)-6, Toll-like receptor 3, IL-1β, and IFNβ expression, as well as IFNγ-induced IL-6 expression. Topical application of SCD-153 to C57BL/6 mice in the resting (telogen) phase of the hair cycle induced significant hair growth that was statistically superior to vehicle (dimethyl sulfoxide), the less cell-permeable itaconate analogues 4-MI and dimethyl itaconate, and the JAK inhibitor tofacitinib. Our results suggest that SCD-153 is a promising topical candidate for treating alopecia areata.

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Laser resurfacing treatments for photoaged skin have improved dramatically over the past decades, but few studies have examined the molecular mechanisms underlying differences in clinical response. Seventeen white female participants with moderate-to-severe photoaging received nonablative fractional laser treatment on the face and forearm once monthly for 6 months. Biopsies for microarray analysis were performed at baseline and 7 days after facial treatment and at baseline and 1, 7, 14, and 29 days after forearm treatment in each participant, resulting in 119 total samples. Participants were stratified into fast (n = 11) and slow (n = 6) responders on the basis of the presence of clinical improvement after the first treatment. Microarray analysis revealed the upregulation of genes associated with matrix metalloproteinases, collagen and extracellular components, TGF-β signaling, double-stranded RNA signaling, and retinoic acid synthesis after treatment that did not differ significantly between fast and slow responders. Cluster and enrichment analyses suggested significantly greater activation of lipid metabolism and keratinocyte differentiation in fast responders, who showed greater upregulation of acyltransferases, fatty acid elongases, fatty acid 2-hydroxylase, fatty acid desaturases, and specific keratins that may contribute to epidermal barrier function. These results create, to our knowledge, a previously unreported atlas of molecular changes that correlate with improvements in photoaging after laser therapy.

Traumatic brain injury (TBI) is a common source of functional impairment among athletes, military personnel, and the general population. Professional fighters in both boxing and mixed martial arts (MMA) are at particular risk for repetitive TBI and may provide valuable insight into both the pathophysiology of TBI and its consequences. Currently, effects of fighter weight class on brain volumetrics (regional and total) and functional outcomes are unknown. Fifty-three boxers and 103 MMA fighters participating in the Professional Fighters Brain Health Study (PRBHS) underwent volumetric magnetic resonance imaging (MRI) and neuropsychological testing. Fighters were divided into lightweight (≤139.9 lb), middleweight (140.0–178.5 lb), and heavyweight (>178.5 lb). Compared with lightweight fighters, heavyweights displayed greater yearly reductions in regional brain volume (boxers: bilateral thalami; MMA: left thalamus, right putamen) and functional performance (boxers: processing speed, simple and choice reaction; MMA: Trails A and B tests). Lightweights suffered greater reductions in regional brain volume on a per-fight basis (boxers: left thalamus; MMA: right putamen). Heavyweight fighters bore greater yearly burden of regional brain volume and functional decrements, possibly related to differing fight dynamics and force of strikes in this division. Lightweights demonstrated greater volumetric decrements on a per-fight basis. Although more research is needed, greater per-fight decrements in lightweights may be related to practices of weight-cutting, which may increase vulnerability to neurodegeneration post-TBI. Observed decrements associated with weight class may result in progressive impairments in fighter performance, suggesting interventions mitigating the burden of TBI in professional fighters may both improve brain health and increase professional longevity.

A long period of elevated asset valuation raises some fundamental questions. How can assets sustain prices way above their fundamental value for extended periods of time? Why are investors willing to bid up expensive assets? The authors show that for an expensive asset to sustain its valuation, the probability of further price increases must be high. Currency and equity option markets provide evidence. They also show that asset managers might have incentives to go long expensive assets if their prices are more likely to increase. Furthermore, the presence of return-chasing investors could drive prices above their value. TOPICS:Options, equity portfolio management, currency Key Findings • For an expensive asset to sustain its valuation, the probability of further price increases must be high. • Because expensive assets are likely to become more expensive, asset managers might have incentives to go long, rather than short, them. • The presence of momentum and value investors could explain the life cycle of a bubble.

The key trade-off among equity-risk-mitigation strategies is their expected return versus their ability to diversify equity risk. In particular, the more reliable a strategy’s equity-hedging proper...

Traumatic brain injury (TBI) may alter dementia progression, although co-occurring neuropsychiatric symptoms (NPS) have received less attention. Originally designed to evaluate behavioral disruption prior to dementia diagnosis, the mild behavioral impairment (MBI) construct relates NPS to underlying neural circuit disruptions, with probable relevance across the progression of neurodegenerative disease. Therefore, the MBI construct may represent a valuable tool to identify and evaluate related NPS both preceding diagnosis of all-cause dementia throughout the progression of disease, representing an important area of inquiry regarding TBI and dementia. This investigation sought to evaluate the effect of TBI on NPS related by the MBI construct in participants progressing from normal cognitive status to all-cause dementia.Using National Alzheimer's Coordinating Center data, individuals progressing from normal cognition to all-cause dementia (clinician diagnosed) over 7.6 ± 3.0 years were studied to estimate prevalence of MBI domains in 124 participants with prior TBI history (57 with loss of consciousness [LOC]5 minutes, 22 with LOC5 min, 45 unknown severity) compared to 822 without. MBI domain prevalence was evaluated (1) prior to dementia onset (including only time points preceding time at dementia diagnosis, as per MBI's original definition) and (2) throughout dementia progression (evaluating all available time points, including both before and after dementia diagnosis).More severe TBI (LOC5 minutes) was associated with the social inappropriateness MBI domain (adjusted odds ratio = 4.034;TBI history is associated with particular MBI profiles prior to onset and throughout progression of dementia. Understanding TBI's impact on inter-related NPS may help elucidate underlying neuropathology with implications for surveillance, detection, and treatment of behavioral concerns in aging TBI survivors.The mild behavioral impairment (MBI) construct links related neuropsychiatric symptoms (NPS) by probable underlying neural network dysfunction.Traumatic brain injury (TBI) with loss of consciousness (LOC)5 minutes was associated with pre-dementia social inappropriateness.TBI was associated with decreased motivation looking across dementia progression.TBI with LOC5 minutes was associated with abnormal perception/thought content.The MBI construct may be useful for examining related NPS across dementia progression.

Cancer cells bypass cell death by changing the expression of the BCL-2 family of proteins, which are apoptotic pathway regulators. Upregulation of pro-survival BCL-2 proteins or downregulation of cell death effectors BAX and BAK interferes with the initiation of the intrinsic apoptotic pathway. In normal cells, apoptosis can occur through pro-apoptotic BH3-only proteins interacting and inhibiting pro-survival BCL-2 proteins. When cancer cells over-express pro-survival BCL-2 proteins, a potential remedy is the sequestration of these pro-survival proteins through a class of anti-cancer drugs called BH3 mimetics that bind in the hydrophobic groove of pro-survival BCL-2 proteins. To improve the design of these BH3 mimetics, the packing interface between BH3 domain ligands and pro-survival BCL-2 proteins was analyzed using the Knob-Socket model to identify the amino acid residues responsible for interaction affinity and specificity. A Knob-Socket analysis organizes all the residues in a binding interface into simple 4 residue units: 3-residue sockets defining surfaces on a protein that pack a 4th residue knob from the other protein. In this way, the position and composition of the knobs packing into sockets across the BH3/BCL-2 interface can be classified. A Knob-Socket analysis of 19 BCL-2 protein and BH3 helix co-crystals reveal multiple conserved binding patterns across protein paralogs. Conserved knob residues such as a Gly, Leu, Ala and Glu most likely define binding specificity in the BH3/BCL-2 interface, whereas other residues such as Asp, Asn, and Val are important for forming surface sockets that bind these knobs. These findings can be used to inform the design of BH3 mimetics that are specific to pro-survival BCL-2 proteins for cancer therapeutics.

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Structure-based computational peptide design methods have gained significant interest in recent years owing to the availability of structural insights into protein–protein interactions obtained from the crystal structures. The majority of these approaches design new peptide ligands by connecting the crucial amino acid residues from the protein interface and are generally not based on any predicted receptor–ligand interaction. In this work, a peptide design method based on the Knob–Socket model was used to identify the specific ligand residues packed into the receptor interface. This method enables peptide ligands to be designed rationally by predicting amino acid residues that will fit best at the binding site of the receptor protein. In this, specific peptide ligands were designed for the model receptor CD13, overexpression of which has been observed in several cancer types. From the initial library of designed peptides, three potential candidates were selected based on simulated energies in the CD13 bin...

This study reports a novel method to design peptides that mimic antibody binding. Using the Knob-Socket model for protein-protein interaction, the interaction surface between Cetuximab and EGFR was mapped. EGFR binding peptides were designed based on geometry and the probability of the mapped knob-sockets pairs. Designed peptides were synthesized and then characterized for binding specificity, affinity, cytotoxicity of drug-peptide conjugate and inhibition of phosphorylation. In cell culture studies, designed peptides specifically bind and internalize to EGFR overexpressing cells with three to four-fold higher uptake compared to control cells that do not overexpress EGFR. The designed peptide, Pep11, bound to EGFR with KD of 252 nM. Cytotoxicity of Monomethyl Auristatin E (MMAE)-EGFR-Pep11 peptide-drug conjugate was more than 2,000 fold higher against EGFR overexpressing cell lines A431, MDA MB 468 than control HEK 293 cells which lack EGFR overexpression. MMAE-EGFR-Pep11 conjugate also showed more than 90-fold lower cytotoxicity towards non-EGFR overexpressing HEK 293 cells when compared with cytotoxicity of MMAE itself. In conclusion, a method that can rationally design peptides using knob-socket model is presented. This method was successfully applied to create peptides based on the antigen-antibody interaction to mimic the specificity, affinity and functionality of antibody.

Palmoplantar skin has several unique characteristics such as increased thickness, high resilience, hypopigmentation, and lack of hair follicles. The establishment of palmoplantar identity occurs through keratinocyte-fibroblast interactions, with keratin 9 expression and Wnt signaling playing key roles. Understanding how palmoplantar features develop may help efforts to reproduce them at both palmoplantar and non-palmoplantar body sites.

We solve for asset prices in a general affine representative-agent economy with isoelastic recursive utility and rare events. Our novel solution method is exact in two special cases: no preference for early resolution of uncertainty and elasticity of intertemporal substitution equal to one. Our results clarify model properties governed by the elasticity of intertemporal substitution, by risk aversion, and by the preference for early resolution of uncertainty. Finally, we show in a general setting that the linear relation between normal-times covariances and expected returns need not hold in a model with rare events.

ObjectiveTo evaluate the relationship between professional fighter weight class and neuropsychiatric outcomes.BackgroundTraumatic brain injury (TBI) is a common source of functional impairment among athletes, military personnel, and the general population. Professional fighters in both boxing and mixed martial arts (MMA) are at particular risk for repetitive TBI and may provide valuable insight into both the pathophysiology of TBI and its consequences. Currently, effects of fighter weight class on brain volumetrics (regional and total) and functional outcomes are unknown.Design/Methodsn = 53 boxers and n = 103 MMA fighters participating in the Professional Fighters Brain Health Study (PRBHS) underwent volumetric magnetic resonance imaging (MRI) and neuropsychological testing. Fighters were divided into lightweight (=139.9 lb), middleweight (140.0–178.5 lb), and heavyweight (>178.5 lb).ResultsCompared with lightweight fighters, heavyweights displayed greater yearly reductions in regional brain volume (boxers: bilateral thalami; MMA: left thalamus, right putamen) and functional performance (boxers: processing speed, simple and choice reaction; MMA: Trails A and B tests). Lightweights suffered greater reductions in regional brain volume on a per-fight basis (boxers: left thalamus; MMA: right putamen). Heavyweight fighters bore greater yearly burden of regional brain volume and functional decrements, possibly related to differing fight dynamics and force of strikes in this division. Lightweights demonstrated greater volumetric decrements on a per-fight basis.ConclusionsAlthough more research is needed, greater per-fight decrements in lightweights may be related to practices of weight-cutting, which may increase vulnerability to neurodegeneration post-TBI. Observed decrements associated with weight class may result in progressive impairments in fighter performance, suggesting interventions mitigating the burden of TBI in professional fighters may both improve brain health and increase professional longevity.

Given the widespread use of systemic antibiotics for treatment of moderate to severe acne, it is important to understand the associations of such antibiotic use with changes not only in Cutibacterium acnes (formerly Propionibacterium acnes) but also in the complete bacterial community of the skin.To examine the composition, diversity, and resilience of skin microbiota associated with systemic antibiotic perturbation in individuals with acne.This longitudinal cohort study conducted at an academic referral center in Maryland from February 11 to September 23, 2014, included 4 female participants who had received a recent diagnosis of acne vulgaris, showed comedonal and inflammatory acne on the face, were at least 18 years old, and had no recent use of systemic or topical treatments for acne, including antibiotics and retinoids. Data analysis was performed between July 5, 2017, and November 7, 2018.Participants were prescribed oral minocycline, 100 mg, twice daily for 4 weeks. Skin areas on the forehead, cheek, and chin were sampled for 16S ribosomal RNA gene sequencing at baseline, 4 weeks after starting minocycline treatment, and then 1 week and 8 weeks after discontinuation of treatment.Skin microbiota examined with respect to relative abundance of bacterial taxa, α diversity (represents within-sample microbial diversity), and β diversity (represents between-sample microbial diversity). Acne status evaluated with photography and lesion count.Of the 4 patients included in this study, 2 were 25 years old, 1 was 29 years old, and 1 was 35 years old; 2 were white women, 1 was an African American woman, and 1 was an Asian woman. Across all 4 patients, antibiotic treatment was associated with a 1.4-fold reduction in the level of C acnes (difference, -10.3%; 95% CI, -19.9% to -0.7%; P = .04) with recovery following cessation of treatment. Distinct patterns of change were identified in multiple bacterial genera, including a transient 5.6-fold increase in the relative abundance of Pseudomonas species (difference, 2.2%; 95% CI, 0.9%-3.4%; P .001) immediately following antibiotic treatment, as well as a persistent 1.7-fold increase in the relative abundance of Streptococcus species (difference, 5.4%; 95% CI, 0.3%-10.6%; P = .04) and a 4.7-fold decrease in the relative abundance of Lactobacillus species (difference, -0.8%; 95% CI, -1.4% to -0.2%; P = .02) 8 weeks following antibiotic treatment withdrawal. In general, antibiotic administration was associated with an initial decrease from baseline of bacterial diversity followed by recovery. Principal coordinates analysis results showed moderate clustering of samples by patient (analysis of similarity, R = 0.424; P = .001) and significant clustering of samples by time in one participant (analysis of similarity, R = 0.733; P = .001).In this study, systemic antibiotic treatment of acne was associated with changes in the composition and diversity of skin microbiota, with variable rates of recovery across individual patients and parallel changes in specific bacterial populations. Understanding the association between systemic antibiotic use and skin microbiota may help clinicians decrease the likelihood of skin comorbidities related to microbial dysbiosis.

One difficult aspect of the protein-folding problem is characterizing the nonspecific interactions that define packing in protein tertiary structure. To better understand tertiary structure, this work extends the knob-socket model by classifying the interactions of a single knob residue packed into a set of contiguous sockets, or a pocket made up of 4 or more residues. The knob-socket construct allows for a symbolic two-dimensional mapping of pockets. The two-dimensional mapping of pockets provides a simple method to investigate the variety of pocket shapes to understand the geometry of protein tertiary surfaces. The diversity of pocket geometries can be organized into groups of pockets that share a common core, which suggests that some interactions in pockets are ancillary to packing. Further analysis of pocket geometries displays a preferred configuration that is right-handed in α-helices and left-handed in β-sheets. The amino acid composition of pockets illustrates the importance of nonpolar amino acids in packing as well as position specificity. As expected, all pocket shapes prefer to pack with hydrophobic knobs; however, knobs are not selective for the pockets they pack. Investigating side-chain rotamer preferences for certain pocket shapes uncovers no strong correlations. These findings allow a simple vocabulary based on knobs and sockets to describe protein tertiary packing that supports improved analysis, design, and prediction of protein structure.

After lying dormant for more than two decades, the rare disaster framework has emerged as a leading contender to explain facts about the aggregate market, interest rates, and financial derivatives. In this article, we survey recent models of disaster risk that provide explanations for the equity premium puzzle, the volatility puzzle, return predictability, and other features of the aggregate stock market. We show how these models can also explain violations of the expectations hypothesis in bond pricing as well as the implied volatility skew in option pricing. We review both modeling techniques and results and consider both endowment and production economies. We show that these models provide a parsimonious and unifying framework for understanding puzzles in asset pricing.

Spider dragline silk represents a biomaterial with outstanding mechanical properties, possessing high-tensile strength and toughness. In black widows at least eight different proteins have been identified as constituents of dragline silk. These represent major ampullate spidroins MaSp1, MaSp2, MaSp&rsquo, and several low-molecular weight cysteine-rich protein (CRP) family members, including CRP1, CRP2, and CRP4. Molecular modeling predicts that CRPs contain a cystine slipknot motif, but experimental evidence to support this assertion remains to be reported. To advance scientific knowledge regarding CRP function, we recombinantly expressed and purified CRP1 and CRP4 from bacteria and investigated their secondary structure using circular dichroism (CD) under different chemical and physical conditions. We demonstrate by far-UV CD spectroscopy that these proteins contain similar secondary structure, having substantial amounts of random coil conformation, followed by lower levels of beta sheet, alpha helical and beta turn structures. CRPs are thermally and pH stable, however, treatment with reagents that disrupt disulfide bonds impact their structural conformations. Cross-linking mass spectrometry (XL-MS) data also support computational models of CRP1. Taken together, the chemical and thermal stability of CRPs, the cross-linking data, coupled with the structural sensitivity to reducing agents, are experimentally consistent with the supposition CRPs are cystine slipknot proteins.

To advance our understanding of protein tertiary structure, the development of the knob-socket model is completed in an analysis of the packing in irregular coil and turn secondary structure packing as well as between mixed secondary structure. The knob-socket model simplifies packing based on repeated patterns of two motifs: a three-residue socket for packing within secondary (2°) structure and a four-residue knob-socket for tertiary (3°) packing. For coil and turn secondary structure, knob-sockets allow identification of a correlation between amino acid composition and tertiary arrangements in space. Coil contributes almost as much as α-helices to tertiary packing. In irregular sockets, Gly, Pro, Asp, and Ser are favored, while in irregular knobs, the preference order is Arg, Asp, Pro, Asn, Thr, Leu, and Gly. Cys, His,Met, and Trp are not favored in either. In mixed packing, the knob amino acid preferences are a function of the socket that they are packing into, whereas the amino acid composition of the sockets does not depend on the secondary structure of the knob. A unique motif of a coil knob with an XYZ β-sheet socket may potentially function to inhibit β-sheet extension. In addition, analysis of the preferred crossing angles for strands within a β-sheet and mixed α-helice/β-sheet identifies canonical packing patterns useful in protein design. Lastly, the knob-socket model abstracts the complexity of protein tertiary structure into an intuitive packing surface topology map.

We solve for asset prices in a general affine representative-agent economy with isoelastic recursive utility and rare events. Our novel solution method is exact in two special cases: no preference for early resolution of uncertainty and elasticity of intertemporal substitution equal to one. Our results clarify model properties governed by the elasticity of intertemporal substitution, by risk aversion, and by the preference for early resolution of uncertainty. Finally, we show in a general setting that the linear relation between normal-times covariances and expected returns need not hold in a model with rare events.

Dragline silk has been proposed to contain two main protein constituents, MaSp1 and MaSp2. However, the mechanical properties of synthetic spider silks spun from recombinant MaSp1 and MaSp2 proteins have yet to approach natural fibers, implying the natural spinning dope is missing critical factors. Here we report the discovery of novel molecular constituents within the spinning dope that are extruded into dragline silk. Protein studies of the liquid spinning dope from the major ampullate gland, coupled with the analysis of dragline silk fibers using mass spectrometry, demonstrate the presence of a new family of low-molecular-weight cysteine-rich proteins (CRPs) that colocalize with the MA fibroins. Expression of the CRP family members is linked to dragline silk production, specifically MaSp1 and MaSp2 mRNA synthesis. Biochemical data support that CRP molecules are secreted into the spinning dope and assembled into macromolecular complexes via disulfide bond linkages. Sequence analysis supports that CRP molecules share similarities to members that belong to the cystine slipknot superfamily, suggesting that these factors may have evolved to increase fiber toughness by serving as molecular hubs that dissipate large amounts of energy under stress. Collectively, our findings provide molecular details about the components of dragline silk, providing new insight that will advance materials development of synthetic spider silk for industrial applications.

We sought to determine the prevalence of carotid artery stenosis (CAS)50% in a large, multi-institutional health maintenance organization found during duplex ultrasonography screening before cardiac surgery and to identify risk factors to increase the yield of a preoperative screening program.This retrospective review study was conducted on 722 patients who had undergone duplex ultrasonography screening of the carotid artery before cardiac surgery between June 2008 and February 2011. The primary outcome was CAS50% detected on duplex ultrasonography screening.Seven hundred twenty-two patients (66.2% men; median age: 71 years) underwent duplex ultrasonography screening of the carotid artery before cardiac surgery. The main indications for cardiac surgery were valvular disease (39.5%) and coronary artery disease (36.3%). One hundred eighteen patients (16.3%) had CAS≥50%. Among the patients found to have carotid stenosis, 38 patients (32.2%) had bilateral stenosis50% and 37 patients (31.4%) had at least 70% unilateral stenosis. The presence of peripheral vascular disease (odds ratio [OR]: 2.93 [95% confidence interval {CI}: 1.87-4.60]; P0.001), and history of cerebrovascular disease within 12 months (OR: 4.57 [95% CI: 1.18-17.77]; P=0.028) were risk factors associated with CAS. Patients who have coronary artery disease with cardiac catheterization showing left main disease (OR: 6.80 [95% CI: 3.02-15.29]; P0.001), 3-vessel disease or more (OR: 2.78 [95% CI: 1.43-5.43]; P=0.003), or both (OR: 4.13 [95% CI: 1.89-9.06]; P0.001) were found to be significantly more likely to have CAS50%.Independent risk factors that are predictive of the presence of CAS are peripheral vascular disease, having had a previous cerebrovascular accident, and coronary artery disease with left main or 3-vessel disease. Routine carotid duplex ultrasonography scanning may not be necessary for all patients undergoing cardiac surgery, and selective carotid screening programs may be considered in patients with symptomatic atherosclerosis disease or advanced coronary artery disease.

To understand the relationship between protein sequence and structure, this work extends the knob-socket model in an investigation of β-sheet packing. Over a comprehensive set of β-sheet folds, the contacts between residues were used to identify packing cliques: sets of residues that all contact each other. These packing cliques were then classified based on size and contact order. From this analysis, the two types of four-residue packing cliques necessary to describe β-sheet packing were characterized. Both occur between two adjacent hydrogen bonded β-strands. First, defining the secondary structure packing within β-sheets, the combined socket or XY:HG pocket consists of four residues i, i+2 on one strand and j, j+2 on the other. Second, characterizing the tertiary packing between β-sheets, the knob-socket XY:H+B consists of a three-residue XY:H socket (i, i+2 on one strand and j on the other) packed against a knob B residue (residue k distant in sequence). Depending on the packing depth of the knob B residue, two types of knob-sockets are found: side-chain and main-chain sockets. The amino acid composition of the pockets and knob-sockets reveal the sequence specificity of β-sheet packing. For β-sheet formation, the XY:HG pocket clearly shows sequence specificity of amino acids. For tertiary packing, the XY:H+B side-chain and main-chain sockets exhibit distinct amino acid preferences at each position. These relationships define an amino acid code for β-sheet structure and provide an intuitive topological mapping of β-sheet packing. Proteins 2014; 82:2128–2140. © 2014 Wiley Periodicals, Inc.

Context Increasing popularity of strong magnets as toys has led to their ingestion by children, putting them at risk of potentially harmful gastrointestinal tract injuries. Objectives To heighten physician awareness of the potential complications of magnetic foreign body ingestion, and to provide an updated algorithm for management of a patient who is suspected to have ingested magnets. Design A retrospective review of magnet ingestions treated over a two-year period at our institutions in the Southern California Permanente Medical Group. Data including patient demographics, clinical information, radiologic images, and surgical records were used to propose a management strategy. Results Five patients, aged 15 months to 18 years, presented with abdominal symptoms after magnet ingestion. Four of the 5 patients suffered serious complications, including bowel necrosis, perforation, fistula formation, and obstruction. All patients were successfully treated with laparoscopic-assisted exploration with or without endoscopy. Total days in the hospital averaged 5.2 days (range = 3 to 9 days). Average time to discharge following surgery was 4 days (range = 2 to 7 days). Ex vivo experimentation with toy magnetic beads were performed to reveal characteristics of the magnetic toys. Conclusions Physicians should have a heightened sense of caution when treating a patient in whom magnetic foreign body ingestion is suspected, because of the potential gastrointestinal complications. An updated management strategy is proposed that both prevents delays in surgical care and avoids unnecessary surgical exploration.

Trichotillomania (TTM) and skin-picking disorder (SPD) have been characterized as body-focused repetitive behavior disorders (BFRBs). Because BFRBs frequently co-occur, we sought to discover the similarities and differences for individuals having both TTM and SPD as opposed to 1 of these disorders.Participants with primary TTM (N = 421) were evaluated regarding the comorbidity of SPD, and participants with primary SPD (N = 124) were evaluated regarding the comorbidity of TTM. The effects of comorbidity overlap on demographic and clinical measures were evaluated.Of the 421 participants with primary TTM, 61 (14.5%) had co-occurring SPD. Of 124 participants with primary SPD, 21 (16.9%) had comorbid TTM. Participants with primary TTM and comorbid SPD had significantly more severe trichotillomania symptoms and were more likely to have major depressive disorder than those with TTM alone. Participants with primary SPD and comorbid TTM reported significantly more severe skin-picking symptoms than those who had only SPD.Individuals with co-occurring TTM and SPD may have more problematic symptoms with the primary repetitive behavior. Hair pullers with comorbid SPD were more likely to have comorbid depression. Evaluating patients for multiple BFRBs may be important to assess the severity of symptoms and may have treatment implications.

Why do value stocks have higher average returns than growth stocks, despite having lower risk? Why do these stocks exhibit positive abnormal performance, while growth stocks exhibit negative abnormal performance? This paper offers a rare-event-based explanation that can also account for the high equity premium and volatility of the aggregate market. The model explains other puzzling aspects of the data, such as joint patterns in time-series predictablity of aggregate market and value and growth returns, long periods in which growth outperforms value, and the association between positive skewness and low realized returns.

Cellular functions are mediated by protein-protein interactions. How proteins bind interaction partners is largely an open problem. The state of our understanding in protein-protein interactions could benefit greatly from a simple model to probe the complexities of the subject. The knob-socket model has been shown to be an important motif for protein tertiary structure packing. The knob-socket is a four residue tetrahedral motif calculated using Voronoi Polyhedra, where the knob from one secondary structure element packs into a socket formed by three residues from another secondary structure element. It has been shown that the knob-socket model naturally leads to an amino acid code for protein structure. The work presented extends the knob-socket analysis of protein tertiary structure to quaternary structure packing. Using the 3D Complex database of protein-protein interactions, the amino acid composition of knob-sockets at the interface between proteins is described. The extent to which protein tertiary and quaternary structure are similar is described in terms of the knob-socket construct. Furthermore, this work illustrates how knob-socket data can design helices that homodimerize in solution. In conclusion, knob-socket approaches to protein-protein interactions provide a clear and concise classification of protein-protein interactions into three separate classes. Class 1 is defined through peptide-protein interactions. Here, the peptide provides knobs that pack into the already established free sockets of the protein interaction surface. Class 2 is characterized by knobs-sockets shared between the two protein interaction partners. Class 3 is characterized by structure formation upon interaction. Class 3 exhibits induction of protein structure with knob-socket packing from both chains. This can occur for both protein-protein interactions as well as peptide-protein interactions. This knob-socket analysis provides unique insights into the complexity of protein-protein interactions.

Understanding protein-nucleic acid packing interactions is a fundamental step in deciphering how proteins specifically recognize and bind DNA. A knob-socket analysis of protein-DNA interfaces simply and clearly identifies the packing contributions to binding specificity. All of the approximately 3,500 protein-DNA complexes in the NDB database were evaluated using the knob-socket approach, where this study focuses on α-helix binding to DNA. Amino acid and DNA base composition in sockets and knobs is presented as well as a protein-DNA packing surface topology map. Generally, DNA packing naturally divides into specific interactions with the nucleic acid bases and non-specific interactions with the phosphate backbone groups. The ∼280,000 four-body packing cliques were found to be the dominant packing interaction similar to protein-protein packing interfaces. Among these four-body cliques, about 9% are DNA sockets formed by 2 adjacent bases packing with a knob from a protein and about 27% are protein sockets packing against a DNA base acting as a knob. A general pattern can be characterized for α-helix binding to DNA. The α-helical knobs are aligned along the i±4 ridge and pack into very regular diamond pockets (multiple sockets) on the DNA double helix. This i±4 ridge of knobs divides the binding of the α-helix into 2 regions of sockets that recognize blocks of DNA bases: one on the coding strand and the other on the non-coding strand. Therefore, an α-helix splits DNA sequence recognition to a part on the coding and the other part on the non-coding strands. The pocket pattern and amino acid composition on α-helices provide specificity for DNA base recognition. The results demonstrate that the knob-socket model can rationally investigate and produce clear insight into protein-DNA binding interfaces.

Native DNA lesions in general destabilize DNA secondary structures such as duplex and G-quadruplex because they disrupt optimized interactions in DNA defined by nature. In this paper, we report the first example of a native DNA lesion (8-oxo-7,8-dihydrodeoxyadenosine, OxodA) that stabilizes human telomeric G-quadruplex DNA. CD thermal denaturation studies explicitly displayed increased melting temperatures of telomeric G-quadruplex DNAs that contain OxodA(s) in different DNA loops, suggesting enhanced thermal stability. Conformation studies of G-quadruplex DNAs containing OxodA(s) in the loops using CD and native PAGE revealed that they adopt a similar antiparallel conformation in Na + but have much more versatile conformations in K + . According to computational calculations, the observed stabilization may result from the tight binding of K + into the pocket formed by the O8 of OxodA and its loop. The study reported here may provide better understanding of the effect of DNA lesions on G-quadruplex stability and conformation.

Template based protein structure prediction (commonly referred to as homology or comparative modeling) uses knowledge of solved structures to model a protein sequence's native or true fold. First, a parent structure is found and then a template structure is built by mapping the target sequence onto the parent structure. This putative structure is refined using a combination of backbone moves, side-chain packing, and loop modeling. Template based protein structure prediction has always held great promise to produce atomically accurate models close to the native conformation based on two major assumptions. First, similar sequences exhibit similar protein folds. Second, soluble proteins populate a discrete fold space with many representatives already solved in our Protein Data Bank (PDB). Ironically, beginning so close to the native structure is also the primary source of problems confronting this method and is the reason for the lack of progress in this category of structure prediction. In this review, the general concepts and procedures for template based structure prediction are outlined based on the following topics: sequence alignment, parent structure selection, template structure building, refinement, evaluation, and final structure selection. Then, a description of established software and algorithms is provided where the advantages and limitations of the different methods will be pointed out. This is followed by a discussion of the developments in template based structure prediction up to the 7th Critical Assessment of Structure Prediction meeting. Lastly, we will address the increased difficulty in improving templates that start so close to the native structure, and discuss the improvements needed in this field.

To investigate the nature of hydrophobic collapse considered to be the driving force in protein folding, we have simulated aqueous solutions of two model hydrophobic solutes, methane and isobutylene. Using a novel methodology for determining contacts, we can precisely follow hydrophobic aggregation as it proceeds through three stages: dispersed, transition, and collapsed. Theoretical modeling of the cluster formation observed by simulation indicates that this aggregation is cooperative and that the simulations favor the formation of a single cluster midway through the transition stage. This defines a minimum solute hydrophobic core volume. We compare this with protein hydrophobic core volumes determined from solved crystal structures. Our analysis shows that the solute core volume roughly estimates the minimum core size required for independent hydrophobic stabilization of a protein and defines a limiting concentration of nonpolar residues that can cause hydrophobic collapse. These results suggest that the physical forces driving aggregation of hydrophobic molecules in water is indeed responsible for protein folding.

Grouping the 20 residues is a classic strategy to discover ordered patterns and insights about the fundamental nature of proteins, their structure, and how they fold. Usually, this categorization is based on the biophysical and/or structural properties of a residue's side-chain group. We extend this approach to understand the effects of side chains on backbone conformation and to perform a knowledge-based classification of amino acids by comparing their backbone phi, psi distributions in different types of secondary structure. At this finer, more specific resolution, torsion angle data are often sparse and discontinuous (especially for nonhelical classes) even though a comprehensive set of protein structures is used. To ensure the precision of Ramachandran plot comparisons, we applied a rigorous Bayesian density estimation method that produces continuous estimates of the backbone phi, psi distributions. Based on this statistical modeling, a robust hierarchical clustering was performed using a divergence score to measure the similarity between plots. There were seven general groups based on the clusters from the complete Ramachandran data: nonpolar/beta-branched (Ile and Val), AsX (Asn and Asp), long (Met, Gln, Arg, Glu, Lys, and Leu), aromatic (Phe, Tyr, His, and Cys), small (Ala and Ser), bulky (Thr and Trp), and, lastly, the singletons of Gly and Pro. At the level of secondary structure (helix, sheet, turn, and coil), these groups remain somewhat consistent, although there are a few significant variations. Besides the expected uniqueness of the Gly and Pro distributions, the nonpolar/beta-branched and AsX clusters were very consistent across all types of secondary structure. Effectively, this consistency across the secondary structure classes implies that side-chain steric effects strongly influence a residue's backbone torsion angle conformation. These results help to explain the plasticity of amino acid substitutions on protein structure and should help in protein design and structure evaluation.

Background The common grading systems for female pattern hair loss (FPHL), such as Ludwig and Savin scales, are subjective to visual inspection. To provide a more objective evaluation of baldness, the authors have developed a method to calculate baldness quantitatively through a computer-aided imaging system (CAIS). Objective To investigate the use of CAIS on Chinese women with FPHL. Materials and methods Thirty-eight Chinese women with FPHL (Savin Scale I-2 to II-2) were recruited. A total of 215 photographs were taken. The central balding areas (CBAs) were calculated after exposure correction by CAIS for comparison with clinical staging. Results The average CBA was 9,391.12 mm in all patients, 3,828.84 mm in Type I-2, 5,880.38 mm in I-3, 8,267.44 mm in I-4, 12,999.26 mm in II-1, and 15,979.71 mm in II-2. The values of CBA correlated with clinical staging using Savin scales. A 7.53% difference was found in the calculated CBA by exposure correction. Conclusion The CAIS allows physicians to evaluate the severity of baldness more accurately through quantitative calculation, rather than qualitative visual observation. The values of the CBA measured by the CAIS, used in conjunction with the present grading systems, may be more precise and efficient to evaluate the severity of FPHL.

The tremendous therapeutic potential of peptides has not yet been realized, mainly owing to their short in vivo half-life. Although conjugation to macromolecules has been a mainstay approach for enhancing protein half-life, the steric hindrance of macromolecules often harms the binding of peptides to target receptors, compromising the in vivo efficacy. Here we report a new strategy for enhancing the in vivo half-life of peptides without compromising their potency. Our approach involves endowing peptides with a small molecule that binds reversibly to the serum protein transthyretin. Although there are a few molecules that bind albumin reversibly, we are unaware of designed small molecules that reversibly bind other serum proteins and are used for half-life extension in vivo. We show here that our strategy was effective in enhancing the half-life of an agonist for GnRH receptor while maintaining its binding affinity, which was translated into superior in vivo efficacy.

To advance our understanding of protein tertiary structure, the development of the knob-socket model is completed in an analysis of the packing in irregular coil and turn secondary structure packing as well as between mixed secondary structure. The knob-socket model simplifies packing based on repeated patterns of 2 motifs: a 3 residue socket for packing within 2° structure and a 4 residue knob-socket for 3° packing. For coil and turn secondary structure, knob-sockets allow identification of a correlation between amino acid composition and tertiary arrangements in space. Coil contributes almost as much as α-helices to tertiary packing. Irregular secondary structure involves 3 residue cliques of consecutive contacting residues or XYZ sockets. In irregular sockets, Gly, Pro, Asp and Ser are favored, while Cys, His, Met and Trp are not. For irregular knobs, the preference order is Arg, Asp, Pro, Asn, Thr, Leu, and Gly, while Cys, His, Met and Trp are not. In mixed packing, the knob amino acid preferences are a function of the socket that they are packing into, whereas the amino acid composition of the sockets does not depend on the secondary structure of the knob. A unique motif of a coil knob with an XYZ β-sheet socket may potentially function to inhibit β-sheet extension. In addition, analysis of the preferred crossing angles for strands within a β-sheet and mixed α-helices/β-sheets identifies canonical packing patterns useful in protein design. Lastly, the knob-socket model abstracts the complexity of protein tertiary structure into an intuitive packing surface topology map.

One difficult aspect of the protein-folding problem is characterizing the non-specific interactions that define packing in protein tertiary structure. To better understand tertiary structure, this work extends the knob-socket model by classifying the interactions of a single knob residue packed into a set of contiguous sockets, or a pocket made up of 4 or more residues. The knob-socket construct allows for a symbolic two-dimensional mapping of pockets. The two-dimensional mapping of pockets provides a simple method to investigate the variety of pocket shapes in order to understand the geometry of protein tertiary surfaces. The diversity of pocket geometries can be organized into groups of pockets that share a common core, which suggests that some interactions in pockets are ancillary to packing. Further analysis of pocket geometries displays a preferred configuration that is right-handed in α-helices and left-handed in β-sheets. The amino acid composition of pockets illustrates the importance of non-polar amino acids in packing as well as position specificity. As expected, all pocket shapes prefer to pack with hydrophobic knobs; however, knobs are not selective for the pockets they pack. Investigating side-chain rotamer preferences for certain pocket shapes uncovers no strong correlations. These findings allow a simple vocabulary based on knobs and sockets to describe protein tertiary packing that supports improved analysis, design and prediction of protein structure.