Comparing side chain packing in soluble proteins, protein-protein interfaces, and transmembrane proteins.

We compare side chain prediction and packing of core and non-core regions of soluble proteins, protein-protein interfaces, and transmembrane proteins. We first identified or created comparable databases of high-resolution crystal structures of these 3 protein classes. We show that the solvent-inaccessible cores of the 3 classes of proteins are equally densely packed. As a result, the side chains of core residues at protein-protein interfaces and in the membrane-exposed regions of transmembrane proteins can be predicted by the hard-sphere plus stereochemical constraint model with the same high prediction accuracies (>90%) as core residues in soluble proteins. We also find that for all 3 classes of proteins, as one moves away from the solvent-inaccessible core, the packing fraction decreases as the solvent accessibility increases. However, the side chain predictability remains high (80% within 30°) up to a relative solvent accessibility, rSASA≲0.3, for all 3 protein classes. Our results show that ≈40% of the interface regions in protein complexes are "core", that is, densely packed with side chain conformations that can be accurately predicted using the hard-sphere model. We propose packing fraction as a metric that can be used to distinguish real protein-protein interactions from designed, non-binding, decoys. Our results also show that cores of membrane proteins are the same as cores of soluble proteins. Thus, the computational methods we are developing for the analysis of the effect of hydrophobic core mutations in soluble proteins will be equally applicable to analyses of mutations in membrane proteins.

Neurocognitive and behavioral functioning in adolescents with sleep-disordered breathing: a population-based, dual-energy X-ray absorptiometry study.

BACKGROUND/OBJECTIVES: Sleep-disordered breathing (SDB) has been associated with neurocognitive and behavioral problems in young children; however, this association is less studied in adolescents. Evidence suggests that obesity plays a key role in the development of SDB, although its relative association with neurobehavioral functioning remains unclear. We examined whether SDB and obesity are associated with neurocognitive and behavioral problems in adolescents. SUBJECTS/METHODS: A total of 421 adolescents (17.0±2.2y, 53.9% male) from the Penn State Child Cohort, a general population sample, underwent a 9-h polysomnography, clinical history, physical examination, neurocognitive evaluation and Dual-energy X-ray Absorptiometry (DXA) scan, and completed the Child or Adult Behavior Checklist. Obstructive sleep apnea (OSA) was defined as an apnea-hypopnea index (AHI)⩾2, primary snoring (PS) as AHI<2+snoring and no-SDB as AHI<2 without snoring. Body weight measures included body mass index (BMI) percentile, waist circumference (WC) and DXA-measured total adipose tissue (TAT). RESULTS: WC and TAT were significantly associated with impaired vigilance, processing speed, working memory, and control interference and greater internalizing and externalizing behaviors, while BMI percentile was marginally associated. SDB per se (PS, AHI or OSA) was not significantly associated with impaired neurocognitive outcomes or greater behavioral problems. However, TAT was significantly associated with impaired vigilance and greater internalizing and externalizing behaviors and, to a lesser extent, slower processing speed and greater control interference, only in adolescents with OSA. CONCLUSIONS: Central obesity, an etiopathogenic mechanism of OSA, is more strongly associated with neurocognitive and behavioral problems in adolescents than SDB alone. Deficits in low-order (vigilance) and high-order (executive) functions and behavioral problems observed in adolescents with OSA are primarily associated with increased central adiposity, a finding not entirely captured with less precise measures of obesity. These data support that OSA and its associated neurocognitive and behavioral morbidity are related to underlying metabolic dysfunction as early as adolescence.

Schizencephaly in Hereditary Hemorrhagic Telangiectasia.

BACKGROUND AND PURPOSE: The presence of malformations of cortical development in patients with hereditary hemorrhagic telangiectasia has been reported on previous occasions. We evaluated a sample of adults with hereditary hemorrhagic telangiectasia for the presence of malformations of cortical development, spatial coincidence of malformations of cortical development and AVMs, and the coincidence of brain and pulmonary AVMs. MATERIALS AND METHODS: A total of 141 patients 18 years of age or older who were referred to the Augusta University hereditary hemorrhagic telangiectasia clinic and underwent brain MR imaging between January 19, 2018, and December 3, 2020, were identified. MR imaging examinations were reviewed retrospectively by 2 experienced neuroradiologists, and the presence of malformations of cortical development and AVMs was confirmed by consensus. Demographic and clinical information was collected for each case, including age, sex, hereditary hemorrhagic telangiectasia status by the Curacao Criteria, mutation type, presence of malformations of cortical development, presence of brain AVMs, presence of pulmonary AVMs, and a history of seizures or learning disabilities. RESULTS: Five of 141 (3.5%) patients with hereditary hemorrhagic telangiectasia had malformations of cortical development. Two of the 5 patients with polymicrogyria also had closed-lip schizencephaly. One of the patients had a porencephalic cavity partially lined with heterotopic GM. The incidence of spatially coincident polymicrogyria and brain AVMs was 40% (2/5 cases). Of the patients with hereditary hemorrhagic telangiectasia and malformations of cortical development, 4/5 (80%) had pulmonary AVMs and 2/5 (40%) had brain AVMs. CONCLUSIONS: To our knowledge, we are the first group to report the presence of schizencephaly in patients with hereditary hemorrhagic telangiectasia. The presence of schizencephaly and porencephaly lends support to the hypothesis of regional in utero cerebral hypoxic events as the etiology of malformations of cortical development in hereditary hemorrhagic telangiectasia.

Childhood obesity, weight loss and developmental trajectories predict the persistence and remission of childhood sleep-disordered breathing.

BACKGROUND: Obesity has been recognized as a risk factor for childhood sleep-disordered breathing (SDB), yet it remains unclear how obesity and weight change predict the course of childhood SDB. OBJECTIVE: The objective of the study is to investigate the role of body weight, upper airway abnormalities and developmental trajectories on the persistence and remission of childhood SDB in the transition to adolescence. METHODS: The Penn State Child Cohort is a representative population sample of 700 children (5-12 years), of whom 421 were followed up as adolescents (12-23 years). Participants underwent a clinical history, physical examination and polysomnography at both time points. RESULTS: Obesity and enlarged tonsils were cross-sectionally associated with childhood SDB. Longitudinally, baseline obesity predicted the persistence of childhood SDB (OR = 3.75, 95% CI = 2.00-7.05), while weight loss predicted its remission (OR = 1.67, 95% CI = 1.11-2.50). Children with enlarged tonsils who remitted from SDB had not experienced significant weight loss and only 4.4% had undergone adeno/tonsillectomy. Body fat distribution/composition at follow-up was similar in those who had remitted from childhood SDB as compared with those who had never experienced SDB, while those who persisted with childhood SDB showed significant android distribution and visceral adiposity at follow-up. CONCLUSIONS: Our data support a causal role for obesity and weight loss in the chronicity and remission, respectively, of childhood SDB in the transition to adolescence and suggest that remission of SDB is related to developmental trajectories of the upper airway in a significant proportion of children. Thus, targeting childhood obesity and weight gain should be a priority in the prevention and treatment of SDB during this critical developmental period.

Addressing location uncertainties in GPS-based activity monitoring: A methodological framework.

Location uncertainty has been a major barrier in information mining from location data. Although the development of electronic and telecommunication equipment has led to an increased amount and refined resolution of data about individuals' spatio-temporal trajectories, the potential of such data, especially in the context of environmental health studies, has not been fully realized due to the lack of methodology that addresses location uncertainties. This article describes a methodological framework for deriving information about people's continuous activities from individual-collected Global Positioning System (GPS) data, which is vital for a variety of environmental health studies. This framework is composed of two major methods that address critical issues at different stages of GPS data processing: (1) a fuzzy classification method for distinguishing activity patterns; and (2) a scale-adaptive method for refining activity locations and outdoor/indoor environments. Evaluation of this framework based on smartphone-collected GPS data indicates that it is robust to location errors and is able to generate useful information about individuals' life trajectories.

Packing in protein cores.

Proteins are biological polymers that underlie all cellular functions. The first high-resolution protein structures were determined by x-ray crystallography in the 1960s. Since then, there has been continued interest in understanding and predicting protein structure and stability. It is well-established that a large contribution to protein stability originates from the sequestration from solvent of hydrophobic residues in the protein core. How are such hydrophobic residues arranged in the core; how can one best model the packing of these residues, and are residues loosely packed with multiple allowed side chain conformations or densely packed with a single allowed side chain conformation? Here we show that to properly model the packing of residues in protein cores it is essential that amino acids are represented by appropriately calibrated atom sizes, and that hydrogen atoms are explicitly included. We show that protein cores possess a packing fraction of [Formula: see text], which is significantly less than the typically quoted value of 0.74 obtained using the extended atom representation. We also compare the results for the packing of amino acids in protein cores to results obtained for jammed packings from discrete element simulations of spheres, elongated particles, and composite particles with bumpy surfaces. We show that amino acids in protein cores pack as densely as disordered jammed packings of particles with similar values for the aspect ratio and bumpiness as found for amino acids. Knowing the structural properties of protein cores is of both fundamental and practical importance. Practically, it enables the assessment of changes in the structure and stability of proteins arising from amino acid mutations (such as those identified as a result of the massive human genome sequencing efforts) and the design of new folded, stable proteins and protein-protein interactions with tunable specificity and affinity.

Collective repacking reveals that the structures of protein cores are uniquely specified by steric repulsive interactions.

Protein core repacking is a standard test of protein modeling software. A recent study of six different modeling software packages showed that they are more successful at predicting side chain conformations of core compared to surface residues. All the modeling software tested have multicomponent energy functions, typically including contributions from solvation, electrostatics, hydrogen bonding and Lennard-Jones interactions in addition to statistical terms based on observed protein structures. We investigated to what extent a simplified energy function that includes only stereochemical constraints and repulsive hard-sphere interactions can correctly repack protein cores. For single residue and collective repacking, the hard-sphere model accurately recapitulates the observed side chain conformations for Ile, Leu, Phe, Thr, Trp, Tyr and Val. This result shows that there are no alternative, sterically allowed side chain conformations of core residues. Analysis of the same set of protein cores using the Rosetta software suite revealed that the hard-sphere model and Rosetta perform equally well on Ile, Leu, Phe, Thr and Val; the hard-sphere model performs better on Trp and Tyr and Rosetta performs better on Ser. We conclude that the high prediction accuracy in protein cores obtained by protein modeling software and our simplified hard-sphere approach reflects the high density of protein cores and dominance of steric repulsion.

Spatially Analyzing the Inequity of the Hong Kong Urban Heat Island by Socio-Demographic Characteristics.

Recent studies have suggested that some disadvantaged socio-demographic groups face serious environmental-related inequities in Hong Kong due to the rising ambient urban temperatures. Identifying heat-vulnerable groups and locating areas of Surface Urban Heat Island (SUHI) inequities is thus important for prioritizing interventions to mitigate death/illness rates from heat. This study addresses this problem by integrating methods of remote sensing retrieval, logistic regression modelling, and spatial autocorrelation. In this process, the SUHI effect was first estimated from the Land Surface Temperature (LST) derived from a Landsat image. With the scale assimilated to the SUHI and socio-demographic data, a logistic regression model was consequently adopted to ascertain their relationships based on Hong Kong Tertiary Planning Units (TPUs). Lastly, inequity "hotspots" were derived using spatial autocorrelation methods. Results show that disadvantaged socio-demographic groups were significantly more prone to be exposed to an intense SUHI effect: over half of 287 TPUs characterized by age groups of 60+ years, secondary and matriculation education attainment, widowed, divorced and separated, low and middle incomes, and certain occupation groups of workers, have significant Odds Ratios (ORs) larger than 1.2. It can be concluded that a clustering analysis stratified by age, income, educational attainment, marital status, and occupation is an effective way to detect the inequity hotspots of SUHI exposure. Additionally, inequities explored using income, marital status and occupation factors were more significant than the age and educational attainment in these areas. The derived maps and model can be further analyzed in urban/city planning, in order to mitigate the physical and social causes of the SUHI effect.

Relationships between microvascular function and capillary structure in diabetic and nondiabetic human skin.

Despite the commonly held view that abnormalities in capillary morphology, in particular thickening of the capillary basement membrane, are partly responsible for diabetic ischemia, few studies have correlated anatomic and hemodynamic variables in the same diabetic subjects. In a previous study of 24 type II (non-insulin-dependent) diabetic subjects and 24 age-matched control subjects, we showed that a standard finger exercise vasodilated cutaneous forearm vessels nearly equally (51%), but the postarteriolar flow responded differently between groups. Nondiabetic subjects increased flow by recruitment of capillaries, whereas diabetic subjects did so by capillary flow augmentation. Moreover, resting permeability-surface area product (PS) to pentetic acid was 85% higher in diabetic than nondiabetic subjects. In this study, these same subjects had their forearm skin biopsied and examined morphometrically by electron microscopy for capillary radius, basement membrane thickness, endothelial cell density, and a folding index of luminal membrane reduplication. All morphological variables were correlated stepwise in a saturated, analysis of covariance model with the physiological results. The correlations were sparse and specifically excluded basement membrane thickness. The highest r2 value was .432 between resting PS and a ratio of capillary density to endothelial cell number per capillary. These studies show little evidence that diabetic microvascular physiological variables are tightly connected to morphometric changes except for minor permeability changes, which rise with capillary density and decrease with endothelial cell number. Because PS to pentetic acid is increased in diabetic subjects at any level of capillary density, it seems reasonable that permeability may be increased above that of nondiabetic subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Parathyroid hormone as a possible causal factor in osteopetrosis of the tl rat.

The possibility of parathyroid dysfunction as a causal factor in the osteopetrosis of the tl rats was explored by evaluating serum calcium (Ca) and immunoreactive parathyroid hormone (iPTH) concentrations in this strain of rats, as compared with those of phenotypically normal littermate (LM) and non-littermate (NLM) control groups. The mean serum Ca concentration in the tl rat was not significantly different from that of the NLM group, although it was less than that of the LM group. However, all Ca values were within the normal range. The mean serum iPTH concentration in the tl rats was not significantly different from those of either control group. The data indicate that the adult tl rat has adequate but not excessive PTH secretion. Therefore, osteopetrosis and its manifestations in the adult tl are not caused by an abnormality of parathyroid function.

Plasma lipid and lipoprotein responses to dietary fat and cholesterol: a meta-analysis.

Quantitative relations between dietary fat and cholesterol and plasma lipid concentrations have been the subject of much study and some controversy during the past 40 y. Previous meta-analyses have focused on the most tightly controlled, highest-quality experiments. To test whether the findings of these investigations are generalizable to broader experimental settings and to the design of practical dietary education interventions, data from 224 published studies on 8143 subjects in 366 independent groups including 878 diet-blood lipid comparisons were subjected to weighted multiple-regression analysis. Inclusion criteria specified intervention studies published in English between 1966 and 1994 reporting quantitative data on changes in dietary cholesterol and fat and corresponding changes in serum cholesterol, triacylglycerol, and lipoprotein cholesterol concentrations. Regression models are reported for serum total cholesterol, triacylglycerol, and low-density-high-density-, and very-low-density-lipoprotein cholesterol, with multiple correlations of 0.74, 0.65, 0.41, 0.14, and 0.34, respectively. Interactions of dietary factors, initial dietary intakes and serum concentrations, and study and subject characteristics had little effect on these models. Predictions indicated that compliance with current dietary recommendations (30% of energy from fat, < 10% from saturated fat, and < 300 mg cholesterol/d) will reduce plasma total and low-density-lipoprotein-cholesterol concentrations by approximately 5% compared with amounts associated with the average American diet.

Treatment of infants with acute diarrhea: what's recommended and what's practiced.

In 1985, the American Academy of Pediatrics (AAP) published a policy statement on the treatment of infants with acute diarrhea complicated by mild to moderate dehydration. To determine how closely physicians in the United States follow the AAP's treatment guidelines, a questionnaire was sent to 457 pediatricians and 360 family practitioners. The questionnaire presented a hypothetical infant with acute diarrhea complicated by mild to moderate dehydration and included questions regarding the number of such patients seen yearly, length of time used to rehydrate the infant, and how formula or solids are introduced following rehydration. Complete responses were received from 53% of pediatricians and 40% of family practitioners. The number of patients with acute diarrhea seen per year did not affect physician's treatment. Pediatricians and family practitioners responded similarly to most questions. Contrary to the AAP's guidelines to rehydrate in 4 to 6 hours, 62% of responding physicians extend the rehydration period to 12 to 24 hours. Also contrary to the AAP's recommendations, 62% of pediatricians and family practitioners use a lactose-free formula. The majority of responding physicians do follow the AAP's treatment guidelines to initiate feedings with diluted formula. Significantly more pediatricians than family practitioners advance to a full-strength formula within 1 day (P = .011). Fewer than 50% of physicians polled started solids within 24 hours as suggested by the AAP. Overall, the findings suggest that very few pediatricians and family practitioners follow all aspects of the AAP's treatment guidelines for infants with acute diarrhea complicated by mild to moderate dehydration.

The pathology of alkaptonuric ochronosis.

The gross and microscopic pathology of alkaptonuric ochronosis is presented from a study of pathologic specimens from six cases in our files and from a review of the literature. Emphasis is placed on the most clinically relevant organ systems involved by ochronosis: musculoskeletal, cardiovascular, genitourinary, eye, and skin. Recent electron microscopic discoveries from several affected organs, including the synovium, articular cartilage, cardiovascular system, eye, and skin, are included in this report. In addition, the molecular pathology of alkaptonuria is briefly discussed. The pathologic literature regarding alkaptonurin ochronosis is fragmented, as most cases of this rare entity are reported individually or as small series of cases. A comprehensive review of alkaptonuria has not appeared since the clinicopathologic review of the world literature by O'Brien et al in 1963. The purpose of this report is to present an updated and unified pathologic study of alkaptonuric ochronosis.

Closure of membranous ventricular septal defect of heart by septal leaflet of tricuspid valve.

A case of spontaneous closure of a membranous ventricular septal defect by adhesion of the septal leaflet of the tricuspid valve is reported. There was evidence to suggest that thrombi developed in a pouch formed by the adherent leaflet, giving rise to emboli producing remote and recent infarcts in the brain.

An ultrastructural and light microscopic study of the synovium in ochronotic arthropathy.

The synovium in two well-documented cases of alkaptonuric ochronosis was studied by transmission electron and light microscopy. A feature of alkaptonuria previously unreported in the English-language literature was the presence of phagocytosis of large collagen fibrils by synovial macrophages in both cases. The origin of these fibrils appeared to have been shards of ochronotic cartilage and areas of metaplastic cartilage. This finding suggests that active remodeling of the synovial tissues occurs in advanced ochronotic arthropathy. Numerous shards of ochronotic cartilage were embedded in the synovium. In addition, small aggregates of large collagen fibrils encrusted with apparent ochronotic pigment were occasionally noted in the interstitium. These aggregates of ochronotic collagen are best described as microshards, and they have not generally been recognized in the literature. What appeared by light microscopy to represent ochronotic pigment deposition in interstitial collagen actually represented embedded microshards of ochronotic cartilage in the interstitium. Slender and elongated microshards were most likely to be confused by light microscopy as ochronotic interstitial collagen.

Echocardiographic profiles of the long-term cardiac changes in cystic fibrosis.

In this echocardiographic study, assessment of the heart in children with cystic fibrosis has shown that changes occur in not only the right ventricle but also in the left ventricle and aorta, as compared with normal. Echocardiograms could be successfully performed in 34 of 37 patients. The thickness of the right ventricular anterior wall and the dimension of the right ventricular cavity were abnormal, even in patients with mild disease (National Institutes of Health [NIH] score for severity of disease of 85 or greater). Larger, older children with lower NIH score had disproportionately larger right ventricular anterior walls and cavities. The thickness of the septal wall, the thickness of the left ventricular posterior wall, and the aortic dimensions were increased in those with severe disease. The dimensions of the left ventricular cavity for the population were slightly but significantly smaller than normal in systole and in diastole throughout the course of the disease. This study demonstrates that echocardiography is an effective noninvasive means of assessing the long-term changes in children with cystic fibrosis. These changes occur in both sides of the heart and appear to worsen as the disease progresses.

Ochronotic arthropathy. A comparative scanning electron microscopic and light microscopic study of the synovium in ochronosis.

The synovium in two cases of ochronosis was studied by scanning electron microscopy and light microscopy. Several features not yet described were seen by scanning electron microscopic examination and correlated with the light microscopic findings. This is the first report in the English language literature comparing scanning electron microscopic findings with the light microscopic findings in ochronosis.

Serum prostate-specific antigen and prostate pathology in men having simple prostatectomy.

Prostate-specific antigen (PSA) is a sensitive and specific serum marker for monitoring disease activity in men with prostatic carcinoma. Despite reports of elevation of levels of this analyte in men with benign prostatic hyperplasia, no information is available correlating the serum levels with the actual prostatic abnormalities in men having prostatectomy for presumed benign disease. In the present investigation, the authors compared preoperative serum PSA levels with prostate disease in 81 men with bladder outlet obstruction. Five pathologic groups were found: incidental high-grade carcinoma (n = 3), low-grade carcinoma (n = 11), acute inflammation (n = 16) with or without chronic inflammation, Prostatic intraepithelial neoplasia (PIN) (n = 25), and benign hyperplasia (n = 26). Serum PSA levels were significantly elevated in both low- and high-grade carcinoma, acute inflammation, and PIN when compared with the patients with benign hyperplasia with and without chronic inflammation. Within the four groups with elevated levels, use of PSA levels could separate only the high-grade cancer patients who were subsequently shown to have metastatic disease. Only one patient with simple hyperplasia had PSA levels in the abnormal range.

Susceptibility of Bordetella pertussis to five quinolone antimicrobic drugs.

Five quinolone antimicrobic agents were tested to determine the mean inhibitory concentration (MIC) of each of 17 clinical strains of Bordetella pertussis by the agar dilution method. Ciprofloxacin demonstrated the best in vitro activity with an MIC90 of 0.06 microgram/ml. Norfloxacin, ofloxacin and enoxacin were also highly active with MIC90s of 0.25, 0.25, and 0.5, respectively. Cinoxacin was only moderately active (MIC90 4.0 microgram/ml).