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1.  Higher Educational Attainment but not Higher Income is Protective for Cardiovascular Risk in Deaf American Sign Language (ASL) Users 
Disability and health journal  2013;7(1):49-55.
Higher educational attainment and income provide cardiovascular protection in the general population. It is unknown if the same effect is seen among Deaf American Sign Language (ASL) users who face communication barriers in healthcare settings.
We sought to examine whether educational attainment and/or annual household income were inversely associated with cardiovascular risk in a sample of Deaf ASL users.
This cross-sectional study included 302 Deaf respondents aged 18-88 years from the Deaf Health Survey (2008), an adapted and translated Behavioral Risk Factor Surveillance System (BRFSS) administered in sign language. Associations between the self-reported cardiovascular disease equivalents (CVDE; any of the following: diabetes, myocardial infarction (MI), cerebral vascular attack (CVA), and angina) with educational attainment (≤high school [low education], some college, and ≥4 year college degree [referent]), and annual household income (<$25,000, $25,000-<$50,000, or ≥$50,000 [referent]) were assessed using a multivariate logistic regression adjusting for age, sex, race/ethnicity, and smoking history.
Deaf respondents who reported ≤high school education were more likely to report the presence of a CVDE (OR 5.92; 95% CI 2.12-16.57) compared to Deaf respondents who reported having ≥4 year college degree after adjustment. However, low-income Deaf individuals (i.e. household incomes <$25,000) were not more likely to report the presence of a CVDE (OR=2.24; 95% CI 0.76-6.68) compared to high-income Deaf respondents after adjustment.
Low educational attainment was associated with higher likelihood of reported cardiovascular equivalents among Deaf individuals. Higher income did not appear to provide a cardiovascular protective effect for Deaf respondents.
PMCID: PMC3893794  PMID: 24411507
Deaf; cardiovascular health; education; income; health disparities
3.  Perlecan is recruited by dystroglycan to nodes of Ranvier and binds the clustering molecule gliomedin 
The Journal of Cell Biology  2015;208(3):313-329.
Dystroglycan promotes nodogenesis in part through recruitment of perlecan to nodes of Ranvier, where it binds to gliomedin and may thereby promote sodium channel clustering.
Fast neural conduction requires accumulation of Na+ channels at nodes of Ranvier. Dedicated adhesion molecules on myelinating cells and axons govern node organization. Among those, specific laminins and dystroglycan complexes contribute to Na+ channel clustering at peripheral nodes by unknown mechanisms. We show that in addition to facing the basal lamina, dystroglycan is found near the nodal matrix around axons, binds matrix components, and participates in initial events of nodogenesis. We identify the dystroglycan-ligand perlecan as a novel nodal component and show that dystroglycan is required for the selective accumulation of perlecan at nodes. Perlecan binds the clustering molecule gliomedin and enhances clustering of node of Ranvier components. These data show that proteoglycans have specific roles in peripheral nodes and indicate that peripheral and central axons use similar strategies but different molecules to form nodes of Ranvier. Further, our data indicate that dystroglycan binds free matrix that is not organized in a basal lamina.
PMCID: PMC4315246  PMID: 25646087
4.  The Effects of Written Emotional Disclosure and Coping Skills Training in Rheumatoid Arthritis: A Randomized Clinical Trial 
Two psychological interventions for rheumatoid arthritis (RA) are cognitive-behavioral coping skills training (CST) and written emotional disclosure (WED). These approaches have developed independently, and their combination may be more effective than either one alone. Furthermore, most studies of each intervention have methodological limitations, and each needs further testing.
We randomized 264 adults with RA in a 2 × 2 factorial design to one of two writing conditions (WED vs. control writing) followed by one of two training conditions (CST vs. arthritis education control training). Patient-reported pain and functioning, blinded evaluations of disease activity and walking speed, and an inflammatory marker (C-reactive protein) were assessed at baseline and 1-, 4-, and 12-month follow-ups.
Completion of each intervention was high (> 90% of patients), and attrition was low (10.2% at 12-month follow-up). Hierarchical linear modeling of treatment effects over the follow-up period, and ANCOVAs at each assessment point, found no interactions between writing and training; however, both interventions had main effects on outcomes, with small effect sizes. Compared to control training, CST decreased pain and psychological symptoms through 12 months. The effects of WED were mixed: compared with control writing, WED reduced disease activity and physical disability at 1 month only, but WED had more pain than control writing on one of two measures at 4 and 12 months.
The combination of WED and CST does not improve outcomes, perhaps because each intervention has unique effects at different time points. CST improves health status in RA and is recommended for patients, whereas WED has limited benefits and needs strengthening or better targeting to appropriate patients.
PMCID: PMC4115002  PMID: 24865870
Rheumatoid arthritis; emotional disclosure; expressive writing; cognitive behavioral therapy; coping skills training; pain
5.  Crime and Psychiatric Disorders Among Youth in the US Population: An Analysis of National Comorbidity Survey-Adolescent Supplement 
Current knowledge regarding psychiatric disorders and crime in youth is limited to juvenile justice and community samples. This study examined relationships between psychiatric disorders and self-reported crime involvement in a sample of youth representative of the US population.
The National Comorbidity Survey-Adolescent Supplement (N=10,123; ages 13–17; 2001–2004) was used to examine the relationship between lifetime DSM-IV-based diagnoses, reported crime (property, violent, other), and arrest history. Logistic regression compared the odds of reported crime involvement with specific psychiatric disorders to those without any diagnoses, and examined the odds of crime by psychiatric comorbidity.
Prevalence of crime was 18.4%. Youth with lifetime psychiatric disorders, compared to no disorders, had significantly greater odds of crime, including violent crime. For violent crime resulting in arrest, conduct disorder (CD; OR=57.5; 95% CI=30.4,108.8), alcohol use disorders (OR=19.5; 95% CI=8.8,43.2), and drug use disorders (OR=16.1; 95% CI=9.3,27.7) had the greatest odds with similar findings for violent crime with no arrest. Psychiatric comorbidity increased the odds of crime. Youth with 3 or more diagnoses (16.0% of population) accounted for 54.1% of those reporting arrest for violent crime. Youth with at least 1 diagnosis committed 85.8% of crime, which was reduced to 67.9% by removing those with CD. Importantly, 88.2% of youth with mental illness report never committing any crime.
Our findings highlight the importance of improving access to mental health services for youthful offenders in community settings given the substantial associations found between mental illness and crime in this nationally representative epidemiological sample.
PMCID: PMC4137504  PMID: 25062596
youth; psychiatric disorders; crime; arrest; US population
6.  Integrin α3β1 regulates kidney collecting duct development via TRAF6-dependent K63-linked polyubiquitination of Akt 
Molecular Biology of the Cell  2015;26(10):1857-1874.
This study demonstrates that integrin α3β1 interactions with both α3- and α5-containing laminins regulate ureteric bud (UB) development by functionally modulating the Akt signaling pathway. In addition, the work done shows that K63-linked polyubiquitination plays a previously unrecognized role in integrin α3β1–dependent cell signaling required for UB development and that this may be a novel general mechanism whereby integrins regulate signaling pathways.
The collecting system of the kidney develops from the ureteric bud (UB), which undergoes branching morphogenesis, a process regulated by multiple factors, including integrin–extracellular matrix interactions. The laminin (LM)-binding integrin α3β1 is crucial for this developmental program; however, the LM types and LM/integrin α3β1–dependent signaling pathways are poorly defined. We show that α3 chain–containing LMs promote normal UB branching morphogenesis and that LM-332 is a better substrate than LM-511 for stimulating integrin α3β1–dependent collecting duct cell functions. We demonstrate that integrin α3β1–mediated cell adhesion to LM-332 modulates Akt activation in the developing collecting system and that Akt activation is PI3K independent but requires decreased PTEN activity and K63-linked polyubiquitination. We identified the ubiquitin-modifying enzyme TRAF6 as an interactor with the integrin β1 subunit and regulator of integrin α3β1–dependent Akt activation. Finally, we established that the developmental defects of TRAF6- and integrin α3–null mouse kidneys are similar. Thus K63-linked polyubiquitination plays a previously unrecognized role in integrin α3β1–dependent cell signaling required for UB development and may represent a novel mechanism whereby integrins regulate signaling pathways.
PMCID: PMC4436831  PMID: 25808491
7.  A scoping review of biomechanical testing for proximal humerus fracture implants 
Fixation failure is a relatively common sequela of surgical management of proximal humerus fractures (PHF). The purpose of this study is to understand the current state of the literature with regard to the biomechanical testing of proximal humerus fracture implants.
A scoping review of the proximal humerus fracture literature was performed, and studies testing the mechanical properties of a PHF treatment were included in this review. Descriptive statistics were used to summarize the characteristics and methods of the included studies.
1,051 proximal humerus fracture studies were reviewed; 67 studies met our inclusion criteria. The most common specimen used was cadaver bone (87 %), followed by sawbones (7 %) and animal bones (4 %). A two-part fracture pattern was tested most frequently (68 %), followed by three-part (23 %), and four-part (8 %). Implants tested included locking plates (52 %), intramedullary devices (25 %), and non-locking plates (25 %). Hemi-arthroplasty was tested in 5 studies (7 %), with no studies using reverse total shoulder arthroplasty (RTSA) implants. Torque was the most common mode of force applied (51 %), followed by axial loading (45 %), and cantilever bending (34 %). Substantial testing diversity was observed across all studies.
The biomechanical literature was found to be both diverse and heterogeneous. More complex fracture patterns and RTSA implants have not been adequately tested. These gaps in the current literature will need to be addressed to ensure that future biomechanical research is clinically relevant and capable of improving the outcomes of challenging proximal humerus fracture patterns.
Electronic supplementary material
The online version of this article (doi:10.1186/s12891-015-0627-x) contains supplementary material, which is available to authorized users.
PMCID: PMC4520267  PMID: 26223275
Proximal humerus fracture; Biomechanics; Proximal humerus fracture implant
8.  Mental Disorders and Their Association With Disability Among Internally Displaced Persons and Returnees in Georgia 
Journal of Traumatic Stress  2014;27(5):509-518.
There remains limited evidence on comorbidity of mental disorders among conflict-affected civilians, particularly internally displaced persons (IDPs) and former IDPs who have returned to their home areas (returnees). The study aim was to compare patterns of mental disorders and their influence on disability between IDPs and returnees in the Republic of Georgia. A cross-sectional household survey was conducted with adult IDPs from the conflicts in the 1990s, the 2008 conflict, and returnees. Posttraumatic stress disorder (PTSD), depression, anxiety, and disability were measured using cut scores on Trauma Screening Questionnaire, Patient Health Questionnaire 9, Generalised Anxiety Disorder 7, and the WHO Disability Assessment Schedule 2.0. Among the 3,025 respondents, the probable prevalence of PTSD, depression, anxiety, and comorbidity (>1 condition) was 23.3%, 14.0%, 10.4%, 12.4%, respectively. Pearson correlation coefficients (p < .001) were .40 (PTSD with depression), .38 (PTSD with anxiety), and .52 (depression with anxiety). Characteristics associated with mental disorders in regression analyses included displacement (particularly longer-term), cumulative trauma exposure, female gender, older age, poor community conditions, and bad household economic situation; coefficients ranged from 1.50 to 3.79. PTSD, depression, anxiety, and comorbidity were associated with increases in disability of 6.4%, 9.7%, 6.3%, and 15.9%, respectively. A high burden of psychiatric symptoms and disability persist among conflict-affected persons in Georgia.
PMCID: PMC4496794  PMID: 25322880
9.  Pierpont Syndrome: A Collaborative Study 
Pierpont syndrome is a multiple congenital anomaly syndrome with learning disability first described in 1998. There are only three patients with Pierpont syndrome who have previously been published in the literature. Details of a series of patients with features of this condition were therefore obtained retrospectively to better characterize its key features. These patients were noted to have distinctive shared facial characteristics, in addition to plantar fat pads and other limb abnormalities. Further individuals with equally striking hand and foot findings were identified whose facies were less characteristic, and hence we considered them unlikely to be affected with the same condition. Despite several patients with possible Pierpont syndrome having had high-resolution array CGH or SNP array, the etiology of this phenotype remains unknown. Whilst it is as yet unclear whether it is a single entity, there appears to be a group of patients in whom Pierpont syndrome may be a recognizable condition, with typical facies, particularly when smiling, and characteristic hand and foot findings. © 2011 Wiley-Liss, Inc.
PMCID: PMC4495254  PMID: 21834056
Pierpont syndrome; fetal digital pads; plantar fat pads; learning disability
10.  Polarized Trafficking of AQP2 Revealed in Three Dimensional Epithelial Culture 
PLoS ONE  2015;10(7):e0131719.
In renal collecting duct (CD) principal cells (PCs), vasopressin (VP) acts through its receptor, V2R, to increase intracellular cAMP leading to phosphorylation and apical membrane accumulation of the water channel aquaporin 2 (AQP2). The trafficking and function of basolaterally located AQP2 is, however, poorly understood. Here we report the successful application of a 3-dimensional Madin-Darby canine kidney (MDCK) epithelial model to study polarized AQP2 trafficking. This model recapitulates the luminal architecture of the CD and bi-polarized distribution of AQP2 as seen in kidney. Without stimulation, AQP2 is located in the subapical and basolateral regions. Treatment with VP, forskolin (FK), or 8-(4-Chlorophenylthio)-2′-O-methyladenosine 3′,5′-cyclic monophosphate monosodium hydrate (CPT-cAMP) leads to translocation of cytosolic AQP2 to the apical membrane, but not to the basolateral membrane. Treating cells with methyl-β-cyclodextrin (mβCD) to acutely block endocytosis causes accumulation of AQP2 on the basolateral membrane, but not on the apical membrane. Our data suggest that AQP2 may traffic differently at the apical and basolateral domains in this 3D epithelial model. In addition, application of a panel of phosphorylation specific AQP2 antibodies reveals the polarized, subcellular localization of differentially phosphorylated AQP2 at S256, S261, S264 and S269 in the 3D culture model, which is consistent with observations made in the CDs of VP treated animals, suggesting the preservation of phosphorylation dependent regulatory mechanism of AQP2 trafficking in this model. Therefore we have established a 3D culture model for the study of trafficking and regulation of both the apical and basolaterally targeted AQP2. The new model will enable further characterization of the complex mechanism regulating bi-polarized trafficking of AQP2 in vitro.
PMCID: PMC4493001  PMID: 26147297
11.  Understanding the modifiable health systems barriers to hypertension management in Malaysia: a multi-method health systems appraisal approach 
The growing burden of non-communicable diseases in middle-income countries demands models of care that are appropriate to local contexts and acceptable to patients in order to be effective. We describe a multi-method health system appraisal to inform the design of an intervention that will be used in a cluster randomized controlled trial to improve hypertension control in Malaysia.
A health systems appraisal was undertaken in the capital, Kuala Lumpur, and poorer-resourced rural sites in Peninsular Malaysia and Sabah. Building on two systematic reviews of barriers to hypertension control, a conceptual framework was developed that guided analysis of survey data, documentary review and semi-structured interviews with key informants, health professionals and patients. The analysis followed the patients as they move through the health system, exploring the main modifiable system-level barriers to effective hypertension management, and seeking to explain obstacles to improved access and health outcomes.
The study highlighted the need for the proposed intervention to take account of how Malaysian patients seek treatment in both the public and private sectors, and from western and various traditional practitioners, with many patients choosing to seek care across different services. Patients typically choose private care if they can afford to, while others attend heavily subsidised public clinics. Public hypertension clinics are often overwhelmed by numbers of patients attending, so health workers have little time to engage effectively with patients. Treatment adherence is poor, with a widespread belief, stemming from concepts of traditional medicine, that hypertension is a transient disturbance rather than a permanent asymptomatic condition. Drug supplies can be erratic in rural areas. Hypertension awareness and education material are limited, and what exist are poorly developed and ineffective.
Despite having a relatively well funded health system offering good access to care, Malaysia's health system still has significant barriers to effective hypertension management.
The study uncovered major patient-related barriers to the detection and control of hypertension which will have an impact on the design and implementation of any hypertension intervention. Appropriate models of care must take account of the patient modifiable health systems barriers if they are to have any realistic chance of success; these findings are relevant to many countries seeking to effectively control hypertension despite resource constraints.
PMCID: PMC4489127  PMID: 26135302
12.  Evidence that α2-antiplasmin becomes covalently ligated to plasma fibrinogen in the circulation: a new role for plasma factor XIII in fibrinolysis regulation 
Plasma alpha2-antiplasmin (α2AP) is a rapid and effective inhibitor of the fibrinolytic enzyme plasmin. Congenital α2AP deficiency results in a severe hemorrhagic disorder due to accelerated fibrinolysis. It is well established that in the presence of thrombin-activated factor XIII (FXIIIa), α2AP becomes covalently ligated to the distal α chains of fibrin or fibrinogen at lysine 303 (two potential sites per molecule). Some time ago we showed that α2AP is covalently linked to plasma fibrinogen. That singular observation led to our hypothesis that native plasma factor XIII (FXIII), which is known to catalyze covalent cross-linking of fibrinogen in the presence of calcium ions, can also incorporate α2AP into fibrinogen in the circulation.
Results and Conclusions
We now provide evidence that FXIII incorporates I125-labelled α2AP into the Aα-chain sites on fibrinogen or fibrin. We also measured the content of α2AP in isolated plasma fibrinogen fractions by ELISA and found that substantial amounts were present (1.2–1.8 moles per mole fibrinogen). We propose that α2AP becomes ligated to fibrinogen while in the circulation through the action of FXIII, and that its immediate presence in plasma fibrinogen contributes to regulation of in vivo fibrinolysis.
PMCID: PMC4489681  PMID: 18564219
factor XIII; fibrinogen; fibrinolysis; serpin; α2-antiplasmin
15.  S100A1 in Human Heart Failure: Lack of Recovery Following LVAD Support 
Circulation. Heart failure  2014;7(4):612-618.
We hypothesized that S100A1 is regulated during human hypertrophy and heart failure (HF), and that it may be implicated in remodeling after left ventricular assist device (LVAD). S100A1 is decreased in animal and human HF and restoration produces functional recovery in animal models and in failing human myocytes. With the potential for gene therapy, it is important to carefully explore human cardiac S100A1 regulation and its role in remodeling.
Methods and Results
We measured S100A1, the sarcoplasmic endoplasmic reticulum Ca2+ATPase (SERCA), phospholamban (PLB) and ryanodine receptor (RYR) proteins as well as β-adrenergic receptor density (β-AR) in non-failing (NF), hypertrophied (LVH), failing (F) and failing LVAD-supported (F+LVAD) hearts. We determined functional consequences of protein alterations in isolated contracting muscles from the same hearts. S100A1, SERCA and PLB were normal in LVH, but decreased in F, while RYR was unchanged in either group. Baseline muscle contraction was not altered in LVH or F. β-AR and inotropic response were decreased in F. In F+LVAD, S100A1 and SERCA showed no recovery, while PLB, β-AR and the inotropic response fully recovered.
S100A1 and SERCA, both key Ca2+-regulatory proteins, are decreased in human HF and these changes are not reversed following LVAD. The clinical significance of these findings for cardiac recovery remains to be addressed.
PMCID: PMC4102621  PMID: 24842913
S100A1; SERCA; PLB; β-adrenergic; LVAD
16.  Association between neuropathology and brain volume in the Framingham Heart Study 
Studies of clinical and community cohorts have shown that antemortem imaging measures of hippocampal volume have correlated with postmortem Alzheimer's pathology. Fewer studies have examined the relationship between both Alzheimer's and cerebrovascular pathology, and antemortem brain imaging. The aim of this study was to correlate antemortem brain magnetic resonance imaging (MRI) volumes with postmortem brain pathology (both Alzheimer-related and cerebrovascular) in a community-derived cohort from the Framingham Heart Study (FHS). Participants (n=59) from the FHS were included if they were enrolled in the brain autopsy program and underwent antemortem clinical evaluation, neuropsychological testing and brain MRI. Cortical neurofibrillary tangle pathology correlated with lower total cerebral brain (beta±SE=−0.04±0.01, p=0.004) and hippocampal volumes (beta±SE=−0.03±0.02, p=0.044) and larger temporal horns (log-transformed, beta±SE=0.05±0.01, p=0.001). Similar findings were seen between total/cortical neuritic plaques and total cerebral brain and temporal horn volume. White matter hyperintensities (also log-transformed) were best predicted by the presence of deep nuclei microinfarcts (beta±SE=0.53±0.21, p=0.016), whereas hippocampal volume was significantly decreased in the presence of hippocampal sclerosis (beta±SE =−1.23±0.30, p<0.001). This study showed that volumetric MRI measures correlated with postmortem Alzheimer-related and cerebrovascular neuropathology in this community-derived cohort, confirming that these MRI measures are important antemortem surrogates for these dementia-related pathologies.
PMCID: PMC4139422  PMID: 24614264
17.  The effects of maternal immunity and age structure on population immunity to measles 
Theoretical ecology  2015;8(2):261-271.
Measles was successfully eradicated in the Pan-American Health Region in 2002. However, maintenance of elimination in parts of Africa, Europe, the USA, and other regions is proving difficult, despite apparently high vaccine coverage. This may be due to the different age structure in developed and developing populations, as well as to differences in the duration of maternal immunity. We explore the interaction between maternal immunity and age structure and quantify the resulting immunity gap between vaccine coverage and population immunity; we use this immunity gap as a novel metric of vaccine program success as it highlights the difference between actual and estimated immunity. We find that, for some combinations of maternal immunity and age structure, the accepted herd immunity threshold is not maintainable with a single-dose vaccine strategy for any combination of target age and coverage. In all cases, the herd immunity threshold is more difficult to maintain in a population with developing age structure. True population immunity is always improved if the target age at vaccination is chosen for the specific combination of maternal immunity and age structure.
PMCID: PMC4485449  PMID: 26140058
Context-dependent management; Disease elimination; Maternal immunity; Measles; Vaccination
18.  Hybrid Supramolecular and Colloidal Hydrogels that Bridge Multiple Length Scales** 
Hybrid nanocomposites were constructed based on colloidal nanofibrillar hydrogels with interpenetrating supramolecular hydrogels, displaying enhanced rheological yield strain and a synergistic improvement in storage modulus. The supramolecular hydrogel consists of naphthyl-functionalized hydroxyethyl cellulose and a cationic polystyrene derivative decorated with methylviologen moieties, physically cross-linked with cucurbit[8]uril macrocyclic hosts. Fast exchange kinetics within the supramolecular system are enabled by reversible cross-linking through the binding of the naphthyl and viologen guests. The colloidal hydrogel consists of nanofibrillated cellulose that combines a mechanically strong nanofiber skeleton with a lateral fibrillar diameter of a few nanometers. The two networks interact through hydroxyethyl cellulose adsorption to the nanofibrillated cellulose surfaces. This work shows methods to bridge the length scales of molecular and colloidal hybrid hydrogels, resulting in synergy between reinforcement and dynamics.
PMCID: PMC4471571  PMID: 25772264
hydrogels; nanocellulose; nanocomposites; supramolecular chemistry
19.  Congenital Ulnar Drift in a Surgeon 
Case Reports in Orthopedics  2015;2015:135350.
Windblown hand is a term used in many instances to describe ulnar deviations of the fingers with or without other malformations. In 1994 Wood reviewed all of the descriptions of cases of windblown hand and pointed out how many variants of congenital ulnar drift there are, suggesting that the many variations seen may all belong to a larger type of arthrogryposis. While the most common cause of ulnar deviation of the fingers is rheumatoid arthritis, it can also be caused by other conditions such as windblown hand or Jaccoud's arthropathy. While most hand surgeons are familiar with presentations of congenital ulnar drift, few of them are knowledgeable about Jaccoud's arthropathy as this is usually discussed within medical communities such as Rheumatology. We present a case of a surgeon who has had noticeable ulnar deviation of the digits at the level of the metacarpophalangeal joint since his early 20s. We propose that the current case is a demonstration of a type of windblown hand that has some hereditary component but is not immediately obvious at birth and presents physically more like Jaccoud's arthropathy than traditional windblown hand.
PMCID: PMC4488582  PMID: 26167318
20.  Using Substrate Specificity of Antiplasmin-Cleaving Enzyme for Fibroblast Activation Protein Inhibitor Design† 
Biochemistry  2009;48(23):5149-5158.
Circulating antiplasmin-cleaving enzyme (APCE), a prolyl-specific serine proteinase, is essentially identical to membrane-inserted fibroblast activation protein (FAP) that is transiently expressed during epithelial-derived cancer growth. Human precursive α2-antiplasmin (Met-α2AP), the only known physiologic substrate for APCE, is cleaved N-terminally to Asn-α2AP that is rapidly cross-linked to fibrin and protects it from digestion by plasmin. Identifying a specific inhibitor of APCE/FAP continues to be intensely pursued. Recombinant FAP cleavage of peptide libraries of short amino acid sequences surrounding the scissile bond, -Pro12-Asn13-, indicated that P2 Gly and P1 Pro are required, just as we found for APCE. We examined cleavage of P4–P4′ peptides, using 19 amino acid substitutions at each position and selected ones in P8–P5. Km values determined for peptide substrates showed that P7 Arg has the highest affinity for APCE. Peptide cleavage rate increased with Arg in P6 rather than P5 or native P7. Placing Arg in P4 or P8 reduced cleavage rates dramatically. Cleavage of substrates with extended peptide sequences before or after the scissile bond showed endopeptidase to be superior to dipeptidase activity for APCE. A substrate analogue inhibitor, Phe-Arg-(8-amino-3,6-dioxaoctanoic acid)-Gly-[r]-fluoropyrrolidide, inhibited APCE with a Ki of 54 μM but not dipeptidyl peptidase IV even at 2 mM. The inhibitor also blocked cleavage of Met-α2AP with an IC50 of 91 μM. Replacing Arg with Gly at the same distance from fluoropyrrolidide as P7 Arg is from P1 Pro reduced its inhibition of APCE ∼10-fold. Results indicate that Arg at P5, P6, or P7 distances from P1 enhances affinity and efficiency of substrates or inhibitors toward APCE or FAP.
PMCID: PMC4470291  PMID: 19402713
21.  Nucleic acids within urinary exosomes/microvesicles are potential biomarkers for renal disease 
Kidney international  2010;78(2):191-199.
Urinary exosomes or microvesicles are being studied intensively to identify potential new biomarkers for renal disease. We sought to identify whether these microvesicles contain nucleic acids. We isolated microvesicles from human urine in the same density range as that previously described for urinary exosomes and found them to have an RNA integrity profile similar to that of kidney tissue, including 18S and 28S rRNA. This profile was better preserved in urinary microvesicles compared with whole cells isolated from urine, suggesting that microvesicles may protect RNA during urine passage. We were able to detect mRNA in the human urinary microvesicles encoding proteins from all regions of the nephron and the collecting duct. Further, to provide a proof of principle, we found that microvesicles isolated from the urine of the V-ATPase B1 subunit knockout mice lacked mRNA of this subunit while containing a normal amount of the B2 subunit and aquaporin 2. The microvesicles were found to be contaminated with extraneous DNA potentially on their surface; therefore, we developed a rapid and reliable means to isolate nucleic acids from within urine microvesicles devoid of this extraneous contamination. Our study provides an experimental strategy for the routine isolation and use of urinary microvesicles as a novel and non-invasive source of nucleic acids to further renal disease biomarker discovery.
PMCID: PMC4451567  PMID: 20428099
acute kidney injury; chronic kidney disease; exosome; transcriptional profiling
22.  A review of hydrofluoric acid burn management 
Plastic Surgery  2014;22(2):95-98.
The clinical presentation and severity of hydrofluoric acid burns vary considerably, making management particularly challenging. Given that current knowledge of HF burns is derived from small case series, case reports, animal studies and anecdotal evidence, this narrative review discusses the current understanding of the effects associated with severe hydrofluoric acid burns, describing the mechanism of injury, systemic toxicity and treatment options.
Hydrofluoric acid (HF) causes a unique chemical burn. Much of the current treatment knowledge of HF burns is derived from case reports, small case series, animal studies and anecdotal evidence. The management can be challenging because clinical presentation and severity of these burns vary widely. Plastic surgeons managing burn patients must have a basic understanding of the pathophysiology, the range of severity in presentation and the current treatment options available for HF burns.
The present article reviews the current understanding of the pathophysiology and systemic effects associated with severe HF burns. Furthermore, it distinguishes between minor and life-threatening HF burns and describes several of the basic techniques that are available to treat patients with HF burns.
PMCID: PMC4116323  PMID: 25114621
Acid; Hydrofluoric; Review
23.  Hyperglycosylated Stable Core Immunogens Designed To Present the CD4 Binding Site Are Preferentially Recognized by Broadly Neutralizing Antibodies 
Journal of Virology  2014;88(24):14002-14016.
The HIV-1 surface envelope glycoprotein (Env) trimer mediates entry into CD4+ CCR5+ host cells. Env possesses conserved antigenic determinants, such as the gp120 primary receptor CD4 binding site (CD4bs), a known neutralization target. Env also contains variable regions and protein surfaces occluded within the trimer that elicit nonneutralizing antibodies. Here we engineered additional N-linked glycans onto a cysteine-stabilized gp120 core (0G) deleted of its major variable regions to preferentially expose the conformationally fixed CD4bs. Three, 6, 7, and 10 new NXT/S glycan (G) motifs were engineered into 0G to encode 3G, 6G, 7G, and 10G cores. Following purification, most glycoproteins, except for 10G, were recognized by broadly neutralizing CD4bs-directed antibodies. Gel and glycan mass spectrometry confirmed that additional N-glycans were posttranslationally added to the redesigned cores. Binding kinetics revealed high-affinity recognition by seven broadly neutralizing CD4bs-directed antibodies and low to no binding by non-broadly neutralizing CD4bs-directed antibodies. Rabbits inoculated with the hyperglycosylated cores elicited IgM and IgG responses to each given protein that were similar in their neutralization characteristics to those elicited by parental 0G. Site-specific glycan masking effects were detected in the elicited sera, and the antisera competed with b12 for CD4bs-directed binding specificity. However, the core-elicited sera showed limited neutralization activity. Trimer priming or boosting of the core immunogens elicited tier 1-level neutralization that mapped to both the CD4bs and V3 and appeared to be trimer dependent. Fine mapping at the CD4bs indicated that conformational stabilization of the cores and addition of N-glycans altered the molecular surface of Env sites of vulnerability to neutralizing antibody, suggesting an explanation for why the elicited neutralization was not improved by this rational design strategy.
IMPORTANCE Major obstacles to developing an effective HIV-1 vaccine include the variability of the envelope surface glycoproteins and its high-density glycan shield, generated by incorporation of host (human) glycosylation. HIV-1 does harbor highly conserved sites on the exposed envelope protein surface of gp120, one of which is the virus receptor (CD4) binding site. Several broadly neutralizing antibodies elicited from HIV patients do target this gp120 CD4 binding site (CD4bs); however, gp120 immunogens do not elicit broadly neutralizing antibodies. In this study, we targeted the CD4bs by conformational stabilization and additional glycan masking. We used the atomic-level structure to reengineer gp120 cores to preferentially present the cysteine-stabilized CD4bs and to mask (by glycan) nonneutralizing determinants. Importantly, glycan masking did successfully focus antibody responses to the CD4bs; however, the elicited CD4bs-directed antibodies did not neutralize HIV or bind to unmodified gp120, presumably due to the structure-guided modifications of the modified gp120 core.
PMCID: PMC4249138  PMID: 25253346
24.  Efficacy and Moderators of a Family Group Cognitive-Behavioral Preventive Intervention for Children of Depressed Parents 
Building on an earlier study (Compas et al., 2011), tests of main effects and potential moderators of a family group cognitive-behavioral (FGCB) preventive intervention for children of parents with a history of depression are reported in a sample of 180 families (242 children ages 9-15 years) in a randomized controlled trial assessed at 2-, 6-, 12-, 18- and 24-months after baseline. Significant effects favoring the FGCB intervention over a written information (WI) comparison condition were found on measures of children's symptoms of depression, mixed anxiety/depression, internalizing problems, and externalizing problems, with multiple effects maintained at 18- and 24-months, and on incidence of child episodes of major depressive disorder over the 24-months. Effects were stronger for child self-reports than for parent-reports. Minimal evidence was found for child age, child gender, parental education, parental depressive symptoms, or presence of a current parental depressive episode at baseline as moderators of the FGCB intervention. The findings provide support for sustained and robust effects of this preventive intervention.
PMCID: PMC4445475  PMID: 26009786
parental depression; prevention; moderation
25.  Loss-of-function HDAC8 mutations cause a phenotypic spectrum of Cornelia de Lange syndrome-like features, ocular hypertelorism, large fontanelle and X-linked inheritance 
Kaiser, Frank J. | Ansari, Morad | Braunholz, Diana | Concepción Gil-Rodríguez, María | Decroos, Christophe | Wilde, Jonathan J. | Fincher, Christopher T. | Kaur, Maninder | Bando, Masashige | Amor, David J. | Atwal, Paldeep S. | Bahlo, Melanie | Bowman, Christine M. | Bradley, Jacquelyn J. | Brunner, Han G. | Clark, Dinah | Del Campo, Miguel | Di Donato, Nataliya | Diakumis, Peter | Dubbs, Holly | Dyment, David A. | Eckhold, Juliane | Ernst, Sarah | Ferreira, Jose C. | Francey, Lauren J. | Gehlken, Ulrike | Guillén-Navarro, Encarna | Gyftodimou, Yolanda | Hall, Bryan D. | Hennekam, Raoul | Hudgins, Louanne | Hullings, Melanie | Hunter, Jennifer M. | Yntema, Helger | Innes, A. Micheil | Kline, Antonie D. | Krumina, Zita | Lee, Hane | Leppig, Kathleen | Lynch, Sally Ann | Mallozzi, Mark B. | Mannini, Linda | Mckee, Shane | Mehta, Sarju G. | Micule, Ieva | Mohammed, Shehla | Moran, Ellen | Mortier, Geert R. | Moser, Joe-Ann S. | Noon, Sarah E. | Nozaki, Naohito | Nunes, Luis | Pappas, John G. | Penney, Lynette S. | Pérez-Aytés, Antonio | Petersen, Michael B. | Puisac, Beatriz | Revencu, Nicole | Roeder, Elizabeth | Saitta, Sulagna | Scheuerle, Angela E. | Schindeler, Karen L. | Siu, Victoria M. | Stark, Zornitza | Strom, Samuel P. | Thiese, Heidi | Vater, Inga | Willems, Patrick | Williamson, Kathleen | Wilson, Louise C. | Hakonarson, Hakon | Quintero-Rivera, Fabiola | Wierzba, Jolanta | Musio, Antonio | Gillessen-Kaesbach, Gabriele | Ramos, Feliciano J. | Jackson, Laird G. | Shirahige, Katsuhiko | Pié, Juan | Christianson, David W. | Krantz, Ian D. | Fitzpatrick, David R. | Deardorff, Matthew A.
Human Molecular Genetics  2014;23(11):2888-2900.
Cornelia de Lange syndrome (CdLS) is a multisystem genetic disorder with distinct facies, growth failure, intellectual disability, distal limb anomalies, gastrointestinal and neurological disease. Mutations in NIPBL, encoding a cohesin regulatory protein, account for >80% of cases with typical facies. Mutations in the core cohesin complex proteins, encoded by the SMC1A, SMC3 and RAD21 genes, together account for ∼5% of subjects, often with atypical CdLS features. Recently, we identified mutations in the X-linked gene HDAC8 as the cause of a small number of CdLS cases. Here, we report a cohort of 38 individuals with an emerging spectrum of features caused by HDAC8 mutations. For several individuals, the diagnosis of CdLS was not considered prior to genomic testing. Most mutations identified are missense and de novo. Many cases are heterozygous females, each with marked skewing of X-inactivation in peripheral blood DNA. We also identified eight hemizygous males who are more severely affected. The craniofacial appearance caused by HDAC8 mutations overlaps that of typical CdLS but often displays delayed anterior fontanelle closure, ocular hypertelorism, hooding of the eyelids, a broader nose and dental anomalies, which may be useful discriminating features. HDAC8 encodes the lysine deacetylase for the cohesin subunit SMC3 and analysis of the functional consequences of the missense mutations indicates that all cause a loss of enzymatic function. These data demonstrate that loss-of-function mutations in HDAC8 cause a range of overlapping human developmental phenotypes, including a phenotypically distinct subgroup of CdLS.
PMCID: PMC4014191  PMID: 24403048

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