Paternal Age and Transgenerational Telomere Length Maintenance: A Simulation Model.

Telomere length (TL) in offspring is positively correlated with paternal age at the time of the offspring conception. The paternal-age-at-conception (PAC) effect on TL is puzzling, and its biological implication at the population level is unknown. Using a probabilistic model of transgenerational TL and population dynamics, we simulated the effect of PAC on TL in individuals over the course of 1,000 years. Findings suggest a key role for an isometric PAC midpoint (PACmp) in modulating TL across generations, such that offspring conceived by males younger than the isometric PACmp have comparatively short telomeres, while offspring conceived by males older than the isometric PACmp have comparatively long telomeres. We further show that when cancer incidence escalates, the average PAC drops below the isometric PACmp and transgenerational adaptation to cancer ensues through TL shortening. We propose that PAC serves to maintain an optimal TL across generations.

Structure-based inhibitors of tau aggregation.

Aggregated tau protein is associated with over 20 neurological disorders, which include Alzheimer's disease. Previous work has shown that tau's sequence segments VQIINK and VQIVYK drive its aggregation, but inhibitors based on the structure of the VQIVYK segment only partially inhibit full-length tau aggregation and are ineffective at inhibiting seeding by full-length fibrils. Here we show that the VQIINK segment is the more powerful driver of tau aggregation. Two structures of this segment determined by the cryo-electron microscopy method micro-electron diffraction explain its dominant influence on tau aggregation. Of practical significance, the structures lead to the design of inhibitors that not only inhibit tau aggregation but also inhibit the ability of exogenous full-length tau fibrils to seed intracellular tau in HEK293 biosensor cells into amyloid. We also raise the possibility that the two VQIINK structures represent amyloid polymorphs of tau that may account for a subset of prion-like strains of tau.

Clinical Evaluation of the Cepheid Xpert TV Assay for Detection of Trichomonas vaginalis with Prospectively Collected Specimens from Men and Women.

Trichomoniasis is the most prevalent curable sexually transmitted disease (STD). It has been associated with preterm birth and the acquisition and transmission of HIV. Recently, nucleic acid amplification tests (NAAT) have been FDA cleared in the United States for detection of Trichomonas vaginalis in specimens from both women and men. This study reports the results of a multicenter study recently conducted using the Xpert TV (T. vaginalis) assay to test specimens from both men and women. On-demand results were available in as little as 40 min for positive specimens. A total of 1,867 women and 4,791 men were eligible for inclusion in the analysis. In women, the performance of the Xpert TV assay was compared to the patient infected status (PIS) derived from the results of InPouch TV broth culture and Aptima NAAT for T. vaginalis The diagnostic sensitivities and specificities of the Xpert TV assay for the combined female specimens (urine samples, self-collected vaginal swabs, and endocervical swabs) ranged from 99.5 to 100% and 99.4 to 99.9%, respectively. For male urine samples, the diagnostic sensitivity and specificity were 97.2% and 99.9%, respectively, compared to PIS results derived from the results of broth culture for T. vaginalis and bidirectional gene sequencing of amplicons. Excellent performance characteristics were seen using both female and male specimens. The ease of using the Xpert TV assay should result in opportunities for enhanced screening for T. vaginalis in both men and women and, hopefully, improved control of this infection.

A Health Services Research Agenda for Bariatric Surgery Within the Veterans Health Administration.

In 2016, the Veterans Health Administration (VHA) held a Weight Management State of the Art conference to identify evidence gaps and develop a research agenda for population-based weight management for veterans. Included were behavioral, pharmacologic, and bariatric surgery workgroups. This article summarizes the bariatric surgery workgroup (BSWG) findings and recommendations for future research. The BSWG agreed that there is evidence from randomized trials and large observational studies suggesting that bariatric surgery is superior to medical therapy for short- and intermediate-term remission of type 2 diabetes, long-term weight loss, and long-term survival. Priority evidence gaps include long-term comorbidity remission, mental health, substance abuse, and health care costs. Evidence of the role of endoscopic weight loss options is also lacking. The BSWG also noted the limited evidence regarding optimal timing for bariatric surgery referral, barriers to bariatric surgery itself, and management of high-risk bariatric surgery patients. Clinical trials of pre- and post-surgery interventions may help to optimize patient outcomes. A registry of overweight and obese veterans and a workforce assessment to determine the VHA's capacity to increase bariatric surgery access were recommended. These will help inform policy modifications and focus the research agenda to improve the ability of the VHA to deliver population-based weight management.

The formation, function and regulation of amyloids: insights from structural biology.

Amyloid diseases are characterized by the accumulation of insoluble, ß-strand-rich aggregates. The underlying structural conversions are closely associated with cellular toxicity, but can also drive the formation of functional protein assemblies. In recent years, studies in the field of structural studies have revealed astonishing insights into the origins, mechanisms and implications of amyloid formation. Notably, high-resolution crystal structures of peptides in amyloid-like fibrils and prefibrillar oligomers have become available despite their challenging chemical nature. Nuclear magnetic resonance spectroscopy has revealed that dynamic local polymorphisms in the benign form of the prion protein affect the transformation into amyloid fibrils and the transmissibility of prion diseases. Studies of the structures and interactions of chaperone proteins help us to understand how the cellular proteostasis network is able to recognize different stages of aberrant protein folding and prevent aggregation. In this review, we will focus on recent developments that connect the different aspects of amyloid biology and discuss how understanding the process of amyloid formation and the associated defence mechanisms can reveal targets for pharmacological intervention that may become the first steps towards clinically viable treatment strategies.

Brain-derived neurotrophic factor (BDNF) Val(66)Met polymorphism differentially predicts hippocampal function in medication-free patients with schizophrenia.

A Val(66)Met single-nucleotide polymorphism (SNP) in the brain-derived neurotrophic factor (BDNF) gene impairs activity-dependent BDNF release in cultured hippocampal neurons and predicts impaired memory and exaggerated basal hippocampal activity in healthy humans. Several clinical genetic association studies along with multi-modal evidence for hippocampal dysfunction in schizophrenia indirectly suggest a relationship between schizophrenia and genetically determined BDNF function in the hippocampus. To directly test this hypothesized relationship, we studied 47 medication-free patients with schizophrenia or schizoaffective disorder and 74 healthy comparison individuals with genotyping for the Val(66)Met SNP and [(15)O]H(2)O positron emission tomography (PET) to measure resting and working memory-related hippocampal regional cerebral blood flow (rCBF). In patients, harboring a Met allele was associated with significantly less hippocampal rCBF. This finding was opposite to the genotype effect seen in healthy participants, resulting in a significant diagnosis-by-genotype interaction. Exploratory analyses of interregional resting rCBF covariation revealed a specific and significant diagnosis-by-genotype interaction effect on hippocampal-prefrontal coupling. A diagnosis-by-genotype interaction was also found for working memory-related hippocampal rCBF change, which was uniquely attenuated in Met allele-carrying patients. Thus, both task-independent and task-dependent hippocampal neurophysiology accommodates a Met allelic background differently in patients with schizophrenia than in control subjects. Potentially consistent with the hypothesis that cellular sequelae of the BDNF Val(66)Met SNP interface with aspects of schizophrenic hippocampal and frontotemporal dysfunction, these results warrant future investigation to understand the contributions of unique patient trait or state variables to these robust interactions.

Dynamical coupling of intrinsically disordered proteins and their hydration water: comparison with folded soluble and membrane proteins.

Hydration water is vital for various macromolecular biological activities, such as specific ligand recognition, enzyme activity, response to receptor binding, and energy transduction. Without hydration water, proteins would not fold correctly and would lack the conformational flexibility that animates their three-dimensional structures. Motions in globular, soluble proteins are thought to be governed to a certain extent by hydration-water dynamics, yet it is not known whether this relationship holds true for other protein classes in general and whether, in turn, the structural nature of a protein also influences water motions. Here, we provide insight into the coupling between hydration-water dynamics and atomic motions in intrinsically disordered proteins (IDP), a largely unexplored class of proteins that, in contrast to folded proteins, lack a well-defined three-dimensional structure. We investigated the human IDP tau, which is involved in the pathogenic processes accompanying Alzheimer disease. Combining neutron scattering and protein perdeuteration, we found similar atomic mean-square displacements over a large temperature range for the tau protein and its hydration water, indicating intimate coupling between them. This is in contrast to the behavior of folded proteins of similar molecular weight, such as the globular, soluble maltose-binding protein and the membrane protein bacteriorhodopsin, which display moderate to weak coupling, respectively. The extracted mean square displacements also reveal a greater motional flexibility of IDP compared with globular, folded proteins and more restricted water motions on the IDP surface. The results provide evidence that protein and hydration-water motions mutually affect and shape each other, and that there is a gradient of coupling across different protein classes that may play a functional role in macromolecular activity in a cellular context.

Adherence to oral second-generation antipsychotic medications in patients with schizophrenia and bipolar disorder: physicians' perceptions of adherence vs. pharmacy claims.

OBJECTIVE: To compare physician-reported adherence of specific patients to oral second-generation antipsychotics vs. actual adherence rates determined from the patients' pharmacy claims. METHODS: Claims data from the HealthCore Integrated Research Database identified patients with schizophrenia or bipolar disorder with ≥ 1 oral second-generation antipsychotic prescription. The prescribing physicians were identified from the pharmacy claims and asked to complete an Internet survey assessing their perception of medication adherence for 1-2 of their patients and their beliefs regarding adherence to second-generation antipsychotics in general for a 1-year period. Adherence to second-generation antipsychotics was determined for each patient by pharmacy claims for the same period. Physician survey data were merged with patient claims data via unique patient identifiers, and physician-reported adherence rates were compared with claims-based rates as measured by the medication possession ratio. RESULTS: One hundred and fifty-three physicians responded to the survey, representing 214 patients (44 with claims for schizophrenia, 162 with bipolar disorder, 8 with claims for bipolar disorder and schizophrenia). Most physicians (60%) had no formal adherence training. More than two-thirds (68%) reported emphasising the importance of adherence and reported approximately 76% of their patients were adherent (≥ 71% of the time). In the schizophrenia group, 16 of 17 (94%) patients with low-to-moderate (≤ 70%) adherence levels had high (≥ 71%) physician-estimated adherence. In the bipolar disorder group, 62 of 92 (67%) patients with low-to-moderate adherence levels had high physician-estimated adherence. CONCLUSIONS/INTERPRETATION: These analyses suggest that, even when physicians are asked about specific patients in their practice, there is discordance between physician perceptions and adherence as measured through pharmacy claims. This disparity may delay appropriate interventions, potentially contributing to relapses.

Non-3D domain swapped crystal structure of truncated zebrafish alphaA crystallin.

In previous work on truncated alpha crystallins (Laganowsky et al., Protein Sci 2010; 19:1031-1043), we determined crystal structures of the alpha crystallin core, a seven beta-stranded immunoglobulin-like domain, with its conserved C-terminal extension. These extensions swap into neighboring cores forming oligomeric assemblies. The extension is palindromic in sequence, binding in either of two directions. Here, we report the crystal structure of a truncated alphaA crystallin (AAC) from zebrafish (Danio rerio) revealing C-terminal extensions in a non three-dimensional (3D) domain swapped, "closed" state. The extension is quasi-palindromic, bound within its own zebrafish core domain, lying in the opposite direction to that of bovine AAC, which is bound within an adjacent core domain (Laganowsky et al., Protein Sci 2010; 19:1031-1043). Our findings establish that the C-terminal extension of alpha crystallin proteins can be either 3D domain swapped or non-3D domain swapped. This duality provides another molecular mechanism for alpha crystallin proteins to maintain the polydispersity that is crucial for eye lens transparency.

Infliximab improves health-related quality of life in the presence of comorbidities among patients with moderate-to-severe psoriasis.

BACKGROUND: Psoriasis affects patients both physically and psychologically. OBJECTIVES: To investigate the effect of comorbidities on health-related quality of life (HRQoL) and to determine whether infliximab improved HRQoL in the presence of these conditions. METHODS: In this multicentre, double-blind study, 835 patients with moderate-to-severe plaque psoriasis were randomized to receive infliximab 3 or 5 mg kg(-1) or placebo at weeks 0, 2 and 6. Infliximab-treated patients were re-randomized at week 14 to receive the same treatment every 8 weeks or as needed through week 46; placebo patients crossed over to infliximab 5 mg kg(-1) at week 16. Disease severity (Psoriasis Area and Severity Index, PASI) and HRQoL (Dermatology Life Quality Index, DLQI; 36-item Short-Form Health Survey, SF-36) were measured at various time points. The effect of patient comorbidities on baseline HRQoL was assessed using multiple regression models. The impact of key comorbidities on infliximab treatment effect was also assessed. RESULTS: Disease severity (PASI), depression and psoriatic arthritis (PsA) were predictors of poor baseline HRQoL. At week 10, infliximab 3 and 5 mg kg(-1) significantly improved physical and mental health dimensions of the SF-36 and the DLQI (all P < 0.001). Consistent improvement in HRQoL with infliximab treatment was observed regardless of baseline patient characteristics or comorbidities. Through week 50, HRQoL and PASI scores were most improved with infliximab 5 mg kg(-1) administered every 8 weeks. CONCLUSIONS: Disease severity, depression and PsA were significant predictors of poor HRQoL. Infliximab significantly improved HRQoL, regardless of these characteristics.

Rain, temperature, and child-adolescent height among Native Amazonians in Bolivia.

BACKGROUND: Global climate change and recent studies on early-life origins of well-being suggest that climate events early in life might affect health later in life. AIM: The study tested hypotheses about the association between the level and variability of rain and temperature early in life on the height of children and adolescents in a foraging-farming society of native Amazonians in Bolivia (Tsimane'). SUBJECT AND METHODS: Measurements were taken for 525 children aged 2-12 and 218 adolescents aged 13-23 in 13 villages in 2005. Log of standing height was regressed on mean annual level and mean intra-annual monthly coefficient of variation (CV) of rain and mean annual level of temperature during gestation, birth year, and ages 2-4. Controls include age, quinquennium and season of birth, parent's attributes, and dummy variables for surveyors and villages. RESULTS: Climate variables were only related with the height of boys age 2-12. The level and CV of rain during birth year and the CV of rain and level of temperature during ages 2-4 were associated with taller stature. There were no secular changes in temperature (1973-2005) or rain (1943-2005). CONCLUSION: The height of young females and males is well protected from climate events, but protection works less well for boys ages 2-12.

High throughput crystallography of TB drug targets.

Tuberculosis (TB) infects one-third of the world population. Despite 50 years of available drug treatments, TB continues to increase at a significant rate. The failure to control TB stems in part from the expense of delivering treatment to infected individuals and from complex treatment regimens. Incomplete treatment has fueled the emergence of multi-drug resistant (MDR) strains of Mycobacterium tuberculosis (Mtb). Reducing non-compliance by reducing the duration of chemotherapy will have a great impact on TB control. The development of new drugs that either kill persisting organisms, inhibit bacilli from entering the persistent phase, or convert the persistent bacilli into actively growing cells susceptible to our current drugs will have a positive effect. We are taking a multidisciplinary approach that will identify and characterize new drug targets that are essential for persistent Mtb. Targets are exposed to a battery of analyses including microarray experiments, bioinformatics, and genetic techniques to prioritize potential drug targets from Mtb for structural analysis. Our core structural genomics pipeline works with the individual laboratories to produce diffraction quality crystals of targeted proteins, and structural analysis will be completed by the individual laboratories. We also have capabilities for functional analysis and the virtual ligand screening to identify novel inhibitors for target validation. Our overarching goals are to increase the knowledge of Mtb pathogenesis using the TB research community to drive structural genomics, particularly related to persistence, develop a central repository for TB research reagents, and discover chemical inhibitors of drug targets for future development of lead compounds.

Virally-directed fluorescent imaging (VFI) can facilitate endoscopic staging.

BACKGROUND: Replication-competent, tumor specific herpes simplex virus NV1066 expresses green fluorescent protein (GFP) in infected cancer cells. We sought to determine the feasibility of GFP-guided imaging technology in the intraoperative detection of small tumor nodules. METHODS: Human cancer cell lines were infected with NV1066 at multiplicities of infection of 0.01, 0.1 and 1. Cancer cell specific infectivity, vector spread and GFP signal intensity were measured by flow cytometry and time-lapse digital imaging (in vitro); and by use of a stereomicroscope and endoscope equipped with a fluorescent filter (in vivo). RESULTS: NV1066 infected all cancer cell lines and expressed GFP at all MOIs. GFP signal was significantly higher than the autofluorescence of normal cells. One single dose of NV1066 spread within and across body cavities and selectively infected tumor nodules sparing normal tissue. Tumor nodules undetectable by conventional thoracoscopy and laparoscopy were identified by GFP fluorescence. CONCLUSION: Virally-directed fluorescent imaging (VFI) is a real-time novel molecular imaging technology that has the potential to enhance the intraoperative detection of endoluminal or endocavitary tumor nodules.

The added value of spiral computed tomographic angiography after lung scintigraphy for the diagnosis of pulmonary embolism.

OBJECTIVES: The objectives of this study were to evaluate the added clinical value of spiral computed tomographic angiography (CTA) after ventilation-perfusion lung scintigraphy (V/Q) for the management of patients with suspected pulmonary embolism (PE). METHODS: Of 987 patients who had V/Q during 2001, 64 patients (6%) had CTA performed for further evaluation. V/Q and CTA findings were retrospectively analyzed by 2 clinicians who were blinded to the patients' outcome. Patient management was determined based on clinical and V/Q data and was reassessed after the addition of CTA data. RESULTS: CTA was performed in 2 patients with normal V/Q, 16 patients with low probability, 28 patients with intermediate, 4 patients with high probability, and 14 patients with nonconclusive V/Q. Three patients (19%) with low probability, 9 (32%) with intermediate probability, 4 (29%) with nonconclusive, and 4 (100%) with high probability V/Q had PE diagnosed by CTA. CTA findings changed the management in 2 patients (13%) with low probability, 15 (54%) with intermediate probability, and 4 (29%) with nonconclusive V/Q. CONCLUSION: In our institution, V/Q remains the main imaging modality for evaluation of patients with clinically suspected PE. CTA was performed after V/Q in 6% of patients. Patients with intermediate probability and those with nonconclusive V/Q, and to a much lesser extent, patients with low probability V/Q could benefit from the addition of CTA after V/Q. In patients with normal V/Q and those with high-probability V/Q, the addition of CTA does not seem to influence patient management.

The TB structural genomics consortium: a resource for Mycobacterium tuberculosis biology.

The TB Structural Genomics Consortium is an organization devoted to encouraging, coordinating, and facilitating the determination and analysis of structures of proteins from Mycobacterium tuberculosis. The Consortium members hope to work together with other M. tuberculosis researchers to identify M. tuberculosis proteins for which structural information could provide important biological information, to analyze and interpret structures of M. tuberculosis proteins, and to work collaboratively to test ideas about M. tuberculosis protein function that are suggested by structure or related to structural information. This review describes the TB Structural Genomics Consortium and some of the proteins for which the Consortium is in the progress of determining three-dimensional structures.