Familial spontaneous coronary artery dissection: evidence for genetic susceptibility.
Spontaneous coronary artery dissection (SCAD) is a major cause of acute coronary syndrome in young women, especially among those without traditional cardiovascular risk factors. Prior efforts to study SCAD have been hampered by underrecognition and lack of registry-based studies. Risk factors and pathogenesis remain largely undefined, and inheritability has not been reported. Using novel research methods, patient champions, and social media, the Mayo Clinic SCAD Registry has been able to better characterize this condition, which was previously considered rare. Of 412 patient enrollees, we identified 5 familial cases of SCAD comprising affected mother-daughter, identical twin sister, sister, aunt-niece, and first-cousin pairs, implicating both recessive and dominant modes of inheritance. The mother-daughter pair also reported fatal myocardial infarction in 3 maternal relatives. None of the participants had other potential risk factors for SCAD, including connective tissue disorders or peripartum status. To our knowledge, this series is the first to identify a familial association in SCAD suggesting a genetic predisposition. Recognition of SCAD as a heritable disorder has implications for at-risk family members and furthers our understanding of the pathogenesis of this complex disease. Whole-exome sequencing provides a unique opportunity to identify the molecular underpinnings of SCAD susceptibility.


Materials Nanoarchitecturing via Cation-Mediated Protein Assembly: Making Limpet Teeth without Mineral.
Teeth are designed to deliver high forces while withstanding the generated stresses. Aside from isolated mineral-free exception (e.g., marine polychaetes and squids), minerals are thought to be indispensable for tooth-hardening and durability. Here, the unmineralized teeth of the giant keyhole limpet (Megathura crenulata) are shown to attain a stiffness, which is twofold higher than any known organic biogenic structures. In these teeth, protein and chitin fibers establish a stiff compact outer shell enclosing a less compact core. The stiffness and its gradients emerge from a concerted interaction across multiple length-scales: packing of hydrophobic proteins and folding into secondary structures mediated by Ca2+ and Mg2+ together with a strong spatial control in the local fiber orientation. These results integrating nanoindentation, acoustic microscopy, and finite-element modeling for probing the tooth's mechanical properties, spatially resolved small- and wide-angle X-ray scattering for probing the material ordering on the micrometer scale, and energy-dispersive X-ray scattering combined with confocal Raman microscopy to study structural features on the molecular scale, reveal a nanocomposite structure hierarchically assembled to form a versatile damage-tolerant protein-based tooth, with a stiffness similar to mineralized mammalian bone, but without any mineral.


Isomeric Equilibria, Nuclear Quantum Effects, and Vibrational Spectra of M+(H2O) n=1-3 Clusters, with M = Li, Na, K, Rb, and Cs, through Many-Body Representations.
A quantitative characterization of the molecular mechanisms that regulate ion solvation is key to the microscopic understanding of fundamental processes taking place in aqueous environments with major implications for different fields, from atmospheric chemistry to materials research and biochemistry. This study presents a systematic analysis of isomeric equilibria for small M+(H2O) n clusters, with M = Li, Na, K, Rb, and Cs, from 0 to 200 K. To determine the relative stability of different isomers of each M+(H2O) n cluster as a function of temperature, replica exchange simulations are carried out at both classical and quantum levels with the recently developed many-body MB-nrg potential energy functions, which have been shown to exhibit chemical accuracy. Anharmonic vibrational spectra are then calculated within the local monomer approximation and found to be in agreement with the available experimental data, providing further support for the accuracy of the MB-nrg potential energy functions. The present analysis indicates that nuclear quantum effects become increasingly important for larger M+(H2O) n clusters containing the heavier alkali metal ions, which is explained in terms of competing ion-water and water-water interactions along with the interplay between energetic and entropic effects. By directly connecting experimental measurements with molecular properties calculated at the quantum mechanical level, this study represents a further step toward the development of a consistent picture of ion hydration from the gas to the condensed phase.


Selective BRAFV600E inhibitor PLX4720, requires TRAIL assistance to overcome oncogenic PIK3CA resistance.
Documented sensitivity of melanoma cells to PLX4720, a selective BRAFV600E inhibitor, is based on the presence of mutant BRAF(V600E) alone, while wt-BRAF or mutated KRAS result in cell proliferation. In colon cancer appearance of oncogenic alterations is complex , since BRAF, like KRAS mutations, tend to co-exist with those in PIK3CA and mutated PI3K has been shown to interfere with the successful application of MEK inhibitors. When PLX4720 was used to treat colon tumours, results were not encouraging and herein we attempt to understand the cause of this recorded resistance and discover rational therapeutic combinations to resensitize oncogene driven tumours to apoptosis. Treatment of two genetically different BRAF(V600E) mutant colon cancer cell lines with PLX4720 conferred complete resistance to cell death. Even though p-MAPK/ ERK kinase (MEK) suppression was achieved, TRAIL, an apoptosis inducing agent, was used synergistically in order to achieve cell death by apoptosis in RKO(BRAFV600E/PIK3CAH1047) cells. In contrast, for the same level of apoptosis in HT29(BRAFV600E/PIK3CAP449T) cells, TRAIL was combined with 17-AAG, an Hsp90 inhibitor. For cells where PLX4720 was completely ineffective, 17-AAG was alternatively used to target mutant BRAF(V600E). TRAIL dependence on the constitutive activation of BRAF(V600E) is emphasised through the overexpression of BRAF(V600E) in the permissive genetic background of colon adenocarcinoma Caco-2 cells. Pharmacological suppression of the PI3K pathway further enhances the synergistic effect between TRAIL and PLX4720 in RKO cells, indicating the presence of PIK3CA(MT) as the inhibitory factor. Another rational combination includes 17-AAG synergism with TRAIL in a BRAF(V600E) mutant dependent manner to commit cells to apoptosis, through DR5 and the amplification of the apoptotic pathway. We have successfully utilised combinations of two chemically unrelated BRAF(V600E) inhibitors in combination with TRAIL in a BRAF(V600E) mutated background and provided insight for new anti-cancer strategies where the activated PI3KCA mutation oncogene should be suppressed.


Extracellular matrix rigidity modulates neuroblastoma cell differentiation and N-myc expression.
Neuroblastoma is a pediatric malignancy characterized by tremendous clinical heterogeneity, in which some tumors are extremely aggressive while others spontaneously differentiate into benign forms. Because the degree of differentiation correlates with prognosis, and because differentiating agents such as retinoic acid (RA) have proven to decrease mortality, much effort has been devoted to identifying critical regulators of neuroblastoma differentiation in the cellular microenvironment, including cues encoded in the extracellular matrix (ECM). While signaling between tumor cells and the ECM is classically regarded to be based purely on biochemical recognition of ECM ligands by specific cellular receptors, a number of recent studies have made it increasingly clear that the biophysical properties of the ECM may also play an important role in this cross-talk. Given that RA-mediated neuroblastoma differentiation is accompanied by profound changes in cell morphology and neurite extension, both of which presumably rely upon mechanotransductive signaling systems, it occurred to us that mechanical cues from the ECM might also influence RA-mediated differentiation, which in turn might regulate clinically-relevant aspects of neuroblastoma biology. In this study, we tested this hypothesis by subjecting a series of neuroblastoma culture models to ECM microenvironments of varying mechanical stiffness and examined the regulatory role of ECM stiffness in proliferation, differentiation, and expression of tumor markers. We find that increasing ECM stiffness enhances neuritogenesis and suppresses cell proliferation. Remarkably, increasing ECM stiffness also reduces expression of N-Myc, a transcription factor involved in multiple aspects of oncogenic proliferation that is used for evaluating prognosis and clinical grading of neuroblastoma. Furthermore, the addition of RA enhances all of these effects for all ECM stiffnesses tested. Together, our data strongly support the notion that the mechanical signals from the cellular microenvironment influence neuroblastoma differentiation and do so synergistically with RA. These observations support further investigation of the role of microenvironmental mechanical signals in neuroblastoma proliferation and differentiation and suggest that pharmacological agents that modulate the underlying mechanotransductive signaling pathways may have a role in neuroblastoma therapy.


PDMAC: A Priority-Based Enhanced TDMA Protocol for Warning Message Dissemination in VANETs.
Vehicular ad hoc networks (VANETs) are the key enabling technology for intelligent transportation systems. Carrier-sense multiple access with collision avoidance (CSMA/CA) is the de facto media access standard for inter-vehicular communications, but its performance degrades in high-density networks. Time-division multiple access (TDMA)-based protocols fill this gap to a certain extent, but encounter inefficient clock synchronization and lack of prioritized message delivery. Therefore, we propose a priority-based direction-aware media access control (PDMAC) as a novel protocol for intra-cluster and inter-cluster clock synchronization. Furthermore, PDMAC pioneers a three-tier priority assignment technique to enhance warning messages delivery by taking into account the direction component, message type, and severity level on each tier. Analytical and simulation results validate the improved performance of PDMAC in terms of clock synchronization, channel utilization, message loss rate, end-to-end delays, and network throughput, as compared with eminent VANET MAC protocols.


Dual protection to address the global syndemic of HIV and unintended pregnancy in Brazil.
Syndemic HIV and unintended pregnancy is prevalent in Brazil, where 79% of female HIV cases occur in women of reproductive age and 55% of all pregnancies are unintended. Although increasing condom use to prevent HIV may decrease non-barrier contraception and increase unintended pregnancy, few studies focus on dual protection or dual methods (condoms with another modern contraceptive). To describe the correlates of dual method use and consistent condom use in women of reproductive age in Brazil. Data are from the 2006 Pesquisa Nacional de Demografia e Saúde da Mulher e da Criança, a decennial nationally representative household survey of women of reproductive age in Brazil. Multivariate logistic regression models identify the socio-demographic, sexual debut, fertility and relationship factors associated with dual method use and consistent condom use. Two-thirds of contracepting women in Brazil used dual protection (40% exclusive condoms, 27% dual methods). Consistent condom use in the past year occurred among 61% of exclusive condom users and 27% of dual method users. Dual methods (vs exclusive condoms) was associated with some high school education [relative risk ratio (RRR)=1.69, p<0.05], living in the Southern region (RRR=1.59, p<0.01), and number of children (RRR=1.22, p<0.01), net of other factors. Consistent condom use was associated with condom use at sexual debut [adjusted odds ratio (AOR)=1.84, p<0.001], wants no (more) children (AOR=1.86, p<0.001), single/separated relationship status (AOR=2.77/2.45, p<0.001) and using exclusive condoms (vs dual methods: AOR=0.19, p<0.001). Findings highlight that targeting and delivering integrated HIV and family planning services should focus on completed/large families. single/separated individuals, and promoting dual protection at sexual debut.


Role of natural killer cells on engraftment of human lymphoid cells and on metastasis of human T-lymphoblastoid leukemia cells in C57BL/6J-scid mice and in C57BL/6J-scid bg mice.
The severe combined immunodeficiency (scid) mutation was backcrossed onto the C57BL/6J strain background in order to study the role of natural killer (NK) cells in rejection of normal and malignant human lymphohematopoietic cells. C57BL/6J-scid/scid mice showed severe loss of mature T and B cells accompanied by increased percentages of NK1.1+ cells and myeloid cells. Although little or no serum immunoglobulin was detectable prior to 2 months of age, all mice tested had circulating immunoglobulin by 7.5 months of age. C57BL/6J-scid/scid mice had markedly elevated levels of both hemolytic complement activity and NK cell activity compared with C57BL/6J - (+/+) controls. Weekly injections with anti-NK1.1 antibody resulted in elimination of NK cell activity in C57BL/6J-scid/scid mice throughout 8 weeks of treatment. Although human CEM-C7 T lymphoblastoid tumor cells grew slowly in unmanipulated C57BL/6J-scid/scid mice, anti-NK1.1 treatment resulted in increased growth accompanied by metastasis of human lymphoma cells to the brain, liver, and kidney. In contrast to T lymphoblastoid tumor cells, nonmalignant human peripheral blood mononuclear cells engrafted at low levels in anti-NK1.1-treated as well as in unmanipulated C57BL/6-scid/scid mice. Backcrossing of the beige (bgJ) mutation onto the C57BL/6-scid/scid genetic stock caused decreased NK cell activity accompanied by granulocyte defects. C57BL/6-scid/scid bgJ)/bgJ) mice showed metastasis of human CEM-C7 cells to the brain and other organs but supported only low levels of engraftment with human peripheral blood mononuclear cells. These results demonstrate that NK cells, in the absence of an adaptive immune system, function in resistance to metastasis of human lymphomas and suggest that innate immune factors in addition to NK cell function mediate resistance to engraftment of normal human peripheral blood leukocytes.


Estimating the resources needed and savings anticipated from roll-out of adult male circumcision in Sub-Saharan Africa.
Trials in Africa indicate that medical adult male circumcision (MAMC) reduces the risk of HIV by 60%. MAMC may avert 2 to 8 million HIV infections over 20 years in sub-Saharan Africa and cost less than treating those who would have been infected. This paper estimates the financial and human resources required to roll out MAMC and the net savings due to reduced infections. We developed a model which included costing, demography and HIV epidemiology. We used it to investigate 14 countries in sub-Saharan Africa where the prevalence of male circumcision was lower than 80% and HIV prevalence among adults was higher than 5%, in addition to Uganda and the Nyanza province in Kenya. We assumed that the roll-out would take 5 years and lead to an MC prevalence among adult males of 85%. We also assumed that surgery would be done as it was in the trials. We calculated public program cost, number of full-time circumcisers and net costs or savings when adjusting for averted HIV treatments. Costs were in USD, discounted to 2007. 95% percentile intervals (95% PI) were estimated by Monte Carlo simulations. In the first 5 years the number of circumcisers needed was 2 282 (95% PI: 2 018 to 2 959), or 0.24 (95% PI: 0.21 to 0.31) per 10,000 adults. In years 6-10, the number of circumcisers needed fell to 513 (95% PI: 452 to 664). The estimated 5-year cost of rolling out MAMC in the public sector was $919 million (95% PI: 726 to 1 245). The cumulative net cost over the first 10 years was $672 million (95% PI: 437 to 1,021) and over 20 years there were net savings of $2.3 billion (95% PI: 1.4 to 3.4). A rapid roll-out of MAMC in sub-Saharan Africa requires substantial funding and a high number of circumcisers for the first five years. These investments are justified by MAMC's substantial health benefits and the savings accrued by averting future HIV infections. Lower ongoing costs and continued care savings suggest long-term sustainability.


Food deprivation and acquisition of intravenous cocaine self-administration in rats: effect of naltrexone and haloperidol.
In order to create optimal conditions for the acquisition of i.v. cocaine self-administration in the rat, three groups of rats were deprived of food to different extents in order to obtain body weight reductions of 5 to 15, 15 to 25 and 25 to 35% of the pre-experimental body weights, and were tested for five consecutive 6-hr sessions in a continuous reinforcement procedure for self-administration of cocaine (0.12 mg/ml) or saline. Self-administration interacted with weight loss and indicated that: 1) a minimum level of 15 to 25% weight loss was required to obtain cocaine self-administration; 2) weight loss-induced potentiation of cocaine self-administration resulted from an interaction of increased nonspecific lever pressing activity and increased reinforcing effects of the compound; and 3) optimal differentiation between cocaine- and saline-induced responding was obtained at 15 to 25% weight loss. Daily pretreatment during the five test sessions, with 0.1 to 1.0 mg/kg of naltrexone or 43 to 375 micrograms/kg of haloperidol, dose-dependently decreased the number of cocaine (0.12 mg/ml) self-injections. Naltrexone pretreatment, and to a lesser extent haloperidol pretreatment, appeared to affect cocaine self-administration in a specific manner; both treatments affected responding on the reinforced lever, but not responding on the nonreinforced lever. Self-administration of 0.06 mg/ml of cocaine tended to be decreased by naltrexone (1 mg/kg) and haloperidol (375 micrograms/kg); whereas self-administration induced by 0.25 mg/ml of cocaine was not significantly affected by naltrexone or haloperidol. Both treatments failed to affect self-administration of saline.(ABSTRACT TRUNCATED AT 250 WORDS)


Sexual behaviour among adolescents living with the human immunodeficiency virus in Zimbabwe: educational implications.
The incidence of HIV infection is increasing among adolescents in Zimbabwe. This rise in incidence is partly due to risky sexual behaviours yet there are no published research studies on sexual behaviours of HIV-positive adolescents in Zimbabwe. Hence, this study, which examined the sexual behaviours of HIV-positive adolescents. This study utilised a cross-sectional design with a conveniently selected sample of 341 HIV-positive adolescents. Data were collected through a questionnaire. Data were analysed using descriptive and analytical statistics. The study revealed that approximately 37 (11%) of the adolescents had engaged in sexual intercourse, and approximately 14 (60%) of these did not use condoms. Approximately 11 (30%) of the sexually active adolescents had multiple sexual partners, and only 9 (24.3%) of them had disclosed their HIV serostatus to their partners before sexual intercourse. A bivariate analysis revealed factors that were associated with being sexually activity. Examples of these include age (OR = 1.56, p < 0.001) and being treated by a psychiatrist (OR = 47.9, p < 0.001). A multivariate logistic regression analysis was carried out, revealing factors that were independently associated with being sexually active. Examples of these include age (AOR = 1.91, p < 0.01) and exposure to erotic television programmes (AOR = 3.9, p < 0.04). The results of the study indicate that the sexual risk behaviours of HIV-positive adolescents contributes to the increase in incidence and prevalence of HIV/AIDS in Zimbabwe. The development and rolling out of a health education programme will help health care workers to address this concern.


Antioxidants counteract nicotine and promote migration via RacGTP in oral fibroblast cells.
Smoking is associated with an increased risk of oral health and dental problems. The aim of this study is to address the hypothesis that nicotine impairs wound healing by increasing reactive oxygen species and inhibiting cell migration, and antioxidants (AOs) may counteract nicotine effects. Primary human gingival fibroblasts (HGFs) and human periodontal ligament (HPDL) fibroblasts were grown to confluence, pretreated with 6 mM nicotine for 2 hours, and treated with AOs in the presence of nicotine. The pure AO compounds ferulic acid (F), phloretin (P), tetrahydrocurcuminoid Cockroft Gault (T), and resveratrol (R) were tested in single, double, or triple combinations (10(-5) M). The migratory behavior at a scratch-wound edge was recorded every 15 minutes for 10 hours by using live-cell imaging. The active form of the Rho-associated protein (Rac) and guanosine triphosphate (GTP) (RacGTP) was immunolabeled and analyzed using confocal microscopy. Combinations of double and triple AOs had a greater effect than single AOs on migration rates and Rac activation. The triple combinations PFR and RFT clearly and unambiguously counteracted the effects of nicotine and significantly increased migration rates in HGF and HPDL fibroblast. Treatment with AO combinations clearly counteracted the effects of nicotine by restoring and increasing cell-migration rates. We found the combination of PFR was the most effective in HGFs, whereas, RFT was the most effective combination in HPDL fibroblast. These results clearly demonstrate that PF, RFT, and PFR counteract the negative effects of nicotine on cultured oral fibroblasts via the RacGTP signal-transduction pathway.


Delta and conjugated bilirubin as complementary markers of early rejection in liver-transplant recipients.
For 51 liver allograft recipients, we evaluated whether serum profiles of delta (Bd) and conjugated bilirubins (Bc) could be used to diagnose rejection during the first 30-50 postoperative days, in comparison with histology as the "gold standard." Daily measurements of aspartate aminotransferase, alkaline phosphatase, total bilirubin, Bd, and Bc were made, the last two by liquid chromatography. In 34 patients without any biochemical or histological evidence of rejection, within seven to 10 postoperative days Bd increased to greater than 40-50% of total bilirubin, while Bc decreased to less than 10%. In patients with severe rejections resulting in death, Bc increased rapidly to greater than 50%, while Bd remained less than 30%. In 24 histologically proven episodes of rejection in 17 patients there was either a rapid decrease in Bd or its persistence at 30%, plus either a steep increase in Bc, or its remaining at greater than 50% total bilirubin. Treatment of rejection resulted in a prompt reversal of these trends. Individually promising as prognostic adjuncts to existing liver-function markers, Bd and Bc also complemented each other, rendering the diagnosis of liver rejection much more incisive.


Spatiotemporal spread of sarcoptic mange in the red fox (Vulpes vulpes) in Switzerland over more than 60 years: lessons learnt from comparative analysis of multiple surveillance tools.
Sarcoptic mange is a contagious skin disease of wild and domestic mammals caused by the mite Sarcoptes scabiei. Reports of sarcoptic mange in wildlife increased worldwide in the second half of the 20th century, especially since the 1990s. The aim of this study was to provide new insights into the epidemiology of mange by (i) documenting the emergence of sarcoptic mange in the red fox (Vulpes vulpes) in the last decades in Switzerland; and (ii) describing its spatiotemporal spread combining data obtained through different surveillance methods. Retrospective analysis of archived material together with prospective data collection delivered a large dataset from the 19th century to 2018. Methods included: (i) a review of historical literature; (ii) screening of necropsy reports from general health surveillance (1958-2018); (iii) screening of data on mange (1968-1992) collected during the sylvatic rabies eradication campaign; (iv) a questionnaire survey (<1980-2017) and (v) evaluation of camera-trap bycatch data (2005-2018). Sarcoptic mange in red foxes was reported as early as 1835 in Switzerland. The first case diagnosed in the framework of the general health surveillance was in 1959. Prior to 1980, sarcoptic mange occurred in non-adjacent surveillance districts scattered all over the country. During the period of the rabies epidemic (1970s-early 1990s), the percentage of foxes tested for rabies with sarcoptic mange significantly decreased in subregions with rabies, whereas it remained high in the few rabies-free subregions. Sarcoptic mange re-emerged in the mid-1990s and continuously spread during the 2000-2010s, to finally extend to the whole country in 2017. The yearly prevalence of mange in foxes estimated by camera-trapping ranged from 0.1-12%. Sarcoptic mange has likely been endemic in Switzerland as well as in other European countries at least since the mid-19th century. The rabies epidemics seem to have influenced the pattern of spread of mange in several locations, revealing an interesting example of disease interaction in free-ranging wildlife populations. The combination of multiple surveillance tools to study the long-term dynamics of sarcoptic mange in red foxes in Switzerland proved to be a successful strategy, which underlined the usefulness of questionnaire surveys.


On-slide tissue digestion for mass spectrometry based glycomic and proteomic profiling.
We describe a protocol for glycomic and proteomic profiling that uses serial enzyme digestions from the surface of fresh frozen or fixed tissue slides. The abundances of the extracted glycans and peptides are determined using liquid chromatography-mass spectrometry. In a typical experiment, our method quantifies 14 heparan sulfate disaccharides, 11 chondroitin sulfate disaccharides, 50 N-glycan compositions and approximately 1200 proteins from a 1.8 mm circle, on the surface of a fresh frozen tissue slide from rat brain. Each enzymatic digestion is incubated overnight with direct application of enzyme on the tissue surface. Overall, the sample preparation process for multiple tissue slides takes a day per biomolecule class. This protocol saves time by simultaneous digestion of large N-glycans and small HS disaccharides and subsequent separation using size exclusion chromatography. Compared to wet tissue analysis, this method requires less time by a factor of two. By comparison, MALDI-imaging provides higher spatial resolution of glycans and proteins but lower depth of coverage. MALDI dissociates fragile glycan substituents including sulfates and is not recommended for analysis of glycosaminoglycans (GAGs).


Learning from noisy information in FasArt and FasBack neuro-fuzzy systems.
Neuro-fuzzy systems have been in the focus of recent research as a solution to jointly exploit the main features of fuzzy logic systems and neural networks. Within the application literature, neuro-fuzzy systems can be found as methods for function identification. This approach is supported by theorems that guarantee the possibility of representing arbitrary functions by fuzzy systems. However, due to the fact that real data are often noisy, generation of accurate identifiers is presented as an important problem. Within the Adaptive Resonance Theory (ART), PROBART architecture has been proposed as a solution to this problem. After a detailed comparison of these architectures based on their design principles, the FasArt and FasBack models are proposed. They are neuro-fuzzy identifiers that offer a dual interpretation, as fuzzy logic systems or neural networks. FasArt and FasBack can be trained on noisy data without need of change in their structure or data preprocessing. In the simulation work, a comparative study is carried out on the performances of Fuzzy ARTMAP, PROBART, FasArt and FasBack, focusing on prediction error and network complexity. Results show that FasArt and FasBack clearly enhance the performance of other models in this important problem.


Associations of maternal and fetal 25-hydroxyvitamin D levels with childhood lung function and asthma: the Generation R Study.
Exposure to low levels of vitamin D in fetal life might be a risk factor for childhood asthma. We examined whether 25-hydroxyvitamin D levels in mid-gestation and at birth were associated with higher airway resistance and inflammation, and increased risks of wheezing and asthma in school-age children. We performed a population-based prospective cohort study among 3130 mothers and their children. Maternal blood samples in mid-gestation and umbilical cord blood samples at birth were used to determine 25-hydroxyvitamin D levels. At age of 6, airway resistance (Rint) was measured by interrupter technique and airway inflammation by fractional exhaled nitric oxide (FENO) using NIOX chemiluminescence analyser. Wheezing and asthma were prospectively assessed by annual questionnaires until age 6. Maternal levels of 25-hydroxyvitamin D in mid-gestation were not associated with Rint, FeNO, wheezing patterns, or asthma. Children in the lowest tertile of 25-hydroxyvitamin D levels at birth had a higher Rint (Z-score (95% confidence interval [95% CI]): -0.42 (-0.84, -0.01), P-value for trend< 0.05), compared to those in the highest tertile group. The effect estimate attenuated when child's current 25-hydroxyvitamin D level was taken into account [Z-score (95% CI): -0.55 (-1.08, 0.01)]. Low levels of 25-hydroxyvitamin D at birth were associated with a higher airway resistance in childhood. Additional adjustment for child's current 25-hydroxyvitamin D level reduced the effect size of the association. Further studies are needed to replicate these findings and to examine mechanisms underlying the observed association and the long-term consequences.


The Intersection of Gender Identity and Violence: Victimization Experienced by Transgender College Students.
College students disproportionately experience victimization, stalking, and relationship violence when compared with other groups. Few studies explore victimization by the gender identity of college students, including those who identify as transgender. The purpose of this study is to explore the rates of violence experienced by transgender students compared with male and female college students. This study utilized the National College Health Assessment-II (NCHA-II) and included data from students (n = 82,538) across fall 2011, 2012, and 2013. Bivariate statistics and binary logistic regression were conducted to test the relationships between gender identity and victimization. Transgender students (n = 204) were compared with male (n = 27,322) and female (n = 55,012) students. After adjusting for individual factors, transgender students had higher odds of experiencing all nine types of violence when compared with males and higher odds of experiencing eight types of violence than females. Transgender students experienced the highest odds in crimes involving sexual victimization, including attempted sexual penetration (adjusted odds ratio [aOR]: 9.49, 95% confidence interval [CI] = [6.17, 14.59], d = 1.00), sexual penetration without consent (aOR: 9.06, 95% CI = [5.64, 14.53], d = 0.94), and being in a sexually abusive relationship (aOR: 6.48, 95% CI = [4.01, 10.49], d = 0.48), than did male students. Findings reveal increased odds of victimization among transgender students when compared with male and female students. Results demonstrate the need for more comprehensive violence prevention efforts in college settings.


[From the municipal dog pound to the pet shelter in Barcelona, Spain].
This article aims to present changes in public health policy and services related to pet dogs and cats in the city of Barcelona from 1983 to 2001. Initially the center's activity was limited to the custody and euthanasia of stray animals, serving not only the city but also the rest of the province. With the formulation of a city Plan for Pet Animals, the activities were redirected, concentrating on services within the city limits and stimulating adoption. Participation of both professional and humane organizations was sought, premises were renovated, responsible ownership of animals was promoted, controlled urban colonies of cats were established, and adoptions become the cornerstone of policy, centering the activity of the shelter toward its clients. Changes in the shelter's activity since 1998 reflects a clear decrease in the number of animals retained, as well as in the proportion subjected to euthanasia. This decrease may reflect an improvement in the problem of stray animals. These developments have also resulted in a positive change in the relationship with the media and animal welfare organizations.


Emergency Surgery in a Critically Ill Patient with Major Drug-Induced Bleeding and Severe Ischaemic Heart Failure.
Anticoagulant overdose frequently occurs in elderly populations especially in remote areas where medical services are scarce. When emergency surgery is required, such patients offer major anaesthetic challenges. We describe the case of an elderly patient admitted to a surgical ward with acute abdominal pain, on dual anti-platelet therapy and acenocoumarol for a recent acute myocardial infarction treated percutaneously with two drug-eluting stents. Laboratory tests showed severe anticoagulant overdose with uncoagulable INR. The decision was made to use of both light transmission aggregometry [LTA] for platelet function testing and thromboelastography to aid in the management of perioperative haemostasis in order to prevent both severe bleeding and stent thrombosis. Surgery revealed haemoperitoneum, volvulus of the ileum and a venous mesenteric infarction. Intraoperative blood loss was minimal and no blood products were administered. Postoperative course was uneventful without either thrombotic or haemorrhagic complications and the patient was discharged from the Postanaesthesia Care Unit on postoperative day two. The use of aggregometry and thrombography helped in both evaluation and management of haemostasis of a high-risk patient by goal-directed administration of pro-and anti-coagulants.


Manage at work: a randomized, controlled trial of a self-management group intervention to overcome workplace challenges associated with chronic physical health conditions.
The percentage of older and chronically ill workers is increasing rapidly in the US and in many other countries, but few interventions are available to help employees overcome the workplace challenges of chronic pain and other physical health conditions. While most workers are eligible for job accommodation and disability compensation benefits, other workplace strategies might improve individual-level coping and problem solving to prevent work disability. In this study, we hypothesize that an employer-sponsored group intervention program employing self-management principles may improve worker engagement and reduce functional limitation associated with chronic disorders. In a randomized controlled trial (RCT), workers participating in an employer-sponsored self-management group intervention will be compared with a no-treatment (wait list) control condition. Volunteer employees (n = 300) will be recruited from five participating employers and randomly assigned to intervention or control. Participants in the intervention arm will attend facilitated group workshop sessions at work (10 hours total) to explore methods for improving comfort, adjusting work habits, communicating needs effectively, applying systematic problem solving, and dealing with negative thoughts and emotions about work. Work engagement and work limitation are the principal outcomes. Secondary outcomes include fatigue, job satisfaction, self-efficacy, turnover intention, sickness absence, and health care utilization. Measurements will be taken at baseline, 6-, and 12-month follow-up. A process evaluation will be performed alongside the randomized trial. This study will be most relevant for organizations and occupational settings where some degree of job flexibility, leeway, and decision-making autonomy can be afforded to affected workers. The study design will provide initial assessment of a novel workplace approach and to understand factors affecting its feasibility and effectiveness. Clinicaltrials.gov: NCT01978392 (Issued November 6, 2013).


Adsorption of anionic dyes in aqueous solution using chemically modified barley straw.
An agricultural waste derived adsorbent was prepared by chemically modified barley straw with NaOH and a cationic surfactant hexadecylpyridinium chloride monohydrate (CPC). The prepared adsorbent, BMBS, was used for removal of anionic dyes; Acid Blue (AB40) and Reactive Blue 4 (RB4) from aqueous solution in a batch adsorption system. The adsorbent was characterized by FT-IR and elemental composition. The stability of CPC adsorbed on straw surface was also evaluated by exposing to aqueous solution. In adsorption tests, influence of operation parameters such as contact time, initial concentration and pH of solution on AB40 and RB4 uptake were investigated and discussed. The CPC was observed strongly attached to straw surface and removal percentage of AB40 and RB4 was increased with increasing in contact time. The adsorption of dyes on modified straw surface was favorable at high acidic condition and desorption was found relatively low upon exposing to the desorption agent (i.e water). Dynamic experiment revealed that the kinetic data fitted well to the pseudo-second-order model for both of the dyes. The isotherm study also indicated that RB4 and AB40 adsorption suited well with the Langmuir model, The maximum adsorption capacity determined from the Langmuir isotherm at 25 degrees C was 51.95 mg g(-1) and 31.5 for AB40 and RB4, respectively.


Silicon ring isolators with bonded nonreciprocal magneto-optic garnets.
A ring isolator is demonstrated for the first time by directly bonding a cerium-substituted yttrium iron garnet (Ce:YIG) onto a silicon ring resonator using oxygen plasma enhanced bonding. The silicon waveguide is 600 nm wide and 295 nm thick with 500-nm-thick Ce:YIG on the top to have reasonable nonreciprocal effect and low optical loss. With a radial magnetic field applied to the ring isolator, it exhibits 9-dB isolation at resonance in the 1550 nm wavelength regime.


Patients prone to recurrence after endovascular treatment: periprocedural results of the PRET randomized trial on large and recurrent aneurysms.
Some patients with large or recurrent aneurysms may be at increased risk of recurrence postcoiling. The Patients Prone to Recurrence after Endovascular Treatment (PRET) trial was designed to assess whether hydrogel coils were superior to platinum coils in these high-risk patients. This article reports periprocedural safety and operator-assessed angiographic results from the PRET trial. PRET was a pragmatic, multicenter, randomized controlled trial. Patients had ≥10-mm aneurysms (PRET-1) or a major recurrence after coiling of an aneurysm of any size (PRET-2). Patients were randomly allocated to hydrogel or control arms (any platinum coil) by using concealed allocation with minimization. Assist devices could be used as clinically required. Aneurysms could be unruptured or recently ruptured. Analyses were on an intent-to-treat basis. Four hundred forty-seven patients were recruited (250 PRET-1; 197 PRET-2). Aneurysms were recently ruptured in 29% of PRET-1 and 4% of PRET-2 patients. Aneurysms were ≥10 mm in all PRET-1 and in 50% of PRET-2 patients. They were wide-neck (≥4 mm) in 70% and in the posterior circulation in 24% of patients. Stents were used in 28% of patients (35% in PRET-2). Coiling was successful in 98%. Adverse events occurred in 28 patients with hydrogel and 23 with platinum coils. Mortality (n=2, unrelated to treatment) and morbidity (defined as mRS>2 at 1 month) occurred in 25 patients (5.6%; 12 hydrogel, 13 platinum), related to treatment in 10 (4 hydrogel; 6 platinum) (or 2.3% of 444 treated patients). No difference was seen between hydrogel and platinum for any of the indices used to assess safety up to at least 30 days after treatment. At 1 month, 95% of patients were home with a good outcome (mRS≤2 or unchanged). Operator-assessed angiographic outcomes were satisfactory (complete occlusion or residual neck) in 339 of 447 or 76.4% of patients, with no significant difference between groups. Endovascular treatment of large and recurrent aneurysms can be performed safely with platinum or hydrogel coils.


Antibiotic-resistant Staphylococcus aureus in dermatology and burn wards.
Staphylococcus aureus isolated between 1967 and 1975 from the nose and skin lesions of patients in dermatology wards and from the burns of patients in a burns unit in Birmingham showed a high incidence of multiple antibiotic-resistant strains in both environments. Over 20% of the strains isolated from patients on admission to the dermatology wards were multiresistant. Resistance to benzylpenicillin, tetracycline, erythromycin, and fusidic acid was common in the dermatology wards; a smaller proportion of strains were resistant to lincomycin, and few (since 1972 none) were resistant to methicillin; resistance to novobiocin and chloramphenicol was uncommon. In the burns unit, fusidic acid resistance was uncommon, but resistance to benzylpenicillin, tetracycline, erythromycin, novobiocin, neomycin, methicilin, and lincomycin was common. Several of the antibiotics to which resistance was common in the burns unit were rarely if ever used there; strains resistant to these antibiotics probably remained common in the ward through the frequent use of other antibiotics, especially erythromycin, to which these strains were also resistant.


Could Parkinson's disease follow intra-uterine influenza?: a speculative hypothesis.
Patients with idiopathic Parkinson's disease do not appear to be distributed smoothly with respect to year of birth. Individuals born within the years 1892, 1904, 1909, 1918, 1919 and 1929 appear to have had an increased risk of developing idiopathic Parkinson's disease in later life. These years are close to those of the influenza pandemics of the period 1890-1930. The estimated risk of an individual developing idiopathic Parkinson's disease shows a significant correlation with the crude influenza mortality for the year of his birth, within the range 1900 to 1930. It is suggested that intra-uterine influenza may be cytotoxic to the developing foetal substantia nigra, and that an affected individual may be born without evident disability but with limited striatal neurochemical reserves and a reduced nigral cell count. In later life normal cellular involution with ageing or exposure to environmental neurotoxic factors may further erode these reserves to a level where the substantia nigra fails and idiopathic Parkinson's disease becomes clinically apparent.


Increased ATP-binding cassette transporter A1 expression in Alzheimer's disease hippocampal neurons.
ATP-binding cassette transporter A1 (ABCA1) reduces amyloid-beta burden in transgenic mouse models of Alzheimer's disease (AD). Associations between ABCA1 polymorphisms and AD risk are also established. Little is known regarding the regulation of ABCA1 expression in the brain and how this may be affected by AD. In the present study we assessed ABCA1 mRNA and protein expression in the hippocampus of AD cases compared to controls. ABCA1 was clearly expressed in hippocampal neurons and expression was increased two- to three-fold in AD cases. The increased hippocampal ABCA1 expression was associated with increased APOE and PUMA gene expression, implying an association with neuronal stress. Consistent with this, treatment of SK-N-SH neurons with amyloid-beta peptide resulted in a 48% loss in survival and a significant upregulation of ABCA1, APOE, and PUMA gene expression. Studies in young (2 month) and old (12 month) transgenic mice expressing a familial AD form of human amyloid-beta protein precursor and presenilin-1 revealed a significant age-dependent upregulation of hippocampal Abca1 compared to wild-type control mice. However, hippocampal Apoe and Puma gene expression were not correlated with increased Abca1 expression in mice. Our data indicate that ABCA1 is upregulated in AD hippocampal neurons potentially via an amyloid-beta-mediated pathway.


Determining Fingerprint Age with Mass Spectrometry Imaging via Ozonolysis of Triacylglycerols.
Despite the common use of fingerprints as a trusted means of identification, no method currently exists to reliably establish the time since deposition of latent fingerprints. A reproducible method of establishing latent fingerprint age would allow forensic personnel to determine if a latent fingerprint was relevant to a crime. This work investigates the ambient aging of triacylglycerols (TGs) and other lipids in latent fingerprint residue utilizing matrix-assisted laser desorption/ionization mass spectrometry imaging. Unsaturated TGs were found to undergo ambient ozonolysis resulting in a decrease over time. At the same time, two series of compounds related to the degradation of unsaturated TGs due to ambient ozonolysis emerged with time and were detectable within a single day of aging. Tracking the degradation of unsaturated TGs over time proved to be relatively reproducible in multiple individuals and is suggested as a means of establishing latent fingerprint age.


Cluster headache--acute and prophylactic therapy.
Cluster headache (CH) pain is the most severe of the primary headache syndromes. It is characterized by periodic attacks of strictly unilateral pain associated with ipsilateral cranial autonomic symptoms. The majority of patients have episodic CH, with cluster periods that typically occur in a circannual rhythm, while 10% suffer from the chronic form, with no significant remissions between cluster periods. Sumatriptan injection or oxygen inhalation is the first-line therapy for acute CH attacks, with the majority of patients responding to either treatment. The calcium channel blocker verapamil is the drug of choice for CH prevention. Other drugs that may be used for this purpose include lithium carbonate, topiramate, valproic acid, gabapentin, and baclofen. Transitional prophylaxis, most commonly using corticosteroids, helps to control the attacks at the beginning of a cluster period. Peripheral neural blockade is effective for short-term pain control. Recently, the therapeutic options for refractory CH patients have expanded with the emergence of both peripheral (mostly occipital nerve) and central (hypothalamic) neurostimulation. With the emergence of these novel treatments, the role of ablative surgery in CH has declined.


Proteoglycans and glycosaminoglycans induce gap junction synthesis and function in primary liver cultures.
Intercellular communication via gap junctions, as measured by dye and electrical coupling, disappears within 12 h in primary rat hepatocytes cultured in serum-supplemented media or within 24 h in cells in a serum-free, hormonally defined medium (HDM) designed for hepatocytes. Glucagon and linoleic acid/BSA were the primary factors in the HDM responsible for the extended life span of the electrical coupling. After 24 h of culture, no hormone or growth factor tested could restore the expression of gap junctions. After 4-5 d of culture, the incidence of coupling was undetectable in a serum-supplemented medium and was only 4-5% in HDM alone. However, treatment with glycosaminoglycans or proteoglycans of 24-h cultures, having no detectable gap junction protein, resulted in synthesis of gap junction protein and of reexpression of electrical and dye coupling within 48 h. Most glycosaminoglycans were inactive (heparan sulfates, chondroitin-6 sulfates) or only weakly active (dermatan sulfates, chondroitin 4-sulfates, hyaluronates), the weakly active group increasing the incidence of coupling to 10-30% with the addition of 50-100 micrograms/ml of the factor. Treatment of the cells with 50-100 micrograms/ml of heparins derived from lung or intestine resulted in cells with intermediate levels of coupling (30-50%). By contrast, 10-20 micrograms/ml of chondroitin sulfate proteoglycan, dermatan sulfate proteoglycan, or liver-derived heparin resulted in dye coupling in 80-100% of the cells, with numerous cells showing dye spread from a single injected cell. Sulfated polysaccharides of glucose (dextran sulfates) or of galactose (carrageenans) were inactive or only weakly active except for lambda-carrageenan, which induced up to 70% coupling (albeit no multiple coupling in the cultures). The abundance of mRNA (Northern blots) encoding gap junction protein and the amounts of the 27-kD gap junction polypeptide (Western blots) correlated with the degree of electrical and dye coupling indicating that the active glycosaminoglycans and proteoglycans are inducing synthesis and expression of gap junctions. Thus, proteoglycans and glycosaminoglycans, especially those found in abundance in the extracellular matrix of liver cells, are important in the regulation of expression of gap junctions and, thereby, in the regulation of intercellular communication in the liver. The relative potencies of heparins from different tissue sources at inducing gap junction expression are suggestive of functional tissue specificity for these glycosaminoglycans.


Double-blind comparison of tolamolol, propranolol, practolol, and placebo in the treatment of angina pectoris.
Forty-two patients with angina pectoris have completed a randomized, double-blind trial comparing tolamolol 100 mg and 200 mg with propranolol 80 mg, practolol 100 mg, and placebo, all given three times a day. Tolamolol 200 mg thrice daily was found to be equivalent to propranolol 80 mg thrice daily in anti-anginal efficacy. Anginal attack rates and trinitrin consumption were significantly reduced by all active treatments as compared with the placebo but tolamolol and propranolol were the most effective. Tolamolol 200 mg thrice daily was most effective in reducing blood pressure, while propranolol was most effective in reducing the resting heart rate. All treatments except the placebo significantly increased the amount of exercise which could be performed before angina appeared (exercise work), while tolamolol 200 mg thrice daily significantly reduced Robinson's index when compared with all other active agents. The degree of S-T segment depression induced by exercise was significantly lessened by both tolamolol and propranolol but not by practolol or placebo. There was no difference in patient preference between tolamolol and propranolol but tolamolol at both dose levels was preferred to practolol. Both tolamolol and propranolol are potent adrenergic beta-receptor antagonists and equal in anti-anginal efficacy but tolamolol has the advantage of being cardioselective. It is superior to practolol.


Acute encephalopathy with bilateral thalamotegmental involvement in infants and children: imaging and pathology findings.
To investigate the imaging and pathologic characteristics of acute encephalopathy with bilateral thalamotegmental involvement in infants and children. Five Japanese children ranging in age from 11 to 29 months were studied. We performed CT imaging in all patients, 10 MR examinations in four patients, and an autopsy in one patient. The encephalopathy affected the thalami, brain stem tegmenta, and cerebral and cerebellar white matter. The brain of the autopsied case showed fresh necrosis and brain edema without inflammatory cell infiltration. Petechiae and congestion were demonstrated mainly in the thalamus. CT and MR images showed symmetric focal lesions in the same areas in the early phase. These lesions became more demarcated and smaller in the intermediate phase. The ventricles and cortical sulci enlarged. MR images demonstrated T1 shortening in the thalami. The prognosis was generally poor; one patient died, three patients were left with severe sequelae, and only one patient improved. The encephalopathy might be a postviral or postinfectious brain disorder. T1 shortening in the thalami indicated the presence of petechiae.


Direct self-focusing synthesis of monodisperse [Au8(PPh3)7]2+ nanoclusters.
Direct and scalable synthesis of monodisperse gold nanoclusters is highly desired but remains a great challenge due to the complexity of chemical reactions. In this regard, a suitable precursor is important as it can simplify the synthesis processes and offer controllability in tuning the product. In this study, we found that Au(PPh3)2Cl could be used as an effective precursor for the direct synthesis of atomically monodisperse [Au8(PPh3)7]2+ nanoclusters without the need of tedious post-synthetic purification steps. The Au(PPh3)2Cl precursor could be directly reduced by NaBH4 (0.25 molar equivalent) in a dichloromethane solution; this produced Au8 clusters with a 35% reaction yield. Time-dependent mass spectrometry and in situ UV-vis absorption spectroscopy reveal that the synthesis process is initiated by the rapid formation of the Au6-Au8 mixture, followed by a slow spontaneous self-focusing process that converges the mixture into atomically monodisperse Au8. The success of this direct synthesis has been hypothesized to arise from the relatively stronger Au(i)Au(i) aurophilic attraction between Au(i)-PPh3 complexes that facilitates the aggregation of Au(i)-PPh3 on Au(0) cores.


Dating of Pregnancy in First versus Second Trimester in Relation to Post-Term Birth Rate: A Cohort Study.
To evaluate in a national standardised setting whether the performance of ultrasound dating during the first rather than the second trimester of pregnancy had consequences regarding the definition of pre- and post-term birth rates. A cohort study of 8,551 singleton pregnancies with spontaneous delivery was performed from 2006 to 2012 at Copenhagen University Hospital, Holbæk, Denmark. We determined the duration of pregnancy calculated by last menstrual period, crown rump length (CRL), biparietal diameter (1st trimester), BPD (2nd trimester), and head circumference and compared mean and median durations, the mean differences, the systematic discrepancies, and the percentages of pre-term and post-term pregnancies in relation to each method. The primary outcomes were post-term and pre-term birth rates defined by different dating methods. The change from use of second to first trimester measurements for dating was associated with a significant increase in the rate of post-term deliveries from 2.1-2.9% and a significant decrease in the rate of pre-term deliveries from 5.4-4.6% caused by systematic discrepancies. Thereby 25.1% would pass 41 weeks when GA is defined by CRL and 17.3% when BPD (2nd trimester) is used. Calibration for these discrepancies resulted in a lower post-term birth rate, from 3.1-1.4%, when first compared to second trimester dating was used. Systematic discrepancies were identified when biometric formulas were used to determine duration of pregnancy. This should be corrected in clinical practice to avoid an overestimation of post-term birth and unnecessary inductions when first trimester formulas are used.


Pericardial fat is associated with prevalent atrial fibrillation: the Framingham Heart Study.
Obesity represents an important risk factor for atrial fibrillation (AF). We tested the hypothesis that pericardial fat, a unique fat deposit in close anatomic proximity to cardiac structures and autonomic fibers, is associated with prevalent AF. Participants from the Framingham Heart Study underwent multidetector computed tomography from 2002 to 2005. We estimated the association between quantitative pericardial, intrathoracic and visceral adipose tissue volumes (per standard deviation of volume) with prevalent AF adjusting for established AF risk factors (age, sex, systolic blood pressure, blood pressure treatment, PR interval, and clinically significant valvular disease). Of the 3217 eligible participants (mean age, 50.6+/-10.1 years; 48% women), 54 had a confirmed diagnosis of AF. Pericardial fat but not intrathoracic or visceral abdominal fat was associated with prevalent AF in multivariable-adjusted models (odds ratio per standard deviation of pericardial fat volume, 1.28; 95% confidence intervals, 1.03 to 1.58). Further adjustments for body mass index, heart failure, myocardial infarction, and intrathoracic fat volume did not materially change the association between pericardial fat and AF. Pericardial fat was associated with prevalent AF even after adjustment for AF risk factors, including body mass index. If this association is replicated, further investigations into the mechanisms linking pericardial fat to AF are merited.


Amino acid selective cross-saturation method for identification of proximal residue pairs in a protein-protein complex.
We describe an NMR-based approach, the amino acid selective cross-saturation (ASCS) method, to identify the pairs of the interface residues of protein-protein complexes. ASCS uses a "cross-saturation (CS)-donor" protein, in which only one amino acid is selectively (1)H-labeled in a (2)H-background, and a "CS-acceptor" protein with uniform (2)H, (15)N labeling. Irradiation of the (1)H-labeled amino acid, which exists only in the donor, decreases the intensity of the (1)H- (15)N HSQC signals of the acceptor residues proximal to the (1)H-labeled CS-source residue(s) through the CS phenomenon. Given the three-dimensional structure of each protein in the complex, but not the complex structure, the combinatorial analysis of multiple ASCS results specify the CS-source residue(s), based on the spatial complementarity between the CS-source residues on the CS donor and the cross-saturated amide protons on the acceptor. NMR investigations of the labeling selectivity and efficiency in an E. coli host, which are critical for ASCS, revealed that Ala, Arg, His, Ile, Leu, Lys, Met, Phe, Pro, Trp, and Tyr are selectively labeled with a high (1)H/(2)H ratio. The observation of the ASCS was then confirmed using the known structure of the yeast ubiquitin (Ub) and yeast ubiquitin hydrolase 1 (YUH1). Conversely, reasonable candidates for the CS-source residues were suggested by the analysis of the ASCS results, with reference to the individual structures of YUH1 and Ub. The pairwise distance information between the CS-source residues and the cross-saturated amide groups obtained by ASCS will be useful for modeling protein-protein complexes.


MRI of cellular layers in mouse brain in vivo.
Noninvasive imaging of the brain of animal models demands the detection of increasingly smaller structures by in vivo MRI. The purpose of this work was to elucidate the spatial resolution and structural contrast that can be obtained for studying the brain of C57BL/6J mice by optimized T2-weighted fast spin-echo MRI at 9.4 T. As a prerequisite for high-resolution imaging in vivo, motion artifacts were abolished by combining volatile anesthetics and positive pressure ventilation with a specially designed animal bed for fixation. Multiple substructures in the cortex, olfactory bulb, hippocampus, and cerebellum were resolved at 30 to 40 microm in-plane resolution and 200 to 300 microm section thickness as well as for relatively long echo times of 65 to 82 ms. In particular, the approach resulted in the differentiation of up to five cortical layers. In the olfactory bulb the images unraveled the mitral cell layer which has a thickness of mostly single cells. In the hippocampus at least five substructures could be separated. The molecular layer, Purkinje layer, and granular layer of the cerebellum could be clearly differentiated from the white matter. In conclusion, even without the use of a contrast agent, suitable adjustments of a widely available T2-weighted MRI sequence at high field allow for structural MRI of living mice at near single-cell layer resolution.


Immunization of mice with single PspA fragments induces antibodies capable of mediating complement deposition on different pneumococcal strains and cross-protection.
PspA is an important candidate for a vaccine with serotype-independent immunity against pneumococcal infections. Based on sequence relatedness, PspA has been classified into three families comprising six clades. We have previously addressed the cross-reactivity of antibodies against PspA fragments containing the N-terminal and proline-rich regions of PspA from clades 1 to 5 (PspA1, PspA2, PspA3, PspA4, and PspA5) by Western blot analysis and reported that anti-PspA4 and anti-PspA5 were able to recognize pneumococci expressing PspA proteins from all of the clades analyzed. We have now analyzed the functional capacity of these antibodies to bind and to mediate complement deposition on intact bacteria in vitro. Our results show that both PspA4 and PspA5 elicit antibodies that are able to bind and to mediate complement deposition efficiently on pneumococcal strains bearing PspA proteins from clades 1 to 5. Moreover, mice immunized with PspA4 and PspA5 were protected against an intranasal lethal challenge with strains expressing PspA proteins from the two major families. PspA4 and PspA5 are thus able to induce antibodies with a high degree of cross-reactivity in vitro, which is reflected in cross-protection of mice. We have also analyzed the contribution of the nonproline (NonPro) block within the conserved proline-rich region to the reactivity of anti-PspA antibodies, and the results indicate that N-terminal alpha-helical region, the blocks of proline repeats, and the NonPro region can influence the degree of cross-reactivity of antibodies to PspA.


[Correlation between the number of sites, transcript levels and transposition frequency of retrotransposon copia in Drosophila melanogaster].
Numbers of copia transcripts in testes of files from five Drosophila melanogaster lines were compared by means of Northern blot hybridization. Four of these lines were closely related differing only by transposition rates and the number of copia sites in the genome. The fifth line, which was not related to the others, was characterized by lack of transpositions and the lowest copia copy number. Positive correlation between total copia transcript level and its copy number and transposition rate was observed. Therefore, transcription rate of copia retrotransposon in tests is largely controlled by the level of its transcription, which, in turn, is regulated by the number of retrotransposon copies in the genome. These data contradict the hypothesis on self-regulation of retrotransposon copy number in the genome.


Incidence and prevalence of uveitis in Northern California; the Northern California Epidemiology of Uveitis Study.
To determine the incidence and prevalence of uveitis in a large, well-defined population in Northern California. Cross-sectional study using retrospective database and medical record review. A group of 2070 people within 6 Northern California medical center communities (N = 731 898) who had a potential diagnosis of uveitis. The patient database of a large health maintenance organization (2 805 443 members at time of the study) was searched for all patients who, during a 12-month period, had the potential diagnosis of uveitis. Detailed quarterly gender- and age-stratified population data were available. Medical records of patients who potentially had uveitis and who were members of the 6 target communities were reviewed by 2 uveitis subspecialists to confirm the diagnosis of uveitis and to establish time of onset. Demographic and clinical data were gathered for patients meeting the clinical definition of uveitis. Incidence rates were calculated by using a dynamic population model. Prevalence rates were based on the mid-study period population. Presence and date of onset of uveitis. At midstudy, the population for the 6 communities was 731 898. During the target period, 382 new cases of uveitis were diagnosed; 462 cases of uveitis were diagnosed before the target period. These data yielded an incidence of 52.4/100 000 person-years and a period prevalence of 115.3/100 000 persons. The incidence and prevalence of disease were lowest in pediatric age groups and were highest in patients 65 years or older (P<0.0001). The prevalence of uveitis was higher in women than in men (P<0.001), but the difference in incidence between men and women was not statistically significant. Comparison between the group of patients who had onset of uveitis before the target period (ongoing uveitis) and the entire cohort of uveitis patients showed that women had a higher prevalence of ongoing uveitis than men and that this difference was largest in the older age groups (P<0.001). In this largest population-based uveitis study in the United States to date, the incidence of uveitis was approximately 3 times that of previous U.S. estimates and increased with the increasing age of patients. Women had a higher prevalence of uveitis than men, and the largest differences were in older age groups.


Increased salivary cortisol after waking in depression.
Cortisol hypersecretion is regarded as important in the pathophysiology of major depression. However, recent studies in community-based samples have been inconclusive. To determine whether acutely depressed, medication-free subjects show an exaggerated release of cortisol in saliva in relation to awakening. We studied the pattern of waking salivary cortisol in 20 unmedicated acutely depressed subjects and 40 healthy controls. In both groups, salivary cortisol increased rapidly after waking, peaking at 30 min. Overall, patients with acute depression secreted approximately 25% more cortisol than controls, though 60 min after waking, their cortisol levels were similar. Depressed patients in the community appear to have increased early morning cortisol secretion, but the demonstration of this effect requires control for time of waking.


The noninvasive prediction of cardiac mortality in men and women with known or suspected coronary artery disease. Economics of Noninvasive Diagnosis (END) Study Group.
The association between myocardial perfusion imaging defects and cardiac mortality in women is undefined. We examined whether myocardial perfusion imaging predicted cardiac mortality in men and women and compared this with other variables influencing prognosis. Six academic institutions with high-volume nuclear cardiology laboratories consecutively studied 5,009 men aged 62 +/- 12 years (mean ISD) and 3,402 women aged 66 +/- 11 years with symptomatic known or suspected coronary artery disease undergoing exercise (n = 7,486) or pharmacologic stress (n = 925) myocardial perfusion imaging. A pretest clinical risk index was calculated from age, history of myocardial infarction, diabetes, hypertension, and hypercholesterolemia. Myocardial perfusion images were analyzed for stress-induced defects or any defect in the territories of the three major coronary arteries. Stress-induced perfusion defects were seen in 39% of men and 25% of women (P = 0.0001). Extensive stress-induced or fixed defects (>2 vascular territories) were less common in women than men (10% vs 19%, and 4% vs 18%, both P = 0.0001). During a mean of 2.4 +/- 1.5 years of follow-up, 143 patients died of cardiac causes. The clinical risk index and number of territories with perfusion defects were associated with cardiac mortality in women and men. In women undergoing exercise myocardial perfusion imaging, the number of abnormal territories remained the strongest correlate of mortality after adjustment for exercise variables. The results of myocardial perfusion imaging are important, independent predictors of survival in both women and men.


Functional characterization of a trafficking-defective HCN4 mutation, D553N, associated with cardiac arrhythmia.
Hyperpolarization-activated cyclic nucleotide-gated channel 4 gene HCN4 is a pacemaker channel that plays a key role in automaticity of sinus node in the heart, and an HCN4 mutation was reported in a patient with sinus node dysfunction. Expression of HCN4 in the heart is, however, not confined to the sinus node cells but is found in other tissues, including cells of the conduction system. On the other hand, mutations in another cardiac ion channel gene, SCN5A, also cause sinus node dysfunction as well as other cardiac arrhythmias, including long QT syndrome, Brugada syndrome, idiopathic ventricular fibrillation, and progressive cardiac conduction disturbance. These observations imply that HCN4 abnormalities may be involved in the pathogenesis of various arrhythmias, similar to the SCN5A mutations. In this study, we analyzed patients suffering from sinus node dysfunction, progressive cardiac conduction disease, and idiopathic ventricular fibrillation for mutations in HCN4. A missense mutation, D553N, was found in a patient with sinus node dysfunction who showed recurrent syncope, QT prolongation in electrocardiogram, and polymorphic ventricular tachycardia, torsade de pointes. In vitro functional study of the D553N mutation showed a reduced membranous expression associated with decreased If currents because of a trafficking defect of the HCN4 channel in a dominant-negative manner. These data suggest that the loss of function of HCN4 is associated with sinus nodal dysfunction and that a consequence of pacemaker channel abnormality might underlie clinical features of QT prolongation and polymorphic ventricular tachycardia developed under certain conditions.


Pump pulse width and temperature effects in lithium niobate for efficient THz generation.
We present a study on THz generation in lithium niobate pumped by a powerful and versatile Yb:CaF(2) laser. The unique laser system delivers transform-limited pulses of variable duration (0.38-0.65 ps) with pulse energies up to 15 mJ and center wavelength of 1030 nm. From previous theoretical investigations, it is expected that such laser parameters are ideally suited for efficient THz generation. Here, we present experimental results on both the conversion efficiency and the THz spectral shape for variable pump pulse durations and for different crystal temperatures, down to 25 K. We experimentally verify the optimum pump parameters for the most efficient and broadband THz generation.


American Thyroid Association guidelines for detection of thyroid dysfunction.
To define the optimal approach to identify patients with thyroid dysfunction. The 8-member Standards of Care Committee of the American Thyroid Association prepared a draft, which was reviewed by the association's 780 members, 50 of whom responded with suggested revisions. Relevant published studies were identified through MEDLINE and the association membership's personal resources. Consensus was reached at group meetings. The first draft was prepared by a single author (P.W.L.) after group discussion. Suggested revisions were incorporated after consideration by the committee. The American Thyroid Association recommends that adults be screened for thyroid dysfunction by measurement of the serum thyrotropin concentration, beginning at age 35 years and every 5 years thereafter. The indication for screening is particularly compelling in women, but it can also be justified in men as a relatively cost-effective measure in the context of the periodic health examination. Individuals with symptoms and signs potentially attributable to thyroid dysfunction and those with risk factors for its development may require more frequent serum thyrotropin testing.


Clinical differences in patients with Alzheimer's disease according to the presence or absence of anosognosia: implications for perceived quality of life.
This study aimed to determine the factors that predict anosognosia in patients with Alzheimer's disease (AD) and to examine the effect of anosognosia on patient and caregiver perceptions of the patient's quality of life (QoL-p), using a cross-sectional design with 164 patients and their caregivers. Instruments of measurement included Anosognosia Questionnaire-Dementia, Geriatric Depression Scale, Quality of Life in AD (QoL-AD), Disability Assessment for Dementia, Neuropsychiatric Inventory, and the Global Deterioration Scale (GDS). A binary logistic regression analysis was performed to identify the factors that predict anosognosia, while a linear regression analysis was conducted to determine the factors associated with QoL-AD. The degree of anosognosia increased in line with GDS stage (F (2,161) = 41.3, p < 0.001). In the binary regression analysis, the variables that predicted anosognosia were more neuropsychiatric symptoms (OR = 1.11, 95% CI: 1.06-1.17, p < 0.001), deficits in ADL (OR = 0.88, 95% CI: 0.83-0.94, p < 0.001), less depression (OR = 0.66, 95% CI: 0.54-0.82, p < 0.001), and older age (OR = 1.08, 95% CI: 1.00-1.15, p = 0.027). With regards to QoL-p, the multiple linear regression analysis for patients (r2 = 0.486) showed that less depression (β = -0.52, p < 0.001) and greater anosognosia (β = 0.40, p < 0.001) explained 33% and 10% of the variance in QoL-AD, respectively. Greater anosognosia was associated with better perceived QoL-p, especially in advanced GDS stages. Anosognosia was associated with greater caregiver burden and a greater discrepancy between patient and caregiver ratings of QoL-p.


Revised age of late Neanderthal occupation and the end of the Middle Paleolithic in the northern Caucasus.
Advances in direct radiocarbon dating of Neanderthal and anatomically modern human (AMH) fossils and the development of archaeostratigraphic chronologies now allow refined regional models for Neanderthal-AMH coexistence. In addition, they allow us to explore the issue of late Neanderthal survival in regions of Western Eurasia located within early routes of AMH expansion such as the Caucasus. Here we report the direct radiocarbon ((14)C) dating of a late Neanderthal specimen from a Late Middle Paleolithic (LMP) layer in Mezmaiskaya Cave, northern Caucasus. Additionally, we provide a more accurate chronology for the timing of Neanderthal extinction in the region through a robust series of 16 ultrafiltered bone collagen radiocarbon dates from LMP layers and using Bayesian modeling to produce a boundary probability distribution function corresponding to the end of the LMP at Mezmaiskaya. The direct date of the fossil (39,700 ± 1,100 (14)C BP) is in good agreement with the probability distribution function, indicating at a high level of probability that Neanderthals did not survive at Mezmaiskaya Cave after 39 ka cal BP ("calendrical" age in kiloannum before present, based on IntCal09 calibration curve). This challenges previous claims for late Neanderthal survival in the northern Caucasus. We see striking and largely synchronous chronometric similarities between the Bayesian age modeling for the end of the LMP at Mezmaiskaya and chronometric data from Ortvale Klde for the end of the LMP in the southern Caucasus. Our results confirm the lack of reliably dated Neanderthal fossils younger than ∼ 40 ka cal BP in any other region of Western Eurasia, including the Caucasus.


Direct estimates of natural selection in Iberia indicate calcium absorption was not the only driver of lactase persistence in Europe.
Lactase persistence (LP) is a genetically determined trait whereby the enzyme lactase is expressed throughout adult life. Lactase is necessary for the digestion of lactose--the main carbohydrate in milk--and its production is downregulated after the weaning period in most humans and all other mammals studied. Several sources of evidence indicate that LP has evolved independently, in different parts of the world over the last 10,000 years, and has been subject to strong natural selection in dairying populations. In Europeans, LP is strongly associated with, and probably caused by, a single C to T mutation 13,910 bp upstream of the lactase (LCT) gene (-13,910*T). Despite a considerable body of research, the reasons why LP should provide such a strong selective advantage remain poorly understood. In this study, we examine one of the most widely cited hypotheses for selection on LP--that fresh milk consumption supplemented the poor vitamin D and calcium status of northern Europe's early farmers (the calcium assimilation hypothesis). We do this by testing for natural selection on -13,910*T using ancient DNA data from the skeletal remains of eight late Neolithic Iberian individuals, whom we would not expect to have poor vitamin D and calcium status because of relatively high incident UVB light levels. None of the eight samples successfully typed in the study had the derived T-allele. In addition, we reanalyze published data from French Neolithic remains to both test for population continuity and further examine the evolution of LP in the region. Using simulations that accommodate genetic drift, natural selection, uncertainty in calibrated radiocarbon dates, and sampling error, we find that natural selection is still required to explain the observed increase in allele frequency. We conclude that the calcium assimilation hypothesis is insufficient to explain the spread of LP in Europe.


Local therapy for breast cancer in the molecular era: relevant or relic?
Local therapy (surgery and radiation) is an essential component of breast cancer treatment. Yet, based on clinical trial results dating from the 1980s, the magnitude of local therapy interventions has been decreasing. Now, with the emergence of tailored systemic therapies, their increasing use in the neoadjuvant setting, and their high rates of pathologic complete response (pCR), the relevance of local therapy is being questioned. However, given our present inability to assess pathologic response without surgery, the low pCR rates in common subtypes of breast cancer, and the survival advantages with nodal radiation, local therapy remains not only relevant but crucial to a comprehensive breast cancer treatment plan. In the future, as gene profiling of individual patient tumors progresses and allows for precise tailoring of therapy, it is conceivable that surgery and/or radiation would not be required in some patients. However, the notion that brief, low-morbidity local therapy options, which synergize with prolonged and potentially morbid systemic regimens, would not be relevant for most patients is beyond the horizon at the moment.


In vivo fluorescence imaging of primate retinal ganglion cells and retinal pigment epithelial cells.
The ability to resolve single cells noninvasively in the living retina has important applications for the study of normal retina, diseased retina, and the efficacy of therapies for retinal disease. We describe a new instrument for high-resolution, in vivo imaging of the mammalian retina that combines the benefits of confocal detection, adaptive optics, multispectral, and fluorescence imaging. The instrument is capable of imaging single ganglion cells and their axons through retrograde transport in ganglion cells of fluorescent dyes injected into the monkey lateral geniculate nucleus (LGN). In addition, we demonstrate a method involving simultaneous imaging in two spectral bands that allows the integration of very weak signals across many frames despite inter-frame movement of the eye. With this method, we are also able to resolve the smallest retinal capillaries in fluorescein angiography and the mosaic of retinal pigment epithelium (RPE) cells with lipofuscin autofluorescence.


Injection therapy and denervation procedures for chronic low-back pain: a systematic review.
Injection therapy and denervation procedures are commonly used in the management of chronic low-back pain (LBP) despite uncertainty regarding their effectiveness and safety. To provide an evaluation of the current evidence associated with the use of these procedures, a systematic review was performed. Existing systematic reviews were screened, and the Cochrane Back Review Group trial register was searched for randomized controlled trials (RCTs) fulfilling the inclusion criteria. Studies were included if they recruited adults with chronic LBP, evaluated the use of injection therapy or denervation procedures and measured at least one clinically relevant outcome (such as pain or functional status). Two review authors independently assessed studies for eligibility and risk of bias (RoB). A meta-analysis was performed with clinically homogeneous studies, and the GRADE approach was used to determine the quality of evidence. In total, 27 RCTs were included, 14 on injection therapy and 13 on denervation procedures. 18 (66%) of the studies were determined to have a low RoB. Because of clinical heterogeneity, only two comparisons could be pooled. Overall, there is only low to very low quality evidence to support the use of injection therapy and denervation procedures over placebo or other treatments for patients with chronic LBP. However, it cannot be ruled out that in carefully selected patients, some injection therapy or denervation procedures may be of benefit.


Cellular asymmetry in Chlamydomonas reinhardtii.
Although largely bilaterally symmetric, the two sides of the unicellular alga Chlamydomonas reinhardtii can be distinguished by the location of the single eyespot. When viewed from the anterior end, the eyespot is always closer to one flagellum than the other, and located at an angle of approximately 45 degrees clockwise of the flagellar plane. This location correlates with the position of one of four acetylated microtubule bundles connected to the flagellar apparatus. Each basal body is attached to two of these microtubule rootlets. The rootlet that positions the eyespot is always attached to the same basal body, which is the daughter of the parental/daughter basal body pair. At mitosis, the replicated basal body pairs segregate in a precise orientation that maintains the asymmetry of the cell and results in mitotic poles that have an invariant handedness. The fusion of gametic cells during mating is also asymmetric. As a result of asymmetric, but different, locations of the plus and minus mating structures, mating preferentially results in quadriflagellate dikaryons with parallel flagellar pairs and both eyespots on the same side of the cell. This asymmetric fusion, as well as all the other asymmetries described, may be necessary for the proper phototactic behavior of these cells. The invariant handedness of the spindle pole, eyespot position, and mating structure position appears to be based on the inherent asymmetry of the basal body pair, providing an example of how an intracellular pattern can be determined and maintained.


Fertility knowledge and beliefs about fertility treatment: findings from the International Fertility Decision-making Study.
How good is fertility knowledge and what are treatment beliefs in an international sample of men and women currently trying to conceive? The study population had a modest level of fertility knowledge and held positive and negative views of treatment. Few studies have examined general fertility treatment attitudes but studies of specific interventions show that attitudes are related to characteristics of the patient, doctor and context. Further, research shows that fertility knowledge is poor. However, the majority of these studies have examined the prevalence of infertility, the optimal fertile period and/or age-related infertility in women, in university students and/or people from high-resource countries making it difficult to generalize findings. A cross-sectional sample completed the International Fertility Decision-making Study (IFDMS) over a 9-month period, online or via social research panels and in fertility clinics. Participants were 10 045 people (8355 women, 1690 men) who were on average 31.8 years old, had been trying to conceive for 2.8 years with 53.9% university educated. From a total of 79 countries, sample size was >100 in 18 countries. All 79 countries were assigned to either a very high Human Development Index (VH HDI) or a not very high HDI (NVH HDI). The IFDMS was a 45-min, 64-item English survey translated into 12 languages. The inclusion criteria were the age between 18 and 50 years and currently trying to conceive for at least 6 months. Fertility knowledge was assessed using a 13-item correct/incorrect scale concerned with risk factors, misconceptions and basic fertility facts (range: 0-100% correct). Treatment beliefs were assessed with positive and negative statements about fertility treatment rated on a five-point agree/disagree response scale. Average correct score for Fertility Knowledge was 56.9%, with greater knowledge significantly related to female gender, university education, paid employment, VH HDI and prior medical consultation for infertility (all P < 0.001). The mean agreement scores for treatment beliefs showed that agreement for positive items (safety, efficacy) was correlated with agreement for negative items (short/long-term physical/emotional effects) (P > 0.001). People who had given birth/fathered a child, been trying to conceive for less than 12 months, who had never consulted for a fertility problem and who lived in a country with an NVH HDI agreed less with negative beliefs. HDI, duration of trying to conceive and help-seeking were also correlates of higher positive beliefs, alongside younger age, living in an urban area and having stepchildren. Greater fertility knowledge was associated with stronger agreement on negative treatment beliefs items (P < 0.001) but was unrelated to positive treatment beliefs items. There was volunteer bias insofar as more women, people of higher education and people with fertility problems (i.e. met criteria for infertility, had consulted a medical doctor, had conceived with fertility treatment) participated and this was true in VH and NVH HDI countries. The bias may mean that people in this sample had better fertility knowledge and less favourable treatment beliefs than is the case in the general population. Educational interventions should be directed at improving knowledge of fertility health. Future prospective research should be aimed at investigating how fertility knowledge and treatment beliefs affect childbearing and help-seeking decision-making.


A low-complexity ECG feature extraction algorithm for mobile healthcare applications.
This paper introduces a low-complexity algorithm for the extraction of the fiducial points from the Electrocardiogram (ECG). The application area we consider is that of remote cardiovascular monitoring, where continuous sensing and processing takes place in low-power, computationally constrained devices, thus the power consumption and complexity of the processing algorithms should remain at a minimum level. Under this context, we choose to employ the Discrete Wavelet Transform (DWT) with the Haar function being the mother wavelet, as our principal analysis method. From the modulus-maxima analysis on the DWT coefficients, an approximation of the ECG fiducial points is extracted. These initial findings are complimented with a refinement stage, based on the time-domain morphological properties of the ECG, which alleviates the decreased temporal resolution of the DWT. The resulting algorithm is a hybrid scheme of time and frequency domain signal processing. Feature extraction results from 27 ECG signals from QTDB, were tested against manual annotations and used to compare our approach against the state-of-the art ECG delineators. In addition, 450 signals from the 15-lead PTBDB are used to evaluate the obtained performance against the CSE tolerance limits. Our findings indicate that all but one CSE limits are satisfied. This level of performance combined with a complexity analysis, where the upper bound of the proposed algorithm, in terms of arithmetic operations, is calculated as 2:423N + 214 additions and 1:093N + 12 multiplications for N 861 or 2:553N + 102 additions and 1:093N +10 multiplications for N > 861 (N being the number of input samples), reveals that the proposed method achieves an ideal trade-off between computational complexity and performance, a key requirement in remote CVD monitoring systems.


Cancer Neoantigens: Challenges and Future Directions for Prediction, Prioritization, and Validation.
Prioritization of immunogenic neoantigens is key to enhancing cancer immunotherapy through the development of personalized vaccines, adoptive T cell therapy, and the prediction of response to immune checkpoint inhibition. Neoantigens are tumor-specific proteins that allow the immune system to recognize and destroy a tumor. Cancer immunotherapies, such as personalized cancer vaccines, adoptive T cell therapy, and immune checkpoint inhibition, rely on an understanding of the patient-specific neoantigen profile in order to guide personalized therapeutic strategies. Genomic approaches to predicting and prioritizing immunogenic neoantigens are rapidly expanding, raising new opportunities to advance these tools and enhance their clinical relevance. Predicting neoantigens requires acquisition of high-quality samples and sequencing data, followed by variant calling and variant annotation. Subsequently, prioritizing which of these neoantigens may elicit a tumor-specific immune response requires application and integration of tools to predict the expression, processing, binding, and recognition potentials of the neoantigen. Finally, improvement of the computational tools is held in constant tension with the availability of datasets with validated immunogenic neoantigens. The goal of this review article is to summarize the current knowledge and limitations in neoantigen prediction, prioritization, and validation and propose future directions that will improve personalized cancer treatment.


3D porous ZnO-SnS p-n heterojunction for visible light driven photocatalysis.
A novel two-step solution approach is put forward to design a unique three dimensional (3D) porous ZnO-SnS p-n heterojunction under mild conditions. This special 3D structure is induced via flower-like ZnO in which SnS serves as an efficient photosensitizer to improve the light harvesting across the whole visible range. A profound investigation of the mechanism shows that this 3D porous ZnO-SnS material effectively integrates the large surface area and high redox potential of ZnO, and wide visible-light harvesting of SnS, which largely promotes the transfer and separation rate of carriers. The systematic study on the active species generated during the photocatalysis illustrates that it is the photoelectrons, ˙OH and O2˙- that play the crucial role in the degradation of dyes. As a result, the noble-metal free photocatalyst degrades nearly 100% of rhodamine B (RhB) within 80 min and methylene blue (MB) in 40 min under visible light. The photocatalytic activity is 10 times higher than that of the pure flower-like ZnO and two times higher than that of the SnS material. Moreover, the photocatalyst is easily separated and reused at least four times without obvious change in efficiency and properties. This work provides an effective strategy for the synthesis of 3D porous p-n heterojunction semiconductor-based photocatalysts with low cost and low toxicity, which present promising applications in the field of solar energy storage and conversion.


National identity predicts public health support during a global pandemic.
Changing collective behaviour and supporting non-pharmaceutical interventions is an important component in mitigating virus transmission during a pandemic. In a large international collaboration (Study 1, N = 49,968 across 67 countries), we investigated self-reported factors associated with public health behaviours (e.g., spatial distancing and stricter hygiene) and endorsed public policy interventions (e.g., closing bars and restaurants) during the early stage of the COVID-19 pandemic (April-May 2020). Respondents who reported identifying more strongly with their nation consistently reported greater engagement in public health behaviours and support for public health policies. Results were similar for representative and non-representative national samples. Study 2 (N = 42 countries) conceptually replicated the central finding using aggregate indices of national identity (obtained using the World Values Survey) and a measure of actual behaviour change during the pandemic (obtained from Google mobility reports). Higher levels of national identification prior to the pandemic predicted lower mobility during the early stage of the pandemic (r = -0.40). We discuss the potential implications of links between national identity, leadership, and public health for managing COVID-19 and future pandemics.


Nucleotide insertion opposite a cis-syn thymine dimer by a replicative DNA polymerase from bacteriophage T7.
Ultraviolet-induced DNA damage poses a lethal block to replication. To understand the structural basis for this, we determined crystal structures of a replicative DNA polymerase from bacteriophage T7 in complex with nucleotide substrates and a DNA template containing a cis-syn cyclobutane pyrimidine dimer (CPD). When the 3' thymine is the templating base, the CPD is rotated out of the polymerase active site and the fingers subdomain adopts an open orientation. When the 5' thymine is the templating base, the CPD lies within the polymerase active site where it base-pairs with the incoming nucleotide and the 3' base of the primer, while the fingers are in a closed conformation. These structures reveal the basis for the strong block of DNA replication that is caused by this photolesion.


Phase II clinical trial of pazopanib for patients with unresectable or metastatic malignant peripheral nerve sheath tumors.
Malignant peripheral nerve sheath tumor (MPNST) often does not respond well to chemotherapy and develops against a background of NF1. The purpose of our study was to examine the efficacy of pazopanib against MPNST. Our study was designed as a physician-initiated phase II clinical trial in patients with advanced MPNST. Patients were registered from 11 large hospitals. The primary endpoint was set to clarify the clinical benefit rate (CBR) at 12 weeks according to response evaluation criteria in solid tumors (RECIST). Progression-free survival (PFS), overall survival (OS) and the CBR based on modified Choi evaluation at week 12 were set as secondary endpoints along with treatment-related safety. The study enrolled 12 patients. Median age was 49 years. Seven had Grade 2 and five Grade 3 according to the FNCLCC evaluation. Median follow-up period was 10.6 months. CBR at 12 weeks was both 50.0% (RECIST and Choi). The median PFS was 5.4 months for both RECIST and Choi, and the median OS was 10.6 months. Of special interest, the median PFS was 2.9 months for patients with FNCLCC Grade 2 and 10.2 months for Grade 3 (both RECIST and Choi). Grade 4 adverse events of neutropenia and lipase elevation were noted in one patient each. The results of this pazopanib therapy were generally better than those of any of the other single molecular targeted therapies reported previously. Although accumulation of more cases remains necessary, we conclude pazopanib treatment for MPNST to be a safe and promising treatment after doxorubicin-based chemotherapy.


Central poststroke pain: somatosensory abnormalities and the presence of associated myofascial pain syndrome.
Central post-stroke pain (CPSP) is a neuropathic pain syndrome associated with somatosensory abnormalities due to central nervous system lesion following a cerebrovascular insult. Post-stroke pain (PSP) refers to a broader range of clinical conditions leading to pain after stroke, but not restricted to CPSP, including other types of pain such as myofascial pain syndrome (MPS), painful shoulder, lumbar and dorsal pain, complex regional pain syndrome, and spasticity-related pain. Despite its recognition as part of the general PSP diagnostic possibilities, the prevalence of MPS has never been characterized in patients with CPSP patients. We performed a cross-sectional standardized clinical and radiological evaluation of patients with definite CPSP in order to assess the presence of other non-neuropathic pain syndromes, and in particular, the role of myofascial pain syndrome in these patients. CPSP patients underwent a standardized sensory and motor neurological evaluation, and were classified according to stroke mechanism, neurological deficits, presence and profile of MPS. The Visual Analogic Scale (VAS), McGill Pain Questionnaire (MPQ), and Beck Depression Scale (BDS) were filled out by all participants. Forty CPSP patients were included. Thirty-six (90.0%) had one single ischemic stroke. Pain presented during the first three months after stroke in 75.0%. Median pain intensity was 10 (5 to 10). There was no difference in pain intensity among the different lesion site groups. Neuropathic pain was continuous-ongoing in 34 (85.0%) patients and intermittent in the remainder. Burning was the most common descriptor (70%). Main aggravating factors were contact to cold (62.5%). Thermo-sensory abnormalities were universal. MPS was diagnosed in 27 (67.5%) patients and was more common in the supratentorial extra-thalamic group (P <0.001). No significant differences were observed among the different stroke location groups and pain questionnaires and scales scores. Importantly, CPSP patients with and without MPS did not differ in pain intensity (VAS), MPQ or BDS scores. The presence of MPS is not an exception after stroke and may present in association with CPSP as a common comorbid condition. Further studies are necessary to clarify the role of MPS in CPSP.