Nasopharyngeal Pneumococcal Carriage among Healthy Children in Cyprus Post Widespread Simultaneous Implementation of PCV10 and PCV13 Vaccines.
The objective of the study was to describe the incidence of pneumococcal nasopharyngeal carriage, serotype distribution and antibiotic resistance profile of pneumococcal nasopharyngeal isolates in healthy children aged 6 to 36 months following the implementation of conjugate vaccines. A nasopharyngeal swab was collected from 1105 healthy children following a stratified random sampling between September 2013 and April 2014. Demographics, vaccination status and data on possible risk factors were recorded. Isolates were serotyped and tested for antibiotic susceptibility. The nasopharyngeal carriage rate was 25.3%. Among 1105 children enrolled, 393 had received PCV13 and 685 PCV10. The prevailing isolated serotypes were: 23A (14.3%), 15A (8.9%), 6C (8.6%), 23B (7.5%), 19A (5.4%) and 15B (5%). The proportion of non-vaccine serotypes, PCV10 serotypes, PCV13 additional serotypes (3, 6A, 19A) was 76.8%, 2.1% and 10.4% respectively. Although children, who were fully or partially vaccinated with PCV13, were 63% less likely to be colonized with additional PCV13 serotypes compared to those vaccinated with PCV10, the difference is not significant (95%Cl = 0.14-1.02, p = 0.053). The highest antibiotic non-susceptible rates were found for erythromycin (28.2%) and penicillin (27.9%). The overall multidrug resistance rate was 13.2%, with serotypes 24F (4/6), 15A (14/25) and 19A (6/15) being the main contributors. Carriage rate was similar between children vaccinated with PCV10 or PCV13. The high incidence of 15A serotype which is also multidrug resistant should be underlined. Ongoing surveillance is needed to monitor the dynamics on nasopharyngeal carriage.


Diagnostic Testing for Differential Diagnosis in Thrombotic Microangiopathies
Thrombotic microangiopathies (TMAs) are multiple disease entities with different etiopathogeneses, characterized by thrombocytopenia, microangiopathic hemolytic anemia (MAHA) with schistocytosis, variable symptoms including fever, and multi-organ failure such as mild renal impairment and neurological deficits. The two paradigms of TMAs are represented on one hand by acquired thrombotic thrombocytopenic purpura (TTP) and on the other by hemolytic uremic syndrome (HUS). The differential diagnosis between these two paradigmatic forms of TMA is based on the presence of either frank renal failure in HUS or a severe deficiency (<10%) of the zinc-protease ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) in TTP. ADAMTS13 is an enzyme involved in the proteolytic processing of von Willebrand factor (vWF), and its deficiency results in formation of high-molecular-weight vWF-rich microthrombi in the environment of the microvasculature. The presence of these ultra-large vWF multimers in the microcirculation can recruit platelets, promoting multi-organ ischemic lesions. The presence of ADAMTS13 activity at >10% could rule out the presence of a TTP form. However, it is often difficult to differentiate either a TTP or HUS clinical scenario presenting with typical symptoms of TMA. There are in fact several additional diagnoses that should be considered in patients with ADAMTS13 activity of >10%. Widespread inflammation with endothelial damage and adverse reactions to drugs play a central role in the pathogenesis of several forms of TMA, and in these cases, the differential diagnosis should be directed at the underlying disease. Hence, a correct etiologic diagnosis of TMA should involve a critical illness, cancer-associated TMA, drug-induced TMA, and hematopoietic transplant-associated TMA. A complete assessment of all the possible etiologies for TMA symptoms, including acquired or congenital TTP, will allow for a more accurate diagnosis and application of a more appropriate treatment.


Training winner-take-all simultaneous recurrent neural networks.
The winner-take-all (WTA) network is useful in database management, very large scale integration (VLSI) design, and digital processing. The synthesis procedure of WTA on single-layer fully connected architecture with sigmoid transfer function is still not fully explored. We discuss the use of simultaneous recurrent networks (SRNs) trained by Kalman filter algorithms for the task of finding the maximum among N numbers. The simulation demonstrates the effectiveness of our training approach under conditions of a shared-weight SRN architecture. A more general SRN also succeeds in solving a real classification application on car engine data.


A double-blind, placebo-controlled randomized trial of creatine for the cancer anorexia/weight loss syndrome (N02C4): an Alliance trial.
Multiple pilot studies, including one in colorectal cancer patients, suggest that creatine, an amino acid derivative, augments muscle, improves strength, and thereby could palliate the cancer anorexia/weight loss syndrome. In this randomized, double-blind, placebo-controlled trial, incurable patients with this syndrome were assigned creatine (20 g/day load×5 days followed by 2 g/day orally) versus identical placebo. Patients were weighed once a week for 1 month and then monthly. Patients were also assessed over 1 month for appetite and quality of life (validated questionnaires), fist grip strength, body composition (bioelectrical impedance), and adverse events. The primary endpoint was 10% or greater weight gain from baseline during the first month. Within this combined cohort of 263 evaluable patients (134 received creatine and 129 placebo), only 3 gained ≥10% of their baseline weight by 1 month: two creatine-treated and the other placebo-exposed (P = 1.00). Questionnaire data on appetite, quality of life, and activities of daily living showed no statistically significant differences between groups. Similarly, no statistically significant differences between groups were observed for fist-grip strength or body composition. Rates and severity of adverse events were comparable between groups. Finally, a median survival of 230 and 239 days were observed in the creatine and placebo groups, respectively (P = 0.70). Creatine, as prescribed in this trial, had no effect on the cancer anorexia/weight loss syndrome.


Expression of the Receptor for Hyaluronic Acid-Mediated Motility (RHAMM) in Endometrial Cancer is Associated With Adverse Histologic Parameters and Tumor Progression.
Endometrial cancer is one of the most common gynecologic malignancies worldwide. Only 2 agents have been approved by Food and Drug Administration for endometrial cancer since 1971. There is a need to identify molecular targets to treat advanced endometrial cancer. The receptor for hyaluronic acid-mediated motility (RHAMM) is upregulated in various types of cancer. Here, we aimed to determine the clinical significance of RHAMM expression in endometrial cancer. Two hundred twenty-five cases of endometrial cancer, including serous and endometrioid types, and 8 cases of normal endometrium were used for studying RHAMM protein levels. The Cancer Genome Atlas database was also queried for RHAMM mRNA expression in endometrial cancer. Increased expression of RHAMM protein was seen in endometrial cancer compared with no or weak expression in normal endometrium. RHAMM expression positively correlated with tumor grade. RHAMM expression was significantly increased in endometrial serous carcinomas, which are high-grade, aggressive types of endometrial cancer, compared with the relatively less aggressive endometrioid carcinomas. RHAMM expression also correlated with the presence of lymphovascular invasion. RHAMM mRNA expression correlated with decreased survival in The Cancer Genome Atlas cohort. Therefore, increased RHAMM expression in endometrial cancer is associated with high-grade tumors and is indicative of more aggressive behavior. These findings suggest RHAMM as a prognostic factor in endometrial cancer and as a potential therapeutic target in advanced endometrial cancer for future studies.


Multiple gene genealogies reveal recent dispersion and hybridization in the human pathogenic fungus Cryptococcus neoformans.
Cryptococcus neoformans (= Filobasidiella neoformans) is a significant emerging fungal pathogen of humans. To understand the evolution of this pathogen, 34 strains were obtained from various locations around the world and fragments of four genes were sequenced from each. These strains represented all three varieties and five serotypes. The four sequenced genes are: (i) the mitochondrial large ribosomal subunit RNA; (ii) the internal transcribed spacer region of the nuclear rRNA, including ITS1, 5.8S rRNA subunit and ITS2; (iii) orotidine monophosphate pyrophosphorylase; and (iv) diphenol oxidase. Phylogenetic analyses indicated considerable divergence among lineages, which corresponded to the current classification of C. neoformans into three varieties. However, there is no apparent phylogeographic pattern. Significant incongruences were observed among gene genealogies. The analyses indicated that the major lineages in C. neoformans diverged tens of millions of years ago but have undergone recent dispersion and hybridization.


Regression of a giant pseudopolyp in a patient with colonic Crohn's disease after therapy with infliximab.
Giant inflammatory pseudopolyps (> 15 mm) are an uncommon complication of inflammatory bowel disease (IBD) and a differential diagnosis with adenomas and carcinomas is challenging. Although usually asymptomatic, they may result in intestinal obstruction or intussusception due to their size. The standard management involves lesion biopsies and endoscopic excision for selected cases; surgery is usually reserved for size-associated complications or an uncertain pathology. We report the case of a 43-year-old female patient with Crohn's disease (CD) in clinical remission, with no specific treatment at the time. A giant pseudopolyp of 40-mm was found during a screening colonoscopy. Therapy was initiated with infliximab and azathioprine in an attempt to reduce the size of the polyp and allow an endoscopic resection. Additional colonoscopies were performed following induction doses at weeks 0, 2, and 6, which revealed a reduced lesion size. Mucosal resection was attempted but failed due to severe fibrosis, which prevented base injections from lifting up the polyp. However, a follow-up colonoscopy three months later showed that the lesion had completely disappeared. The evidence in the literature regarding giant pseudopolyp management is scarce, but reports indicate that they rarely disappear with medical therapy alone and usually require surgery or endoscopic resection.


Controlling intraoperative hemorrhage during burn surgery: A prospective, randomized trial comparing NuStat® hemostatic dressing to the historic standard of care.
One of the primary intraoperative challenges during burn surgery is to adequately excise the burn while avoiding massive hemorrhage. This has become increasingly important, as we see more burn patients that are older and with more medical comorbidities. While adequate excision down to healthy tissues for deep burns is essential for skin graft to take, it also leads to active bleeding that can be a challenge to control. Good hemostasis is imperative as a hematoma is the most common cause of graft loss. Several new products have become available to help control intraoperative hemorrhage. A new hemostatic dressing, NuStat®, is available and approved by FDA in United States. A single institution prospective randomized control trial was completed at Regional Burn Center of the University of South Alabama comparing NuStat® with the institutional historic standard of care. Twenty such patients were included in our study. A cost analysis was also completed as part of the study retrospectively. For dressings used to treat the burn site, blood loss on the side treated with NuStat® was on average less (27g/100cm2) than the side treated with our historic standard of care (31g/100cm2), though it was not statistically significant (p=0.81). Similarly, on the donor site, blood loss on the side treated with NuStat® was on average less (14g/100cm2) than the side treated with our historic standard of care (15g/100cm2), but it was also not statistically significant (p=0.92). Average total blood loss from both excision and donor sites was also less with NuStat® (10g/100cm2) compared to the historic standard of care (12g/100cm2), but it was also not significant (p=0.77). There was no difference in the number of cycles required to achieve hemostasis for either the burn (1.15 NuStat® vs. 1.1 for historic standard of care, p=0.70) or the donor site (1 vs. 1, p=1.0). When comparing the cost of NuStat® versus the historic standard of care, the actual costs incurred for the wounds was less for the portion treated with NuStat® ($148.43) when compared to the historic standard of care ($186.45) (p<0.001). Based on these findings, NuStat® hemostatic action should be comparable to the historic standard of care, and these newer hemostatic agents evaluated further in burn surgery and bleeding during other procedures such as trauma surgery.


Optimizing fat oxidation through exercise and diet.
Interventions aimed at increasing fat metabolism could potentially reduce the symptoms of metabolic diseases such as obesity and type 2 diabetes and may have tremendous clinical relevance. Hence, an understanding of the factors that increase or decrease fat oxidation is important. Exercise intensity and duration are important determinants of fat oxidation. Fat oxidation rates increase from low to moderate intensities and then decrease when the intensity becomes high. Maximal rates of fat oxidation have been shown to be reached at intensities between 59% and 64% of maximum oxygen consumption in trained individuals and between 47% and 52% of maximum oxygen consumption in a large sample of the general population. The mode of exercise can also affect fat oxidation, with fat oxidation being higher during running than cycling. Endurance training induces a multitude of adaptations that result in increased fat oxidation. The duration and intensity of exercise training required to induce changes in fat oxidation is currently unknown. Ingestion of carbohydrate in the hours before or on commencement of exercise reduces the rate of fat oxidation significantly compared with fasted conditions, whereas fasting longer than 6 h optimizes fat oxidation. Fat oxidation rates have been shown to decrease after ingestion of high-fat diets, partly as a result of decreased glycogen stores and partly because of adaptations at the muscle level.


Smoking and financial stress.
Stress relief is commonly provided as a reason for smoking. However, it is plausible that the cost of smoking may create financial stress, particularly among the poor. The aim of the study was to examine the relationship between smoking and financial stress. Cross sectional survey of households from private dwellings conducted by the Australian Bureau of Statistics (ABS), using a stratified multistage area sample design. Australia, 1998-99. Nationally representative sample of households (n = 6892). The outcome measures of objective financial stress were two dichotomous variables indicating whether the household had experienced any financial stress or severe financial stress in the past 12 months. The odds of experiencing any financial stress were 1.5 (95% confidence interval (CI) 1.3 to 1.7) times greater, and the odds of severe financial stress were twice (95% CI 1.6 to 2.5) as large for smoking households than non-smoking households. The effect of smoking on financial stress did not vary significantly across categories of income. Among smoking households, higher percentage of total household expenditure on tobacco was significantly related to financial stress. Given data were cross sectional, firm conclusions cannot be drawn about the causal relationship between smoking and financial stress. It is likely that they both affect each other. Undoubtedly, expenditure on tobacco will reduce available funds that could otherwise be used to ameliorate financial stress.


Sun exposure of indoor workers in the UK - survey on the time spent outdoors.
Assessment of ultraviolet (UV) exposure is essential for evaluation of the risks and benefits to optimise public health outcomes. The exposure depends on available environmental UV radiation and individual behaviour, and it can be obtained from dosimetry studies; however, the use of dosimeters is often not feasible for large population groups or over long periods of time. In this study, a lifestyle questionnaire has been used to obtain information on the time spent outdoors by indoor workers that could be used in combination with dosimetry studies in smaller targeted groups to quantify UV exposure for health risk/benefit analysis. 894 office and laboratory workers at the Public Health England, UK, responded to the survey. Questions addressed the time of day and the duration of time; staff were outdoors on weekdays, at weekends and during holidays. The majority of the responders spent negligible time outdoors on weekdays. Outdoor activities before and after work were constrained by the work pattern and commuting. The average time for those who go outdoors before and after commuting was 22.5 ± 16.2 min and 30.4 ± 21.4 min, respectively. Only 7% of participants regularly spent their lunch break outdoors for 21.5 ± 12.2 min and weekday exposure may contribute less than 13% of the daily available erythema dose. At the weekend, on average responders spend 5.0 ± 2.6 h outdoors over the two days: if taken around midday, it accounts for approximately 50% of available UV exposure. In winter months in the UK, November to March, the combination of very low environmental UV and low ambient temperatures results in negligible UV exposure. Holidays contributed to the majority of the annual UV exposure. In summer, 45% of responders went to destinations where the UV levels may be up to 2 times higher than in the UK; durations of overseas holidays are also longer than UK breaks. The UV dose from two weeks of holiday in extreme UV index level destinations could be comparable to a 1.5-2 summer months holiday in the UK. The survey data were validated with 6 months of dosimetry within the same cohort; very strong and strong correlation was found between the survey and measurements. This shows that a lifestyle survey can be used in combination with targeted dosimetry studies in small groups to obtain information about the time spent outdoors.


Incidence, effects, and management of sickle cell disease in Brazil.
Forty-five percent of the 121 million persons who live in Brazil have morphological indications of Black admixture, and 5-6% of them are carriers of the hemoglobin S gene. But even in persons identified as white, the hemoglobin AS genotype is present in about 1%. The total number of people with sickle cell disease is estimated as 45,000. The present analysis is based in 409 patients studied in Rio de Janeiro. The observed frequency of deformities of the vertebrae (18%), bone infarcts (12%), and gnathopathy (4%) was lower than those found in any other series. The proportion of adults with splenomegaly was also lower than that of other studies. Chest pains were more frequent in males, while bone or joint pains and splenic sequestration crises seemed to be more common in females. Effects of the disease in the viability and fertility of these patients were quantified. Fetal loss in 67 pregnancies was 48%. Hemoglobin F levels showed a clear age effect, and higher levels were associated with a more benign course of the disease. Information about the services for prevention and treatment of sickle cell disease that exist in Brazil and one place in Venezuela, is provided. Treatment is only symptomatic in 12 centers, while in São Paulo piracetam is being successfully used in the treatment of crises. A brief overview about the current Brazilian studies on this disease is also presented.


Atomistic Molecular Dynamics Simulations of the Lower Critical Solution Temperature Transition of Poly( N-vinylcaprolactam) in Aqueous Solutions.
Poly( N-vinylcaprolactam) (PVCL) is a thermo-responsive polymer, which exhibits a lower critical solution temperature (LCST) in an aqueous solution. The LCST of this hydrophilic-to-hydrophobic transition is found to be strongly dependent on the salt-type and salt-concentration as well as on the molecular weight and concentration of the polymer. Here, atomistic molecular dynamics simulations have been successfully conducted for the first time to investigate the LCST transition of a 100 degree of polymerization PVCL chain in water, 1 M NaCl, 3.5 M NaCl, and 0.5 M CaCl2 solutions. Our results show that steric hindrance resulting from the bulky 7-member ring on the PVCL chain plays a critical role in the conformational transition. Moreover, the degrees of hydration and dehydration below or above the transition temperature are highly dependent on the specific solution condition and temperature. Water molecules are found to be trapped inside the collapsed polymer chains leading to the varying degrees of hydration and dehydration of the polymer chain in different solutions. Calculated water diffusion coefficients for both trapped and free water molecules agree very well with experimental measurements.


Antagonists of the system L neutral amino acid transporter (LAT) promote endothelial adhesivity of human red blood cells.
The system L neutral amino acid transporter (LAT; LAT1, LAT2, LAT3, or LAT4) has multiple functions in human biology, including the cellular import of S-nitrosothiols (SNOs), biologically active derivatives of nitric oxide (NO). SNO formation by haemoglobin within red blood cells (RBC) has been studied, but the conduit whereby a SNO leaves the RBC remains unidentified. Here we hypothesised that SNO export by RBCs may also depend on LAT activity, and investigated the role of RBC LAT in modulating SNO-sensitive RBC-endothelial cell (EC) adhesion. We used multiple pharmacologic inhibitors of LAT in vitro and in vivo to test the role of LAT in SNO export from RBCs and in thereby modulating RBC-EC adhesion. Inhibition of human RBC LAT by type-1-specific or nonspecific LAT antagonists increased RBC-endothelial adhesivity in vitro, and LAT inhibitors tended to increase post-transfusion RBC sequestration in the lung and decreased oxygenation in vivo. A LAT1-specific inhibitor attenuated SNO export from RBCs, and we demonstrated LAT1 in RBC membranes and LAT1 mRNA in reticulocytes. The proadhesive effects of inhibiting LAT1 could be overcome by supplemental L-CSNO (S-nitroso-L-cysteine), but not D-CSNO or L-Cys, and suggest a basal anti-adhesive role for stereospecific intercellular SNO transport. This study reveals for the first time a novel role of LAT1 in the export of SNOs from RBCs to prevent their adhesion to ECs. The findings have implications for the mechanisms of intercellular SNO signalling, and for thrombosis, sickle cell disease, and post-storage RBC transfusion, when RBC adhesivity is increased.


Recruitment of a critically endangered sawfish into a riverine nursery depends on natural flow regimes.
The freshwater sawfish (Pristis pristis) was recently listed as the most Evolutionarily Distinct and Globally Endangered (EDGE) animal. The Fitzroy River in the remote Kimberley region of north-western Australia represents a significant stronghold for the species, which uses the freshwater reaches of the river as a nursery. There is also mounting pressure to develop the water resources of the region for agriculture that may substantially affect life history dynamics of sawfish in this system. However, the relationship between hydrology and population dynamics of freshwater sawfish was unknown. We used standardized catch data collected over 17 years to determine how wet season volume influences recruitment of freshwater sawfish into their riverine nursery. Negligible recruitment occurred in years with few days of high flood levels (above 98th percentile of cease-to-flow stage height), and relatively high recruitment occurred in years with 14 or more days of high flood levels. This relationship is indicative of a distinct boom-or-bust cycle, whereby freshwater sawfish rely almost entirely on the few years with large wet season floods, and the brief periods of highest water levels within these years, to replenish juvenile populations in the Fitzroy River nursery. This has direct implications for sustainable water resource management for the Fitzroy River basin in order to preserve one of the last known intact nursery habitats for this globally threatened species.


PLK1 Is transcriptionally activated by NF-κB during cell detachment and enhances anoikis resistance through inhibiting β-catenin degradation in esophageal squamous cell carcinoma.
To investigate the molecular mechanisms through which polo-like kinase-1 (PLK1) takes part in anoikis resistance of esophageal squamous cell carcinoma (ESCC) cells. The role of PLK1 in cell anoikis resistance was examined by ectopic gene expression and siRNA-mediated knockdown. Glutathione S-transferase pull-down and co-immunoprecipitation assays were utilized to investigate PLK1-interacting proteins. Electrophoretic mobility shift assay, chromatin immunoprecipitation, and reporter gene assays were carried out to identify the transcription factors responsible for PLK1 expression during anoikis resistance. We found that detachment of ESCC cells triggers the upregulation of PLK1. Elevated PLK1 expression contributes to protection against anoikis in cancer cells through the regulation of β-catenin expression. Moreover, we showed that, through direct binding to the PLK1 promoter, the NF-κB subunit RelA transcriptionally activates PLK1, which inhibits the ubiquitination and degradation of β-catenin. Inhibition of the NF-κB pathway restores the sensitivity of cancer cells to anoikis by downregulating PLK1/β-catenin expression. In addition, RelA gene amplification and protein overexpression was significantly correlated with PLK1 expression in ESCC tissues. Our findings suggest that upregulation of PLK1 triggered by cell detachment is regulated by RelA at the transcriptional level. PLK1 protects esophageal carcinoma cells from anoikis through modulation of β-catenin protein levels by inhibiting their degradation. Taken together, this study reveals critical mechanisms involved in the role of RelA/PLK1/β-catenin in anoikis resistance of ESCC cells.


Treatment of renal allograft acute rejection with methylprednisolone: effect of fixed dose versus dose per body mass index.
Considerable interpatient variability in steroid pharmacokinetics has been observed in renal transplant recipients. The purpose of this retrospective study is to evaluate the relationship between the dose of methylprednisolone (MP) used to treat acute rejection (AR) after renal transplantation and the response to treatment. 117 first AR episodes from 408 renal transplants were reviewed. The dose of MP used to treat AR was < 45 mg/kg/m2 in 60 patients and > and = 45 mg/kg/m2 in 57 patients. The correlation between fixed dose ( < 1.25 vs. > and = 1.25 g) and dose based on BMI was evaluated by simple linear regression analysis (r2 = 0.78, p < 0.0005). Response to treatment was as follows: MP successful (Group 1, n = 80); MP failed, OKT3 successful (Group 2, n = 17); MP and OKT3 failed (Group 3, n = 3) and MP failed, no further treatment (n = 17). No relationship was observed between the dose of MP, whether fixed or based on BMI, and (1) response to treatment of the first AR, (2) incidence of a second AR and (3) response to subsequent treatment with OKT3. Actuarial graft survival was higher in Group 1 compared to Group 2 (p < 0.0005), lower in Black recipients (p = 0.02) and higher when > and = 45 mg/kg/m2 of MP was used to treat AR (p = 0.06). In conclusion, no relationship between the dose of MP, whether fixed or based on BMI, and the response to treatment of AR was observed. MP dosage based on BMI may be a reasonable alternative to a fixed-dose regimen with the advantage of limiting steroid exposure and the consequent side-effects.


Endocrine treatment options for advanced breast cancer--the role of fulvestrant.
For many years, tamoxifen has been the 'gold standard' amongst anti-oestrogen therapies for breast cancer. However, the selective aromatase inhibitors (AIs), anastrozole, letrozole and exemestane, have demonstrated advantages over tamoxifen as first-line treatments for advanced disease. Anastrozole is also more effective as an adjuvant treatment in early, operable breast cancer and is being increasingly used in the adjuvant setting. Generally, the selective oestrogen receptor modulators (SERMs), such as toremifene, droloxifene, idoxifene, raloxifene, and arzoxifene, show minimal activity in tamoxifen-resistant disease and show no superiority over tamoxifen as first-line treatments. In addition to these agents, other treatment options for advanced disease include high-dose oestrogens and progestins. Response rates for high-dose oestrogens and tamoxifen are similar, but the use of oestrogens is limited by their toxicity profile. Consequently, there is a need for new endocrine treatment options for breast cancer, particularly for use in disease that is resistant to tamoxifen or AIs. Fulvestrant ('Faslodex') is a new type of steroidal oestrogen receptor (ER) antagonist that downregulates cellular levels of the ER and progesterone receptor and has no agonist activity. This paper reviews the key efficacy and tolerability data for fulvestrant in postmenopausal women in the context of other endocrine therapies and explores the potential role of fulvestrant within the sequencing of endocrine therapies for advanced breast cancer.


Thalamotomy versus thalamic stimulation for multiple sclerosis tremor.
Disabling intractable tremor occurs frequently in patients with multiple sclerosis (MS). There is currently no effective medical treatment available, and the results of surgical intervention have been variable. Thalamotomy has been the mainstay of neurosurgical therapy for intractable MS tremor, however the popularisation of deep brain stimulation (DBS) has led to the adoption of chronic thalamic stimulation in an attempt to ameliorate this condition. With the goal of examining the relative efficacy and adverse effects of these two surgical strategies, we studied twenty carefully selected patients with intractable MS tremor. Thalamotomy was performed in 10 patients, with chronic DBS administered to the remaining 10. Both thalamotomy and thalamic stimulation produced improvements in postural and intention tremor. The mean improvement in postural tremor at 16.2 months following surgery was 78%, compared with a 64% improvement after thalamic stimulation (14.6 month follow-up) (P > 0.05). Intention tremor improved by 72% in the group undergoing thalamotomy, a significantly larger gain than the 36% tremor reduction following DBS (P < 0.05). Early postoperative complications were common in both groups. Permanent complications related to surgery occurred in four patients overall. Following thalamotomy, long-term adverse effects were observed in three patients (30%), and comprised hemiparesis and seizures. Only one patient in the thalamic stimulation group experienced a permanent deficit (monoparesis). We conclude that thalamotomy is a more efficacious surgical treatment for intractable MS tremor, however the higher incidence of persistent neurological deficits in patients receiving lesional surgery may support the use of DBS as the preferred surgical strategy.


Humans use visual and remembered information about object location to plan pointing movements.
We investigated whether humans use a target's remembered location to plan reaching movements to targets according to the relative reliabilities of visual and remembered information. Using their index finger, subjects moved a virtual object from one side of a table to the other, and then went back to a target. In some trials, the target shifted unnoticed while the finger made the first movement. We regressed subjects' movement trajectories against the initial and shifted target locations to infer the weights that subjects gave to remembered and visual locations. We measured the reliability of vision and memory by adding conditions in which the target only appeared after subjects made the first movement (vision only) and in which the target was initially present but disappeared during the first movement (memory only). When both visual and remembered information were available, movement trajectories were biased to the remembered target location. The different weights that subjects gave to memory and visual information on average matched the weights predicted by the variance associated with the use of vision and memory alone. This suggests that humans integrate remembered information about object locations with peripheral visual information by taking into account the relative reliability of the two sources of information.


A tissue-dependent hypothesis of dental caries.
Current understanding of dental caries considers this disease a demineralization of the tooth tissues due to the acid produced by sugar-fermenting microorganisms. Thus, caries is considered a diet- and pH-dependent process. We present here the first metagenomic analysis of the bacterial communities present at different stages of caries development, with the aim of determining whether the bacterial composition and biochemical profile are specific to the tissue affected. The data show that microbial composition at the initial, enamel-affecting stage of caries is significantly different from that found at subsequent stages, as well as from dental plaque of sound tooth surfaces. Although the relative proportion of Streptococcus mutans increased from 0.12% in dental plaque to 0.72% in enamel caries, Streptococcus mitis and Streptococcus sanguinis were the dominant streptococci in these lesions. The functional profile of caries-associated bacterial communities indicates that genes involved in acid stress tolerance and dietary sugar fermentation are overrepresented only at the initial stage (enamel caries), whereas other genes coding for osmotic stress tolerance as well as collagenases and other proteases enabling dentin degradation are significantly overrepresented in dentin cavities. The results support a scenario in which pH and diet are determinants of the disease during the degradation of enamel, but in dentin caries lesions not only acidogenic but also proteolytic bacteria are involved. We propose that caries disease is a process of varying etiology, in which acid-producing bacteria are the vehicle to penetrate enamel and allow dentin degrading microorganisms to expand the cavity.


Barbarigenesis and the collapse of complex societies: Rome and after.
"Barbarism" is perhaps best understood as a recurring syndrome among peripheral societies in response to the threats and opportunities presented by more developed neighbors. This article develops a mathematical model of barbarigenesis-the formation of "barbarian" societies adjacent to more complex societies-and its consequences, and applies the model to the case of Europe in the first millennium CE. A starting point is a game (developed by Hirshleifer) in which two players allocate their resources either to producing wealth or to fighting over wealth. The paradoxical result is that a richer and potentially more powerful player may lose out to a poorer player, because the opportunity cost of fighting is greater for the former. In a more elaborate spatial model with many players, the outcome is a wealth-power mismatch: central regions have comparatively more wealth than power, peripheral regions have comparatively more power than wealth. In a model of historical dynamics, a wealth-power mismatch generates a long-lasting decline in social complexity, sweeping from more to less developed regions, until wealth and power come to be more closely aligned. This article reviews how well this model fits the historical record of late Antiquity and the early Middle Ages in Europe both quantitatively and qualitatively. The article also considers some of the history left out of the model, and why the model doesn't apply to the modern world.


Cognitive mechanisms of diazepam administration: a healthy volunteer model of emotional processing.
Benzodiazepine drugs continue to be prescribed relatively frequently for anxiety disorders, especially where other treatments have failed or when rapid alleviation of anxiety is imperative. The neuropsychological mechanism by which these drugs act to relieve symptoms, however, remains underspecified. Cognitive accounts of anxiety disorders emphasise hypervigilance for threat in the maintenance of the disorders. The current study examined the effects of 7- or 8-day administration of diazepam in healthy participants (n = 36) on a well-validated battery of tasks measuring emotional processing, including measures of vigilance for threat and physiological responses to threat. Compared to placebo, diazepam reduced vigilant-avoidant patterns of emotional attention (p < 0.01) and reduced general startle responses (p < .05). Diazepam administration had limited effects on emotional processing, enhancing the response to positive vs negative words in the emotional categorisation task (p < .05), modulating emotional memory in terms of false accuracy (p < .05) and slowing the recognition of all facial expressions of emotion (p = .01). These results have implications for our understanding of the cognitive mechanisms of benzodiazepine treatment. The data reported here suggests that diazepam modulates emotional attention, an effect which may be involved in its therapeutic actions in anxiety.


The Fennel, Foeniculum vulgare incorporated diet shows anxiolytic potential: A pre-clinical study.
This novel study was conducted with objective to evaluate the anxiolytic potential of whole-crushed seeds of Foeniculum vulgare (FV) which were incorporated in diet. Albino mice were divided in three groups: Control-group, Study-group 2% FV and Study-group 4% FV, each having 10 mice. Special dietary pellets containing whole-crushed Foeniculum vulgare seeds were prepared in 2% and 4% ratio, respectively and were fed to respective Study groups whereas Control-group was given regular rodent diet for 2 months. Animal behaviour was assessed using Home Cage Activity test, Head Dip test, Light and Dark Box test and Open Field test at intervals of 15 days for a period of 2 months. The results of this study showed, decrease in Cage Crossing activity, more number of Head Dips, increased time spent in Light box and increase in number of transitions between Light and Dark Box, increased number of Central Squares Crossed and increased time spent in Central Squares of Open Field arena for both study groups in comparison with control group. Foeniculum vulgare whole-crushed seeds diet of 2% and 4% was found to have anxiolytic effect.


Bursty communication patterns facilitate spreading in a threshold-based epidemic dynamics.
Records of social interactions provide us with new sources of data for understanding how interaction patterns affect collective dynamics. Such human activity patterns are often bursty, i.e., they consist of short periods of intense activity followed by long periods of silence. This burstiness has been shown to affect spreading phenomena; it accelerates epidemic spreading in some cases and slows it down in other cases. We investigate a model of history-dependent contagion. In our model, repeated interactions between susceptible and infected individuals in a short period of time is needed for a susceptible individual to contract infection. We carry out numerical simulations on real temporal network data to find that bursty activity patterns facilitate epidemic spreading in our model.


LncExpDB: an expression database of human long non-coding RNAs.
Expression profiles of long non-coding RNAs (lncRNAs) across diverse biological conditions provide significant insights into their biological functions, interacting targets as well as transcriptional reliability. However, there lacks a comprehensive resource that systematically characterizes the expression landscape of human lncRNAs by integrating their expression profiles across a wide range of biological conditions. Here, we present LncExpDB (https://bigd.big.ac.cn/lncexpdb), an expression database of human lncRNAs that is devoted to providing comprehensive expression profiles of lncRNA genes, exploring their expression features and capacities, identifying featured genes with potentially important functions, and building interactions with protein-coding genes across various biological contexts/conditions. Based on comprehensive integration and stringent curation, LncExpDB currently houses expression profiles of 101 293 high-quality human lncRNA genes derived from 1977 samples of 337 biological conditions across nine biological contexts. Consequently, LncExpDB estimates lncRNA genes' expression reliability and capacities, identifies 25 191 featured genes, and further obtains 28 443 865 lncRNA-mRNA interactions. Moreover, user-friendly web interfaces enable interactive visualization of expression profiles across various conditions and easy exploration of featured lncRNAs and their interacting partners in specific contexts. Collectively, LncExpDB features comprehensive integration and curation of lncRNA expression profiles and thus will serve as a fundamental resource for functional studies on human lncRNAs.


Image-based feedback and analysis system for digital microfluidics.
Digital microfluidics (DMF) is a technology that provides a means of manipulating nL-μL volumes of liquids on an array of electrodes. By applying an electric potential to an electrode, these discrete droplets can be controlled in parallel which can be transported, mixed, reacted, and analyzed. Typically, an automation system is interfaced with a DMF device that uses a standard set of basic instructions written by the user to execute droplet operations. Here, we present the first feedback method for DMF that relies on imaging techniques that will allow online detection of droplets without the need to reactivate all destination electrodes. Our system consists of integrating open-source electronics with a CMOS camera and a zoom lens for acquisition of the images that will be used to detect droplets on the device. We also created an algorithm that uses a Hough transform to detect a variety of droplet sizes and to detect singular droplet dispensing and movement failures on the device. As a first test, we applied this feedback system to test droplet movement for a variety of liquids used in cell-based assays and to optimize different feedback actuation schemes to improve droplet movement fidelity. We also applied our system to a colorimetric enzymatic assay to show that our system is capable of biological analysis. Overall, we believe that using our approach of integrating imaging and feedback for DMF can provide a platform for automating biological assays with analysis.


Effect of peroxide on neutralization-potential values of siderite and other carbonate minerals.
To assess quantitatively the effect of peroxide addition to standard static tests of the neutralization potential (NP) of mine wastes, 10 specimens of carbonate minerals, including five of siderite (FeCO3) and two of rhodochrosite (MnCO3), were analyzed by electron microprobe. The compositions of the siderite span a range from 60 to 86 mol % Fe. Tests of NP for the siderite diluted with 80% (w/w) kaolinite gave values of 647 to 737 kg CaCO3 equivalent per Mg for determinations by the standard Sobek method. However, if it is assumed that the ferrous carbonate component of the mineral does not contribute to NP in field situations because oxidation of Fe(II) to Fe(III) and the subsequent hydrolysis of Fe(III) leads to the release of an equivalent amount of acid, then the calculated NP for the samples ranges from 110 to 390 kg CaCO3 equivalent per Mg. Two different methods involving the addition of peroxide to the test solutions were successful in bringing the measured NP values closer to the theoretical ones. By contrast, the tests with rhodochrosite indicated the Mn(II) to be stable. For long-term environmental planning, especially for wastes from metalliferous sulfide-poor deposits in which gradual dissolution of silicate and aluminosilicate minerals may be involved in attenuating the acidity, consideration in the overall NP budget needs to be given to the ferrous iron content of those minerals. The presence of Fe2+-bearing minerals, especially carbonates, in tested mine-waste materials may lead to overestimated Sobek NP values, thus increasing the risk of poor-quality drainage and the need for costly remediation.


Comparison of false negative rates among breast cancer screening modalities with or without mammography: Miyagi trial.
False negative rates were compared in two screening modalities, physical examination with or without mammography, in an intervention study for women aged over 50 in Miyagi Prefecture. Thirty-five breast cancers were detected in 12,515 subjects who participated in the trial consisting of physical examination and mammography, whereas 44 breast cancers were detected in 50,105 subjects who received physical examination alone, so that the detection rates were 0.28% and 0.09%, respectively. Among 50,061 subjects who received physical examination alone, 8 women were diagnosed as having breast cancer within 12 months after the screening, while only one of 12,480 screenees receiving the combined modality was so diagnosed, implying false negative rates of 15.4% and 2.8%, respectively. When the screening sensitivity in the combined system was analyzed according to each single modality, the false negative rate provided by physical examination with mammography turned out to be 2.8%, significantly lower than that (33.3%) by the physical examination alone. Minimal breast cancers represented 25.7% of all screen-detected cancers in the combined modality, compared with 9.1% in the modality without mammography. The trial thus indicates that physical examination combined with mammography may be an appropriate modality for breast cancer screening in women aged over 50 on the basis of screening sensitivity.


MicroRNA: mechanism of gene regulation and application to livestock.
Posttranscriptional regulation of gene expression plays a role in multiple cellular pathways. MicroRNA (miRNA) are an emerging class of small RNA that regulate gene translation. However, the mechanisms by which miRNA regulate this process remain controversial. By altering posttranscriptional regulation, miRNA have a role in guiding developmental decisions, including cell fate, cell cycle progression, apoptosis, adipocyte differentiation, and processes that alter muscle development and growth. The role of miRNA in developmental decisions that affect animal biology is of significant interest, yet the current literature is limited in livestock models. Therefore, a review of the mechanisms by which miRNA alter gene translation and the current research evaluating miRNA in production livestock is needed.


Protein expression in pectoral skeletal muscle of chickens as influenced by dietary methionine.
Effects of dietary methionine (Met) on pectoralis muscle development and the effect that Met as a nutritional substrate has on protein expression of skeletal muscle cells of pectoralis muscle of chickens were evaluated in this study. Broiler chickens received a common pretest diet up to 21 d of age and were subsequently fed either a low (LM) or high Met (HM) diet (0.41 vs. 0.51% of diet) from 21 to 42 d of age. Dietary deficiency was shown in vivo judging by the depression in breast meat weight and yield when broilers were fed the LM diet. Global protein expression was analyzed by quantitative high-performance liquid chromatography nanospray ionization tandem mass spectrometry. Up- and downregulated proteins were analyzed via Ingenuity Pathways Analysis to identify the metabolic pathways affected. Four canonical pathways related to muscle development were identified as being differentially regulated between LM- and HM-fed chickens. These pathways included the citrate cycle and calcium, actin cytoskeleton, and clathrin-mediated endocytosis signaling. The HM diet may have allowed for increased muscle growth by an increased availability of nutrients to muscle cells. Although the Met supplementation was associated with enhanced breast muscle growth, contraction fiber concentrations in muscles decreased and were associated with a lower calcium transportation rate and sensitivity and with a lower energy supply. It is further suggested that increased muscle protein deposition, that was induced by Met supplementation, may have been largely due to sarcoplasmic rather myofibrillar hypertrophy.


Chronic inflammatory polyradiculoneuropathy.
The diagnostic criteria, natural history, nerve conduction characteristics, pathology, laboratory features, and efficacy of corticosteroid treatment have been evaluated personally in 53 patients with chronic inflammatory polyradiculoneuropathy (CIP) who were followed up for an average of about 7.5 years. These were patients whose monophasic neurologic deficit had not crested by 6 months, patients with recurrences, and patients with a steady or stepwise progression. The typical features of CIP include absence of an associated disease, frequent history of preceding infection or receipt of foreign protein, and tendency to involve cranial, truncal, and proximal as well as distal limb structures and to have diffusely slow conduction velocity of peripheral nerves. The most marked slowing is often very proximal. The pathologic features include serous edema, mononuclear cell infiltrates (especially in perivascular areas, but without evidence of vasculitis), macrophage-induced segmental demyelination, and hypertrophic neuritis. If our patients are representative, complete recovery occurs only infrequently; about 60% of patients are able to be ambulatory and work, 25% become confined to a wheelchair or become bedridden, and approximately 10% die from their disease. Although the bulk of the pathologic changes affect spinal roots and proximal nerves, the brain and spinal cord may be involved also. Degeneration into linear rows of myelin ovoids is the predominant type of myelinated fiber degeneration of the sural nerve at the ankle.


Allelic heterogeneity at the serotonin transporter locus (SLC6A4) confers susceptibility to autism and rigid-compulsive behaviors.
Autism is a spectrum of neurodevelopmental disorders with a primarily genetic etiology exhibiting deficits in (1) development of language and (2) social relationships and (3) patterns of repetitive, restricted behaviors or interests and resistance to change. Elevated platelet serotonin (5-HT) in 20%-25% of cases and efficacy of selective 5-HT reuptake inhibitors (SSRIs) in treating anxiety, depression, and repetitive behaviors points to the 5-HT transporter (5-HTT; SERT) as a strong candidate gene. Association studies involving the functional insertion/deletion polymorphism in the promoter (5-HTTLPR) and a polymorphism in intron 2 are inconclusive, possibly because of phenotypic heterogeneity. Nonetheless, mounting evidence for genetic linkage of autism to the chromosome 17q11.2 region that harbors the SERT locus (SLC6A4) supports a genetic effect at or near this gene. We confirm recent reports of sex-biased genetic effects in 17q by showing highly significant linkage driven by families with only affected males. Association with common alleles fails to explain observed linkage; therefore, we hypothesized that preferential transmission of multiple alleles does explain it. From 120 families, most contributing to linkage at 17q11.2, we found four coding substitutions at highly conserved positions and 15 other variants in 5' noncoding and other intronic regions transmitted in families exhibiting increased rigid-compulsive behaviors. In the aggregate, these variants show significant linkage to and association with autism. Our data provide strong support for a collection of multiple, often rare, alleles at SLC6A4 as imposing risk of autism.


CpG-adjuvanted stable prefusion SARS-CoV-2 spike protein protected hamsters from SARS-CoV-2 challenge.
The COVID-19 pandemic presents an unprecedented challenge to global public health. Rapid development and deployment of safe and effective vaccines are imperative to control the pandemic. In the current study, we applied our adjuvanted stable prefusion SARS-CoV-2 spike (S-2P)-based vaccine, MVC-COV1901, to hamster models to demonstrate immunogenicity and protection from virus challenge. Golden Syrian hamsters immunized intramuscularly with two injections of 1 µg or 5 µg of S-2P adjuvanted with CpG 1018 and aluminum hydroxide (alum) were challenged intranasally with SARS-CoV-2. Prior to virus challenge, the vaccine induced high levels of neutralizing antibodies with 10,000-fold higher IgG level and an average of 50-fold higher pseudovirus neutralizing titers in either dose groups than vehicle or adjuvant control groups. Six days after infection, vaccinated hamsters did not display any weight loss associated with infection and had significantly reduced lung pathology and most importantly, lung viral load levels were reduced to lower than detection limit compared to unvaccinated animals. Vaccination with either 1 μg or 5 μg of adjuvanted S-2P produced comparable immunogenicity and protection from infection. This study builds upon our previous results to support the clinical development of MVC-COV1901 as a safe, highly immunogenic, and protective COVID-19 vaccine.


Frequency and perturbations of various peripheral blood cell populations before and after eculizumab treatment in paroxysmal nocturnal hemoglobinuria.
While red blood cells (RBCs) and granulocytes have been more studied, platelets and reticulocytes are not commonly used in paroxysmal nocturnal hemoglobinuria (PNH) flow-cytometry and less is known about susceptibility to complement-mediated destruction and effects of anti-complement therapy on these populations. We performed flow-cytometry of RBCs and granulocytes in 90 PNH patients and of platelets and reticulocytes in a subgroup (N = 36), to unveil perturbations of these populations during PNH disease course before and after anti-complement treatment. We found that platelets and reticulocytes were less sensitive to complement-mediated lysis than RBCs but not as resistant as granulocytes, as shown by mean sensitive fraction (difference in a given PNH population vs. PNH granulocyte clone size). In treated patients, reticulocytes, platelets, RBCs (with differences between type II and III) and granulocytes significantly increased post-treatment, confirming the role of PNH hematopoiesis within the context of anti-complement therapy. Moreover, we found that PNH platelet clone size reflects PNH granulocyte clone size. Finally, we established correlations between sensitive fraction of PNH cell-types and thrombosis. In sum, we applied a flow-cytometry panel for investigation of PNH peripheral blood populations' perturbations before and after eculizumab treatment to explore complement-sensitivity and kinetics of these cells during the disease course.


Global profiling of the cell surface proteome of cancer cells uncovers an abundance of proteins with chaperone function.
There is currently limited data available pertaining to the global characterization of the cell surface proteome. We have implemented a strategy for the comprehensive profiling and identification of surface membrane proteins. This strategy has been applied to cancer cells, including the SH-SY5Y neuroblastoma, the A549 lung adenocarcinoma, the LoVo colon adenocarcinoma, and the Sup-B15 acute lymphoblastic leukemia (B cell) cell lines and ovarian tumor cells. Surface membrane proteins of viable, intact cells were subjected to biotinylation then affinity-captured and purified on monomeric avidin columns. The biotinylated proteins were eluted from the monomeric avidin columns as intact proteins and were subsequently separated by two-dimensional PAGE, transferred to polyvinylidene difluoride membranes, and visualized by hybridization with streptavidin-horseradish peroxidase. Highly reproducible, but distinct, two-dimensional patterns consisting of several hundred biotinylated proteins were obtained for the different cell populations analyzed. Identification of a subset of biotinylated proteins among the different cell populations analyzed using matrix-assisted laser desorption ionization and tandem mass spectrometry uncovered proteins with a restricted expression pattern in some cell line(s), such as CD87 and the activin receptor type IIB. We also identified more widely expressed proteins, such as CD98, and a sushi repeat-containing protein, a member of the selectin family. Remarkably, a set of proteins identified as chaperone proteins were found to be highly abundant on the cell surface, including GRP78, GRP75, HSP70, HSP60, HSP54, HSP27, and protein disulfide isomerase. Comprehensive profiling of the cell surface proteome provides an effective approach for the identification of commonly occurring proteins as well as proteins with restricted expression patterns in this compartment.


A 3D-printed mini-hydrocyclone for high throughput particle separation: application to primary harvesting of microalgae.
The separation of micro-sized particles in a continuous flow is crucial part of many industrial processes, from biopharmaceutical manufacturing to water treatment. Conventional separation techniques such as centrifugation and membrane filtration are largely limited by factors such as clogging, processing time and operation efficiency. Microfluidic based techniques have been gaining great attention in recent years as efficient and powerful approaches for particle-liquid separation. Yet the production of such systems using standard micro-fabrication techniques is proven to be tedious, costly and have cumbersome user interfaces, which all render commercialization difficult. Here, we demonstrate the design, fabrication and evaluation based on CFD simulation as well as experimentation of 3D-printed miniaturized hydrocyclones with smaller cut-size for high-throughput particle/cell sorting. The characteristics of the mini-cyclones were numerically investigated using computational fluid dynamics (CFD) techniques previously revealing that reduction in the size of the cyclone results in smaller cut-size of the particles. To showcase its utility, high-throughput algae harvesting from the medium with low energy input is demonstrated for the marine microalgae Tetraselmis suecica. Final microalgal biomass concentration was increased by 7.13 times in 11 minutes of operation time using our designed hydrocyclone (HC-1). We expect that this elegant approach can surmount the shortcomings of other microfluidic technologies such as clogging, low-throughput, cost and difficulty in operation. By moving away from production of planar microfluidic systems using conventional microfabrication techniques and embracing 3D-printing technology for construction of discrete elements, we envision 3D-printed mini-cyclones can be part of a library of standardized active and passive microfluidic components, suitable for particle-liquid separation.


Why do sleep disorders belong to mental disorder classifications? A network analysis of the "Sleep-Wake Disorders" section of the DSM-5.
This article proposes to investigate how Sleep disorders have been conceptualized within the DSM-5 through symptom network analysis of the diagnostic criteria of the "Sleep-Wake Disorders" section in the DSM-5. We hypothesize that the analysis of the most central symptoms will allow us to better analyze the position of Sleep disorders in Mental disorders. We thus i) extracted the symptoms of the DSM-5 diagnostic criteria of Sleep-Wake disorders, ii) built the Sleep-Wake disorder DSM-5 network representation, and iii) quantified its structure at local and global levels using classical symptom network analysis. Thirty-four different symptoms were identified among the 53 DSM-5 diagnostic criteria of the 9 main disorders of the "Sleep-Wake Disorders" section. The symptom network structure of this section showed that the most central sleep symptoms are "Daytime Sleepiness", the Insomnia symptoms group ("Insomnia initiating", "Insomnia maintaining" and "Non-restorative sleep"), and Behavioral sleep symptoms (such as "Altered oniric activity", "Ambulation", "Abnormal responsiveness"). This network analysis shown that the belonging of Sleep-Wake disorders in the DSM-5 have been associated with central sleep symptoms considered as "Mental", given their phenomenality (qualitative nature of the experience) and subjectivity (in personal mental lives). Such a symptom network analysis can serve as an organizing framework to better understand the complexity of Sleep-Wake disorders by promoting research to connect the architecture of the symptom network to relevant biological, psychological and sociocultural factors.


Improving spinach, radish, and lettuce growth under red light-emitting diodes (LEDs) with blue light supplementation.
Radish (Raphanus sativus L. cv. Cherriette), lettuce (Lactuca sativa L. cv. Waldmann's Green), and spinach (Spinacea oleracea L. cv. Nordic IV) plants were grown under 660-nm red light-emitting diodes (LEDs) and were compared at equal photosynthetic photon flux (PPF) with either plants grown under cool-white fluorescent lamps (CWF) or red LEDs supplemented with 10% (30 micromoles m-2 s-1) blue light (400-500 nm) from blue fluorescent (BF) lamps. At 21 days after planting (DAP), leaf photosynthetic rates and stomatal conductance were greater for plants grown under CWF light than for those grown under red LEDs, with or without supplemental blue light. At harvest (21 DAP), total dry-weight accumulation was significantly lower for all species tested when grown under red LEDs alone than when grown under CWF light or red LEDs + 10% BF light. Moreover, total dry weight for radish and spinach was significantly lower under red LEDs + 10% BF than under CWF light, suggesting that addition of blue light to the red LEDs was still insufficient for achieving maximal growth for these crops.


Weapons of mass retraction.
Twitching motility is a unique form of bacterial propulsion on solid surfaces associated with cycles of extension, tethering and retraction of type IV pili (T4P). Although investigations over the last two decades in a number of species have identified the majority of the genes involved in this process, we are still learning how these pili are assembled and the mechanics by which bacteria use T4P to drag themselves from one place to another. Among the puzzles that remain to be solved is the mechanism by which hydrolysis of ATP is coupled to pilus assembly and disassembly, and how the cell envelope structure is modified to accommodate the passage of the pilus through the periplasm. Unravelling of these and other enigmas in the T4P system will not only teach us more about these important colonization and virulence factors, but also help us to understand related processes such as type II secretion, which relies on a set of proteins homologous to those in the T4P system, and bacterial conjugation, involving retractable pili belonging to the F-like subgroup of the type IV secretion family. This review focuses on recent discoveries relating to the assembly and function of T4P in generation of twitching motility.


[Prevention of osteoporosis by foods and dietary supplements. The effect of fructooligosaccharides (FOS) on the calcium absorption and bone].
Fructooligosaccharides (FOS) are well known as prebiotics which improve intestinal microflaura. FOS also have increasing effect on the intestinal absorption of calcium (Ca), magnesium (Mg) and iron. These effects were inspected by many animal experiments and then by human studies. Especially, FOS clearly prevent the decrease of bone mineral density by gastrectomy in rats. In this report, we mainly explain the preventive effect of FOS on the bone of gastrectomized rats and introduce relationship between another food ingredient or exercise.


Development trends of white matter connectivity in the first years of life.
The human brain is organized into a collection of interacting networks with specialized functions to support various cognitive functions. Recent research has reached a consensus that the brain manifests small-world topology, which implicates both global and local efficiency at minimal wiring costs, and also modular organization, which indicates functional segregation and specialization. However, the important questions of how and when the small-world topology and modular organization come into existence remain largely unanswered. Taking a graph theoretic approach, we attempt to shed light on this matter by an in vivo study, using diffusion tensor imaging based fiber tractography, on 39 healthy pediatric subjects with longitudinal data collected at average ages of 2 weeks, 1 year, and 2 years. Our results indicate that the small-world architecture exists at birth with efficiency that increases in later stages of development. In addition, we found that the networks are broad scale in nature, signifying the existence of pivotal connection hubs and resilience of the brain network to random and targeted attacks. We also observed, with development, that the brain network seems to evolve progressively from a local, predominantly proximity based, connectivity pattern to a more distributed, predominantly functional based, connectivity pattern. These observations suggest that the brain in the early years of life has relatively efficient systems that may solve similar information processing problems, but in divergent ways.


Up-regulation of transient receptor potential canonical 1 (TRPC1) following sarco(endo)plasmic reticulum Ca2+ ATPase 2 gene silencing promotes cell survival: a potential role for TRPC1 in Darier's disease.
The mechanism(s) involved in regulation of store operated calcium entry in Darier's disease (DD) is not known. We investigated the distribution and function of transient receptor potential canonical (TRPC) in epidermal skin cells. DD patients demonstrated up-regulation of TRPC1, but not TRPC3, in the squamous layers. Ca2+ influx was significantly higher in keratinocytes obtained from DD patients and showed enhanced proliferation compared with normal keratinocytes. Similar up-regulation of TRPC1 was also detected in epidermal layers of SERCA2+/- mice. HaCaT cells expressed TRPC1 in the plasma membrane. Expression of sarco(endo)plasmic reticulum Ca2+ ATPase (SERCA)2 small interfering RNA (siRNA) in HaCaT cells increased TRPC1 levels and thapsigargin-stimulated Ca2+ influx, which was blocked by store-operated calcium entry inhibitors. Thapsigargin-stimulated intracellular Ca2+ release was decreased in DD cells. DD keratinocytes exhibited increased cell survival upon thapsigargin treatment. Alternatively, overexpression of TRPC1 or SERCA2-siRNA in HaCaT cells demonstrated resistance to thapsigargin-induced apoptosis. These effects were dependent on external Ca2+ and activation of nuclear factor-kappaB. Isotretinoin reduced Ca2+ entry in HaCaT cells and decreased survival of HaCaT and DD keratinocytes. These findings put forward a novel consequence of compromised SERCA2 function in DD wherein up-regulation of TRPC1 augments cell proliferation and restrict apoptosis. We suggest that the anti-apoptotic effect of TRPC1 could potentially contribute to abnormal keratosis in DD.


Bacillus thuringiensis subsp. israelensis and its dipteran-specific toxins.
Bacillus thuringiensis subsp. israelensis (Bti) is the first Bacillus thuringiensis to be found and used as an effective biological control agent against larvae of many mosquito and black fly species around the world. Its larvicidal activity resides in four major (of 134, 128, 72 and 27 kDa) and at least two minor (of 78 and 29 kDa) polypeptides encoded respectively by cry4Aa, cry4Ba, cry11Aa, cyt1Aa, cry10Aa and cyt2Ba, all mapped on the 128 kb plasmid known as pBtoxis. These six δ-endotoxins form a complex parasporal crystalline body with remarkably high, specific and different toxicities to Aedes, Culex and Anopheles larvae. Cry toxins are composed of three domains (perforating domain I and receptor binding II and III) and create cation-selective channels, whereas Cyts are composed of one domain that acts as well as a detergent-like membrane perforator. Despite the low toxicities of Cyt1Aa and Cyt2Ba alone against exposed larvae, they are highly synergistic with the Cry toxins and hence their combinations prevent emergence of resistance in the targets. The lack of significant levels of resistance in field mosquito populations treated for decades with Bti-bioinsecticide suggests that this bacterium will be an effective biocontrol agent for years to come.


Assessing positive mental health in people with chronic physical health problems: correlations with socio-demographic variables and physical health status.
A holistic perspective on health implies giving careful consideration to the relationship between physical and mental health. In this regard the present study sought to determine the level of Positive Mental Health (PMH) among people with chronic physical health problems, and to examine the relationship between the observed levels of PMH and both physical health status and socio-demographic variables. The study was based on the Multifactor Model of Positive Mental Health (Lluch, 1999), which comprises six factors: Personal Satisfaction (F1), Prosocial Attitude (F2), Self-control (F3), Autonomy (F4), Problem-solving and Self-actualization (F5), and Interpersonal Relationship Skills (F6). The sample comprised 259 adults with chronic physical health problems who were recruited through a primary care center in the province of Barcelona (Spain). Positive mental health was assessed by means of the Positive Mental Health Questionnaire (Lluch, 1999). Levels of PMH differed, either on the global scale or on specific factors, in relation to the following variables: age: global PMH scores decreased with age (r=-0.129; p=0.038); b) gender: men scored higher on F1 (t=2.203; p=0.028) and F4 (t=3.182; p=0.002), while women scored higher on F2 (t -3.086; p=0.002) and F6 (t=-2.744; p=0.007); c) number of health conditions: the fewer the number of health problems the higher the PMH score on F5 (r=-0.146; p=0.019); d) daily medication: polymedication patients had lower PMH scores, both globally and on various factors; e) use of analgesics: occasional use of painkillers was associated with higher PMH scores on F1 (t=-2.811; p=0.006). There were no significant differences in global PMH scores according to the type of chronic health condition. The only significant difference in the analysis by factors was that patients with hypertension obtained lower PMH scores on the factor Autonomy (t=2.165; p=0.032). Most people with chronic physical health problems have medium or high levels of PMH. The variables that adversely affect PMH are old age, polypharmacy and frequent consumption of analgesics. The type of health problem does not influence the levels of PMH. Much more extensive studies with samples without chronic pathology are now required in order to be able to draw more robust conclusions.


Integrating multiple lines of evidence to better understand the evolutionary divergence of humpback dolphins along their entire distribution range: a new dolphin species in Australian waters?
The conservation of humpback dolphins, distributed in coastal waters of the Indo-West Pacific and eastern Atlantic Oceans, has been hindered by a lack of understanding about the number of species in the genus (Sousa) and their population structure. To address this issue, we present a combined analysis of genetic and morphologic data collected from beach-cast, remote-biopsied and museum specimens from throughout the known Sousa range. We extracted genetic sequence data from 235 samples from extant populations and explored the mitochondrial control region and four nuclear introns through phylogenetic, population-level and population aggregation frameworks. In addition, 180 cranial specimens from the same geographical regions allowed comparisons of 24 morphological characters through multivariate analyses. The genetic and morphological data showed significant and concordant patterns of geographical segregation, which are typical for the kind of demographic isolation displayed by species units, across the Sousa genus distribution range. Based on our combined genetic and morphological analyses, there is convincing evidence for at least four species within the genus (S. teuszii in the Atlantic off West Africa, S. plumbea in the central and western Indian Ocean, S. chinensis in the eastern Indian and West Pacific Oceans, and a new as-yet-unnamed species off northern Australia).


Impact of karyotype on treatment outcome in acute myeloid leukemia.
Over the course of the last three decades it has become apparent that the majority of cases of acute myeloid leukemia (AML) are characterized by at least one of a variety of recurrent chromosomal abnormalities. Whilst in many instances it remains uncertain as to which abnormalities represent primary events in the pathogenesis of AML, those which provide critical second hits that are required for progression to full blown leukemia or those that are merely markers of the leukemic process, it is nevertheless clear that diagnostic karyotype is a key determinant of outcome in this disease. Indeed there is mounting evidence to support the notion that cytogenetic analysis can serve to identify biologically distinct subsets of AML that demand tailored therapeutic approaches. This underpins the trend towards more widespread adoption of routine cytogenetic and molecular analysis in the characterization of patients with a diagnosis of acute leukemia. A key challenge for the future is to use this information to achieve greater consensus in risk group assignment of AML which will provide a more reliable framework for determining the most appropriate treatment approach for individual patients with this disease.


Synaptic vesicle abnormality in familial infantile myasthenia.
In familial infantile myasthenia (FIM) the miniature end-plate potential (MEPP) amplitude is normal in rested muscle, but stimulation in vitro at 10 Hz decreases it abnormally, and neuromuscular transmission fails in a few minutes. In search of a morphologic correlate of the transmission failure, we analyzed the densities and diameters of synaptic vesicles in deep and superficial regions of nerve terminals in external intercostal muscles of three FIM patients and three nonweak controls before and after 10-Hz stimulation for 10 minutes. The densities of superficial or deep synaptic vesicles before or after stimulation in FIM were not significantly different from the corresponding control values. The diameters of superficial and deep synaptic vesicles before stimulation were significantly smaller in the three FIM patients than in the three controls. Stimulation in the FIM patients reduced the MEPP amplitude by 51 to 75%, but increased the vesicle diameter in two patients and did not change the vesicle diameter in one patient. Stimulation in the controls reduced the MEPP amplitude by only 16 to 34%, decreased the vesicle diameter in two, and did not change the vesicle diameter in one. Stimulation after treatment with 1 mg/dl hemicholinium markedly reduced the MEPP amplitude in the controls, had no further effect on the transmission defect in FIM, and had no consistent effect on vesicle diameter in FIM or controls. We conclude that synaptic vesicles are abnormally small in rested muscle in FIM, but vesicle size cannot be reliably correlated with the MEPP amplitude in FIM or controls.


Characterization of endothelin-converting enzyme activities in ARPE-19 cells, a human retinal pigmented epithelial cell line.
Elevated endothelin-1 (ET-1) levels are detected in patients with glaucoma. ET-1 is produced from its precursor, Big ET-1, by endothelin-converting enzyme (ECE). Characterization of ET- 1 secretion and ECE activity was performed in ARPE-19 cells, a human retinal pigmented epithelial cell-line. The ET(B) receptor but not the ET(A) receptor was detected by immunoblotting and cross-linking using 125I-ET-1 at the plasma membrane (PM). Tumor necrosis factor-alpha (10 nmol/L) induced a 700% increase in ET-1 levels and such an effect was further potentiated by BQ788, an ET(B) receptor antagonist, suggesting the involvement of ET(B) receptor in ET-1 clearance. Big ET-1-converting activities were detected in both the PM and cytosol. Phosphoramidon, thiorphan, acidification, and phenanthroline inhibited PM ECE activity; the cytosolic ECE activity was not affected by phenanthroline but was inhibited by the others. In contrast, ECE cytosolic activities were activated by acidification (pH 6.4), suggesting the involvement of ECE-2 or cathepsin-like activity. Pepstatin, a potent inhibitor of cathepsins, and phosphoramidon, a potent inhibitor of ECE, inhibited the cytosolic conversion of Big ET-1 peptide by 46% and 35%, respectively, whereas the combination of both inhibited the cytosolic activity by 93%. Based on immunoblotting, ECE-1 was detected only at the PM, whereas ECE-2 and cathpesins B and D were detected in the cytosol. In summary, ET-1 production in RPE is regulated by at least two isoforms of ECE, (cytosolic and PM) as well as cathepsins.


Robot trajectories comparison: a statistical approach.
The task of planning a collision-free trajectory from a start to a goal position is fundamental for an autonomous mobile robot. Although path planning has been extensively investigated since the beginning of robotics, there is no agreement on how to measure the performance of a motion algorithm. This paper presents a new approach to perform robot trajectories comparison that could be applied to any kind of trajectories and in both simulated and real environments. Given an initial set of features, it automatically selects the most significant ones and performs a statistical comparison using them. Additionally, a graphical data visualization named polygraph which helps to better understand the obtained results is provided. The proposed method has been applied, as an example, to compare two different motion planners, FM(2) and WaveFront, using different environments, robots, and local planners.


Chromatin accessibility dynamics across C. elegans development and ageing.
An essential step for understanding the transcriptional circuits that control development and physiology is the global identification and characterization of regulatory elements. Here, we present the first map of regulatory elements across the development and ageing of an animal, identifying 42,245 elements accessible in at least one Caenorhabditis elegans stage. Based on nuclear transcription profiles, we define 15,714 protein-coding promoters and 19,231 putative enhancers, and find that both types of element can drive orientation-independent transcription. Additionally, more than 1000 promoters produce transcripts antisense to protein coding genes, suggesting involvement in a widespread regulatory mechanism. We find that the accessibility of most elements changes during development and/or ageing and that patterns of accessibility change are linked to specific developmental or physiological processes. The map and characterization of regulatory elements across C. elegans life provides a platform for understanding how transcription controls development and ageing.


Analog and Digital Bipolar Resistive Switching in Solution-Combustion-Processed NiO Memristor.
In this study, a NiO-based resistive memristor was manufactured using a solution combustion method. In this device, both analog and digital bipolar resistive switching were observed. They are dependent on the stressed bias voltage. Prior to the electroforming, the analog bipolar resistive switching was realized through the change of the Schottky barrier at p-type NiO/Ag junction by the local migration of the oxygen ion in the interface. On the basis of the analog resistive switching, several synaptic functions were demonstrated, such as nonlinear transmission characteristics, spike-rate-dependent plasticity, long-term/short-term memory, and "learning-experience" behavior. In addition, once the electroforming operation was carried out using a high applied voltage, the resistive switching was changed from analog to digital. The formation and rupture of the oxygen vacancy filaments is dominant. This novel memristor with the multifunction of analog and digital resistive switching is expected to decrease the manufacturing complexity of the electrocircuits containing analog/digital memristors.


Efficacy of PARP Inhibitor Rucaparib in Orthotopic Glioblastoma Xenografts Is Limited by Ineffective Drug Penetration into the Central Nervous System.
PARP inhibition can enhance the efficacy of temozolomide and prolong survival in orthotopic glioblastoma (GBM) xenografts. The aim of this study was to evaluate the combination of the PARP inhibitor rucaparib with temozolomide and to correlate pharmacokinetic and pharmacodynamic studies with efficacy in patient-derived GBM xenograft models. The combination of rucaparib with temozolomide was highly effective in vitro in short-term explant cultures derived from GBM12, and, similarly, the combination of rucaparib and temozolomide (dosed for 5 days every 28 days for 3 cycles) significantly prolonged the time to tumor regrowth by 40% in heterotopic xenografts. In contrast, the addition of rucaparib had no impact on the efficacy of temozolomide in GBM12 or GBM39 orthotopic models. Using Madin-Darby canine kidney (MDCK) II cells stably expressing murine BCRP1 or human MDR1, cell accumulation studies demonstrated that rucaparib is transported by both transporters. Consistent with the influence of these efflux pumps on central nervous system drug distribution, Mdr1a/b(-/-)Bcrp1(-/-) knockout mice had a significantly higher brain to plasma ratio for rucaparib (1.61 ± 0.25) than wild-type mice (0.11 ± 0.08). A pharmacokinetic and pharmacodynamic evaluation after a single dose confirmed limited accumulation of rucaparib in the brain is associated with substantial residual PARP enzymatic activity. Similarly, matrix-assisted laser desorption/ionization mass spectrometric imaging demonstrated significantly enhanced accumulation of drug in flank tumor compared with normal brain or orthotopic tumors. Collectively, these results suggest that limited drug delivery into brain tumors may significantly limit the efficacy of rucaparib combined with temozolomide in GBM.


Norathyriol suppresses skin cancers induced by solar ultraviolet radiation by targeting ERK kinases.
Ultraviolet (UV) irradiation is the leading factor in the development of skin cancer, prompting great interest in chemopreventive agents for this disease. In this study, we report the discovery of norathyriol, a plant-derived chemopreventive compound identified through an in silico virtual screening of the Chinese Medicine Library. Norathyriol is a metabolite of mangiferin found in mango, Hypericum elegans, and Tripterospermum lanceolatum and is known to have anticancer activity. Mechanistic investigations determined that norathyriol acted as an inhibitor of extracellular signal-regulated kinase (ERK)1/2 activity to attenuate UVB-induced phosphorylation in mitogen-activated protein kinases signaling cascades. We confirmed the direct and specific binding of norathyriol with ERK2 through a cocrystal structural analysis. The xanthone moiety in norathyriol acted as an adenine mimetic to anchor the compound by hydrogen bonds to the hinge region of the protein ATP-binding site on ERK2. Norathyriol inhibited in vitro cell growth in mouse skin epidermal JB6 P+ cells at the level of G(2)-M phase arrest. In mouse skin tumorigenesis assays, norathyriol significantly suppressed solar UV-induced skin carcinogenesis. Further analysis indicated that norathyriol mediates its chemopreventive activity by inhibiting the ERK-dependent activity of transcriptional factors AP-1 and NF-κB during UV-induced skin carcinogenesis. Taken together, our results identify norathyriol as a safe new chemopreventive agent that is highly effective against development of UV-induced skin cancer.


Projected climate and agronomic implications for corn production in the Northeastern United States.
Corn has been a pillar of American agriculture for decades and continues to receive much attention from the scientific community for its potential to meet the food, feed and fuel needs of a growing human population in a changing climate. By midcentury, global temperature increase is expected to exceed 2°C where local effects on heat, cold and precipitation extremes will vary. The Northeast United States is a major dairy producer, corn consumer, and is cited as the fastest warming region in the contiguous U.S. It is important to understand how key agronomic climate variables affect corn growth and development so that adaptation strategies can be tailored to local climate changes. We analyzed potential local effects of climate change on corn growth and development at three major dairy locations in the Northeast (Syracuse, New York; State College, Pennsylvania and Landisville, Pennsylvania) using downscaled projected climate data (2000-2100) from nine Global Climate Models under two emission pathways (Representative Concentration Pathways (RCP) 4.5 and 8.5). Our analysis indicates that corn near the end of the 21st century will experience fewer spring and fall freezes, faster rate of growing degree day accumulation with a reduction in time required to reach maturity, greater frequencies of daily high temperature ≥35°C during key growth stages such as silking-anthesis and greater water deficit during reproductive (R1-R6) stages. These agronomic anomalies differ between the three locations, illustrating varying impacts of climate change in the more northern regions vs. the southern regions of the Northeast. Management strategies such as shifting the planting dates based on last spring freeze and irrigation during the greatest water deficit stages (R1-R6) will partially offset the projected increase in heat and drought stress. Future research should focus on understanding the effects of global warming at local levels and determining adaptation strategies that meet local needs.


Influencing holistic health policy.
Beliefs that health policy-making is an inherently 'ideological' or 'irrational' process appear to have worked to prevent researchers from developing better understandings of the kind of evidence that does work to influence policy. Without a model of policy-making that positions policy decision-makers as capable of being informed by specific forms of evidence that speak to policy contexts, it is difficult for research to begin to shape health policy. Recent years have seen the development of a research industry that focuses on developing and describing research approaches for shaping health and social services policy. This analysis paper offers a highly selective overview of generic features of policy-relevant research for holistic health. It aims to support efforts to develop better evidence for health policy by exploring elements of the genre of policy-relevant research, particularly as it applies to the challenges of holistic health policy-making. First, it offers a conceptual definition of holistic health policy-making, as well as research evidence for this kind of policy making, identifying some of the generic features of policy-relevant research. Second, it outlines some of the key practices for delivering sound evidence for health policy, in ways that highlight the salient differences between doing research for holistic health policy, and doing academic research in health. The paper concludes with directions for developing better evidence for holistic health policy-making that question the assumptions of quality which often inform elite funding agencies, calling for their diversification.


The influence of diet on the assimilation efficiency of 47 polychlorinated biphenyl congeners in Japanese koi (Cyprinus carpio).
The influence of diet on polychlorinated biphenyl (PCB) assimilation was investigated by measuring dietary assimilation efficiencies (AEs) for 47 PCB congeners in juvenile koi (Cyprinus carpio) fed five experimental diets. Two of the diets were naturally contaminated and were obtained by collecting mayflies from Lake Erie (ON, Canada) and emerald shiners from the Detroit River (MI, USA). The remaining diets consisted of commercial fish pellets (lipid contents from 6.7 to 24%) that were contaminated by spiking with a PCB mixture. Experimental fish were held individually to quantify the amount of food consumed per fish and, following a 48-h fasting period to facilitate food digestion and assimilation; AEs were determined by mass balance. Fish fed the benthic invertebrate food exhibited the highest PCB AEs (70-101%) and were significantly elevated compared to the other diet treatments (AEs ranging from 23 to 87%). The PCB AEs for fish fed emerald shiners did not differ from those fed pellet formulations. Variation among PCB AEs was not related to diet lipid content. For all diet treatments, PCB AEs were significantly related to chemical hydrophobicity. The relationship between chemical AE and n-octanol/water partition coefficient (K(OW)) was best explained by a linear model compared to a two-phase resistance model. Overall, PCB AEs were observed to be dependent on both diet type and chemical hydrophobicity, with both factors contributing nearly equally to the variation measured in this toxicokinetic parameter.


Human CTL epitopes prostatic acid phosphatase-3 and six-transmembrane epithelial antigen of prostate-3 as candidates for prostate cancer immunotherapy.
Specific immunotherapy of prostate cancer may be an alternative or be complementary to other approaches for treatment of recurrent or metastasized disease. This study aims at identifying and characterizing prostate cancer-associated peptides capable of eliciting specific CTL responses in vivo. Evaluation of peptide-induced CTL activity in vitro was done following immunization of HLA-A2 transgenic (HHD) mice. An in vivo tumor rejection was tested by adoptive transfer of HHD immune lymphocytes to nude mice bearing human tumors. To confirm the existence of peptide-specific CTL precursors in human, lymphocytes from healthy and prostate cancer individuals were stimulated in vitro in the presence of these peptides and CTL activities were assayed. Two novel immunogenic peptides derived from overexpressed prostate antigens, prostatic acid phosphatase (PAP) and six-transmembrane epithelial antigen of prostate (STEAP), were identified; these peptides were designated PAP-3 and STEAP-3. Peptide-specific CTLs lysed HLA-A2.1+ LNCaP cells and inhibited tumor growth on adoptive immunotherapy. Furthermore, peptide-primed human lymphocytes derived from healthy and prostate cancer individuals lysed peptide-pulsed T2 cells and HLA-A2.1+ LNCaP cells. Based on the results presented herein, PAP-3 and STEAP-3 are naturally processed CTL epitopes possessing anti-prostate cancer reactivity in vivo and therefore may constitute vaccine candidates to be investigated in clinical trials.


Gene signature combinations improve prognostic stratification of multiple myeloma patients.
Multiple myeloma (MM) is a plasma cell neoplasm with significant molecular heterogeneity. Gene expression profiling (GEP) has contributed significantly to our understanding of the underlying biology and has led to several prognostic gene signatures. However, the best way to apply these GEP signatures in clinical practice is unclear. In this study, we investigated the integration of proven prognostic signatures for improved patient risk stratification. Three publicly available MM GEP data sets that encompass newly diagnosed as well as relapsed patients were analyzed using standardized estimation of nine prognostic MM signature indices and simulations of signature index combinations. Cox regression analysis was used to assess the performance of simulated combination indices. Taking the average of multiple GEP signature indices was a simple but highly effective way of integrating multiple GEP signatures. Furthermore, although adding more signatures in general improved performance substantially, we identified a core signature combination, EMC92+HZDCD, as the top-performing prognostic signature combination across all data sets. In this study, we provided a rationale for gene signature integration and a practical strategy to choose an optimal risk score estimation in the presence of multiple prognostic signatures.


Cross-temporal and cross-national poverty and mortality rates among developed countries.
A prime objective of welfare state activities is to take action to enhance population health and to decrease mortality risks. For several centuries, poverty has been seen as a key social risk factor in these respects. Consequently, the fight against poverty has historically been at the forefront of public health and social policy. The relationship between relative poverty rates and population health indicators is less self-evident, notwithstanding the obvious similarity to the debated topic of the relationship between population health and income inequality. In this study we undertake a comparative analysis of the relationship between relative poverty and mortality across 26 countries over time, with pooled cross-sectional time series analysis. We utilize data from the Luxembourg Income Study to construct age-specific poverty rates across countries and time covering the period from around 1980 to 2005, merged with data on age- and gender-specific mortality data from the Human Mortality Database. Our results suggest not only an impact of relative poverty but also clear differences by welfare regime that partly goes beyond the well-known differences in poverty rates between welfare regimes.


Genome-Wide Signatures of Selection in Colletotrichum kahawae Reveal Candidate Genes Potentially Involved in Pathogenicity and Aggressiveness.
Plants and their pathogens are engaged in continuous evolutionary battles, with pathogens evolving to circumvent plant defense mechanisms and plants responding through enhanced protection to prevent or mitigate damage induced by pathogen attack. Managed ecosystems are composed of genetically identical populations of crop plants with few changes from year to year. These environments are highly conducive to the emergence and dissemination of pathogens and they exert selective pressure for both qualitative virulence factors responsible for fungal pathogenicity, and quantitative traits linked to pathogen fitness, such as aggressiveness. In this study, we used a comparative genome-wide approach to investigate the genomic basis underlying the pathogenicity and aggressiveness of the fungal coffee pathogen Colletotrichum kahawae infecting green coffee berries. The pathogenicity was investigated by comparing genomic variation between C. kahawae and its non-pathogenic sibling species, while the aggressiveness was studied by a genome-wide association approach with groups of isolates with different phenotypic profiles. High genetic differentiation was observed between C. kahawae and the most closely related species with 5,560 diagnostic SNPs identified, in which a significant enrichment of non-synonymous mutations was detected. Functional annotation of these non-synonymous mutations revealed a significant enrichment mainly in two gene ontology categories, "oxidation-reduction process" and "integral component of membrane." Finally, the annotation of several genes potentially under-selection revealed that C. kahawae's pathogenicity may be a complex biological process, in which important biological functions, such as, detoxification and transport, regulation of host and pathogen gene expression, and signaling are involved. On the other hand, the genome-wide association analyses for aggressiveness were able to identify 10 SNPs and 15 SNPs of small effect in single and multi-association analysis, respectively, from which 7 were common, giving in total 18 SNPs potentially associated. The annotation of these genomic regions allowed the identification of four candidate genes encoding F-box domain-containing, nitrosoguanidine resistance, Fungal specific transcription factor domain-containing and C6 transcription factor that could be associated with aggressiveness. This study shed light, for the first time, on the genetic mechanisms of C. kahawae host specialization.


Resumptive elements aid comprehension of object relative clauses: evidence from Persian.
The current study investigated the role of resumption in the interpretation of object relative clauses (RCs) in Persian-speaking children. Sixty-four (N=64) children aged 3;2-6;0 (M=4;8) completed a referent selection task that tested their comprehension of subject RCs, gapped object RCs, and object RCs containing either a resumptive pronoun or an object clitic. The results showed that the presence of a resumptive element (pronoun or clitic) had a facilitative effect on children's processing of object RCs. In both cases object RCs with resumptive elements were interpreted more accurately than gapped subject and object RCs, suggesting that resumptive elements ease processing burden in syntactically complex contexts because they provide local cues to thematic role assignment.