Seroprevalence of hepatitis A virus antibodies in Turkish and Moroccan children in Rotterdam.
Seasonal fluctuations in hepatitis A have been observed in the Netherlands related to Turkish and Moroccan children after visiting their home countries. This study determined the prevalence and associated factors of hepatitis A virus (HAV) antibodies in Turkish and Moroccan children in Rotterdam. A random sample was taken of children in Rotterdam, aged 5-16 years, of Turkish and Moroccan origin, together with a random sample of native Dutch children aged 5-7 and 14-16 years. Blood was collected by finger prick on filter paper. IgG and IgM anti-HAV was detected by an enzyme-linked immunoassay (EIA). The 319 Turkish, 329 Moroccan, and 248 native Dutch children participated in the study. In Turkish children, IgG anti-HAV increased from 2.2% to 22.2% over the age groups. In Moroccan children, IgG anti-HAV increased from 10.2% to 57.7%. In native Dutch children, 0.8% had IgG anti-HAV in the youngest and 3.1% in the oldest age group. The percentage IgG-positive also having IgM anti-HAV was 21% in Turkish, and 41% in Moroccan children. No IgG-positive native Dutch children had IgM anti-HAV. The prevalence of IgG anti-HAV was associated with increased age, being Moroccan, longer stay in the country of origin before migrating to the Netherlands, and known contact to HAV. The majority of Turkish and Moroccan children aged 4-16 years in Rotterdam are not protected against HAV, but do have a high risk of becoming infected while visiting their native country. Active vaccination against HAV of these children is indicated, with as primary aim their own protection. Prevention of HAV-transmission in the general community should be seen as a secondary benefit. In addition, possible Dutch contacts of nonvaccinated Turkish and Moroccan children, such as day care workers and teachers, should also be vaccinated against HAV.


Randomized Study to Evaluate the Impact of Telemedicine Care in Patients With Type 1 Diabetes With Multiple Doses of Insulin and Suboptimal HbA1c in Andalusia (Spain): PLATEDIAN Study.
To assess the impact of a telemedicine visit using the platform Diabetic compared with a face-to-face visit on clinical outcomes, patients' health-related quality of life (HRQoL), and physicians' satisfaction in patients with type 1 diabetes. PLATEDIAN (Telemedicine on Metabolic Control in Type 1 Diabetes Mellitus Andalusian Patients) (NCT03332472) was a multicenter, randomized, 6-month follow-up, open-label, parallel-group controlled study performed in patients with type 1 diabetes with suboptimal metabolic control (HbA1c <8% [<64 mmol/mol]), treated with multiple daily injections. A total of 388 patients were assessed for eligibility; 379 of them were randomized 1:1 to three face-to-face visits (control cohort [CC]) (n = 167) or the replacement of an intermediate face-to-face visit by a telemedicine visit using Diabetic (intervention cohort [IC]) (n = 163). The primary efficacy end point was the mean change of HbA1c levels from baseline to month 6. Other efficacy and safety end points were mean blood glucose, glucose variability, episodes of hypoglycemia and hyperglycemia, patient-reported outcomes, and physicians' satisfaction. At month 6, the mean change in HbA1c levels was -0.04 ± 0.5% (-0.5 ± 5.8 mmol/mol) in the CC and 0.01 ± 0.6% (0.1 ± 6.0 mmol/mol) in the IC (P = 0.4941). The number of patients who achieved HbA1c <7% (<53 mmol/mol) was 73 and 78 in the CC and IC, respectively. Significant differences were not found regarding safety end points at 6 months. Changes in HRQoL between the first visit and final visit did not differ between cohorts, and, regarding fear of hypoglycemia (FH-15 score ≥28), statistically significant differences observed at baseline remained unchanged at 6 months (P < 0.05). The use of telemedicine in patients with type 1 diabetes with HbA1c <8% (<64 mmol/mol) provides similar efficacy and safety outcomes as face-to-face visits.


The Combination of Laser Therapy and Metal Nanoparticles in Cancer Treatment Originated From Epithelial Tissues: A Literature Review.
Several methods have been employed for cancer treatment including surgery, chemotherapy and radiation therapy. Today, recent advances in medical science and development of new technologies, have led to the introduction of new methods such as hormone therapy, Photodynamic therapy (PDT), treatments using nanoparticles and eventually combinations of lasers and nanoparticles. The unique features of LASERs such as photo-thermal properties and the particular characteristics of nanoparticles, given their extremely small size, may provide an interesting combined therapeutic effect. The purpose of this study was to review the simultaneous application of lasers and metal nanoparticles for the treatment of cancers with epithelial origin. A comprehensive search in electronic sources including PubMed, Google Scholar and Science Direct was carried out between 2000 and 2013. Among the initial 400 articles, 250 articles applied nanoparticles and lasers in combination, in which more than 50 articles covered the treatment of cancer with epithelial origin. In the future, the combination of laser and nanoparticles may be used as a new or an alternative method for cancer therapy or diagnosis. Obviously, to exclude the effect of laser's wavelength and nanoparticle's properties more animal studies and clinical trials are required as a lack of perfect studies.


Voltage-gated calcium channel blockers deregulate macroautophagy in cardiomyocytes.
Voltage-gated calcium channel blockers are widely used for the management of cardiovascular diseases, however little is known about their effects on cardiac cells in vitro. We challenged neonatal ventricular cardiomyocytes (CMs) with therapeutic L-type and T-type Ca(2+) channel blockers (nifedipine and mibefradil, respectively), and measured their effects on cell stress and survival, using fluorescent microscopy, Q-PCR and Western blot. Both nifedipine and mibefradil induced a low-level and partially transient up-regulation of three key mediators of the Unfolded Protein Response (UPR), indicative of endoplasmic (ER) reticulum stress. Furthermore, nifedipine triggered the activation of macroautophagy, as evidenced by increased lipidation of microtubule-associated protein 1 light chain 3 (LC3), decreased levels of polyubiquitin-binding protein p62/SQSTM1 and ubiquitinated protein aggregates, that was followed by cell death. In contrast, mibefradil inhibited CMs constitutive macroautophagy and did not promote cell death. The siRNA-mediated gene silencing approach confirmed the pharmacological findings for T-type channels. We conclude that L-type and T-type Ca(2+) channel blockers induce ER stress, which is divergently transduced into macroautophagy induction and inhibition, respectively, with relevance for cell viability. Our work identifies VGCCs as novel regulators of autophagy in the heart muscle and provides new insights into the effects of VGCC blockers on CMs homeostasis, that may underlie both noxious and cardioprotective effects.


Heart Failure in a Dedicated Outpatient Clinic: Results after 58 Month Follow-Up. Can it be Enough?
Incidence of chronic heart failure (HF) is rapidly increasing, approaching a 10 per 1000 rate after 65 years of age. In the last decades, despite pharmacological, interventional and supportive innovations, HF prognosis remained poor, with about 30% of death within one year from the diagnosis. Current guidelines recommend for these patients management programs providing follow-up through dedicated outpatient clinic. Limits of these programs are represented by great difficulties in getting patients adherence, being still too elevated the rate of abandonments. In this paper, we analyzed the impact of 58 months of activity in our dedicated to heart failure outpatient clinic on mortality, hospitalization and abandonment rate. 477 HF patients (346 M, 72.5%, mean age 69.6 years) were enrolled. Mean follow-up and visit were 18.2 and 2.6 months respectively. Total mortality rate was 11.5%, 4% of patients per year. Total hospitalizations for acute HF were 212 and, among all patients left in follow-up, the number of hospitalizations for acute de-compensation significantly decreased from 0.49/patient/year before enrollment to 0.29/patient/year during follow-up (p=0.015). Patients who abandoned outpatient clinic were 94 (19%, 1 abandonment every 23 days), mostly observed over the first months of activity. In conclusion, our patients experienced a major decrease in rates of acute de-compensation and need of in-hospital admissions.


[Incidence and characteristics of cerebrovascular disorders in children--critical analysis of 120 cases experienced at a children's general hospital].
Cerebrovascular disorders in children is a rare clinical entity, epidemiologic studies of which are very scarce in Japan. Hence this study analyzed 13,131 sick children admitted to Children's General Hospital in light of the incidence of cerebrovascular accident in children and its specific characteristics. In this paper, the cases of cerebral infarct are analyzed with special reference to their developmental outcomes. The results show that one hundred twenty children (0.85 percent of all sick children) had cerebrovascular disorders documented both in clinical pictures and CT scans. This number accounted for 2.5% of 4,738 CT examinations performed for these sick children. There were 79 cases of intracranial hemorrhage, 24 of cerebral infarction and 17 of vascular anomalies, 65.8%, 20.0% and 14.2% respectively. In the intracranial hemorrhage group, there was a different pathophysiology in each age group. The fact that intraventricular hemorrhage occurred in premature neonates, subarachnoid or posterior fossa subdural hemorrhage in mature neonates and infants, and intracerebral hematoma in elder children due to different causes was very striking. In the cerebral infarct group, the middle cerebral artery was most commonly affected (11 out of 24 cases); others had various lesions such as lacunar stroke, internal carotid artery occlusion and so on. The most impressive but disappointing fact in those children was that their clinical pictures were quite miserable, revealing low IQs. Nine out of 24 children with cerebral infarct had IQs below 20. In the abnormal vessels group, there were Moyamoya disease, arteriovenous malformation, intracranial aneurysm, Sturge-Weber syndrome, Menkes disease and coiling of the internal carotid or vertebral arteries each demonstrating unique angiographic findings.(ABSTRACT TRUNCATED AT 250 WORDS)


Arthroscopic versus open treatment of Bankart lesion of the shoulder: a prospective randomized study.
The purpose of this study was to compare the results of arthroscopic and open repair of isolated Bankart lesions of the shoulder using metallic suture anchors. Prospective randomized clinical study. Sixty patients with traumatic anterior shoulder instability underwent a surgical repair of an isolated Bankart lesion. The patients were divided into 2 groups of 30 patients each. In group 1, an arthroscopic repair was performed, and in group 2, an open procedure was performed. The groups were homogeneous for gender, age, dominance, number of dislocations, time elapsed between first dislocation and surgery, and pathologic findings. In all cases of both groups, the lesion was repaired using metallic suture anchors carrying nonabsorbable braided sutures. Postoperative rehabilitation was the same for the 2 groups. Two years' follow-up evaluation included Constant and Rowe shoulder scores. Statistical analysis of data was performed using an unpaired t test (significance for P <.05). No recurrence of dislocation of the involved shoulder has been reported in either group. Follow-up Constant and Rowe scores of the 2 groups were not significantly different. The only significant difference seen between the 2 groups was for range of motion evaluation with the Constant score. The mean value for group 1 (39.6 +/- 0.8) was significantly greater (P =.017) than that for group 2 (37.8 +/- 2.0). Arthroscopic repair with suture anchors is an effective surgical technique for the treatment of an isolated Bankart lesion. Open repair does not offer a significantly better 2-year result in terms of stability, and furthermore, can negatively affect the recovery of full range of motion of the shoulder. Level I.


Therapeutic efficacy of intranasally delivered mesenchymal stem cells in a rat model of Parkinson disease.
Safe and effective cell delivery remains one of the main challenges in cell-based therapy of neurodegenerative disorders. Graft survival, sufficient enrichment of therapeutic cells in the brain, and avoidance of their distribution throughout the peripheral organs are greatly influenced by the method of delivery. Here we demonstrate for the first time noninvasive intranasal (IN) delivery of mesenchymal stem cells (MSCs) to the brains of unilaterally 6-hydroxydopamine (6-OHDA)-lesioned rats. IN application (INA) of MSCs resulted in the appearance of cells in the olfactory bulb, cortex, hippocampus, striatum, cerebellum, brainstem, and spinal cord. Out of 1 × 10⁶ MSCs applied intranasally, 24% survived for at least 4.5 months in the brains of 6-OHDA rats as assessed by quantification of enhanced green fluorescent protein (EGFP) DNA. Quantification of proliferating cell nuclear antigen-positive EGFP-MSCs showed that 3% of applied MSCs were proliferative 4.5 months after application. INA of MSCs increased the tyrosine hydroxylase level in the lesioned ipsilateral striatum and substantia nigra, and completely eliminated the 6-OHDA-induced increase in terminal deoxynucleotidyl transferase (TdT)-mediated 2'-deoxyuridine, 5'-triphosphate (dUTP)-biotin nick end labeling (TUNEL) staining of these areas. INA of EGFP-labeled MSCs prevented any decrease in the dopamine level in the lesioned hemisphere, whereas the lesioned side of the control animals revealed significantly lower levels of dopamine 4.5 months after 6-OHDA treatment. Behavioral analyses revealed significant and substantial improvement of motor function of the Parkinsonian forepaw to up to 68% of the normal value 40-110 days after INA of 1 × 10⁶ cells. MSC-INA decreased the concentrations of inflammatory cytokines-interleukin-1β (IL-1β), IL-2, -6, -12, tumor necrosis factor (TNF), interferon-γ (IFN-γ, and granulocyte-macrophage colony-stimulating factor (GM-CSF)-in the lesioned side to their levels in the intact hemisphere. IN administration provides a highly promising noninvasive alternative to the traumatic surgical procedure of transplantation and allows targeted delivery of cells to the brain with the option of chronic application.


Association between Obesity and Serum 25(OH)D Concentrations in Older Mexican Adults.
Vitamin D is essential for maintaining bone mineralization and calcium homeostasis, and prevents falls and fractures in older adults. Mexico is undergoing an epidemiologic and demographic transition with increasing obesity rates. The study's aim was to determine the association of obesity with serum 25-hydroxyvitamin D [25(OH)D] concentrations in older Mexican adults. Data from 1772 Mexicans, aged ≥50 years, enrolled in a sub-sample of the 3rd wave of the Mexican Health and Aging Study, were included. Serum 25(OH)D concentrations were used to define vitamin D status, and were categorized into tertiles. Body mass index measures were used to categorize older adults into under/normal weight, overweight, and obese groups. Multinomial logistic regression models were used to assess the relationship, adjusting for potential confounders. Approximately 40% and 37% of older Mexican adults were either overweight or obese, respectively. Compared to under/normal weight older Mexicans, obese adults were 1.78 times (95% Confidence Interval (CI) 1.27-2.48) and 1.94 times (95% CI 1.40-2.68) more associated with the first and second tertile concentrations of serum 25(OH)D, respectively. Overweight adults were 1.52 times (95% CI 1.12-2.06) more associated with the second tertile of serum 25(OH)D concentration than under/normal weight adults. Overweight/Obesity was found to be significantly associated with low concentrations of serum 25(OH) in older Mexican adults.


An emerging consensus on voltage-dependent gating from computational modeling and molecular dynamics simulations.
Developing an understanding of the mechanism of voltage-gated ion channels in molecular terms requires knowledge of the structure of the active and resting conformations. Although the active-state conformation is known from x-ray structures, an atomic resolution structure of a voltage-dependent ion channel in the resting state is not currently available. This has motivated various efforts at using computational modeling methods and molecular dynamics (MD) simulations to provide the missing information. A comparison of recent computational results reveals an emerging consensus on voltage-dependent gating from computational modeling and MD simulations. This progress is highlighted in the broad context of preexisting work about voltage-gated channels.


An altered posterior question-mark incision is associated with a reduced infection rate of cranioplasty after decompressive hemicraniectomy.
Performing a cranioplasty (CP) after decompressive craniotomy is a straightforward neurosurgical procedure, but it remains associated with a high complication rate. Surgical site infection (SSI), aseptic bone resorption (aBR), and need for a secondary CP are the most common complications. This observational study aimed to identify modifiable risk factors to prevent CP failure. A retrospective analysis was performed of all patients who underwent CP following decompressive hemicraniectomy (DHC) between 2010 and 2018 at a single institution. Predictors of SSI, aBR, and need for allograft CP were evaluated in a univariate analysis and multivariate logistic regression model. One hundred eighty-six patients treated with CP after DHC were included. The diagnoses leading to a DHC were as follows: stroke (83 patients, 44.6%), traumatic brain injury (55 patients, 29.6%), subarachnoid hemorrhage (33 patients, 17.7%), and intracerebral hemorrhage (15 patients, 8.1%). Post-CP SSI occurred in 25 patients (13.4%), whereas aBR occurred in 32 cases (17.2%). An altered posterior question-mark incision, ending behind the ear, was associated with a significantly lower infection rate and CP failure, compared to the classic question-mark incision (6.3% vs 18.4%; p = 0.021). The only significant predictor of aBR was patient age, in which those developing resorption were on average 16 years younger than those without aBR (p < 0.001). The primary goal of this retrospective cohort analysis was to identify adjustable risk factors to prevent post-CP complications. In this analysis, a posterior question-mark incision proved beneficial regarding infection and CP failure. The authors believe that these findings are caused by the better vascularized skin flap due to preservation of the superficial temporal artery and partial preservation of the occipital artery. In this trial, the posterior question-mark incision was identified as an easily and costless adaptable technique to reduce CP failure rates.


From channel proteins to industrial biomimetic membrane technology.
Biomimetic membrane technology, based on the use of nano-scale functional additives in the form of channel proteins or artificially made channel structures, represents an attractive way of optimizing membrane separation technology. However, the nano-scale nature of the additives inherently points to the challenge in up-scaling the membranes to square meter areas. Thus, the ability to up-scale the processes involved in manufacturing will be crucial for translating the protein/nano-science into technology. Here we discuss how highly selective aquaporin proteins can be used to enhance the performance of the classical thin film composite membrane, and how this can be used in relevant membrane elements and module form factors. A particular up-scaling challenge lies in securing large scale membrane protein production. We demonstrate our framework for making batch amounts which are compatible with the large scale production of biomimetic membranes for water purification based on the use of the E. coli expression system.


Prognostic significance of acute systolic hypertension after myocardial infarction.
The clinical behaviour and mean peak serum aspartate aminotransferase (SGOT) values of 106 patients admitted to a coronary care unit with acute myocardial infarction who displayed acute systolic hypertension were studied. Another 106 normotensive patients with acute myocardial infarction acted as controls. Neither group had established hypertension. The mortality rate, incidence of cardiac failure, major arrhythmias, and mean peak SGOT were significantly greater in the hypertensive group, within which the duration of hypertension was correlated with mean peak SGOT levels--through there was no definite relation between the height of systolic or diastolic pressure and SGOT. Transient systolic hypertension after acute myocardial infarction was therefore associated with a relatively poor prognosis, but our observations suggest that patients with a systolic blood pressure of at least 170 mm Hg might benefit from early hypotensive treatment.


Phase I Study of Pembrolizumab (MK-3475; Anti-PD-1 Monoclonal Antibody) in Patients with Advanced Solid Tumors.
This phase I study evaluated the safety, maximum tolerated dose, antitumor activity, and pharmacokinetics and pharmacodynamics of pembrolizumab in patients with advanced solid tumors. In a 3 + 3 dose escalation study, 10 patients received pembrolizumab 1, 3, or 10 mg/kg intravenously every 2 weeks until progression or intolerable toxicity. Seven additional patients received 10 mg/kg every 2 weeks. Thirteen patients participated in a 3-week intrapatient dose escalation (dose range, 0.005-10 mg/kg) followed by 2 or 10 mg/kg every 3 weeks. Tumor response was assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. No dose-limiting toxicities were observed. Maximum administered dose was 10 mg/kg every 2 weeks. One patient with melanoma and one with Merkel cell carcinoma experienced complete responses of 57 and 56+ weeks' duration, respectively. Three patients with melanoma experienced partial responses. Fifteen patients with various malignancies experienced stable disease. One patient died of cryptococcal infection 92 days after pembrolizumab discontinuation, following prolonged corticosteroid use for grade 2 gastritis considered drug related. Pembrolizumab exhibited pharmacokinetic characteristics typical of humanized monoclonal antibodies. Maximum serum target engagement was reached with trough levels of doses greater than or equal to 1 mg/kg every 3 weeks. Mechanism-based translational models with a focus on intratumor exposure prediction suggested robust clinical activity would be observed at doses ≥2 mg/kg every 3 weeks. Pembrolizumab was well tolerated and associated with durable antitumor activity in multiple solid tumors. The lowest dose with full potential for antitumor activity was 2 mg/kg every 3 weeks.


Induction of an antibody response in cultures of human peripheral blood lymphocytes.
A culture system is descirbed which provides adequate conditions for in vitro immunization of humand peripheral blood lymphocytes to heterologous erythrocytes. Making use of this method we could obtain, with a number of different donors, an antibody response which peaked at about day 8 of culture with 30-300 plaque-forming cells (PFC) per 10(6) input lymphocytes. However, in a number of experiments poor or negative results were obtained, even with donors that had previously given good response. This variability in the results was shown not to be due to a too low number of precursor cells present in the blood and could be overcome by treating the cells, before initiation of the culture, with a factor produced by mouse T cells educated to sheep erythrocytes (SRBC). Under these conditions a PFC responce was obtained which peaked at about day 8 and which in some experiments could be as high as 20,000 PFC per 10(6) input lymphocytes. Paralleling the increase in PFC was an increase in cell number. The cells recovered from the treated cultures were at all times more numerous than in the nontreated cultures. The height of both the proliferative and antibody-producing responses varied from experiment to experiment, a higher proliferative response, accompanying a higher PFC response. Although the mechanisms that are at the basis of the antibody response in vitro described in this paper still need to be clarified, this system may become a useful tool in studying the immune response in man.


Developing human biomonitoring as a 21st century toolbox within the European exposure science strategy 2020-2030.
Human biomonitoring (HBM) is a crucial approach for exposure assessment, as emphasised in the European Commission's Chemicals Strategy for Sustainability (CSS). HBM can help to improve chemical policies in five major key areas: (1) assessing internal and aggregate exposure in different target populations; 2) assessing exposure to chemicals across life stages; (3) assessing combined exposure to multiple chemicals (mixtures); (4) bridging regulatory silos on aggregate exposure; and (5) enhancing the effectiveness of risk management measures. In this strategy paper we propose a vision and a strategy for the use of HBM in chemical regulations and public health policy in Europe and beyond. We outline six strategic objectives and a roadmap to further strengthen HBM approaches and increase their implementation in the regulatory risk assessment of chemicals to enhance our understanding of exposure and health impacts, enabling timely and targeted policy interventions and risk management. These strategic objectives are: 1) further development of sampling strategies and sample preparation; 2) further development of chemical-analytical HBM methods; 3) improving harmonisation throughout the HBM research life cycle; 4) further development of quality control / quality assurance throughout the HBM research life cycle; 5) obtain sustained funding and reinforcement by legislation; and 6) extend target-specific communication with scientists, policymakers, citizens and other stakeholders. HBM approaches are essential in risk assessment to address scientific, regulatory and societal challenges. HBM requires full and strong support from the scientific and regulatory domain to reach its full potential in public and occupational health assessment and in regulatory decision-making.


Strength and performance asymmetry during maximal velocity sprint running.
The aim of this study was to empirically examine the interaction of athlete-specific kinematic kinetic and strength asymmetry in sprint running. Bilateral ground reaction force and kinematic data were collected during maximal velocity (mean = 9.05 m/s) sprinting for eight athletes. Bilateral ground reaction force data were also collected while the same athletes performed maximal effort squat jumps. Using novel composite asymmetry scores, interactions between kinematic and kinetic asymmetry were compared for the group of sprinters. Asymmetry was greater for kinematic variables than step characteristics, with largest respective values of 6.68% and 1.68%. Kinetic variables contained the largest asymmetry values, peaking at >90%. Asymmetry was present in all kinematic and kinetic variables analyzed during sprint trials. However, individual athlete asymmetry profiles were reported for sprint and jump trials. Athletes' sprint performance was not related to their overall asymmetry. Positive relationships were found between asymmetry in ankle work during sprint running and peak vertical force (r = 0.895) and power (r = 0.761) during jump trials, suggesting that the ankle joint may be key in regulating asymmetry in sprinting and highlighting the individual nature of asymmetry. The individual athlete asymmetry profiles and lack of relationship between asymmetry of limb strength and sprint performance suggest that athletes are not "limb dominant" and that strength imbalances are joint and task specific. Compensatory kinetic mechanisms may serve to reduce the effects of strength or biological asymmetry on the performance outcome of step velocity.


Intratumoral delivery of M-CSF by calcium crosslinked polymer micelles enhances cancer immunotherapy.
Immunotherapy has shown promising results in multiple malignancies. However, there are still significant challenges in cancer immunotherapy including the powerful immunosuppressive tumor microenvironment and adverse off-target side effects. Nanomaterials with defined physico-biochemical properties are versatile drug delivery platforms that may address these key technical challenges faced by cancer immunotherapy. Here, a tumor acidity-responsive biomacromolecule delivery system was designed to intratumorally deliver an immune-activating cytokine, macrophage colony-stimulating factor (M-CSF) and attenuate the acidic microenvironment. This nanoparticle was prepared by introducing CaCO3 as a crosslinker to form an M-CSF-loaded stable micelle (NP/M-CSF/CaCO3). Administration of NP/M-CSF/CaCO3 significantly inhibited tumor growth by enhancing T cell-mediated anti-tumor immune responses and reversing the TAM-mediated immunosuppression. This study provides new avenues for cascade amplification of the antitumor effects by targeting the tumor microenvironment. This approach may also help avoid unwanted complications.


Motor neuron disease: current management and future prospects.
Motor neuron disease (MND) is characterised by progressive neurological deterioration and coexistence of upper and lower motor neuron signs. Over the past decade, evidence has emerged of unique pathophysiological processes, including glutamate-mediated excitotoxicity, which has resulted in the development of novel diagnostic investigations and uncovered potential therapeutic targets. Advances in genetics, including the recently discovered C9orf72 gene, have radically changed the pathological mindset, from MND being classified as a neuromuscular disease to one that MND forms a continuum with other primary neurodegenerative disorders, including frontotemporal dementia. The present review will highlight the improvements that have occurred in clinical care, in conjunction with recent scientific developments.


Influence of Being Embodied in an Obese Virtual Body on Shopping Behavior and Products Perception in VR.
Research in Virtual Reality (VR) showed that embodiment can influence participants' perceptions and behavior when embodied in a different yet plausible virtual body. In this paper, we study the changes an obese virtual body has on products perception (e.g., taste, etc.) and purchase behavior (e.g., number purchased) in an immersive virtual retail store. Participants (of a normal BMI on average) were embodied in a normal (N) or an obese (OB) virtual body and were asked to buy and evaluate food products in the immersive virtual store. Based on stereotypes that are classically associated with obese people, we expected that the group embodied in obese avatars would show a more unhealthy diet, (i.e., buy more food products and also buy more products with high energy intake, or saturated fat) and would rate unhealthy food as being tastier and healthier than participants embodied in "normal weight" avatars. Our participants also rated the perception of their virtual body: the OB group perceived their virtual body as significantly heavier and older. They also rated their sense of embodiment and presence within the immersive virtual store. These measures did not show any significant difference between groups. Finally, we asked them to rate different food products in terms of tastiness, healthiness, sustainability and price. The only difference we noticed is that participants embodied in an obese avatar (OB group) rated the coke as being significantly tastier and the apple as being significantly healthier. Nevertheless, while we hypothesized that participants embodied in a virtual body with obesity would show differences in their shopping patterns (e.g., more "unhealthy" products bought) there were no significant differences between the groups. Stereotype activation failed for our participants embodied in obese avatars, who did not exhibit a shopping behavior following the (negative) stereotypes related to obese people. conversely, while the opposite hypothesis (participants embodied in obese avatars would buy significantly more healthy products in order to "transform" their virtual bodies) could have been made, it was not the case either. We discuss these results and propose hypotheses as to why the behavior of the manipulated group differed from the one we expected. Indeed, unlike previous research, our participants were embodied in virtual avatars which differed greatly from their real bodies. Obese avatars should not only modify users' visual characteristics such as hair or skin color, etc. We hypothesize that an obese virtual body may require some other non-visual stimulus, e.g., the sensation of the extra weight or the change in body size. This main difference could then explain why we did not notice any important modification on participants' behavior and perceptions of food products. We also hypothesize that the absence of stereotype activation and thus of statistical difference between our N and OB groups might be due to higher-level cognitive processes involved while purchasing food products. Indeed our participants might have rejected their virtual bodies when performing the shopping task, while the embodiment and presence ratings did not show significant differences, and purchased products based on their real (non-obese) bodies. This could mean that stereotype activation is more complex that previously thought.


SCF(Cyclin F) controls centrosome homeostasis and mitotic fidelity through CP110 degradation.
Generally, F-box proteins are the substrate recognition subunits of SCF (Skp1-Cul1-F-box protein) ubiquitin ligase complexes, which mediate the timely proteolysis of important eukaryotic regulatory proteins. Mammalian genomes encode roughly 70 F-box proteins, but only a handful have established functions. The F-box protein family obtained its name from Cyclin F (also called Fbxo1), in which the F-box motif (the approximately 40-amino-acid domain required for binding to Skp1) was first described. Cyclin F, which is encoded by an essential gene, also contains a cyclin box domain, but in contrast to most cyclins, it does not bind or activate any cyclin-dependent kinases (CDKs). However, like other cyclins, Cyclin F oscillates during the cell cycle, with protein levels peaking in G2. Despite its essential nature and status as the founding member of the F-box protein family, Cyclin F remains an orphan protein, whose functions are unknown. Starting from an unbiased screen, we identified CP110, a protein that is essential for centrosome duplication, as an interactor and substrate of Cyclin F. Using a mode of substrate binding distinct from other F-box protein-substrate pairs, CP110 and Cyclin F physically associate on the centrioles during the G2 phase of the cell cycle, and CP110 is ubiquitylated by the SCF(Cyclin F) ubiquitin ligase complex, leading to its degradation. siRNA-mediated depletion of Cyclin F in G2 induces centrosomal and mitotic abnormalities, such as multipolar spindles and asymmetric, bipolar spindles with lagging chromosomes. These phenotypes were reverted by co-silencing CP110 and were recapitulated by expressing a stable mutant of CP110 that cannot bind Cyclin F. Finally, expression of a stable CP110 mutant in cultured cells also promotes the formation of micronuclei, a hallmark of chromosome instability. We propose that SCF(Cyclin F)-mediated degradation of CP110 is required for the fidelity of mitosis and genome integrity.


Targeting HER2 expression in cancer: New drugs and new indications.
Functional activation of human epidermal growth factor receptor 2 (HER2) has been shown to strongly promote carcinogenesis, leading to the investigation of HER2-directed agents in cancers with HER2 genomic alterations. This has been best documented in the context of HER2 gene amplification in breast and gastric/gastroesophageal junction carcinomas for which several HER2-directed agents are available and have become a part of standard treatment regimens. Somatic HER2 gene mutations have been recently described at low frequency in a variety of human cancers and have emerged as a novel predictive biomarker for HER2-directed therapies. Preclinical data also indicate that activating HER2 mutations are potent oncogenic drivers in a manner that is analogous to HER2 amplification. HER2 mutations may clinically confer sensitivity to HER2-directed agents as recently shown in a phase II clinical trial with antibody-drug conjugate against HER2 trastuzumab deruxtecan in patients with non-squamous non-small cell lung carcinoma.


Revisiting sesquiterpene biosynthetic pathways leading to santalene and its analogues: a comprehensive mechanistic study.
Santalene and bergamotene are the major olefinic sesquiterpenes responsible for the fragrance of sandalwood oil. Herein we report the details of density functional theory investigations on the biosynthetic pathway of this important class of terpenes. The mechanistic study has been found to be effective toward gaining significant new insight into different possibilities for the formation of the key intermediates involved in santalene and bergamotene biosynthesis. The stereoelectronic features of the transition states and intermediates for (i) ring closure of the initial bisabolyl cation, and (ii) skeletal rearrangements in the ensuing bicyclic carbocationic intermediates leading to (-)-epi-β-santalene, (-)-β-santalene, (-)-α-santalene, (+)-epi-β-santalene, exo-β-bergamotene, endo-β-bergamotene, exo-α-bergamotene, and endo-α-bergamotene are presented. Interesting structural features pertaining to certain new carbocationic intermediates (such as b) resulting from the ring closure of bisabolyl cation are discussed. Extensive conformational sampling of all key intermediates along the biosynthetic pathway offered new insight into the role of the isoprenyl side chain conformation in the formation of santalene and its analogues. Although the major bicyclic products in Santalum album appear to arise from the right or left handed helical form of farnesyl pyrophosphate (FPP), different alternatives for their formation are found to be energetically feasible. The interconversion of the exo and endo isomers of bisabolyl cation and a likely epimerization, both with interesting mechanistic implications, are presented. The exo to endo conversion is identified to be energetically more favorable than another pathway emanating from the left handed helical FPP. The role of pyrophosphate (OPP(-)) in the penultimate deprotonation step leading to olefinic sesquiterpenes is also examined.


NMR-based metabolomics and fluxomics: developments and future prospects.
NMR spectroscopy is an essential analytical technique in metabolomics and fluxomics workflows, owing to its high structural elucidation capabilities combined with its intrinsic quantitative nature. However, routine NMR "omic" analytical methods suffer from several drawbacks that may have limited their use as a method of choice, in particular when compared to another widely used technique, mass spectrometry. This review describes, in a critical and perspective discussion, how some of the most recent developments emerging from the NMR community could act as real game changers for metabolomics and fluxomics in the near future. Advanced developments to make NMR metabolomics more resolutive, more sensitive and more accessible are described, as well as new approaches to improve the identification of biomarkers. We hope that this review will convince a broad end-user community of the increasing role of NMR in the "omic" world at the beginning of the 2020s.


Geometric anomaly detection in data.
The quest for low-dimensional models which approximate high-dimensional data is pervasive across the physical, natural, and social sciences. The dominant paradigm underlying most standard modeling techniques assumes that the data are concentrated near a single unknown manifold of relatively small intrinsic dimension. Here, we present a systematic framework for detecting interfaces and related anomalies in data which may fail to satisfy the manifold hypothesis. By computing the local topology of small regions around each data point, we are able to partition a given dataset into disjoint classes, each of which can be individually approximated by a single manifold. Since these manifolds may have different intrinsic dimensions, local topology discovers singular regions in data even when none of the points have been sampled precisely from the singularities. We showcase this method by identifying the intersection of two surfaces in the 24-dimensional space of cyclo-octane conformations and by locating all of the self-intersections of a Henneberg minimal surface immersed in 3-dimensional space. Due to the local nature of the topological computations, the algorithmic burden of performing such data stratification is readily distributable across several processors.


The effects of spinal manipulation on performance-related outcomes in healthy asymptomatic adult population: a systematic review of best evidence.
The effectiveness of spinal manipulative therapy (SMT) for improving athletic performance in healthy athletes is unclear. Assessing the effect of SMT on other performance outcomes in asymptomatic populations may provide insight into the management of athletes where direct evidence may not be available. Our objective was to systematically review the literature on the effect of SMT on performance-related outcomes in asymptomatic adults. MEDLINE, CINAHL, SPORTDiscus, and Cochrane Central Register of Controlled Trials were systematically searched from 1990 to March 23, 2018. Inclusion criteria was any study examining a performance-related outcome of SMT in asymptomatic adults. Methodological quality was assessed using the SIGN criteria. Studies with a low risk of bias were considered scientifically admissible for a best evidence synthesis. We calculated the between group mean change and 95% confidence intervals. Of 1415 articles screened, 20 studies had low risk of bias, seven were randomized crossover trials, 10 were randomized controlled trials (RCT) and three were RCT pilot trials. Four studies showed SMT had no effect on physiological parameters at rest or during exercise. There was no effect of SMT on scapular kinematics or transversus abdominus thickness. Three studies identified changes in muscle activation of the upper or lower limb, compared to two that did not. Five studies showed changes in range of motion (ROM). One study showed an increase lumbar proprioception and two identified changes in baropodometric variables after SMT. Sport-specific studies show no effect of SMT except for a small increase in basketball free-throw accuracy. The preponderance of evidence suggests that SMT in comparison to sham or other interventions does not enhance performance-based outcomes in asymptomatic adult population. All studies are exploratory with immediate effects. In the few studies suggesting a positive immediate effect, the importance of such change is uncertain. Further high-quality performance specific studies are required to confirm these preliminary findings.


Evaluation of terrestrial carbon cycle models for their response to climate variability and to CO2 trends.
The purpose of this study was to evaluate 10 process-based terrestrial biosphere models that were used for the IPCC fifth Assessment Report. The simulated gross primary productivity (GPP) is compared with flux-tower-based estimates by Jung et al. [Journal of Geophysical Research 116 (2011) G00J07] (JU11). The net primary productivity (NPP) apparent sensitivity to climate variability and atmospheric CO2 trends is diagnosed from each model output, using statistical functions. The temperature sensitivity is compared against ecosystem field warming experiments results. The CO2 sensitivity of NPP is compared to the results from four Free-Air CO2 Enrichment (FACE) experiments. The simulated global net biome productivity (NBP) is compared with the residual land sink (RLS) of the global carbon budget from Friedlingstein et al. [Nature Geoscience 3 (2010) 811] (FR10). We found that models produce a higher GPP (133 ± 15 Pg C yr(-1) ) than JU11 (118 ± 6 Pg C yr(-1) ). In response to rising atmospheric CO2 concentration, modeled NPP increases on average by 16% (5-20%) per 100 ppm, a slightly larger apparent sensitivity of NPP to CO2 than that measured at the FACE experiment locations (13% per 100 ppm). Global NBP differs markedly among individual models, although the mean value of 2.0 ± 0.8 Pg C yr(-1) is remarkably close to the mean value of RLS (2.1 ± 1.2 Pg C yr(-1) ). The interannual variability in modeled NBP is significantly correlated with that of RLS for the period 1980-2009. Both model-to-model and interannual variation in model GPP is larger than that in model NBP due to the strong coupling causing a positive correlation between ecosystem respiration and GPP in the model. The average linear regression slope of global NBP vs. temperature across the 10 models is -3.0 ± 1.5 Pg C yr(-1) °C(-1) , within the uncertainty of what derived from RLS (-3.9 ± 1.1 Pg C yr(-1) °C(-1) ). However, 9 of 10 models overestimate the regression slope of NBP vs. precipitation, compared with the slope of the observed RLS vs. precipitation. With most models lacking processes that control GPP and NBP in addition to CO2 and climate, the agreement between modeled and observation-based GPP and NBP can be fortuitous. Carbon-nitrogen interactions (only separable in one model) significantly influence the simulated response of carbon cycle to temperature and atmospheric CO2 concentration, suggesting that nutrients limitations should be included in the next generation of terrestrial biosphere models.


W246(6.48) opens a gate for a continuous intrinsic water pathway during activation of the adenosine A2A receptor.
The question how G-protein-coupled receptors transduce an extracellular signal by a sequence of transmembrane conformational transitions into an intracellular response remains to be solved at molecular detail. Herein, we use molecular dynamics simulations to reveal distinct conformational transitions of the adenosine A2A receptor, and we found that the conserved W246(6.48) residue in transmembrane helix TM6 performs a key rotamer toggle switch. Agonist binding induces the sidechain of W246(6.48) to fluctuate between two distinct conformations enabling the diffusion of water molecules from the bulk into the center of the receptor. After passing the W246(6.48) gate, the internal water molecules induce another conserved residue, Y288(7.53), to switch to a distinct rotamer conformation establishing a continuous transmembrane water pathway. Further, structural changes of TM6 and TM7 induce local structural changes of the adjacent lipid bilayer.


Recurrence of Dupuytren's contracture: A consensus-based definition.
One of the major determinants of Dupyutren disease (DD) treatment efficacy is recurrence of the contracture. Unfortunately, lack of agreement in the literature on what constitutes recurrence makes it nearly impossible to compare the multiple treatments alternatives available today. The aim of this study is to bring an unbiased pool of experts to agree upon what would be considered a recurrence of DD after treatment; and from that consensus establish a much-needed definition for DD recurrence. To reach an expert consensus on the definition of recurrence we used the Delphi method and invited 43 Dupuytren's research and treatment experts from 10 countries to participate by answering a series of questionnaire rounds. After each round the answers were analyzed and the experts received a feedback report with another questionnaire round to further hone in of the definition. We defined consensus when at least 70% of the experts agreed on a topic. Twenty-one experts agreed to participate in this study. After four consensus rounds, we agreed that DD recurrence should be defined as "more than 20 degrees of contracture recurrence in any treated joint at one year post-treatment compared to six weeks post-treatment". In addition, "recurrence should be reported individually for every treated joint" and afterwards measurements should be repeated and reported yearly. This study provides the most comprehensive to date definition of what should be considered recurrence of DD. These standardized criteria should allow us to better evaluate the many treatment alternatives.


Brawls Bring Buzz: Male Size Influences Competition and Courtship in Diadasia rinconis (Hymenoptera: Apidae).
Sexual selection on male body size in species with a female-biased sexual size dimorphism is common yet often poorly understood. In particular, in the majority of bee species, the relative contribution of intrasexual competition and female choice to patterns of male body size is unknown. In this field study, we examined two possible components of male mating success with respect to body size in the solitary bee Diadasia rinconis Cockerell (Hymenoptera: Apidae): 1) ability to procure a mate and 2) the duration of copulation. We found that larger males were better able to procure mates and copulated for shorter periods of time. Although consistent with sperm competition theory, differences in copulation duration were slight; possibly, the shorter copulations of larger males instead reflect in copulo female choice. Consistent with this notion, males engaged in complex courtship while mounted, characterized for the first time in any bee in such detail via audio recordings and high-speed, high-definition video. The number of pulses in male courtship behavior was also positively associated with copulation duration and may have stimulated females to continue copulating, thereby potentially allowing smaller males to transfer a full ejaculate. Females were shown to be potentially polyandrous and although we did not observe precopulatory rejection in the field, captive females frequently rejected copulation attempts by captive males. Our work indicates that intrasexual competition selects for increased body size in a solitary bee.


Stimulation of AMP-activated protein kinase and enhancement of basal glucose uptake in muscle cells by quercetin and quercetin glycosides, active principles of the antidiabetic medicinal plant Vaccinium vitis-idaea.
Several medicinal plants that stimulate glucose uptake in skeletal muscle cells were identified from among species used by the Cree of Eeyou Istchee of northern Quebec to treat symptoms of diabetes. This study aimed to elucidate the mechanism of action of one of these products, the berries of Vaccinium vitis idaea, as well as to isolate and identify its active constituents using a classical bioassay-guided fractionation approach. Western immunoblot analysis in C2C12 muscle cells revealed that the ethanol extract of the berries stimulated the insulin-independent AMP-activated protein kinase (AMPK) pathway. The extract mildly inhibited ADP-stimulated oxygen consumption in isolated mitochondria, an effect consistent with metabolic stress and the ensuing stimulation of AMPK. This mechanism is highly analogous to that of Metformin. Fractionation guided by glucose uptake activity resulted in the isolation of ten compounds. The two most active, quercetin-3-O-glycosides, enhanced glucose uptake by 38-59% (50 muM; 18 h treatment) in the absence of insulin. Quercetin aglycone, a minor constituent, stimulated uptake by 37%. The quercetin glycosides and the aglycone stimulated the AMPK pathway at concentrations of 25-100 muM, but only the aglycone inhibited ATP synthase in isolated mitochondria (by 34 and 79% at 25 and 100 muM, respectively). This discrepancy suggests that the activity of the glycosides may require hydrolysis to the aglycone form. These findings indicate that quercetin and quercetin 3-O-glycosides are responsible for the antidiabetic activity of V. vitis crude berry extract mediated by AMPK. These common plant products may thus have potential applications for the prevention and treatment of insulin resistance and other metabolic diseases.


WE-C-217A-03: Biology versus Epidemiology: The Need for an Integrated Model of Radiation Risk.
The lifetime attributable risk estimates from the National Academy of Sciences BEIR VII report have been used by a number of authors to estimate cancer mortality caused by radiation exposure from medical diagnostic radiology exams. This controversial practice assumes that the dose response relationship between radiation and cancer is linear with no threshold (LNT). For purposes of protecting public health, use of the LNT model is widely accepted. But is it appropriate for estimating risk to individuals exposed to low doses of radiation from medical procedures? Radiation biology research demonstrates that not all biological processes are linear. Italso has provided data that support not only LNT but supra linear and sub linear response models. Results from epidemiology studies can also be used to support the use of any of these models, but the confidence intervals are much larger. Since we can't prove which model is correct, for purposes of protecting patients we assume that any exposure has the potential for harm and we use optimization to keep exposures as low as reasonably achievable.Several areas of research are contributing insight into this dilemma, but they still leave several important questions unanswered: • How can we accurately extrapolate low-dose biological effects generated in the laboratory to risk in a human? • Is extrapolation from high dose, high dose rate, acute exposures appropriate when human exposures are primarily chronic low dose exposures. Epidemiology alone is unlikely to provide information that will resolve this dilemma. The numbers of individuals required in a sample are too large, and the homogeneity among subjects is lacking. Reliance on radiation biology research alone is problematic because the research is focused primarily on mechanisms and not risk. This paper will present an overview of the issues and suggest areas of research that may contribute to our understanding of the level of risk associated with low doses of medical radiation. 1. List the current biological mechanisms that are affected by low doses of ionizing radiation. 2. Describe the dilemma of risk extrapolation based on current knowledge of biological effects of radiation. 3. Discuss the limitations of extrapolating lifetime attributable risk estimates to cancer mortality for low-dose medical procedures.


Autofluorescent Organelles Within the Retinal Pigment Epithelium in Human Donor Eyes With and Without Age-Related Macular Degeneration.
Human retinal pigment epithelium (RPE) cells contain lipofuscin, melanolipofuscin, and melanosome organelles that impact clinical autofluorescence (AF) imaging. Here, we quantified the effect of age-related macular degeneration (AMD) on granule count and histologic AF of RPE cell bodies. Seven AMD-affected human RPE-Bruch's membrane flatmounts (early and intermediate = 3, late dry = 1, and neovascular = 3) were imaged at fovea, perifovea, and near periphery using structured illumination and confocal AF microscopy (excitation 488 nm) and compared to RPE-flatmounts with unremarkable macula (n = 7, >80 years). Subsequently, granules were marked with computer assistance, and classified by their AF properties. The AF/cell was calculated from confocal images. The total number of granules and AF/cell was analyzed implementing a mixed effect analysis of covariance (ANCOVA). A total of 152 AMD-affected RPE cells were analyzed (fovea = 22, perifovea = 60, and near-periphery = 70). AMD-affected RPE cells showed increased variability in size and a significantly increased granule load independent of the retinal location (fovea: P = 0.02, perifovea: P = 0.04, and near periphery: P < 0.01). The lipofuscin fraction of total organelles decreased and the melanolipofuscin fraction increased in AMD, at all locations (especially the fovea). AF was significantly lower in AMD-affected cells (fovea: <0.01, perifovea: <0.01, and near periphery: 0.02). In AMD RPE, lipofuscin was proportionately lowest in the fovea, a location also known to be affected by accumulation of soft drusen and preservation of cone-mediated visual acuity. Enlarged RPE cell bodies displayed increased net granule count but diminished total AF. Future studies should also assess the impact on AF imaging of RPE apical processes containing melanosomes.


Evidence-based review of the use of the pulmonary artery catheter: impact data and complications.
The pulmonary artery catheter (PAC) was introduced in 1971 for the assessment of heart function at the bedside. Since then it has generated much enthusiasm and controversy regarding the benefits and potential harms caused by this invasive form of hemodynamic monitoring. This review discusses all clinical studies conducted during the past 30 years, in intensive care unit settings or post mortem, on the impact of the PAC on outcomes and complications resulting from the procedure. Although most of the historical observational studies and randomized clinical trials also looked at PAC-related complications among their end-points, we opted to review the data under two main topics: the impact of PAC on clinical outcomes and cost-effectiveness, and the major complications related to the use of the PAC.


Preventing alcohol use problems among blue-collar workers: a field test of the Working People program.
A program designed to prevent alcohol misuse among working adults was developed and presented in four sessions to employees of a medium-sized printing company. The Working People program, based on a social-learning model, was field-tested with 108 employees in the context of a quasi-experimental design. Members of the Program Group (n = 38) and two Comparison Groups (n = 26 and 44) were assessed before and after the program on a questionnaire containing measures of alcohol consumption, attitudes and intentions regarding alcohol use, problem consequences of alcohol use, and health beliefs. Program effects were demonstrated on alcohol consumption, motivation to reduce consumption, and problem consequences of drinking. No effects were found on health beliefs or self-efficacy to reduce drinking. Although the findings are qualified by the self-selected nature of the samples, the results suggest that alcohol consumption can be reduced among adults who participate in this type of worksite program.


In situ quantification of noise as a function of signal in digital images.
An efficient and accurate algorithm for determining the magnitude of noise as a function of signal in an arbitrary digital image is presented and demonstrated. The algorithm is robust and largely independent of the form of the image, returning the noise function with subcount error across the full dynamic range of a synthetic test image where noise of a known form has been added. The noise performance of a CCD under different image recording and processing conditions is examined using the algorithm. The effect of different noise functions on pattern-matching measurements of electronic structure by quantitative convergent beam electron diffraction is investigated.


Infertility: etiologies, evaluation and treatments.
Approximately 12-15% of couples are considered infertile and seek medical care. This review will delineate the current etiologies of infertility and outline a detailed evaluation. Treatment of the infertile couple should be targeted towards specific causes with empiric therapies reserved for those with unexplained infertility. Currently, great advances in the area of assisted reproductive technology allow physicians to treat couples with severe male factor infertility and tubal disease who previously had little hope of conceiving. The most common etiologies of infertility include tubal and peritoneal disorders, ovulatory dysfunction and male factor. Other conditions causing infertility are mentioned in this review for completeness sake. Surgery often corrects infertility due to tubal and peritoneal disease while a variety of medications exist to successfully manage ovulatory dysfunction. Couples who fail to conceive with those conservative measures are candidates for assisted reproductive technology such as in vitro fertilization (IVF). Recent advances in IVF lab techniques allow for correction of severe male factor infertility through use of intracytoplasmic sperm injection.


The efficacy of a novel insecticidal protein, Allium sativum leaf lectin (ASAL), against homopteran insects monitored in transgenic tobacco.
The homopteran group of polyphagous sucking insect pests causes severe damage to many economically important plants including tobacco. Allium sativum leaf lectin (ASAL), a mannose-binding 25-kDa homodimeric protein, has recently been found to be antagonistic to various sucking insects in the homopteran group through artificial diet bioassay experiments. The present study describes, for the first time, the expression of the ASAL coding sequence under the control of the cauliflower mosaic virus (CaMV) 35S promoter in tobacco by Agrobacterium-mediated transformation technology. Molecular analyses demonstrated the integration of the chimeric ASAL gene in tobacco and its inheritance in the progeny plants. Western blot analysis followed by enzyme-linked immunosorbent assay (ELISA) determined the level of ASAL expression in different lines to be in the range of approximately 0.68%-2% of total soluble plant protein. An in planta bioassay conducted with Myzus persicae, peach potato aphid (a devastating pest of tobacco and many other important plants), revealed that the percentage of insect survival decreased significantly to 16%-20% in T0 plants and T1 progeny, whilst approximately 75% of insects survived on untransformed tobacco plants after 144 h of incubation. Ligand analyses of insect brush border membrane vesicle receptors and expressed ASAL in transgenic tobacco showed that the expressed ASAL binds to the aphid gut receptor in the same manner as native ASAL, pointing to the fact that ASAL maintains the biochemical characteristics even in the transgenic situation. These findings in a model plant open up the possibility of expressing the novel ASAL gene in a wide range of crop plants susceptible to various sap-sucking insects.


Genetic and phenotypic variation along an ecological gradient in lake trout Salvelinus namaycush.
Adaptive radiation involving a colonizing phenotype that rapidly evolves into at least one other ecological variant, or ecotype, has been observed in a variety of freshwater fishes in post-glacial environments. However, few studies consider how phenotypic traits vary with regard to neutral genetic partitioning along ecological gradients. Here, we present the first detailed investigation of lake trout Salvelinus namaycush that considers variation as a cline rather than discriminatory among ecotypes. Genetic and phenotypic traits organized along common ecological gradients of water depth and geographic distance provide important insights into diversification processes in a lake with high levels of human disturbance from over-fishing. Four putative lake trout ecotypes could not be distinguished using population genetic methods, despite morphological differences. Neutral genetic partitioning in lake trout was stronger along a gradient of water depth, than by locality or ecotype. Contemporary genetic migration patterns were consistent with isolation-by-depth. Historical gene flow patterns indicated colonization from shallow to deep water. Comparison of phenotypic (Pst) and neutral genetic variation (Fst) revealed that morphological traits related to swimming performance (e.g., buoyancy, pelvic fin length) departed more strongly from neutral expectations along a depth gradient than craniofacial feeding traits. Elevated phenotypic variance with increasing water depth in pelvic fin length indicated possible ongoing character release and diversification. Finally, differences in early growth rate and asymptotic fish length across depth strata may be associated with limiting factors attributable to cold deep-water environments. We provide evidence of reductions in gene flow and divergent natural selection associated with water depth in Lake Superior. Such information is relevant for documenting intraspecific biodiversity in the largest freshwater lake in the world for a species that recently lost considerable genetic diversity and is now in recovery. Unknown is whether observed patterns are a result of an early stage of incipient speciation, gene flow-selection equilibrium, or reverse speciation causing formerly divergent ecotypes to collapse into a single gene pool.


The critical role of dysregulated FOXM1-PLAUR signaling in human colon cancer progression and metastasis.
The mammalian Forkhead Box (Fox) transcription factor FOXM1 is implicated in tumorigenesis including mouse intestinal cancer. However, the clinical significance of FOXM1 signaling in human colorectal cancer pathogenesis remains unknown. We investigated FOXM1 expression in 203 cases of primary colon cancer and matched normal colon tissue specimens and explored the underlying mechanisms of altered FOXM1 expression and the impact of this altered expression on colon cancer growth and metastasis using in vitro and animal models of colon cancer. We found weak expression of FOXM1 protein in the colon mucosa, whereas we observed strong FOXM1 expression in tumor-cell nuclei of colon cancer and lymph node metastases. A Cox proportional hazards model revealed that FOXM1 expression was an independent prognostic factor in multivariate analysis. Experimentally, overexpression of FOXM1 by gene transfer significantly promoted the growth and metastasis of colon cancer cells in orthotopic mouse models, whereas knockdown of FOXM1 expression by siRNA did the opposite. Promotion of colon tumorigenesis by FOXM1 directly and significantly correlated with activation of urokinase-type plasminogen activator receptor (PLAUR) expression and elevation of invasion and metastasis. Given the importance of FOXM1 in regulation of the expression of genes key to cancer biology, dysregulated expression and activation of FOXM1 may play important roles in colon cancer progression and metastasis.


Latent trait cortisol (LTC) during pregnancy: Composition, continuity, change, and concomitants.
Individual differences in the activity of the hypothalamic pituitary adrenal (HPA) axis are often operationalized using summary measures of cortisol that are taken to represent stable individual differences. Here we extend our understanding of a novel latent variable approach to latent trait cortisol (LTC) as a measure of trait-like HPA axis function during pregnancy. Pregnant women (n=380) prospectively collected 8 diurnal saliva samples (4 samples/day, 2 days) within each trimester. Saliva was assayed for cortisol. Confirmatory factor analyses were used to fit LTC models to early morning and daytime cortisol. For individual trimester data, only the daytime LTC models had adequate fit. These daytime LTC models were strongly correlated between trimesters and stable over pregnancy. Daytime LTC was unrelated to the cortisol awakening response and the daytime slope but strongly correlated with the area under the curve from ground. The findings support the validity of LTC as a measure of cortisol during pregnancy and suggest that it is not affected by pregnancy-related changes in HPA axis function.


Magnetism from the atom to the bulk in iron, cobalt, and nickel clusters.
Molecular beam deflection measurements of small iron, cobalt, and nickel clusters show how magnetism develops as the cluster size is increased from several tens to several hundreds of atoms for temperatures between 80 and 1000 K. Ferromagnetism occurs even for the smallest sizes: for clusters with fewer than about 30 atoms the magnetic moments are atomlike; as the size is increased up to 700 atoms, the magnetic moments approach the bulk limit, with oscillations probably caused by surface-induced spin-density waves. The trends are explained in a magnetic shell model. A crystallographic phase transition from high moment to low moment in iron clusters has also been identified.


Case series of pectoralis major muscle tears in joint special operations task force-Philippines soldiers diagnosed by bedside ultrasound.
Pectoralis major muscle tears are an uncommon injury although reported most prevalently among young male athletes (e.g. SOF personnel). We describe two cases occurring in Joint Special Operations Task Force-Philippines (JSOTF-P) Soldiers, review the physical examination and sonographic findings suggestive of a high-grade injury, and discuss treatment options.


Liposomal-encapsulated doxorubicin plus cyclophosphamide as first-line therapy in metastatic breast cancer: a phase II multicentric study.
The objective of this study is to evaluate the efficacy and toxicity of the liposome-encapsulated doxorubicin (TLC D-99) plus cyclophosphamide (CTX) as first-line treatment of metastatic breast cancer in light of the potential cardioprotective effect of TLC D-99 as compared with conventional doxorubicin. Sixty-seven patients as defined according Simon's two-stage phase II design were enrolled. They received TLC D-99 at the dosage of 60 mg/m2 plus CTX 600 mg/m2, with cycles repeated every 3 weeks. Cardiac function was assessed by ultrasonography at baseline and every two cycles. The principal characteristics of the 67 enrolled patients were as follows: median age 60 years (range 33-75), median World Health Organization performance status of 1 (range 0-2) and dominant disease site (viscera/bone/soft tissue): 47/15/15 There were nine complete responses and 32 partial responses for an overall response rate of 64%; a further 14 patients had stable disease and the remaining nine patients progressed. Median number of administered cycles was six. Median duration of response was 10 and 9 months, respectively, for complete responders and partial responders. Median duration of survival was 17+ months (range 3 to 33+). Hematological toxicity consisted in leucopenia (G1-G2) in 21 patients and anemia (G1-G2) in 20 patients; G1 thrombocytopenia was observed only in 2 patients. Non-hematological toxicity was generally mild with G1-G2 nausea/vomiting in 23 patients and G1-G2 mucositis in 10. Hair loss was registered in 30 patients and it was G2 in 14 patients. As to concern cardiac toxicity, one patient developed an asymptomatic 20% decline of left ventricular ejection fraction from the baseline value. The results of our study show that the combination of TLC D-99 plus CTX is active and well tolerated, with no unexpected toxicity.


Circadian dysfunction and fluctuations in gait initiation impairment in Parkinson's disease.
In people with Parkinson's disease (PD), anticipatory postural adjustments may be prolonged, reduced in amplitude, or absent, contributing to impaired gait initiation. In addition to motor symptoms, disturbance of the circadian rhythm (CR) is one of the common non-motor symptoms of PD. The purpose of this study was to investigate whether time of day modulates the magnitude of gait initiation impairment, and furthermore, if there is any relationship between CR dysfunction and impaired postural control in PD. Seven consecutive 24-h periods of wrist actigraphy (as a measure of CR), and then gait initiation studies (at two different times, 9:00 a.m. and 2:30 p.m., of the same day) were conducted in two cohorts of ten subjects each: people with PD, and age-matched control subjects. We found that in the PD group, the amplitude of medial/lateral center of pressure (CoP) excursions were significantly reduced in the afternoon as compared with the morning session across all trials (p < 0.05). Actigraphy results showed that CR amplitude was significantly decreased (p < 0.05) in the PD group, which suggests that the PD group suffered from CR disruption. More importantly, changes in medial/lateral CoP displacement were correlated with abnormal CR amplitude in the PD group. These findings provide novel evidence that diurnal fluctuations in treatment-resistant motor symptoms of PD, such as postural and gait initiation deficits, are associated with CR dysfunction. This study supports the idea that therapeutic correction of circadian misalignment should be considered in combination with pharmaceutical and rehabilitation treatments of motor symptoms in PD.


Expression and steroid hormone regulation of TETs and DNMTs in human endometrium.
DNA methyltransferases (DNMTs) and ten-eleven translocation proteins (TETs) facilitate methylation and hydroxymethylation of DNA, respectively. DNMTs are widely studied with conflicting results on their regulation in the endometrium. While the role of TETs in the endometrium remains relatively unexplored. Deregulated expression of TETs and DNMTs are associated with endometrial pathologies. The aim of this study is to characterize the temporal TET expression in endometrium and to determine the hormonal regulation of TETs in comparison to DNMTs. mRNA expressions were quantified by real-time PCR in endometrial tissues from cycling women and localization was determined by immunohistochemistry. Hormonal regulation was investigated in endometrial epithelial and stromal cell lines following a 24 and 48 h treatment cycle. TET1 and 3 mRNA expressions were significantly upregulated in the mid-secretory phase. TET protein expression was ubiquitous in endometrial epithelium throughout the menstrual cycle except during the late-secretory phase, while stromal staining was scattered. TET1 mRNA was significantly upregulated in response to estrogen in stromal cells. Transcriptions of all three TETs were induced in response to progesterone treatment in epithelial cells. Only DNMT3b in epithelial cells and DNMT1 in stromal cells were significantly upregulated upon 24-h estrogen exposure following a significant decrease of DNMT1 when treated with 24 h of estrogen and progesterone. This study suggests that TETs are expressed in a cell-specific, dynamic manner in the endometrium and are responsive to steroid hormones. Investigating the role of TETs individually and with respect to DNMTs, will help to elucidate gene regulatory mechanisms in endometrial biology and pathologies.


Comprehensive allostatic load risk index is associated with increased frontal and left parietal white matter hyperintensities in mid-life cognitively healthy adults.
To date, there is a considerable heterogeneity of methods to score Allostatic Load (AL). Here we propose a comprehensive algorithm (ALCS) that integrates commonly used approaches to generate AL risk categories and assess associations to brain structure deterioration. In a cohort of cognitively normal mid-life adults (n = 620, age 51.3 ± 5.48 years), we developed a comprehensive composite for AL scoring incorporating gender and age differences, high quartile approach, clinical reference values, and current medications, to then generate AL risk categories. Compared to the empirical approach (ALES), ALCS showed better model fit criteria and a strong association with age and sex. ALSC categories were regressed against brain and white matter hyperintensity (WMH) volumes. Higher AL risk categories were associated with increased total, periventricular, frontal, and left parietal WMH volumes, also showing better fit compared to ALES. When cardiovascular biomarkers were removed from the ALSC algorithm, only left-frontal WMHV remained associated with AL, revealing a strong vascular burden influencing the index. Our results agree with previous evidence and suggest that sustained stress exposure enhances brain deterioration in mid-life adults. Showing better fit than ALES, our comprehensive algorithm can provide a more accurate AL estimation to explore how stress exposure enhances age-related health decline.


Measurement of the W+ W- production cross section and search for anomalous WWγ and WWZ couplings in pp collisions at square root(s)=1.96 TeV.
This Letter describes the current most precise measurement of the W boson pair production cross section and most sensitive test of anomalous WWγ and WWZ couplings in pp collisions at a center-of-mass energy of 1.96 TeV. The WW candidates are reconstructed from decays containing two charged leptons and two neutrinos. Using data collected by the CDF II detector from 3.6 fb(-1) of integrated luminosity, a total of 654 candidate events are observed with an expected background of 320±47 events. The measured cross section is σ(pp→W+ W- +X)=12.1±0.9(stat)-1.4+1.6(syst) pb, which is in good agreement with the standard model prediction. The same data sample is used to place constraints on anomalous WWγ and WWZ couplings.


Early Visual Cortex Dynamics during Top-Down Modulated Shifts of Feature-Selective Attention.
Shifting attention from one color to another color or from color to another feature dimension such as shape or orientation is imperative when searching for a certain object in a cluttered scene. Most attention models that emphasize feature-based selection implicitly assume that all shifts in feature-selective attention underlie identical temporal dynamics. Here, we recorded time courses of behavioral data and steady-state visual evoked potentials (SSVEPs), an objective electrophysiological measure of neural dynamics in early visual cortex to investigate temporal dynamics when participants shifted attention from color or orientation toward color or orientation, respectively. SSVEPs were elicited by four random dot kinematograms that flickered at different frequencies. Each random dot kinematogram was composed of dashes that uniquely combined two features from the dimensions color (red or blue) and orientation (slash or backslash). Participants were cued to attend to one feature (such as color or orientation) and respond to coherent motion targets of the to-be-attended feature. We found that shifts toward color occurred earlier after the shifting cue compared with shifts toward orientation, regardless of the original feature (i.e., color or orientation). This was paralleled in SSVEP amplitude modulations as well as in the time course of behavioral data. Overall, our results suggest different neural dynamics during shifts of attention from color and orientation and the respective shifting destinations, namely, either toward color or toward orientation.


Attitudes toward the integration of smoking cessation treatment into drug abuse clinics.
This article examines the variables associated with the presence of smoking cessation interventions in drug abuse treatment units, as well as staff attitudes toward the integration of smoking cessation services as a component of care. Surveys were administered to 106 organizations, 348 treatment clinics, and 3,786 employees in agencies that participated in the National Drug Abuse Treatment Clinical Trials Network. Organizational factors, attributes of the treatment setting, and staff attitudes toward smoking cessation treatment were assessed. Use of smoking cessation interventions was associated with the number of additional services offered at clinics, residential detoxification services, and attitudes of the staff toward smoking cessation treatment. Staff attitudes toward integrating smoking cessation services in drug treatment were influenced by the number of pregnant women admitted, the number of ancillary services provided, the attitudes of staff toward evidence-based practices, and whether smoking cessation treatment was offered as a component of care.


Prevention of cadmium bioaccumulation by herbal adaptogens.
To evaluate the effect of various herbal adaptogens such as shade-dried powders of Withania somnifera, Ocimum sanctum, Asperagus recemosus, Andrographis paniculata, Asphaltum panjabinum (Shilajith), Gymnema sylvestre, Spirulina platensis, and Panex ginseng on cadmium (Cd)-induced oxidative stress and its accumulation in broiler chicken. A total of 80 male broiler chicks of day old age were randomly assigned to 10 equal groups. Group 1 birds were fed with basal diet throughout the experiment (1-42 days). Group 2-10 chicks were fed with basal diet containing cadmium at 100 ppm from day 1 to day 28 (4 weeks). From 29(th) to 42(nd) day (2 weeks), basal diet alone was fed to group 2 chicks which acted as toxic control and group 3-10 birds were fed with feed containing 0.1% powder of W. somnifera, O. sanctum, Aspe. recemosus, An. paniculata, Asph. panjabinum (Shilajith), G. sylvestre, S. platensis, and P. ginseng, respectively. Body weight gain, levels of non-enzymatic antioxidants such as reduced glutathione (GSH), lipid peroxidation markers such as thiobarbituric acid reacting substances (TBARS), liver functional markers such as serum alanine transaminase (ALT), kidney functional markers such as blood urea nitrogen (BUN) and serum creatinine and concentration of cadmium in liver and kidney were investigated. Body weight gains were significantly decreased in birds of groups 2-10 compared to group 1 at the end of 4(th) week. Supplementation of various medicinal herbs in feed after 4(th) week significantly improved the body weight gain compared to that in group 2 chicks. The increase in TBARS and decrease in GSH concentrations of liver and kidney tissues in cadmium intoxicated birds were significantly reversed by the above-said herbs. The liver and kidney functional markers were also restored to normal levels. Highest concentration of cadmium was found accumulated in kidney, followed by liver in birds of group 2. Herbal supplementation in groups 3-10 prevented Cd bioaccumulation which was most evident in liver, followed by kidney. Administration of herbal adaptogens at the rate of 0.1% in feed significantly prevented the bioaccumulation of Cd and reversed the Cd-induced oxidative tissue damage.


Music education for improving reading skills in children and adolescents with dyslexia.
Dyslexia (or developmental dyslexia or specific reading disability) is a specific learning disorder that has a neurobiological origin. It is marked by difficulties with accurate or fluent recognition of words and poor spelling in people who have average or above average intelligence and these difficulties cannot be attributed to another cause, for example, poor vision, hearing difficulty, or lack of socio-environmental opportunities, motivation, or adequate instruction. Studies have correlated reading skills with musical abilities. It has been hypothesized that musical training may be able to remediate timing difficulties, improve pitch perception, or increase spatial awareness, thereby having a positive effect on skills needed in the development of language and literacy. To study the effectiveness of music education on reading skills (that is, oral reading skills, reading comprehension, reading fluency, phonological awareness, and spelling) in children and adolescents with dyslexia. We searched the following electronic databases in June 2012: CENTRAL (2012, Issue 5), MEDLINE (1948 to May Week 4 2012 ), EMBASE (1980 to 2012 Week 22), CINAHL (searched 7 June 2012), LILACS (searched 7 June 2012), PsycINFO (1887 to May Week 5 2012), ERIC (searched 7 June 2012), Arts and Humanities Citation Index (1970 to 6 June 2012), Conference Proceedings Citation Index - Social Sciences and Humanities (1990 to 6 June 2012), and WorldCat (searched 7 June 2012). We also searched the WHO International Clinical Trials Registry Platform (ICTRP) and reference lists of studies. We did not apply any date or language limits. We planned to include randomized controlled trials. We looked for studies that included at least one of our primary outcomes. The primary outcomes were related to the main domain of the reading: oral reading skills, reading comprehension, reading fluency, phonological awareness, and spelling, measured through validated instruments. The secondary outcomes were self esteem and academic achievement. Two authors (HCM and RBA) independently screened all titles and abstracts identified through the search strategy to determine their eligibility. For our analysis we had planned to use mean difference for continuous data, with 95% confidence intervals, and to use the random-effects statistical model when the effect estimates of two or more studies could be combined in a meta-analysis. We retrieved 851 references via the search strategy. No randomized controlled trials testing music education for the improvement of reading skills in children with dyslexia could be included in this review. There is no evidence available from randomized controlled trials on which to base a judgment about the effectiveness of music education for the improvement of reading skills in children and adolescents with dyslexia. This uncertainty warrants further research via randomized controlled trials, involving a interdisciplinary team: musicians, hearing and speech therapists, psychologists, and physicians.


The impact of therapy on the risk of asthma in type 2 diabetes.
There are limited data about the risk of asthma in people with diabetes. We examined the incidence of asthma in subjects with type 2 diabetes (T2DM) compared to controls, and the association with metformin, sulphonylureas and insulin therapy. We conducted a retrospective cohort study using a representative UK primary care database (N = 894 646 adults). We used 1:1 propensity score matching (age, gender, socio-economic deprivation, body mass index and smoking status) to match 29 217 pairs of T2DM cases and controls. We used Cox proportional hazard regression to compare the incidence of asthma in both groups over 8 years of follow-up. In those with T2DM, we used Cox proportional hazard regression to assess for any impact of antidiabetic medications on asthma incidence. Individuals with T2DM were less likely to develop asthma than matched controls (hazard ratio [HR] 0.85, 95% CI 0.77-0.93). Insulin increased the risk of incident asthma (HR 1.25, 95% CI 1.01-1.56), whilst metformin and sulphonylureas were associated with reduced risk (HR 0.80, 95% CI 0.69-0.93 and HR 0.76, 95% CI 0.60-0.97, respectively). There was no association with diabetes duration, complications or glycaemic control. T2DM may have a protective effect against asthma development. Insulin use was associated with an increased risk of asthma, while metformin and sulphonylureas reduced the risk in those with T2DM.


Inactivation and activity of cholesterol-dependent cytolysins: what structural studies tell us.
The homologous bacterially expressed cholesterol-dependent cytolysins (CDCs) form pores via oligomerization; this must occur preferentially once the target membrane has been engaged. Conformational changes in CDCs then drive partition from an aqueous environment to a lipidic one. This review addresses how premature oligomerization is prevented, how conformational changes are triggered, and how cooperativity between subunits brings about new functionality absent from isolated protomers. Variations are found in the answers provided by the CDCs to these issues. Some toxins use pH as a trigger of activity, but recent results have shown that dimerization in solution is an alternative way of preventing premature oligomerization, in particular for the CDC from Clostridium perfringens, perfringolysin. More controversially, there is still no resolution to the debate as to whether incomplete (arciform) oligomers form pores: recent results again suggest that they do.


Patients' attitudes and perceptions of two health-related quality-of-life questionnaires used to collect patient-reported outcome measures in the English National Health Service: A qualitative study of patients undergoing cardiac interventions.
To explore patients' views on the EuroQol-5D and Coronary Revascularisation Outcome Questionnaire, tools currently used for collecting patient-reported outcome measures in the English National Health Service. The key questions were as follows: (1) whether patients consider them sensitive enough to detect change in their health after cardiovascular disease interventions and (2) whether they consider the health-related quality-of-life questions as meaningful. Data were collected on patients' views using focus groups. We held four focus groups selecting participants on the basis of their baseline and follow-up EuroQol-5D scores. Data were analysed using framework analysis and grounded theory. Focus group participants confirmed that they had derived substantial health benefits from their cardiac interventions despite the lack of measurable effects on the EuroQol-5D scores. Participants felt that the EuroQol-5D questionnaire was limited because of the following reasons: Their health fluctuates from day to day.They had difficulty assessing their general health status on the visual analogue scale.They felt that the Coronary Revascularisation Outcome Questionnaire was limited because of the following reasons: They did not understand the clinical terms used.The impact of tiredness on their quality of life was not captured.They were unable to distinguish between the effects of their heart condition and other health issues.Additionally, neither questionnaire considers the adjustments people have made to their domestic arrangements to improve their health-related quality of life. This study provides evidence that the two questionnaires do not capture some aspects of health that patients consider important. Furthermore, the presence of co-morbidities masks the symptoms relating to the heart disease and the effect of their cardiac interventions. Future work on patient-reported outcome measures should consider developing new questionnaires that address these major concerns.


Ectomycorrhizal Fungal Communities and Their Functional Traits Mediate Plant-Soil Interactions in Trace Element Contaminated Soils.
There is an increasing consensus that microbial communities have an important role in mediating ecosystem processes. Trait-based ecology predicts that the impact of the microbial communities on ecosystem functions will be mediated by the expression of their traits at community level. The link between the response of microbial community traits to environmental conditions and its effect on plant functioning is a gap in most current microbial ecology studies. In this study, we analyzed functional traits of ectomycorrhizal fungal species in order to understand the importance of their community assembly for the soil-plant relationships in holm oak trees (Quercus ilex subsp. ballota) growing in a gradient of exposure to anthropogenic trace element (TE) contamination after a metalliferous tailings spill. Particularly, we addressed how the ectomycorrhizal composition and morphological traits at community level mediate plant response to TE contamination and its capacity for phytoremediation. Ectomycorrhizal fungal taxonomy and functional diversity explained a high proportion of variance of tree functional traits, both in roots and leaves. Trees where ectomycorrhizal fungal communities were dominated by the abundant taxa Hebeloma cavipes and Thelephora terrestris showed a conservative root economics spectrum, while trees colonized by rare taxa presented a resource acquisition strategy. Conservative roots presented ectomycorrhizal functional traits characterized by high rhizomorphs formation and low melanization which may be driven by resource limitation. Soil-to-root transfer of TEs was explained substantially by the ectomycorrhizal fungal species composition, with the highest transfer found in trees whose roots were colonized by Hebeloma cavipes. Leaf phosphorus was related to ectomycorrhizal species composition, specifically higher leaf phosphorus was related to the root colonization by Thelephora terrestris. These findings support that ectomycorrhizal fungal community composition and their functional traits mediate plant performance in metal-contaminated soils, and have a high influence on plant capacity for phytoremediation of contaminants. The study also corroborates the overall effects of ectomycorrhizal fungi on ecosystem functioning through their mediation over the plant economics spectrum.


Can stream and riparian restoration offset climate change impacts to salmon populations?
Understanding how stream temperature responds to restoration of riparian vegetation and channel morphology in context of future climate change is critical for prioritizing restoration actions and recovering imperiled salmon populations. We used a deterministic water temperature model to investigate potential thermal benefits of riparian reforestation and channel narrowing to Chinook Salmon populations in the Upper Grande Ronde River and Catherine Creek basins in Northeast Oregon, USA. A legacy of intensive land use practices in these basins has significantly reduced streamside vegetation and increased channel width across most of the stream network, resulting in water temperatures that far exceed the optimal range for salmon growth and survival. By combining restoration scenarios with climate change projections, we were able to evaluate whether future climate impacts could be offset by restoration actions. A combination of riparian restoration and channel narrowing was predicted to reduce peak summer water temperatures by 6.5 °C on average in the Upper Grande Ronde River and 3.0 °C in Catherine Creek in the absence of other perturbations. These results translated to increases in Chinook Salmon parr abundance of 590% and 67% respectively. Although projected climate change impacts on water temperature for the 2080s time period were substantial (i.e., median increase of 2.7 °C in the Upper Grande Ronde and 1.5 °C in Catherine Creek), we predicted that basin-wide restoration of riparian vegetation and channel width could offset these impacts, reducing peak summer water temperatures by about 3.5 °C in the Upper Grande Ronde and 1.8 °C in Catherine Creek. These results underscore the potential for riparian and stream channel restoration to mitigate climate change impacts to threatened salmon populations in the Pacific Northwest.


A positive-negative mode of population covariation links brain connectivity, demographics and behavior.
We investigated the relationship between individual subjects' functional connectomes and 280 behavioral and demographic measures in a single holistic multivariate analysis relating imaging to non-imaging data from 461 subjects in the Human Connectome Project. We identified one strong mode of population co-variation: subjects were predominantly spread along a single 'positive-negative' axis linking lifestyle, demographic and psychometric measures to each other and to a specific pattern of brain connectivity.


Charge order from orbital-dependent coupling evidenced by NbSe2.
Niobium diselenide has long served as a prototype of two-dimensional charge ordering, believed to arise from an instability of the electronic structure analogous to the one-dimensional Peierls mechanism. Despite this, various anomalous properties have recently been identified experimentally, which cannot be explained by Peierls-like weak-coupling theories. Here, we consider instead a model with strong electron-phonon coupling, taking into account both the full momentum and orbital dependence of the coupling matrix elements. We show that both are necessary for a consistent description of the full range of experimental observations. We argue that NbSe2 is typical in this sense, and that any charge-ordered material in more than one dimension will generically be shaped by the momentum and orbital dependence of its electron-phonon coupling as well as its electronic structure. The consequences will be observable in many charge-ordered materials, including cuprate superconductors.


[Psychiatric diagnosis: label, disorder, comorbidity].
This editorial emphasizes the descriptive character of two of the most widely employed psychiatric diagnostic systems currently in use: DSM-IV and ICD-10. While they cannot be deemed atheoretical, they strive for neutrality and propose a nomenclature devoid of derogatory connotations. It is contended that the lowered "labeling threshold" of these systems tends to identify conditions that, while abnormal in the sense of producing personal discomfort or dysfunction, could not always be considered diseases requiring intervention from healthcare systems. This distinction is useful when evaluating studies which acritically apply screening instruments with a diagnostic purpose. These studies, while producing data, may not always be relevant for empirical studies of comorbidity or prevalence.


Polypodium leucotomos extract: a status report on clinical efficacy and safety.
Various extracts of polypodium leucotomos (PLE) applied topically or taken orally have been shown to have several beneficial antioxidant, photoprotectant, antimutagenic, and immunoregulatory effects. Modern studies have evaluated the efficacy of PLE orally as a photoprotective agent and for use in several photo-aggravated dermatologic disorders such as polymorphous light eruption, other photodermatoses, and melasma. No articles have been published evaluating the safety of PLE. We performed a PUBMED search for any randomized clinical trials related to PLE, or anapsos, a synonym. The primary safety endpoint of the review was any mention of an adverse event, side effect, or toxicity. Overall, 19 human and 6 basic science studies were included spanning over 40 years of research. Oral PLE was administered at daily doses ranging from 120 mg to 1080 mg. No adverse effects were reported in laboratory studies. In humans, side effects (gastrointestinal complaints and pruritus) were mild to moderate and found only in very small numbers of patients overall (16/1016 [2%]). This review concludes PLE is well tolerated at all doses administered and associated with a negligible risk of side effects.