The impact of maternal obesity on mother and neonatal health: study in a tertiary hospital of Astana, Kazakhstan.
This study was aimed to investigate the impact of maternal obesity on mothers and their neonatal health. Our study population consisted of 157 women with completed singleton pregnancies, which included both obese (Body mass index, BMI > or =30) and non-obese women (BMI < 30). Data were collected from case histories, and ante- and postnatal records at the tertiary hospital in Astana, Kazakhstan between January and February of 2008. Associations between pregnancy and delivery-related complications, outcomes, and maternal obesity were estimated as odds ratios (ORs) and 95% confidence intervals (CIs) using a logistic regression model. Women aged 30 years or more were at higher risk of obesity (OR = 3.1, 95% CI = 0.8-11.6) than women less than 30 years old. Multiparous women were also at higher risk of obesity (OR = 4.1, 95% CI = 0.9-19.6) than primiparous ones. Obese women were also more likely to have longer hospital stays of more than 10 days (OR=2.2, 95% CI = 0.8-6.2), and were more prone to eclampsia/preeclampsia (OR = 24.7, 95% CI = 2.2-44.8), cesarean sections (OR = 2.1, 95% CI-0.7-6.2), and abnormal labor (OR = 8.1, 95% CI = 1.0-63.8) compared to non-obese women. Neonatal complications such as pneumonia (OR = 3.4, 95% CI = 0.6-20.2) and fetal macrosomia (OR = 2.2, 95% CI = 0.6-8.0) were also more common among babies born to obese mothers. Congenital baby birth defects were strongly associated with maternal obesity (P = 0.016). We concluded that maternal obesity is associated with increased risks of both maternal and neonatal complications, and that such risks increase with advanced age and parity of the mother. Hence, medical practices must take these complications into account by ensuring an adaptable and early management in order to improve mothers and their neonatal health.


In vivo suppression of delayed hypersensitivity: prolongation of desensitization in guinea pigs.
Administering moderate (milligram) amounts of antigen to a guinea pig immunized with thatntigen leads to a transient loss of all delayed hypersensitivity (DH) responses in that animal. In this study, we demonstrate that this "desentization" can be prolonged for 10 days by repeated injection of antigen. At this time, tolerance to the desensitizing antigen develops in both the humoral and cellular systems of the immune response and DH responsiveness to other antigens returns. Repeated cycles of sensitization and desensitization produce repeated episodes of generalized anergy. Neither cells nor serum from desensitized animals could be shown to exert a suppressor effect when transferred to immunized animals and the cells responded normally to antigen and mitogen in tissue culture. The best generalized depression of DH was seen in those animals producing the best DH before desensitization. The inability of antigen to react with tolerant cells to produce desensitization suggests that this phenomenon is an active rather than a passive one and may represent an exaggeration of a normal regulatory mechanism for DH triggered by a regimen of antigen administration that activates suppressor cells to produce a systemic effect.


Realization of a new type of birefringent filter.
A birefringent filter based upon a new principle described in a theoretical paper by one of the authors has been constructed. The theory developed there has been verified experimentally in all respects. Limitatations on a filter of this type are discussed along with possible applications.


Note: Microelectromechanical systems Coulter counter for cell monitoring and counting.
This note describes the design, fabrication, and testing of a novel microelectromechanical systems Coulter counter. The Coulter counter will be used to detect and monitor impedance changes of cells as a function of time in response to different experimental extracellular environments. The device consists of SU-8 (negative photoresist) microchannels, vertical electroplated electrodes, polydimethylsiloxane cover, and is divided into a passive mixing region, a focusing region using negative dielectrophoretic forces, and a measuring region defined by multiple electroplated electrode pairs. The devices were tested using both microbeads in saline water and fibroblast cells in phosphate buffered saline solution. The results show that the proposed microsystem is capable of monitoring impedance of cells at different positions along the Coulter microchannel.


Chemiluminescence efficiency of catalyzed 1,2-dioxetanone decomposition determined by steric effects.
The chemiluminescent decomposition of 1,2-dioxetanones (α-peroxylactones), catalyzed by an appropriate fluorescent activator, is an important simple model for efficient bioluminescent transformations. In this work, we report experimental data on the catalyzed decomposition of two spiro-substituted 1,2-dioxetanone derivatives, which support the occurrence of an intermolecular electron transfer from the activator to the peroxide. The low efficiency of the studied systems is associated with steric hindrance during the chemiexcitation sequence, rationalized using the concept of supermolecule formation between the peroxide and the catalyst. This approach explains the difference in the chemiexcitation efficiencies in the decomposition of four-membered cyclic peroxide derivatives: 1,2-dioxetanes, 1,2-dioxetanones, and 1,2-dioxetanedione (the intermediate in the peroxyoxalate reaction), which are the most important model compounds for excited-state formation in chemiluminescence and bioluminescence processes.


Two components of cardiac delayed rectifier K+ current. Differential sensitivity to block by class III antiarrhythmic agents.
An envelope of tails test was used to show that the delayed rectifier K+ current (IK) of guinea pig ventricular myocytes results from the activation of two outward K+ currents. One current was specifically blocked by the benzenesulfonamide antiarrhythmic agent, E-4031 (IC50 = 397 nM). The drug-sensitive current, "IKr" exhibits prominent rectification and activates very rapidly relative to the slowly activating drug-insensitive current, "IKs." IKs was characterized by a delayed onset of activation that occurs over a voltage range typical of the classically described cardiac IK. Fully activated IKs, measured as tail current after 7.5-s test pulses, was 11.4 times larger than the fully activated IKr. IKr was also blocked by d-sotalol (100 microM), a less potent benzenesulfonamide Class III antiarrhythmic agent. The activation curve of IKr had a steep slope (+7.5 mV) and a negative half-point (-21.5 mV) relative to the activation curve of IKs (slope = +12.7 mV, half-point = +15.7 mV). The reversal potential (Erev) of IKr (-93 mV) was similar to EK (-94 mV for [K+]o = 4 mM), whereas Erev of IKs was -77 mV. The time constants for activation and deactivation of IKr made up a bell-shaped function of membrane potential, peaking between -30 and -40 mV (170 ms). The slope conductance of the linear portion of the fully activated IKr-V relation was 22.5 S/F. Inward rectification of this relation occurred at potentials greater than -50 mV, resulting in a voltage-dependent decrease in peak IKr at test potentials greater than 0 mV. Peak IKr at 0 mV averaged 0.8 pA/pF (n = 21). Although the magnitude of IKr was small relative to fully activated IKs, the two currents were of similar magnitude when measured during a relatively short pulse protocol (225 ms) at membrane potentials (-20 to +20 mV) typical of the plateau phase of cardiac action potentials.


Modeling the host response to inhalation anthrax.
Inhalation anthrax, an often fatal infection, is initiated by endospores of the bacterium Bacillus anthracis, which are introduced into the lung. To better understand the pathogenesis of an inhalation anthrax infection, we propose a two-compartment mathematical model that takes into account the documented early events of such an infection. Anthrax spores, once inhaled, are readily taken up by alveolar phagocytes, which then migrate rather quickly out of the lung and into the thoracic/mediastinal lymph nodes. En route, these spores germinate to become vegetative bacteria. In the lymph nodes, the bacteria kill the host cells and are released into the extracellular environment where they can be disseminated into the blood stream and grow to a very high level, often resulting in the death of the infected person. Using this framework as the basis of our model, we explore the probability of survival of an infected individual. This is dependent on several factors, such as the rate of migration and germination events and treatment with antibiotics.


Genetic control of natural resistance to Salmonella typhimurium in mice during the late phase of infection.
Previous studies have shown that C57L and DBA/2 mice are able to control the initial net growth of Salmonella typhimurium in splenic and hepatic tissues, but when infected i.p., they ultimately succumb to the typhoid-like disease caused by this Gram-negative bacterium. In this investigation, it was observed that the late-phase susceptibility of both the C57L and DBA/2 strains to murine typhoid was not only evident when mice were challenged i.p., but also when mice were challenged subcutaneously, i.v., and orally. Genetic analyses were then performed to characterize the gene or genes responsible for this susceptibility. The results of such experiments were consistent with the hypothesis that a single autosomal recessive gene is primarily responsible for the susceptibility. This gene was distinct from all other previously defined S. typhimurium response genes. The chromosomal location of the late-phase susceptibility gene could not be determined; no linkage was observed between expression of the late-phase susceptible phenotype and selected markers on chromosomes 1, 2, 4, 5, or 7.


Electrophysiological study of cardiovascular neurons in the rostral ventrolateral medulla in rats.
In urethane-anesthetized rats, electrophysiological recordings of spontaneously active neurons in the vasopressor area of the rostral ventrolateral medulla were analyzed for participation in cardiovascular regulation. A total of 138 units were found which were inhibited by transient increases in mean arterial pressure elicited by intravenous injection of norepinephrine, aortic occlusion, or electrical stimulation of the hypothalamus, with 100% inhibition occurring at 148 mm Hg. Histograms of postsystolic activity showed that these units had pulse-synchronous rhythms which grew more prominent as arterial pressure increased. Furthermore, electrical stimulation of the superior laryngeal nerve, which elicited a vasodepressor response, strongly inhibited these units. Thus, these neurons were termed negatively correlated cardiovascular units. At least half of these cells project to or through the thoracic spinal cord. In addition, arterial pressure sensitivity is conveyed through carotid sinus and aortic arch afferents. Approximately half of the cardiovascular units are also excited by hypothalamic stimulation. Finally, analysis of neighboring cells showed that it is possible to distinguish between cardiovascular and respiratory units. These data are consistent with the concept of a medullary center which supports tonic sympathetic vasomotor tone and which mediates baroreceptor reflexes, as well as vascular responses of the defense reaction.


Evolving the olfactory system with machine learning.
The convergent evolution of the fly and mouse olfactory system led us to ask whether the anatomic connectivity and functional logic of olfactory circuits would evolve in artificial neural networks trained to perform olfactory tasks. Artificial networks trained to classify odor identity recapitulate the connectivity inherent in the olfactory system. Input units are driven by a single receptor type, and units driven by the same receptor converge to form a glomerulus. Glomeruli exhibit sparse, unstructured connectivity onto a larger expansion layer of Kenyon cells. When trained to both classify odor identity and to impart innate valence onto odors, the network develops independent pathways for identity and valence classification. Thus, the defining features of fly and mouse olfactory systems also evolved in artificial neural networks trained to perform olfactory tasks. This implies that convergent evolution reflects an underlying logic rather than shared developmental principles.


Klebsiella pneumoniae Liver Abscess.
Since the mid 1980s, the prevalence of liver abscess caused by hypervirulent Klebsiella pneumoniae strain has increased in Asia, particularly in Taiwan and Korea. This strain is mostly K1 or K2 serotype, and has hypercapsular and hypermucoid phenotypes. Most infections are community acquired, and patients rarely have a hepatobiliary disease prior to infection. Clinical manifestations are characterized by fever and high C-reactive protein, and metastatic infections, such as septic emboli in the lung and endophthalmitis and meningitis are frequently observed. Antibiotic resistance is rare. Antibiotic treatment and abscess drainage are needed, and early diagnosis and treatment of endophthalmitis is also important.


Containment of Antibiotic REsistance-measures to improve antibiotic use in pregnancy, childbirth and young children (CAREChild): a protocol of a prospective, quasiexperimental interventional study in Lao PDR.
Antibiotics are essential to treat infections during pregnancy and to reduce both maternal and infant mortality. Overall use, but especially non-indicated use, and misuse of antibiotics are drivers of antibiotic resistance (ABR). High non-indicated use of antibiotics for uncomplicated vaginal deliveries is widespread in many parts of the world. Similarly, irrational use of antibiotics is reported for children. There is scarcity of evidence regarding antibiotic use and ABR in Lao PDR (Laos). The overarching aim of this project is to fill those knowledge gaps and to evaluate a quality improvement intervention. The primary objective is to estimate the proportion of uncomplicated vaginal deliveries where antibiotics are used and to compare its trend before and after the intervention. This 3-year, prospective, quasiexperimental study without comparison group includes a formative and interventional phase. Data on antibiotic use during delivery will be collected from medical records. Knowledge, attitudes and reported practices on antibiotic use in pregnancy, during delivery and for children, will be collected from women through questionnaires. Healthcare providers' knowledge, attitudes and practices of antibiotics administration for pregnant women, during delivery and for children, will be collected via adapted questionnaires. Perceptions regarding antibiotics will be explored through focus group discussions with women and individual interviews with key stakeholders. Faecal samples for culturing of Escherichia coli and Klebsiella spp. and antibiotic susceptibility testing will be taken before, during and 6 months after delivery to determine colonisation of resistant strains. The planned intervention will comprise training workshops, educational materials and social media campaign and will be evaluated using interrupted time series analysis. The project received ethical approval from the National Ethics Committee for Health Research, Ministry of Health, Laos. The results will be disseminated via scientific publications, conference presentations and communication with stakeholders. ISRCTN16217522; Pre-results.


Caveolin-1 Dependent Endocytosis Enhances the Chemosensitivity of HER-2 Positive Breast Cancer Cells to Trastuzumab Emtansine (T-DM1).
The humanized monoclonal antibody-drug conjugate trastuzumab emtansine (T-DM1, Kadcyla) has been approved by the U.S. FDA to treat human epidermal growth factor receptor 2 (HER-2)-positive metastatic breast cancer. Despite its effectiveness in most patients, some are initially resistant or develop resistance. No biomarker of drug resistance to T-DM1 has been identified. Antibody-drug efficacy is associated with antibody internalization in the cell; therefore, cellular sensitivity of cells to the drug may be linked to cellular vesicle trafficking systems. Caveolin-1 is a 22 KD protein required for caveolae formation and endocytic membrane transport. In this study, the relationship between caveolin-1 expression and the chemosensitivity of HER-2-positive breast cancer cells to T-DM1 was investigated. Samples from 32 human breast cancer biopsy and normal tissue specimens were evaluated immunohistochemically for caveolin-1 expression. Caveolin-1 was shown to be expressed in 68% (22/32) of the breast cancer specimens. In addition, eight (72.7%, 8/11) HER-2 positive breast cancer specimens had a higher caveolin-1 expression than normal tissues. HER-2-positive BT-474 and SKBR-3 breast cancer cells that express low and moderate levels of caveolin-1, respectively, were treated with trastuzumab or its conjugate T-DM1. Cell viability and molecular localizations of caveolin-1, antibody and its conjugate were examined. Confocal microscopy showed that T-DM1 and caveolin-1 colocalized in SKBR-3 cells, which also were five times more sensitive to the conjugate in terms of cell survival than BT-474 cells, although T-DM1 also showed improved drug efficacy in BT-474 cells than trastuzumab treatment. Caveolin-1 expression in these lines was manipulated by transfection of GFP-tagged caveolin-1 or caveolin-1 siRNA. BT-474 cells overexpressing caveolin-1 were more sensitive to T-DM1 treatment than mock-transfected cells, whereas the siRNA-transfected SKBR-3 cells had decreased sensitivity to T-DM1 than mock-transfected SKBR-3 cells. The expression of caveolin-1 could mediate endocytosis and promote the internalization of T-DM1 into HER-2 positive cancer cells. Thus, caveolin-1 protein may be an effective predictor for determining the outcome of T-DM1 treatment in breast cancer patients.


Brain activity patterns in high-throughput electrophysiology screen predict both drug efficacies and side effects.
Neurological drugs are often associated with serious side effects, yet drug screens typically focus only on efficacy. We demonstrate a novel paradigm utilizing high-throughput in vivo electrophysiology and brain activity patterns (BAPs). A platform with high sensitivity records local field potentials (LFPs) simultaneously from many zebrafish larvae over extended periods. We show that BAPs from larvae experiencing epileptic seizures or drug-induced side effects have substantially reduced complexity (entropy), similar to reduced LFP complexity observed in Parkinson's disease. To determine whether drugs that enhance BAP complexity produces positive outcomes, we used light pulses to trigger seizures in a model of Dravet syndrome, an intractable genetic epilepsy. The highest-ranked compounds identified by BAP analysis exhibit far greater anti-seizure efficacy and fewer side effects during subsequent in-depth behavioral assessment. This high correlation with behavioral outcomes illustrates the power of brain activity pattern-based screens and identifies novel therapeutic candidates with minimal side effects.


Oncolytic virus as a cancer stem cell killer: progress and challenges.
Oncolytic viruses (OVs), which were discovered more than one century ago, have been used in multiple clinical trials for cancer therapy. OVs specifically target cancer cells when sparing normal cells by exploiting biochemical differences between normal and tumor cells. Hence oncolytic virotherapy is more specific at targeting cancer cells compared with conventional anti-cancer therapy. Apart from the lack of specificity, conventional anti-cancer therapies also often witness relapse and incomplete cure of cancer. One hypothesis explaining this phenomenon is that a subpopulation of cancer cells, known as cancer stem cells (CSCs), are resistant to conventional therapies, possibly due to its self-renewal and differentiation abilities. With the discovery of CSCs, researchers have been trying to explain whether OVs are well suited to eliminate CSCs. Two explanations for postulating OVs as ideal candidates for cancer therapy have been proposed: first, OVs are not subject to the same mechanisms responsible for chemotherapy and radiation resistance; second, viruses could be harnessed to express therapeutic transgenes that specifically target the features unique to CSCs or the properties CSCs rely on for self-renewal and differentiation. Indeed, initial studies suggest that OVs could effectively target CSCs in multiple tumor types. The focus of this review is to highlight recent studies related to the application of OVs on targeting CSCs, based on which, the challenges and perspectives for further research in this field will also be discussed.


Bacterial Colonization as a Possible Source of Overactive Bladder Symptoms in Pediatric Patients: A Literature Review.
Overactive Bladder (OAB) is a common condition that is known to have a significant impact on daily activities and quality of life. The pathophysiology of OAB is not completely understood. One of the new hypothetical causative factors of OAB is dysbiosis of an individual urinary microbiome. The major aim of the present review was to identify data supporting the role of bacterial colonization in overactive bladder symptoms in children and adolescents. The second aim of our study was to identify the major gaps in current knowledge and possible areas for future clinical research. There is a growing body of evidence indicating some relationship between qualitative and quantitative characteristics of individual urinary microbiome and OAB symptoms in adult patients. There are no papers directly addressing this issue in children or adolescents. After a detailed analysis of papers relating urinary microbiome to OAB, the authors propose a set of future preclinical and clinical studies which could help to validate the concept in the pediatric population.


Final Results of a Randomized, Phase III Study of Rituximab With or Without Idelalisib Followed by Open-Label Idelalisib in Patients With Relapsed Chronic Lymphocytic Leukemia.
A randomized, double-blind, phase III study of idelalisib (IDELA) plus rituximab versus placebo plus rituximab in patients with relapsed chronic lymphocytic leukemia (CLL) was terminated early because of superior efficacy of the IDELA-plus-rituximab (IDELA/R) arm. Patients in either arm could then enroll in an extension study to receive IDELA monotherapy. Here, we report the long-term efficacy and safety data for IDELA-treated patients across the primary and extension studies. Patients were randomly assigned to receive rituximab in combination with either IDELA 150 mg twice daily (IDELA/R; n = 110) or placebo (placebo/R; n = 110). Key end points were progression-free survival (PFS), overall response rate (ORR), overall survival (OS), and safety. The long-term efficacy and safety of treatment with IDELA was assessed in 110 patients who received at least one dose of IDELA in the primary study, 75 of whom enrolled in the extension study. The IDELA/R-to-IDELA group had a median PFS of 20.3 months (95% CI, 17.3 to 26.3 months) after a median follow-up time of 18 months (range, 0.3 to 67.6 months). The ORR was 85.5% (94 of 110 patients; n = 1 complete response). The median OS was 40.6 months (95% CI, 28.5 to 57.3 months) and 34.6 months (95% CI, 16.0 months to not reached) for patients randomly assigned to the IDELA/R and placebo/R groups, respectively. Prolonged exposure to IDELA increased the incidence of all-grade, grade 2, and grade 3 or greater diarrhea (46.4%, 17.3%, and 16.4%, respectively), all-grade and grade 3 or greater colitis (10.9% and 8.2%, respectively) and all-grade and grade 3 or greater pneumonitis (10.0% and 6.4%, respectively) but did not increase the incidence of elevated hepatic aminotransferases. IDELA improved PFS and OS compared with rituximab alone in patients with relapsed CLL. Long-term IDELA was effective and had an expected safety profile. No new IDELA-related adverse events were identified with longer exposure.


Bridging therapies and liver transplantation in acute liver failure, 10 years of MARS experience from Finland.
Acute liver failure is a life-threatening condition in the absence of liver transplantation option. The aetiology of liver failure is the most important factor determining the probability of native liver recovery and prognosis of the patient. Extracorporeal liver assist devices like MARS (Molecular Adsorbent Recirculating System) may buy time for native liver recovery or serve as bridging therapy to liver transplantation, with reduced risk of cerebral complications. MARS treatment may alleviate hepatic encephalopathy even in patients with a completely necrotic liver. Taking this into account, better prognostic markers than hepatic encephalopathy should be used to assess the need for liver transplantation in acute liver failure.


Effects of a modified mindfulness-based cognitive therapy for family caregivers of people with dementia: A pilot randomized controlled trial.
Caregivers of people with dementia experience high stress levels. Mindfulness-based cognitive therapy has been found to be effective in reducing stress and improving the psychological well-being of several populations. To explore the feasibility and preliminary effects of a modified mindfulness-based cognitive therapy for family caregivers of people with dementia. In a single-blinded, parallel-group, randomized controlled trial, 36 caregivers of people with dementia were randomized to either the intervention group, receiving the 7-session modified mindfulness-based cognitive therapy in 10 weeks; or the control group, receiving the usual family care and brief education on dementia care. The brief education sessions were similar in frequency and duration to the intervention group. Various psychological outcomes of caregivers were assessed and compared at baseline, immediately post-intervention, and at the 3-month follow-up. A focus group with eight participants from the intervention group was conducted to identify the strengths, limitations, and difficulties of the intervention. Intervention feasibility was established with a high completion rate of 83% (completing ≥5 out of the 7 sessions) and a low attrition rate of 11.1%. The duration of the average weekly home-based mindfulness practice of the caregivers was 180 minutes (S.D. = 283.8). The intervention group experienced a statistically significant decrease in stress levels (Z = -1.98, p = 0.05, Cohen's d = 0.7) and depressive symptoms (Z = -2.25, p = 0.02, Cohen's d = 0.8) at the post-test; and a decrease in stress (Z = -2.58, p = 0.01, Cohen's d = 0.9), depressive symptoms (Z = -2.20, p = 0.03, Cohen's d = 0.7), and burden (Z = - 2.74, p = 0.006, Cohen's d = 1.0), and improved quality of life (physical) (Z = -1.68, p = 0.09, Cohen's d = 0.6) at the 3-month follow-up compared to the controls. A focus group conducted immediately after the intervention revealed three major themes: Impacts on the family caregivers, Impacts on the people with dementia, and Difficulty in practicing mindfulness. The findings support the feasibility and preliminary effects of the modified mindfulness-based cognitive therapy on reducing the stress of caregivers and improving their psychological well-being. Some potential effects on people with dementia (e.g., improvements in behavioral problems) were reported by the caregivers. A future study with a larger and more diverse sample is proposed to evaluate the longer-term effects and generalizability of the modified mindfulness-based cognitive therapy and the impacts on people with dementia.


Patients' dependence on a nurse for the administration of their intravenous anti-TNF therapy: A phenomenographic study.
Pain, stiffness and functional restriction of the joints are the main problems for many patients with inflammatory rheumatic conditions. When conventional drugs fail to delay the development of the disease, the patient may require biological treatment such as anti-TNF therapy. Some biological drugs are administered in the form of intravenous infusions and thus the patient is obliged to attend a clinic in order to receive his/her medication, which can affect everyday life as well as independence. It is therefore important to focus on the patient perspective. The aim of this study was to describe variations in how patients with rheumatic conditions conceive their dependence on a nurse for the administration of their intravenous anti-TNF therapy. The study had a descriptive qualitative design with a phenomenographic approach. Interviews were conducted with 20 patients. Three descriptive categories and seven sub-categories emerged: Dependence that affords security (encountering continuity, encountering competence and obtaining information); Dependence that creates involvement (being allowed influence and being given freedom); Dependence that invigorates (obtaining relaxation and encountering the environment). The patients had not reflected on the fact that they were dependent on a nurse for the administration of their intravenous anti-TNF therapy, which may be due to their possibility to influence the treatment. The patients' needs should constitute the basis for the nurse's role in the provision of care.


Natural variation and persistent developmental instabilities in geographically diverse accessions of the allopolyploid Arabidopsis suecica.
Allopolyploids arise from the hybridization of two species concomitant to genome doubling. While established allopolyploids are common in nature and vigorous in growth, early generation allopolyploids are often less fertile than their progenitors and display frequent phenotypic instabilities. It is commonly assumed that new allopolyploid species must pass through a bottleneck from which only those lines emerge that have reconciled genomic incompatibilities inherited from their progenitors in their combined genome, yet little is known about the processes following allopolyploidization over evolutionary time. To address the question if a single allopolyploidization event leads to a single new homogeneous species or may result in diverse offspring lines, we have investigated 13 natural accessions of Arabidopsis suecica, a relatively recent allopolyploid derived from a single hybridization event. The studied accessions display low genetic diversity between lines, yet show evidence of heritable phenotypic diversity of traits, some of which may be adaptive. Furthermore, our data show that contrary to the notion that unstable phenotypes in neoallopolyploids are eliminated rapidly in the new species, some instabilities are carried along throughout the species' evolution, persisting in the established allopolyploid. In summary, our results suggest that a single allopolyploidization event may lay the foundation for diverse populations of the new allopolyploid species.


Prevalence and Correlates of Internet Gaming Problem among Internet Users: Results from an Internet Survey.
The current study aimed to establish the prevalence of internet gaming disorder (IGD) and its association with demographic characteristics, game genre, game use (time spent on gaming), as well as psychological distress, social phobia and well-being among current online gamers in Singapore. A total of 1251 participants aged 13 to 40 years completed the study which was administered as a web survey. The online questionnaire was designed using QuestionPro, and consisted of 8 sections and 105 questions. The 9-item Internet Gaming Disorder Questionnaire was used to establish the prevalence of IGD in the study. A series of logistic regression models were used to examine the associations between IGD, demographic characteristics and game genre, as well as IGD and psychological distress, social phobia and well-being. The prevalence of IGD established using a cutoff of 5 among those who were current online gamers was 17.7%. Multiple logistic regressions revealed that those meeting criteria of IGD were more likely to be older, reported an earlier age of onset of playing online games, had primary and secondary education versus tertiary education, were currently students versus being currently employed and played massively multiplayer online role-playing games. Distress and social anxiety were higher while satisfaction with life was significantly lower among those who met criteria for IGD than those who did not meet the criteria. The prevalence of IGD and its negative consequences in our sample of current online gamers was significant and point towards the need for further clinical studies and innovative interventions to address the problem.


Structural transformation of bovine serum albumin induced by dimethyl sulfoxide and probed by fluorescence correlation spectroscopy and additional methods.
Determining the structure of a protein and its transformation under different conditions is key to understanding its activity. The structural stability and activity of proteins in aqueous-organic solvent mixtures, which is an intriguing topic of research in biochemistry, is dependent on the nature of the protein and the properties of the medium. Herein, the effect of a commonly used cosolvent, dimethyl sulfoxide (DMSO), on the structure and conformational dynamics of bovine serum albumin (BSA) protein is studied by fluorescence correlation spectroscopy (FCS) measurements on fluorescein isothiocyanate (FITC)-labeled BSA. The FCS study reveals a change of the hydrodynamic radius of BSA from 3.7 nm in the native state to 7.0 nm in the presence of 40% DMSO, which suggests complete unfolding of the protein under these conditions. Fluorescence self-quenching of FITC has been exploited to understand the conformational dynamics of BSA. The time constant of the conformational dynamics of BSA is found to change from 35 μs in its native state to 50 μs as the protein unfolds with increasing DMSO concentration. The FCS results are corroborated by the near-UV circular dichroism spectra of the protein, which suggest a loss of its tertiary structure with increasing concentration of DMSO. The intrinsic fluorescence of BSA and the fluorescence response of 1-anilinonaphthalene-8-sulfonic acid, used as a probe molecule, provide information that is consistent with the FCS measurements, except that aggregation of BSA is observed in the presence of 40% DMSO in the ensemble measurements.


Expression of emotional valence in pig closed-mouth grunts: Involvement of both source- and filter-related parameters.
Emotion expression plays a crucial role for regulating social interactions. One efficient channel for emotion communication is the vocal-auditory channel, which enables a fast transmission of information. Filter-related parameters (formants) have been suggested as a key to the vocal differentiation of emotional valence (positive versus negative) across species, but variation in relation to emotions has rarely been investigated. Here, whether pig (Sus scrofa domesticus) closed-mouth grunts differ in source- and filter-related features when produced in situations assumed to be positive and negative is investigated. Behavioral and physiological parameters were used to validate the animals' emotional state (both in terms of valence and arousal, i.e., bodily activation). Results revealed that grunts produced in a positive situation were characterized by higher formants, a narrower range of the third formant, a shorter duration, a lower fundamental frequency, and a lower harmonicity compared to negative grunts. Particularly, formant-related parameters and duration made up most of the difference between positive and negative grunts. Therefore, these parameters have the potential to encode dynamic information and to vary as a function of the emotional valence of the emitter in pigs, and possibly in other mammals as well.


Functional adaptation of the N-methyl-D-aspartate receptor to inhibition by ethanol is modulated by striatal-enriched protein tyrosine phosphatase and p38 mitogen-activated protein kinase.
The hippocampal N-methyl-D-aspartate receptor (NMDAR) activity plays important roles in cognition and is a major substrate for ethanol-induced memory dysfunction. This receptor is a glutamate-gated ion channel, which is composed of NR1 and NR2 subunits in various brain areas. Although homomeric NR1 subunits form an active ion channel that conducts Na⁺ and Ca²⁺ currents, the incorporation of NR2 subunits allows this channel to be modulated by the Src family of kinases, phosphatases, and by simple molecules such as ethanol. We have found that short-term ethanol application inhibits the NMDAR activity via striatal enriched protein tyrosine phosphatase (STEP)-regulated mechanisms. The genetic deletion of the active form of STEP, STEP61, leads to marked attenuation of ethanol inhibition of NMDAR currents. In addition, STEP61 negatively regulates Fyn and p38 mitogen-activated protein kinase (MAPK), and these proteins are members of the NMDAR super molecular complex. Here we demonstrate, using whole-cell electrophysiological recording, Western blot analysis, and pharmacological manipulations, that neurons exposed to a 3-h, 45 mM ethanol treatment develop an adaptive attenuation of short-term ethanol inhibition of NMDAR currents in brain slices. Our results suggest that this adaptation of NMDAR responses is associated with a partial inactivation of STEP61, an activation of p38 MAPK, and a requirement for NR2B activity. Together, these data indicate that altered STEP61 and p38 MAPK signaling contribute to the modulation of ethanol inhibition of NMDARs in brain neurons.


Comparison of thermography and Doppler sonography in the evaluation of the cold immersion test in women with excessive vasospastic reaction.
Determining the predisposition to vasospastic reactions in a function test is important at the earliest possible stage of diagnosis. Thermography is an acknowledged procedure for monitoring function tests; however, its availability is limited. The aim of this study was to compare the progression of the cold immersion test in a thermal picture and an US-CD examination with the flow assessment of the small blood vessels of the hand. A group of 16 women declaring high cold tolerance of their hands was compared with a group of 24 women reporting hand complaints when exposed to the cold. The subjects underwent a test in which they immersed their right hand in ice-cold water (0 degrees C). Then images of the temperature distribution in the hand were recorded with a thermovisory camera. At the same time, spectral waveforms were registered in the proper palmar digital artery and in the radial artery at specified time intervals. Data analysis comprised temperature measurements at the level of the nail plate of the middle finger and at the wrist. There were differences between the groups at all the stages of the immersion test (efficient return of temperature to initial values in the reference group, delayed return in subjects with low tolerance to thermal stimuli). Flow resistance analysis using the Doppler method in the studied arteries revealed similar differences between the groups (swift flow normalization and efficient reperfusion in the reference group, higher flow resistance and low reperfusion in subjects with low tolerance to thermal stimuli). Changes in the parameters of hand warmth during the immersion test assessed by thermography and changes in the flow parameters observed by Doppler sonography demonstrated similar progression, which suggests the equivalence of both methods. Doppler sonography may thus serve as a method of monitoring function tests to establish a predisposition to vasospasm.


Imatinib mesylate reduces rituximab-induced tumor-growth inhibition in vivo on Epstein-Barr virus-associated human B-cell lymphoma.
We have reported earlier an increase of tumor-growth inhibition following chemotherapy combined with concomitant administration of imatinib mesylate. Conversely, the combination of imatinib and rituximab has been reported in very few cases of patients and remains controversial. To explore this particular combination of targeted therapies, we therefore investigated the in-vivo impact of rituximab plus imatinib on B-cell lymphoproliferation. Combination of the tyrosine kinase inhibitor imatinib mesylate (STI571) and the anti-CD20 monoclonal antibody rituximab was evaluated on an Epstein-Barr virus-associated B-cell lymphoproliferative disorder xenografted into severe combined immunodeficient or Rag2/gammac-/- (B-, T- and NK-) mice. Using severe combined immunodeficient mice, we found that STI571 diminished the efficacy of rituximab to inhibit tumor growth in vivo. Using alymphoid Rag2/gammac-/- mice, we showed that the effect of STI571 was not dependent on the presence of natural killer cells. In contrast, serum complement administered after STI571 treatment reversed this inhibitory effect. Finally, using nonimmunodeficient mice, we observed an in-vivo decrease of CD4-positive T-cells and mature B-cell lymphocytes after imatinib administration. We found that STI571 decreased the in-vivo efficacy of rituximab via serum protein components that could influence complement-dependent cytotoxicity. In contrast, this effect was not dependent on the presence of natural killer cells.


Comparative Risks of Cancer from Drywall Finishing Based on Stochastic Modeling of Cumulative Exposures to Respirable Dusts and Chrysotile Asbestos Fibers.
Sanding joint compounds is a dusty activity and exposures are not well characterized. Until the mid 1970s, asbestos-containing joint compounds were used by some people such that sanding could emit dust and asbestos fibers. We estimated the distribution of 8-h TWA concentrations and cumulative exposures to respirable dusts and chrysotile asbestos fibers for four worker groups: (1) drywall specialists, (2) generalists, (3) tradespersons who are bystanders to drywall finishing, and (4) do-it-yourselfers (DIYers). Data collected through a survey of experienced contractors, direct field observations, and literature were used to develop prototypical exposure scenarios for each worker group. To these exposure scenarios, we applied a previously developed semi-empirical mathematical model that predicts area as well as personal breathing zone respirable dust concentrations. An empirical factor was used to estimate chrysotile fiber concentrations from respirable dust concentrations. On a task basis, we found mean 8-h TWA concentrations of respirable dust and chrysotile fibers are numerically highest for specialists, followed by generalists, DIYers, and bystander tradespersons; these concentrations are estimated to be in excess of the respective current but not historical Threshold Limit Values. Due to differences in frequency of activities, annual cumulative exposures are highest for specialists, followed by generalists, bystander tradespersons, and DIYers. Cumulative exposure estimates for chrysotile fibers from drywall finishing are expected to result in few, if any, mesothelioma or excess lung cancer deaths according to recently published risk assessments. Given the dustiness of drywall finishing, we recommend diligence in the use of readily available source controls.


Therapeutics discovery: From bench to first in-human trials.
The 'Therapeutics discovery: From bench to first in-human trials' conference, held at the King Abdullah International Medical Research Center (KAIMRC), Ministry of National Guard Health Affairs (MNGHA), Kingdom of Saudi Arabia (KSA) from October 10-12, 2017, provided a unique opportunity for experts worldwide to discuss advances in drug discovery and development, focusing on phase I clinical trials. It was the first event of its kind to be hosted at the new research center, which was constructed to boost drug discovery and development in the KSA in collaboration with institutions, such as the Academic Drug Discovery Consortium in the United States of America (USA), Structural Genomics Consortium of the University of Oxford in the United Kingdom (UK), and Institute of Materia Medica of the Chinese Academy of Medical Sciences in China. The program was divided into two parts. A pre-symposium day took place on October 10, during which courses were conducted on clinical trials, preclinical drug discovery, molecular biology and nanofiber research. The attendees had the opportunity for one-to-one meetings with international experts to exchange information and foster collaborations. In the second part of the conference, which took place on October 11 and 12, the clinical trials pipeline, design and recruitment of volunteers, and economic impact of clinical trials were discussed. The Saudi Food and Drug Administration presented the regulations governing clinical trials in the KSA. The process of preclinical drug discovery from small molecules, cellular and immunologic therapies, and approaches to identifying new targets were also presented. The recommendation of the conference was that researchers in the KSA must invest more fund, talents and infrastructure to lead the region in phase I clinical trials and preclinical drug discovery. Diseases affecting the local population, such as Middle East Respiratory Syndrome and resistant bacterial infections, represent the optimal starting point.


DAF-12 regulates a connected network of genes to ensure robust developmental decisions.
The nuclear receptor DAF-12 has roles in normal development, the decision to pursue dauer development in unfavorable conditions, and the modulation of adult aging. Despite the biologic importance of DAF-12, target genes for this receptor are largely unknown. To identify DAF-12 targets, we performed chromatin immunoprecipitation followed by hybridization to whole-genome tiling arrays. We identified 1,175 genomic regions to be bound in vivo by DAF-12, and these regions are enriched in known DAF-12 binding motifs and act as DAF-12 response elements in transfected cells and in transgenic worms. The DAF-12 target genes near these binding sites include an extensive network of interconnected heterochronic and microRNA genes. We also identify the genes encoding components of the miRISC, which is required for the control of target genes by microRNA, as a target of DAF-12 regulation. During reproductive development, many of these target genes are misregulated in daf-12(0) mutants, but this only infrequently results in developmental phenotypes. In contrast, we and others have found that null daf-12 mutations enhance the phenotypes of many miRISC and heterochronic target genes. We also find that environmental fluctuations significantly strengthen the weak heterochronic phenotypes of null daf-12 alleles. During diapause, DAF-12 represses the expression of many heterochronic and miRISC target genes, and prior work has demonstrated that dauer formation can suppress the heterochronic phenotypes of many of these target genes in post-dauer development. Together these data are consistent with daf-12 acting to ensure developmental robustness by committing the animal to adult or dauer developmental programs despite variable internal or external conditions.


NHS cadet schemes: student experience, commitment, job satisfaction and job stress.
In the context of various policy initiatives concerning widening access to and strengthening recruitment and retention in the health services, cadet schemes--predominantly in nursing--have proliferated over the last few years. As part of a larger national evaluation of National Health Service (NHS) cadet schemes, this paper reports on a survey of senior cadet students across 62 cadet schemes in England and examines their experience of being a cadet on such a scheme. Cadets forming the most senior cohort from each of the 62 schemes (n = 596) were surveyed using a questionnaire. The questionnaire included self-rated measures of job satisfaction, job stress and commitment. A 5% sample of these cadets participated in follow-up telephone interviews. Cadets reported high satisfaction with their courses. One of the most positive aspects of the schemes was the first-hand experience of working in the NHS they provided, whilst also giving cadets the opportunity to gain recognisable skills and qualifications. Cadets scored highly on the job satisfaction scale and, on the job stress scale, showed low stress overall. A significant positive correlation was found between satisfaction and stress, indicating that the cadets who are most satisfied are also more highly stressed. A negative correlation was found between stress and the dimensions of commitment indicating that those cadets who are stressed are less committed to the NHS. A negative correlation was also found between satisfaction and the dimensions of commitment, suggesting that commitment to the NHS is not contingent on high satisfaction. The implications for the findings of the survey are discussed.


The leukemogenicity of AML1-ETO is dependent on site-specific lysine acetylation.
The chromosomal translocations found in acute myelogenous leukemia (AML) generate oncogenic fusion transcription factors with aberrant transcriptional regulatory properties. Although therapeutic targeting of most leukemia fusion proteins remains elusive, the posttranslational modifications that control their function could be targetable. We found that AML1-ETO, the fusion protein generated by the t(8;21) translocation, is acetylated by the transcriptional coactivator p300 in leukemia cells isolated from t(8;21) AML patients, and that this acetylation is essential for its self-renewal-promoting effects in human cord blood CD34(+) cells and its leukemogenicity in mouse models. Inhibition of p300 abrogates the acetylation of AML1-ETO and impairs its ability to promote leukemic transformation. Thus, lysine acetyltransferases represent a potential therapeutic target in AML.


Enzymatic degradation of sulfite-pulped softwoods and the role of LPMOs.
Recent advances in the development of enzyme cocktails for degradation of lignocellulosic biomass, especially the discovery of lytic polysaccharide monooxygenases (LPMOs), have opened new perspectives for process design and optimization. Softwood biomass is an abundant resource in many parts of the world, including Scandinavia, but efficient pretreatment and subsequent enzymatic hydrolysis of softwoods are challenging. Sulfite pulping-based pretreatments, such as in the BALI™ process, yield substrates that are relatively easy to degrade. We have assessed how process conditions affect the efficiency of modern cellulase preparations in processing of such substrates. We show that efficient degradation of sulfite-pulped softwoods with modern, LPMO-containing cellulase preparations requires the use of conditions that promote LPMO activity, notably the presence of molecular oxygen and sufficient reducing power. Under LPMO activity-promoting conditions, glucan conversion after 48-h incubation with Cellic® CTec3 reached 73.7 and 84.3% for Norway spruce and loblolly pine, respectively, at an enzyme loading of 8 mg/g of glucan. The presence of free sulfite ions had a negative effect on hydrolysis efficiency. Lignosulfonates, produced from lignin during sulfite pretreatment, showed a potential to activate LPMOs. Spiking of Celluclast®, a cellulase cocktail with low LPMO activity, with monocomponent cellulases or an LPMO showed that the addition of the LPMO was clearly more beneficial than the addition of any classical cellulase. Addition of the LPMO in reactions with spruce increased the saccharification yield from approximately 60% to the levels obtained with Cellic® CTec3. In this study, we have demonstrated the importance of LPMOs for efficient enzymatic degradation of sulfite-pulped softwood. We have also shown that to exploit the full potential of LPMO-rich cellulase preparations, conditions promoting LPMO activity, in particular the presence of oxygen and reducing equivalents are necessary, as is removal of residual sulfite from the pretreatment step. The use of lignosulfonates as reductants may reduce the costs related to the addition of small molecule reductants in sulfite pretreatment-based biorefineries.


Effects of the once-weekly glucagon-like peptide-1 receptor agonist dulaglutide on ambulatory blood pressure and heart rate in patients with type 2 diabetes mellitus.
Glucagon-like peptide-1 receptor agonists, used to treat type 2 diabetes mellitus, are associated with small reductions in systolic blood pressure (SBP) and increases in heart rate. However, findings based on clinic measurements do not adequately assess a drug's 24-hour pharmacodynamic profile. The effects of dulaglutide, a once-weekly glucagon-like peptide-1 receptor agonist, on BP and heart rate were investigated using ambulatory BP monitoring. Patients (n=755; 56±10 years; 81% white; 48% women), with type 2 diabetes mellitus, taking ≥1 oral antihyperglycemic medication, with a clinic BP between 90/60 and 140/90 mm Hg were randomized to dulaglutide (1.5 or 0.75 mg) or placebo subcutaneously for 26 weeks. Ambulatory BP monitoring was performed at baseline and at 4, 16, and 26 weeks. The primary end point was change from baseline to week 16 in mean 24-hour SBP, a tree gatekeeping strategy compared the effects of dulaglutide to placebo. Both doses of dulaglutide were noninferior to placebo for changes in 24-hour SBP and diastolic blood pressure, and dulaglutide 1.5 mg significantly reduced SBP (least squares mean difference [95% confidence interval]), -2.8 mm Hg [-4.6, -1.0]; P≤0.001). Dulaglutide 0.75 mg was noninferior to placebo (1.6 bpm; [0.3, 2.9]; P≤0.02) for 24-hour heart rate (least squares mean difference [95% confidence interval]), but dulaglutide 1.5 mg was not (2.8 bpm [1.5, 4.2]). Dulaglutide 1.5 mg was associated with a reduction in 24-hour SBP and an increase in 24-hour heart rate. The mechanisms responsible for the observed effects remain to be clarified.


The Potential of Menstrual Blood-Derived Stem Cells in Differentiation to Epidermal Lineage: A Preliminary Report.
Menstrual blood-derived stem cells (MenSCs) are a novel source of stem cells that can be easily isolated non-invasively from female volunteered donor without ethical consideration. These mesenchymal-like stem cells have high rate of proliferation and possess multi lineage differentiation potency. This study was undertaken to isolate the MenSCs and assess their potential in differentiation into epidermal lineage. About 5-10 ml of menstrual blood (MB) was collected using sterile Diva cups inserted into vagina during menstruation from volunteered healthy fertile women aged between 22-30 years. MB was transferred into Falcon tubes containing phosphate buffered saline (PBS) without Ca2(+) or Mg2(+) supplemented with 2.5 µg/ml fungizone, 100 µg/mL streptomycin, 100 U/mL penicillin and 0.5 mM EDTA. Mononuclear cells were separated using Ficoll-Hypaque density gradient centrifugation and washed out in PBS. The cell pellet was suspended in DMEM-F12 medium supplemented with 10% FBS and cultured in tissue culture plates. The isolated cells were co-cultured with keratinocytes derived from the foreskin of healthy newborn male aged 2-10 months who was a candidate for circumcision for differentiation into epidermal lineage. The isolated MenSCs were adhered to the plate and exhibited spindle-shaped morphology. Flow cytometric analysis revealed the expression of mesenchymal markers of CD10, CD29, CD73, and CD105 and lack of hematopoietic stem cells markers. An early success in derivation of epidermal lineage from MenSCs was visible. The MenSCs are a real source to design differentiation to epidermal cells that can be used non-invasively in various dermatological lesions and diseases.


Quantifying multi-ethnic representation in genetic studies of high mortality diseases.
Most GWASs were performed using study populations with Caucasian ethnicity or ancestry, and findings from one ethnic subpopulation might not always translate to another. We curated 4,573 genetic studies on 763 human diseases and identified 3,461 disease-susceptible SNPs with genome-wide significance; only 10% of these had been validated in at least two different ethnic populations. SNPs for autoimmune diseases demonstrated the lowest percentage of cross-ethnicity validation. We used the mortality data from the Center for Disease Control and Prevention and identified 19 diseases killing over 10,000 Americans per year that were still lacking publications of even a single cross-ethnic SNP. Fifteen of these diseases had never been studied in large GWAS in non-Caucasian populations, including chronic liver diseases and cirrhosis, leukemia, and non-Hodgkin's lymphoma. Our results demonstrate that diseases killing most Americans are still lacking genetic studies across ethnicities.


Role of Epigenetics in Biology and Human Diseases.
For a long time, scientists have tried to describe disorders just by genetic or environmental factors. However, the role of epigenetics in human diseases has been considered from a half of century ago. In the last decade, this subject has attracted many interests, especially in complicated disorders such as behavior plasticity, memory, cancer, autoimmune disease, and addiction as well as neurodegenerative and psychological disorders. This review first explains the history and classification of epigenetic modifications, and then the role of epigenetic in biology and connection between the epigenetics and environment are explained. Furthermore, the role of epigenetics in human diseases is considered by focusing on some diseases with some complicated features, and at the end, we have given the future perspective of this field. The present review article provides concepts with some examples to reveal a broad view of different aspects of epigenetics in biology and human diseases.


Differential effects of vasoactive intestinal peptide, substance P, and somatostatin on immunoglobulin synthesis and proliferations by lymphocytes from Peyer's patches, mesenteric lymph nodes, and spleen.
We examined the effect of vasoactive intestinal peptide, substance P, and somatostatin on concanavalin A (1 microgram/ml)-induced lymphocyte proliferation and immunoglobulin (IgA, IgM, and IgG) synthesis by cells from spleens, Peyer's patches, and mesenteric lymph nodes. These neuropeptides (10(-7) to 10(-12) M) modulated immune responses in a dose-dependent manner. For a comparative study, neuropeptides were used at 10(-8) M concentration. Both vasoactive intestinal peptide and somatostatin significantly decreased DNA synthesis (30 to 50%), whereas substance P increased synthesis (40%) in lymphocytes from all organs tested. IgA synthesis was significantly altered by all of the neuropeptides tested, whereas IgM synthesis was less affected and IgG synthesis was virtually unchanged. Somatostatin inhibited IgA (20 to 50%) and IgM (10 to 30%) synthesis in lymphocytes from all three organs. Substance P increased IgA synthesis in mesenteric lymph nodes (50%), spleens (70%), and Peyer's patches (300%). It also increased IgM synthesis in Peyer's patches (20%) and spleens (30%), but was without effect on IgM synthesis in mesenteric lymph nodes. Vasoactive intestinal peptide increased the IgA response in mesenteric lymph nodes (20%) and spleens (30%), but inhibited IgA synthesis in lymphocytes from Peyer's patches (60%). Interestingly, in Peyer's patches, IgM synthesis was increased by vasoactive intestinal peptide (80%), whereas it was unchanged in mesenteric lymph nodes and spleen. Thus, not only did these neuropeptides have different effects on the production of different immunoglobulin isotypes, but their effect was also organ-specific. Because neuropeptides which are abundant in the intestine can modulate IgA and other immunoglobulin synthesis in vitro, they may play a significant regulatory role in mucosal immune responses in vivo.


Structure and dynamics of hnRNP-labelled nuclear bodies induced by stress treatments.
We have previously described HAP, a novel hnRNP protein that is identical both to SAF-B, a component of the nuclear scaffold, and to HET, a transcriptional regulator of the gene for heat shock protein 27. After heat shock, HAP is recruited to a few nuclear bodies. Here we report the characterisation of these bodies, which are distinct from other nuclear components such as coiled bodies and speckles. The formation of HAP bodies is part of a general cell response to stress agents, such as heat shock and cadmium sulfate, which also affect the distribution of hnRNP protein M. Electron microscopy demonstrates that in untreated cells, similar to other hnRNP proteins, HAP is associated to perichromatin fibrils. Instead, in heat shocked cells the protein is preferentially associated to clusters of perichromatin granules, which correspond to the HAP bodies observed in confocal microscopy. Inside such clusters, perichromatin granules eventually merge into a highly packaged 'core'. HAP and hnRNP M mark different districts of these structures. HAP is associated to perichromatin granules surrounding the core, while hnRNP M is mostly detected within the core. BrU incorporation experiments demonstrate that no transcription occurs within the stress-induced clusters of perichromatin granules, which are depots for RNAs synthesised both before and after heat shock.


Platelet aggregation induced by polystyrene and platinum nanoparticles is dependent on surface area.
Nanoparticles are key components underlying recent technological advances in various industrial and medical fields, and thus understanding their mode of interaction with biological systems is essential. However, while several nanoparticle systems have been shown to interact with blood platelets, many questions remain concerning the mechanisms of platelet activation and the role that the physicochemical properties of nanoparticles play in inducing platelet aggregation. Here, using negatively charged polystyrene nanoparticles with sizes of 25, 50, 119, 151, 201 nm and negatively charged platinum nanoparticles with sizes of 7 and 73 nm, we show that it is not the size of the nanoparticles but rather the nanoparticle surface area that is critical in mediating the effects on platelet activation. The nanoparticles stimulate platelet aggregation through passive (agglutination) and activation of integrin αIIbβ3 through a pathway regulated by Src and Syk tyrosine kinase.


Biological, clinical and population relevance of 95 loci for blood lipids.
Plasma concentrations of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides are among the most important risk factors for coronary artery disease (CAD) and are targets for therapeutic intervention. We screened the genome for common variants associated with plasma lipids in >100,000 individuals of European ancestry. Here we report 95 significantly associated loci (P < 5 x 10(-8)), with 59 showing genome-wide significant association with lipid traits for the first time. The newly reported associations include single nucleotide polymorphisms (SNPs) near known lipid regulators (for example, CYP7A1, NPC1L1 and SCARB1) as well as in scores of loci not previously implicated in lipoprotein metabolism. The 95 loci contribute not only to normal variation in lipid traits but also to extreme lipid phenotypes and have an impact on lipid traits in three non-European populations (East Asians, South Asians and African Americans). Our results identify several novel loci associated with plasma lipids that are also associated with CAD. Finally, we validated three of the novel genes-GALNT2, PPP1R3B and TTC39B-with experiments in mouse models. Taken together, our findings provide the foundation to develop a broader biological understanding of lipoprotein metabolism and to identify new therapeutic opportunities for the prevention of CAD.


Metformin in Pregnancy Study (MiPS): protocol for a systematic review with individual patient data meta-analysis.
Gestational diabetes mellitus (GDM) is a common disorder of pregnancy and contributes to adverse pregnancy outcomes. Metformin is often used for the prevention and management of GDM; however, its use in pregnancy continues to be debated. The Metformin in Pregnancy Study aims to use individual patient data (IPD) meta-analysis to clarify the efficacy and safety of metformin use in pregnancy and to identify relevant knowledge gaps. MEDLINE, EMBASE and all Evidence-Based Medicine will be systematically searched for randomised controlled trials (RCT) testing the efficacy of metformin compared with placebo, usual care or other interventions in pregnant women. Two independent reviewers will assess eligibility using prespecified criteria and will conduct data extraction and quality appraisal of eligible studies. Authors of included trials will be contacted and asked to contribute IPD. Primary outcomes include maternal glycaemic parameters and GDM, as well as neonatal hypoglycaemia, anthropometry and gestational age at delivery. Other adverse maternal, birth and neonatal outcomes will be assessed as secondary outcomes. IPD from these RCTs will be harmonised and a two-step meta-analytic approach will be used to determine the efficacy and safety of metformin in pregnancy, with a priori adjustment for covariates and subgroups to examine effect moderators of treatment outcomes. Sensitivity analyses will assess heterogeneity, risk of bias and the impact of trials which have not provided IPD. All IPD will be deidentified and studies contributing IPD will have ethical approval from their respective local ethics committees. This study will provide robust evidence regarding the efficacy and safety of metformin use in pregnancy, and may identify subgroups of patients who may benefit most from this treatment modality. Findings will be published in peer-reviewed journals and disseminated at scientific meetings, providing much needed evidence to inform clinical and public health actions in this area.


Facing the possibility of bioterrorism.
The possibility of bioterrorism has been met by significant financial outlays to map out public health responses. These have included comprehensive audits of potential agents, as well as exploring mechanisms for counteracting their impact. Psychological intervention and communication have been identified as key areas requiring further work, as fear of infection could pose a greater strain on social resources than the pathogens themselves. Bioterrorism provides a powerful metaphor for élite fears of social corrosion from within. Accordingly, a broader historical and cultural perspective is required to understand why individuals and societies feel so vulnerable to what remain largely speculative scenarios.


Diagnosing the plasma formed during acoustic cavitation in [BEPip][NTf2] ionic liquid.
Sonoluminescence (SL) spectra of a very dry [BEPip][NTf2] ionic liquid were measured in the first minutes of sonication under Ar. The intense sonoluminescence allowed us to monitor the time-evolution of the SL spectra. Several molecular emissions were observed. Rovibronic temperatures of C2 and CN were determined giving vibrational temperatures of 5800 ± 500 K and 6000 ± 500 K and rotational temperatures (i.e. translational or gas temperatures) of 4000 ± 500 K. These temperatures stay remarkably constant during the sonolysis, while SL spectra undergo strong changes that illustrate the very fast evolution of the plasma during the first minutes of sonication. The expected strong decrease in the plasma electron energy also reflects in the evolution of the populations of CH electronically excited states. The physical meaning of temperatures derived from molecular emissions in SL spectra is discussed.


On surface O-glycosylation by catalytic microcontact printing.
The generation of carbohydrate patterns on surfaces enables a wide range of analytical and diagnostic applications and efficient methods for carbohydrate immobilization are crucial for this purpose. We report on surface O-glycosylation by catalytic printing as a novel, effective method for the covalent immobilization of carbohydrates in micropatterns. Beside the verification of surface functionalization, the suitability of the generated surface for ligand protein interactions was demonstrated.


Sonic Hedgehog dependent phosphorylation by CK1α and GRK2 is required for ciliary accumulation and activation of smoothened.
Hedgehog (Hh) signaling regulates embryonic development and adult tissue homeostasis through the GPCR-like protein Smoothened (Smo), but how vertebrate Smo is activated remains poorly understood. In Drosophila, Hh dependent phosphorylation activates Smo. Whether this is also the case in vertebrates is unclear, owing to the marked sequence divergence between vertebrate and Drosophila Smo (dSmo) and the involvement of primary cilia in vertebrate Hh signaling. Here we demonstrate that mammalian Smo (mSmo) is activated through multi-site phosphorylation of its carboxyl-terminal tail by CK1α and GRK2. Phosphorylation of mSmo induces its active conformation and simultaneously promotes its ciliary accumulation. We demonstrate that graded Hh signals induce increasing levels of mSmo phosphorylation that fine-tune its ciliary localization, conformation, and activity. We show that mSmo phosphorylation is induced by its agonists and oncogenic mutations but is blocked by its antagonist cyclopamine, and efficient mSmo phosphorylation depends on the kinesin-II ciliary motor. Furthermore, we provide evidence that Hh signaling recruits CK1α to initiate mSmo phosphorylation, and phosphorylation further increases the binding of CK1α and GRK2 to mSmo, forming a positive feedback loop that amplifies and/or sustains mSmo phosphorylation. Hence, despite divergence in their primary sequences and their subcellular trafficking, mSmo and dSmo employ analogous mechanisms for their activation.


Modular mechanism of Wnt signaling inhibition by Wnt inhibitory factor 1.
Wnt morphogens control embryonic development and homeostasis in adult tissues. In vertebrates the N-terminal WIF domain (WIF-1(WD)) of Wnt inhibitory factor 1 (WIF-1) binds Wnt ligands. Our crystal structure of WIF-1(WD) reveals a previously unidentified binding site for phospholipid; two acyl chains extend deep into the domain, and the head group is exposed to the surface. Biophysical and cellular assays indicate that there is a WIF-1(WD) Wnt-binding surface proximal to the lipid head group but also implicate the five epidermal growth factor (EGF)-like domains (EGFs I-V) in Wnt binding. The six-domain WIF-1 crystal structure shows that EGFs I-V are wrapped back, interfacing with WIF-1(WD) at EGF III. EGFs II-V contain a heparan sulfate proteoglycan (HSPG)-binding site, consistent with conserved positively charged residues on EGF IV. This combination of HSPG- and Wnt-binding properties suggests a modular model for the localization of WIF-1 and for signal inhibition within morphogen gradients.


Theoretical study of the 1:1 and 2:1 (homo- and heterochiral) complexes of XOOX' (X, X' = H, CH3) with lithium cation.
A theoretical study of the 1:1 and 2:1 complexes of XOOX' (X, X' = H, CH(3)) with the lithium cation has been carried out by means of ab initio computational methods up to the MP2/aug-cc-pVTZ level. The optical rotatory power and NMR parameters (absolute chemical shielding and indirect coupling constants) have been calculated. In addition, the racemization barriers within the complexes formed have been evaluated. Special attention has been paid concerning the differences between the 2:1 homo- and heterochiral complexes.


Infant feeding practices, dietary adequacy, and micronutrient status measures in the MAL-ED study.
The overall goal of The Etiology, Risk Factors and Interactions of Enteric Infections and Malnutrition and the Consequences for Child Health and Development (MAL-ED) cohort study is to evaluate the roles of repeated enteric infection and poor dietary intakes on the development of malnutrition, poor cognitive development, and diminished immune response. The use of 8 distinct sites for data collection from Latin America, sub-Saharan Africa, and South Asia allow for an examination of these relationships across different environmental contexts. Key to testing study hypotheses is the collection of appropriate data to characterize the dietary intakes and nutritional status of study children from birth through 24 months of age. The focus of the current article is on the collection of data to describe the nature and adequacy of infant feeding, energy and nutrient intakes, and the chosen indicators to capture micronutrient status in children over time.


Dynamic whole-body PET parametric imaging: I. Concept, acquisition protocol optimization and clinical application.
Static whole-body PET/CT, employing the standardized uptake value (SUV), is considered the standard clinical approach to diagnosis and treatment response monitoring for a wide range of oncologic malignancies. Alternative PET protocols involving dynamic acquisition of temporal images have been implemented in the research setting, allowing quantification of tracer dynamics, an important capability for tumor characterization and treatment response monitoring. Nonetheless, dynamic protocols have been confined to single-bed-coverage limiting the axial field-of-view to ~15-20 cm, and have not been translated to the routine clinical context of whole-body PET imaging for the inspection of disseminated disease. Here, we pursue a transition to dynamic whole-body PET parametric imaging, by presenting, within a unified framework, clinically feasible multi-bed dynamic PET acquisition protocols and parametric imaging methods. We investigate solutions to address the challenges of: (i) long acquisitions, (ii) small number of dynamic frames per bed, and (iii) non-invasive quantification of kinetics in the plasma. In the present study, a novel dynamic (4D) whole-body PET acquisition protocol of ~45 min total length is presented, composed of (i) an initial 6 min dynamic PET scan (24 frames) over the heart, followed by (ii) a sequence of multi-pass multi-bed PET scans (six passes × seven bed positions, each scanned for 45 s). Standard Patlak linear graphical analysis modeling was employed, coupled with image-derived plasma input function measurements. Ordinary least squares Patlak estimation was used as the baseline regression method to quantify the physiological parameters of tracer uptake rate Ki and total blood distribution volume V on an individual voxel basis. Extensive Monte Carlo simulation studies, using a wide set of published kinetic FDG parameters and GATE and XCAT platforms, were conducted to optimize the acquisition protocol from a range of ten different clinically acceptable sampling schedules examined. The framework was also applied to six FDG PET patient studies, demonstrating clinical feasibility. Both simulated and clinical results indicated enhanced contrast-to-noise ratios (CNRs) for Ki images in tumor regions with notable background FDG concentration, such as the liver, where SUV performed relatively poorly. Overall, the proposed framework enables enhanced quantification of physiological parameters across the whole body. In addition, the total acquisition length can be reduced from 45 to ~35 min and still achieve improved or equivalent CNR compared to SUV, provided the true Ki contrast is sufficiently high. In the follow-up companion paper, a set of advanced linear regression schemes is presented to particularly address the presence of noise, and attempt to achieve a better trade-off between the mean-squared error and the CNR metrics, resulting in enhanced task-based imaging.


Association of Neighborhood Deprivation With Thrombolysis and Thrombectomy for Acute Stroke in a Health System With Universal Access.
The association between socioeconomic status and acute ischemic stroke treatments remain uncertain, particularly in countries with universal health care systems. This study aimed to investigate the association between neighborhood-level material deprivation and the odds of receiving IV thrombolysis or thrombectomy for acute ischemic stroke within a single-payer, government-funded health care system. We conducted a population-based cohort study using linked administrative data from Ontario, Canada. This study involved all community-dwelling adult Ontario residents hospitalized with acute ischemic stroke between 2017 and 2022. Neighborhood-level material deprivation, measured in quintiles from least to most deprived, was our main exposure. We considered the receipt of thrombolysis or thrombectomy as the primary outcome. We used multivariable logistic regression models adjusted for baseline differences to estimate the association between material deprivation and outcomes. We performed a sensitivity analysis by additionally adjusting for hospital type at initial assessment. Furthermore, we tested whether hospital type modified the associations between deprivation and outcomes. Among 57,704 patients, those in the most materially deprived group (quintile 5) were less likely to be treated with thrombolysis or thrombectomy compared with those in the least deprived group (quintile 1) (16.6% vs 19.6%, adjusted odds ratio [aOR] 0.76, 95% CI 0.63-0.93). The association was consistent when evaluating thrombolysis (13.0% vs 15.3%, aOR 0.78, 95% CI 0.64-0.96) and thrombectomy (6.4 vs 7.8%, aOR 0.73, 95% CI 0.59-0.90) separately. There were no statistically significant differences between the middle 3 quintiles and the least deprived group. These associations persisted after additional adjustment for hospital type, and there was no interaction between material deprivation and hospital type (p interaction >0.1). We observed disparities in the use of thrombolysis or thrombectomy for acute ischemic stroke by socioeconomic status despite access to universal health care. Targeted health care policies, public health messaging, and resource allocation are needed to ensure equitable access to acute stroke treatments for all patients.


Prospective Analysis Reveals Associations between Carbohydrate Intakes, Genetic Predictors of Short-Chain Fatty Acid Synthesis, and Colorectal Cancer Risk.
Whole grain and fiber intakes may decrease the risk of colorectal cancer. The interplay between host genetic factors, colonization of specific bacteria, production of short-chain fatty acids (SCFA), and intake of whole grains and fiber could alter the protective role of carbohydrates against colorectal cancer. Here, we assessed intakes of types and sources of carbohydrates in 114,217 UK Biobank participants with detailed dietary data (2-5 24-hour dietary assessments), and a host polygenic score (PGS) was applied to categorize participants as high or low for intraluminal microbial SCFA production, namely, butyrate and propionate. Multivariable Cox proportional hazards models were used to determine the associations of carbohydrates and SCFA with colorectal cancer incidence. During a median follow-up of 9.4 years, 1,193 participants were diagnosed with colorectal cancer. Risk was inversely associated with intakes of non-free sugar and whole grain fiber. Evidence of heterogeneity was observed by the butyrate PGS; consuming higher amounts of whole grain starch was only associated with a lower risk of colorectal cancer in those with predicted high SCFA production. Similarly, in additional analyses utilizing the larger UK Biobank cohort (N = 343,621) with less detailed dietary assessment, only individuals with a high genetically predicted butyrate production had a lower risk of colorectal cancer per 5 g/day intake of bread and cereal fiber. This study suggests that colorectal cancer risk varies by intake of carbohydrate types and sources, and the impact of whole grain intake may be modified by SCFA production. Prospective population-level analyses provide evidence supporting the importance of butyrate production in reduction of colorectal cancer risk by whole grain consumption.


Time-resolved indirect nanoplasmonic sensing spectroscopy of dye molecule interactions with dense and mesoporous TiO2 films.
Indirect nanoplasmonic sensing (INPS) is an experimental platform exploiting localized surface plasmon resonance (LSPR) detection of processes in nanomaterials, molecular assemblies, and films at the nanoscale. Here we have for the first time applied INPS to study dye molecule adsorption/impregnation of two types of TiO(2) materials: thick (10 μm) mesoporous films of the kind used as photoanode in dye-sensitized solar cells (DSCs), with particle/pore size in the range of 20 nm, and thin (12-70 nm), dense, and flat films. For the thick-film experiments plasmonic Au nanoparticles were placed at the hidden, internal interface between the sensor surface and the mesoporous TiO(2). This approach provides a unique opportunity to selectively follow dye adsorption locally in the hidden interface region inside the material and inspires a generic and new type of nanoplasmonic hidden interface spectroscopy. The specific DSC measurement revealed a time constant of thousands of seconds before the dye impregnation front (the diffusion front) reaches the hidden interface. In contrast, dye adsorption on the dense, thin TiO(2) films exhibited much faster, Langmuir-like monolayer formation kinetics with saturation on a time scale of order 100 s. This new type of INPS measurement provides a powerful tool to measure and optimize dye impregnation kinetics of DSCs and, from a more general point of view, offers a generic experimental platform to measure adsorption/desorption and diffusion phenomena in solid and mesoporous systems and at internal hidden interfaces.


Increased susceptibility to cortical spreading depression in an animal model of medication-overuse headache.
The objective of this article is to evaluate electrically evoked thresholds for cortical spreading depression (CSD) and stress-induced activation of trigeminal afferents in a rat model of medication-overuse headache (MOH). Sumatriptan or saline was delivered subcutaneously by osmotic minipump for six days to Sprague-Dawley rats. Two weeks after pump removal, animals were anesthetized and recording/stimulating electrodes implanted. The animals were pretreated with vehicle or topiramate followed by graded electrical stimulation within the visual cortex. CSD events were identified by decreased EEG amplitude and DC potential shift. Additional unanesthetized sumatriptan or saline-pretreated rats were exposed to bright light environmental stress and periorbital and hindpaw withdrawal thresholds were measured. Following CSD stimulation or environmental stress, immunohistochemical staining for Fos in the trigeminal nucleus caudalis (TNC) was performed. Sumatriptan pre-exposure significantly decreased electrical stimulation threshold to generate a CSD event. Topiramate normalized the decreased CSD threshold as well as stress-induced behavioral withdrawal thresholds in sumatriptan-treated rats compared to saline-treated animals. Moreover, CSD and environmental stress increased Fos expression in the TNC of sumatriptan-treated rats, and these effects were blocked by topiramate. Environmental stress did not elicit cutaneous allodynia or elevate TNC Fos expression in saline-treated rats. A previous period of sumatriptan exposure produced long-lasting increased susceptibility to evoked CSD and environmental stress-induced activation of the TNC that was prevented by topiramate. Lowered CSD threshold, and enhanced consequences of CSD events (increased activation of TNC), may represent an underlying biological mechanism of MOH related to triptans.


The impact of fragility fracture on health-related quality of life : the importance of antifracture therapy.
Both general and specific health status instruments can be utilised in evaluating health-related quality of life (HR-QOL) deficits resulting from osteoporotic fractures. Osteoporotic hip, vertebral and wrist fractures significantly decrease HR-QOL in most HR-QOL domains investigated. The presence of multiple vertebral fractures leads to larger decrements in HR-QOL. More research needs to be completed with these HR-QOL tools to better assess the true burden of osteoporotic fractures, particularly in the case of hip fractures, as the burden is surely being underestimated without recognition of HR-QOL. Only when the burden of fragility fractures is understood, inclusive of HR-QOL, will the value of proven antifracture prevention and treatment therapies be appreciated. Information collected by HR-QOL instruments may provide new insight as to how to improve quality of life for patients with fractures and how to properly allocate healthcare spending.


Potentially inappropriate prescribing in an Irish elderly population in primary care.
* Potentially inappropriate prescribing in older people is a well-documented problem and has been associated with adverse drug reactions and hospitalization. * Beers' criteria, Screening Tool of Older Persons' potentially inappropriate Prescriptions (STOPP) and Screening Tool to Alert doctors to Right Treatment (START) are screening tools that have been formulated to help physicians and pharmacists identify potentially inappropriate prescribing and potential prescribing omissions. * The prevalence of potentially inappropriate prescribing and prescribing omissions in the elderly population presenting to hospital with acute illness is high according to STOPP and START criteria. * Potential errors of prescribing and of omission of medicines are prevalent among medically stable older people in primary care. * Screening tools should be incorporated into the everyday practice of primary care doctors and community pharmacists as a means of preventing potential errors of prescribing commission and prescribing omission in older people. Screening tools have been formulated to identify potentially inappropriate prescribing (IP) in older people. Beers' criteria are the most widely used but have disadvantages when used in Europe. New IP screening tools called Screening Tool of Older Person's Prescriptions (STOPP) and Screening Tool to Alert doctors to Right Treatment (START) have been developed to identify potential IP and potential prescribing omissions (PPOs). The aim was to measure the prevalence rates of potential IP and PPOs in primary care using Beers' criteria, STOPP and START. Case records of 1329 patients >or=65 years old from three general practices in one region of southern Ireland were studied. The mean age +/- SD of the patients was 74.9 +/- 6.4 years, 60.9% were female. Patients' current diagnoses and prescription medicines were reviewed and the Beers' criteria, STOPP and START tools applied. The total number of medicines prescribed was 6684; median number of medicines per patient was five (range 1-19). Overall, Beers' criteria identified 286 potentially inappropriate prescriptions in 18.3% (243) of patients, whilst the corresponding IP rate identified by STOPP was 21.4% (284), in respect of 346 potentially inappropriate prescriptions. A total of 333 PPOs were identified in 22.7% (302) of patients using the START tool. Potentially inappropriate drug prescribing and errors of drug omission are highly prevalent among older people living in the community. Prevention strategies should involve primary care doctors and community pharmacists.


Assessment of changes in utero-ovarian arterial impedance during the peri-implantation period by Doppler sonography in women undergoing assisted reproduction.
To investigate changes in utero-ovarian blood flow during the peri-implantation period and their significance in successful embryo implantation. A prospective longitudinal study was conducted in 317 women undergoing in-vitro fertilization-embryo transfer (IVF-ET) treatment. All of them had at least one good-quality embryo for transfer on the second or third day after oocyte retrieval. Measurement of endometrial thickness and color flow imaging with pulsed waveform analysis of uterine and ovarian arteries were performed before ET and 5-6 days after ET. There were no significant differences in the age of patients, duration of infertility or number of embryos transferred between women who became pregnant (n = 91) and those who did not (n = 226). There was no difference in mean endometrial thickness between the two groups before ET, while a thicker endometrium was found in women who had conceived compared with those who had not 5-6 days after ET (P = 0.02). Mean uterine arterial resistance index (RI) and pulsatility index (PI) values were significantly lower in the pregnant than in the non-pregnant group before ET (P = 0.04 and P = 0.003, respectively), but no significant differences were found between the two groups 5-6 days after ET. In contrast, the mean ovarian arterial RI and PI values were similar between the two groups before ET, yet the pregnant group showed significantly lower RI and PI values compared with the non-pregnant group 5-6 days after ET (P = 0.002 and P = 0.01, respectively). A significantly higher peak systolic velocity (PSV) of intraovarian vessels was also noted in the pregnant group 5-6 days after ET. Different utero-ovarian blood flow changes during the peri-implantation period occur in conception and non-conception cycles in women following IVF. Doppler assessment of uterine arterial resistance can help to determine a time interval within the menstrual cycle that is of optimal endometrial status for embryo implantation in assisted conception programs. Delay in achieving adequate uterine perfusion during the temporal window of embryo implantation may have an impact on endometrial receptivity.


Neuroscience. Stout guards of the central nervous system.
Endocannabinoids have paradoxical effects on the mammalian nervous system: Sometimes they block neuronal excitability and other times they augment it. In their Perspective, Mechoulam and Lichtman discuss new work (Marsicano et al.) showing that activation of the cannabinoid receptor CB1 by the endocannabinoid anandamide protects against excitotoxic damage in a mouse model of kainic acid-induced epilepsy.


Sex steroid hormone regulation of follicle-stimulating hormone subunit messenger ribonucleic acid (mRNA) levels in the rat.
Follicle-stimulating hormone (FSH) beta, luteinizing hormone (LH) beta, and alpha subunit messenger RNA (mRNA) levels were examined in rats after castration and sex-steroid replacement. Subunit mRNAs were determined by blot hybridization using rat FSH beta genomic DNA, and alpha and LH beta complementary DNA (cDNA). Rat FSH beta mRNA is 1.7 kilobase in size. After ovariectomy, female FSH beta mRNA levels increased fourfold, whereas those of LH beta and alpha increased twenty- and eightfold, respectively. With estradiol, all subunits returned toward normal levels. Male LH beta and alpha mRNA levels rose eight- and fourfold, respectively, 40 d postcastration, but FSH beta mRNA levels increased minimally. After 7 d of testosterone propionate, LH beta and alpha mRNAs declined to normal levels, whereas FSH beta mRNA increased slightly. We conclude that in female rats FSH beta is negatively regulated by gonadal steroids, but to a lesser extent than LH beta or alpha mRNAs, and there is a differential regulation of FSH beta mRNA levels in males as compared with females at the time points examined.


Autoantibodies and SLE: the threshold for disease.
The presence of autoantibodies in apparently healthy individuals has been increasingly recognized. Although some of these individuals are in preclinical stages of a disease such as systemic lupus erythematosus (SLE), many will not develop SLE or any other autoimmune disorder. The high prevalence of autoreactivity in the population in fact suggests that autoantibodies are expressed as part of a healthy immune response, and other data have clearly shown that some autoantibodies have important immune regulatory functions. These observations leave open questions regarding when and how benign autoimmunity develops into disease. If the transition from preclinical autoimmunity to a clinical disorder such as SLE could be predicted, early and thus potentially more effective intervention might be possible and cures might even become a reality. Furthermore, increased understanding of mechanisms by which autoantibodies are kept in check can identify new approaches to aborting or preventing disease transformations. In this article, we summarize the current findings regarding the presence of SLE-associated antibodies in apparently healthy individuals, and provide our opinions on what such discoveries might tell us about the roles of autoantibodies in the development of disease.


Bifidobacterium longum alleviates dextran sulfate sodium-induced colitis by suppressing IL-17A response: involvement of intestinal epithelial costimulatory molecules.
Although some bacterial strains show potential to prevent colitis, their mechanisms are not fully understood. Here, we investigated the anti-colitic mechanisms of Bifidobacterium longum subsp. infantis JCM 1222(T), focusing on the relationship between interleukin (IL)-17A secreting CD4(+) T cells and intestinal epithelial costimulatory molecules in mice. Oral administration of JCM 1222(T) to mice alleviated dextran sulfate sodium (DSS)-induced acute colitis. The expression of type 1 helper T (Th1)- and IL-17 producing helper T (Th17)-specific cytokines and transcriptional factors was suppressed by JCM 1222(T) treatment. Intestinal epithelial cells (IECs) from colitic mice induced IL-17A production from CD4(+) T cells in a cell-cell contact-dependent manner, and this was suppressed by oral treatment with JCM 1222(T). Using blocking antibodies for costimulatory molecules, we revealed that epithelial costimulatory molecules including CD80 and CD40, which were highly expressed in IECs from colitic mice, were involved in IEC-induced IL-17A response. Treatment of mice and intestinal epithelial cell line Colon-26 cells with JCM 1222(T) decreased the expression of CD80 and CD40. Collectively, these data indicate that JCM 1222(T) negatively regulate epithelial costimulatory molecules, and this effect might be attributed, at least in part, to suppression of IL-17A in DSS-induced colitis.


Electronic structures and electronic spectra of all-boron fullerene B40.
This study is motivated by the recent discovery of the first all-boron fullerene analogue, a B40 cluster with D(2d) point-group symmetry, dubbed borospherene (Nat. Chem., 2014, 6, 727). Insight into the electronic structures and spectral properties of B40 is timely and important to understand the borospherene and the transition from open-ended plate or ribbon-like structures to a hollow-cage structure at B40. Optimized geometries of borospherene B40 for both the ground state and the first excited state allow us to compute spectral properties including UV-vis absorption, infrared (IR) and Raman spectra. Highly resolved absorption and emission spectra are obtained, for the first time, for the fullerene at the time-dependent density-functional theory (TD-DFT) level within the Franck-Condon approximation and including the Herzberg-Teller effect. Assigned vibrational modes in absorption and emission spectra are readily compared with future spectroscopy measurements to distinguish the hollow-cage structure of D(2d)-B40 from other quasi-planar boron structures.