Spermiotoxicity of nickel nanoparticles in the marine invertebrate Ciona intestinalis (ascidians).
Nickel nanoparticles (Ni NPs) are increasingly used in modern industries as catalysts, sensors, and in electronic applications. Due to this large use, their inputs into marine environment have significantly increased; however, the potential ecotoxicological effects in marine environment have so far received little attention. In particular, little is known on the impact of NPs on gamete quality of marine organisms and on the consequences on fertility potential. The present study examines, for the first time, the impact of Ni NPs exposure on sperm quality of the marine invertebrate Ciona intestinalis (ascidian). Several parameters related with sperm status such as plasma membrane lipid peroxidation, mitochondrial membrane potential (MMP), intracellular pH, DNA integrity, and fertilizing ability were assessed as toxicity end points after exposure to different Ni NPs concentrations. Ni NPs generate oxidative stress that in turn induces lipid peroxidation and DNA fragmentation, and alters MMP and sperm morphology. Furthermore, sperm exposure to Ni NPs affects their fertilizing ability and causes developmental anomalies in the offspring. All together, these results reveal a spermiotoxicity of Ni NPs in ascidians suggesting that the application of these NPs should be carefully assessed as to their potential toxic effects on the health of marine organisms that, in turn, may influence the ecological system. This study shows that ascidian sperm represent a suitable and sensitive tool for the investigation of the toxicity of NPs entered into marine environment, for defining the mechanisms of toxic action and for the environmental monitoring purpose.


Utility of high-sensitivity cardiac troponin T in patients receiving anthracycline chemotherapy.
Anthracycline chemotherapy remains an integral part of the care for curative intent chemotherapy in breast cancer and non-Hodgkin lymphoma patients. Better tools need to be identified to predict cardiac complications of anthracycline chemotherapy. We investigated the utility of high-sensitivity cardiac troponin T (hscTnT), N-terminal pro-B-type natriuretic peptide, cardiac troponin T and I, and creatine kinase (CK)-MB in cancer patients receiving anthracycline-based chemotherapy, in order to determine whether baseline levels or changes in these biomarkers may help predict the onset of congestive heart failure. Eighteen consecutive patients with a pathologic diagnosis of breast cancer or non-Hodgkin lymphoma were enrolled. The median dose of doxorubicin exposure was 240 mg/m(2) (range 240-400 mg/m(2)). After treatment with doxorubicin, the hscTnT increased to 19.1 pg/mL (P<0.001). CKMB and N-terminal pro-B-type natriuretic peptide levels increased to 1.1 ng/mL and 88.3 pg/mL, respectively (P=0.02). When subjects who had a decline in left ventricular ejection fraction (LVEF) by equilibrium radionuclide ventriculography were compared to those who did not have a change in LVEF, there was a suggestion that those subjects with an elevated baseline hscTnT were more likely to have a decline in LVEF (2.7 pg/mL and 0.1 pg/mL, respectively; P=0.07). Spearman correlation demonstrated that patients with higher baseline hscTnT and CKMB tended to have a greater decline in LVEF (Spearman correlation -0.54, 95% confidence interval -0.80 to -0.08 [P=0.02], and -0.49, 95% confidence interval -0.77 to -0.01 [P=0.04], respectively). Elevations in baseline hscTnT levels are suggestive of an oncology subgroup at high risk of developing cardiac complications from their chemotherapy. Early detection by oncologists with the use of baseline biomarkers may be clinically important in designing interventions to prevent serious anthracycline-based chemotherapy complications.


Kinobead/LC-MS Phosphokinome Profiling Enables Rapid Analyses of Kinase-Dependent Cell Signaling Networks.
Kinase-catalyzed protein phosphorylation is fundamental to eukaryotic signal transduction, regulating most cellular processes. Kinases are frequently dysregulated in cancer, inflammation, and degenerative diseases, and because they can be inhibited with small molecules, they became important drug targets. Accordingly, analytical approaches that determine kinase activation states are critically important to understand kinase-dependent signal transduction and to identify novel drug targets and predictive biomarkers. Multiplexed inhibitor beads (MIBs or kinobeads) efficiently enrich kinases from cell lysates for liquid chromatography-mass spectrometry (LC-MS) analysis. When combined with phosphopeptide enrichment, kinobead/LC-MS can also quantify the phosphorylation state of kinases, which determines their activation state. However, an efficient kinobead/LC-MS kinase phospho-profiling protocol that allows routine analyses of cell lines and tissues has not yet been developed. Here, we present a facile workflow that quantifies the global phosphorylation state of kinases with unprecedented sensitivity. We also found that our kinobead/LC-MS protocol can measure changes in kinase complex composition and show how these changes can indicate kinase activity. We demonstrate the utility of our approach in specifying kinase signaling pathways that control the acute steroidogenic response in Leydig cells; this analysis establishes the first comprehensive framework for the post-translational control of steroid biosynthesis.


Bone marrow cell homing to sites of acute tibial fracture: 89Zr-oxine cell labeling with positron emission tomographic imaging in a mouse model.
Bone fracture healing is dependent upon the rapid migration and engraftment of bone marrow (BM) progenitor and stem cells to the site of injury. Stromal cell-derived factor-1 plays a crucial role in recruiting BM cells expressing its receptor CXCR4. Recently, a CXCR4 antagonist, plerixafor, has been used to mobilize BM cells into the blood in efforts to enhance cell migration to sites of injury presumably improving healing. In this study, we employed zirconium-89 (89Zr)-oxine-labeled BM cells imaged with positron emission tomography (PET)/computed tomography (CT) to visualize and quantitate BM cell trafficking following acute bone injury and to investigate the effect of plerixafor on BM cell homing. Unilateral 1-mm incisions were created in the distal tibia of mice either on the same day (d0) or 24 h (d1) after 89Zr-oxine-labeled BM cell transfer (n = 4-6, 2-2.3 × 107 cells at 9.65-15.7 kBq/106 cells). Serial microPET/CT imaging was performed and migration of 89Zr-labeled cells to the bone injury was quantified. The effects of three daily doses of plerixafor on cell trafficking were evaluated beginning on the day of fracture generation (n = 4-6). The labeled cells localizing to the fracture were analyzed by flow cytometry and immunohistochemistry. In d0- and d1-fracture groups, 0.7% and 1.7% of administered BM cells accumulated within the fracture, respectively. Plerixafor treatment reduced BM cell migration to the fracture by approximately one-third (p < 0.05 for both fracture groups). Flow cytometry analysis of donor cells collected from the injured site revealed a predominance of CD45+ stem/progenitor cell populations and subsequent histological analysis demonstrated the presence of donor cells engrafted within sites of fracture repair. 89Zr-oxine labeling enabled visualization and quantitation of BM cell recruitment to acute fractures and further demonstrated that plerixafor plays an inhibitory role in this recruitment.


What Makes Institutional Long-Term Care the Most Appropriate Setting for People With Dementia? Exploring the Influence of Client Characteristics, Decision-Maker Attributes, and Country in 8 European Nations.
To explore the extent to which client characteristics, decision-maker attributes, and country influence judgments of institutional long-term care (ILTC) appropriateness for people with dementia. A total of 161 experts in dementia care from 8 European countries reviewed a series of 14 vignettes representing people with dementia on the cusp of ILTC admission and indicated the most appropriate setting in which to support each case in a simple discrete choice exercise: own home, very sheltered housing, residential home, or nursing home. At least 16 experts participated in each country (Estonia, Finland, France, Germany, the Netherlands, Spain, Sweden, and the United Kingdom). Descriptive statistics were used to characterize the experts and their placement preferences. Logistic regression modeling was used to explore the extent to which the sociodemographic and clinical characteristics of people with dementia, and the profession, workplace, and country of decision-makers were associated with ILTC recommendation. Client characteristics, decision-maker attributes, and country all seemed to play a part in influencing professionals' perceptions of the appropriateness of ILTC for people with dementia. Expert decision-makers were more likely to recommend ILTC for individuals who required help with mobility or had multiple care needs, and appeared to give more weight to carers' than clients' wishes. Community-based social workers were less likely than other professional groups to favor ILTC placement. Experts in Finland, Germany, and the United Kingdom were less likely to recommend ILTC than experts in France, the Netherlands, and Estonia; experts in Sweden and Spain took an intermediate position. This study provides new understanding of the factors that shape professionals' perceptions of ILTC appropriateness and highlights the need to construct multifaceted models of institutionalization when planning services for people with dementia. It also has several important clinical implications (including flagging interventions that could decrease the need for ILTC), and provides a basis for enhancing professionals' decision-making capabilities (including the greater involvement of clients themselves).


Quantitative analysis of microbial contamination in private drinking water supply systems.
Over one million households rely on private water supplies (e.g. well, spring, cistern) in the Commonwealth of Virginia, USA. The present study tested 538 private wells and springs in 20 Virginia counties for total coliforms (TCs) and Escherichia coli along with a suite of chemical contaminants. A logistic regression analysis was used to investigate potential correlations between TC contamination and chemical parameters (e.g. NO3(-), turbidity), as well as homeowner-provided survey data describing system characteristics and perceived water quality. Of the 538 samples collected, 41% (n = 221) were positive for TCs and 10% (n = 53) for E. coli. Chemical parameters were not statistically predictive of microbial contamination. Well depth, water treatment, and farm location proximate to the water supply were factors in a regression model that predicted presence/absence of TCs with 74% accuracy. Microbial and chemical source tracking techniques (Bacteroides gene Bac32F and HF183 detection via polymerase chain reaction and optical brightener detection via fluorometry) identified four samples as likely contaminated with human wastewater.


Photo-aligned ferroelectric liquid crystals in microchannels.
In this Letter we disclose a method to realize a good alignment of ferroelectric liquid crystals (FLCs) in microchannels, based on photo-alignment. The sulfonic azo dye used in our research offers variable anchoring energy depending on the irradiation energy and thus provides good control on the FLC alignment in microchannels. The good FLC alignment has been observed only when anchoring energy normalized to the capillary diameter is less than the elastic energy of the FLC helix. The same approach can also be used for the different microstructures viz. photonic crystal fibers, microwaveguides, etc. which gives an opportunity for designing a photonic devices based on FLC.


Patient response and resource management: another view of clozapine treatment of schizophrenia.
Issues in clozapine treatment were considered in terms of implications for resource management. A critical review of the literature on time course and pattern of response to clozapine was used to address treatment of negative symptoms, late responders, and extent of clinical benefit in ordinary settings. Superior efficacy of clozapine for partial and poor neuroleptic responders is observed in about one-half of the cases. Response is rapid once a therapeutic dose is reached, and the data do not support the proposition that some patients first respond only after 3-12 months of therapy. The cumulative benefit over several months of treatment and the broad range of symptoms involved in response are similar to those for typical neuroleptic drugs, suggesting that clozapine's superiority is based on greater effectiveness rather than a unique profile of treatment effects. Clozapine appears to be effective for secondary, but not primary, negative symptoms. Modal response is moderate, and extensive rehabilitation and clinical services are required to substantially enhance functional outcome. Many more patients merit trials with clozapine. Economic costs and adverse drug effects can be minimized by selecting patients most likely to benefit and discontinuing clozapine treatment when benefit is not observed within 2-4 months. Appropriate patients include 1) those with good responses to typical neuroleptics who experience substantial adverse effects and 2) those whose disorders respond poorly to standard neuroleptics and are defined by psychotic symptoms, thought disorder, and hostility. Treatment of primary negative symptoms is not supported by the current experimental data.


Mesenchymal stromal cells impair the differentiation of CD14(++) CD16(-) CD64(+) classical monocytes into CD14(++) CD16(+) CD64(++) activate monocytes.
Mesenchymal stromal cells (MSC) possess immunomodulatory activity both in vitro and in vivo. However, little information is available regarding their function during the initiation of immunologic responses through their interactions with monocytes. While many studies have shown that MSC impair the differentiation of monocytes into dendritic cells and macrophages, there are few articles showing the interaction between MSC and monocytes and none of them has addressed the question of monocyte subset modulation. To understand better the mechanism behind the benefit of MSC infusion for graft-versus-host treatment through monocyte involvement, we performed mixed leucocyte reactions (MLR) in the presence and absence of MSC. After 3 and 7 days, cultures were analyzed by flow cytometry using different approaches. MSC induced changes in monocyte phenotype in an MLR. This alteration was accompanied by an increase in monocyte counting and CD14 expression. MSC induced monocyte alterations even without contact, although the parameters above were more pronounced with cell-cell contact. Moreover, the presence of MSC impaired major histocompatibility complex (MHC) I and II, CD11c and CCR5 expression and induced CD14 and CD64 expression on monocytes. These alterations were accompanied by a decrease in interleukin (IL)-1β and IL-6 production by these monocytes, but no change was observed taking into account the phagocytosis capacity of these monocytes. Our results suggest that MSC impair the differentiation of CD14(++) CD16(-) CD64(+) classical monocytes into CD14(++) CD16(+) CD64(++) activated monocytes, having an even earlier role than the differentiation of monocytes into dendritic cells and macrophages.


Bidirectional Transfer Study of Polystyrene Nanoparticles across the Placental Barrier in an ex Vivo Human Placental Perfusion Model.
Nanoparticle exposure in utero might not be a major concern yet, but it could become more important with the increasing application of nanomaterials in consumer and medical products. Several epidemiologic and in vitro studies have shown that nanoparticles can have potential toxic effects. However, nanoparticles also offer the opportunity to develop new therapeutic strategies to treat specifically either the pregnant mother or the fetus. Previous studies mainly addressed whether nanoparticles are able to cross the placental barrier. However, the transport mechanisms underlying nanoparticle translocation across the placenta are still unknown. In this study we examined which transport mechanisms underlie the placental transfer of nanoparticles. We used the ex vivo human placental perfusion model to analyze the bidirectional transfer of plain and carboxylate modified polystyrene particles in a size range between 50 and 300 nm. We observed that the transport of polystyrene particles in the fetal to maternal direction was significantly higher than for the maternal to fetal direction. Regardless of their ability to cross the placental barrier and the direction of perfusion, all polystyrene particles accumulated in the syncytiotrophoblast of the placental tissue. Our results indicate that the syncytiotrophoblast is the key player in regulating nanoparticle transport across the human placenta. The main mechanism underlying this translocation is not based on passive diffusion, but is likely to involve an active, energy-dependent transport pathway. These findings will be important for reproductive toxicology as well as for pharmaceutical engineering of new drug carriers.


Assessment of the direct medical costs of diabetes mellitus and its complications in the United Arab Emirates.
Diabetes mellitus (DM) is a major health problem in the United Arab Emirates (UAE) and is well recognized as a major and increasing burden to the country's resources due to its severe, long term debilitating effects on individuals, families and the society at large. The aim of the study was to estimate the direct annual treatment costs of DM and its related complications among patients in Al-Ain city, UAE. A sample of 150 DM patients were enrolled during 2004-2005, and their medical costs over the ensuing 12 months was measured, quantified, analyzed and extrapolated to the population in Al-Ain and UAE, using conventional and inference statistics. The costs were converted from UAE Dirhams to US Dollar, using the official conversion rate of US$ (1 USD = 3.68 AED). The total annual direct treatment costs of DM among patients without complications in Al Ain-UAE, was US $1,605 (SD = 1,206) which is 3.2 times higher than the per capita expenditure for health care in the UAE (US$ 497) during 2004 (WHO, 2004). However, this cost increased 2.2 times with the presence of DM related complications for patients with microvascular complications, by 6.4 times for patients with macrovascular complications and 9.4 times for patients with both micro and macrovascular complications. Likewise, the annual direct hospitalization costs of DM patients increased by 3.7 times for patients with microvascular complications, by 6.6 times for patients with macrovascular complications and by 5 times for patients with both micro and macrovascualr complications. Overall, costs increased with age, diabetes duration and were higher for patients treated with insulin compared to those treated with oral hypoglycemic agents or with diet control only. DM direct treatment costs increased with the presence and progression of chronic DM related complications. Hospitalisation costs constituted a large proportion and were increasingly higher with the presence and progression of DM related complications. To reduce the impact on healthcare resources, efforts should be made to prevent progression to DM complications, by implementing guidelines for diabetes care, screening for complications and better management.


Local genetic ancestry in CDKN2B-AS1 is associated with primary open-angle glaucoma in an African American cohort extracted from de-identified electronic health records.
Glaucoma is a leading cause of blindness in developed countries. Primary open-angle glaucoma (POAG), the most prevalent clinical subtype of glaucoma in the United States, affects African Americans at a higher rate compared with European Americans. Risk factors identified for POAG include increased age and family history, which coupled with heritability estimates, suggest this complex condition is associated with genetic and environmental factors. To date, several genome-wide studies have identified loci significantly associated with POAG risk, but most of these studies were performed in populations of European-descent. To identify population-specific and trans-population genetic associations for POAG, we genotyped 11,521 African Americans using the Illumina Metabochip as part of the Epidemiologic Architecture for Genes Linked to Environment (EAGLE) study accessing BioVU, the Vanderbilt University Medical Center's biorepository linked to de-identified electronic health records. Among this study population, we identified 138 cases of POAG and 1376 controls and performed Metabochip-wide tests of association. We also estimated local genetic ancestry at CDKN2B-AS1, a POAG-associated locus established in European-descent populations. Overall, we did not identify significant single SNP-POAG associations after adjusting for multiple testing. We did, however, detect a significant association between POAG risk and local African genetic ancestry at CDKN2B-AS1, where on average cases were of 90% African descent compared with controls at 58% (p = 2 × 10- 6). These data suggest that CDKN2B-AS1 is an important locus for POAG risk among African Americans, warranting further investigation to identify the variants underlying this association.


Gold promoted arylative cyclization of alkynoic acids with arenediazonium salts.
Alkynoic acids derived from salicylic acid and analogues undergo arylative cyclization with arenediazonium salts promoted by gold in the absence of external ligands. The reaction is thermally induced and proceeds even in the absence of light. A difference in regioselectivity has been found compared with that observed in the cycloisomerization process of the same type of compounds.


A molecular modeling approach to understand the structure and conformation relationship of (GlcpA)Xylan.
The structure and conformation relationships of a heteropolysaccharide (GlcpA)Xylan in terms of various molecular weights, Xylp/GlcpA ratio and the distribution of GlcpA along xylan chain were investigated using computer modeling. The adiabatic contour maps of xylobiose, XylpXylp(GlcpA) and (GlcpA)XylpXylp(GlcpA) indicated that the insertion of the side group (GlcpA) influenced the accessible conformational space of xylobiose molecule. RIS-Metropolis Monte Carlo method indicated that insertion of GlcpA side chain induced a lowering effect of the calculated chain extension at low GlcpA:Xylp ratio (GlcpA:Xylp = 1:3). The chain, however, became extended when the ratio of GlcpA:Xylp above 2/3. It was also shown that the spatial extension of the polymer chains was dependent on the distribution of side chain: the random distribution demonstrated the most flexible structure compared to block and alternative distribution. The present studies provide a unique insight into the dependence of both side chain ratio and distribution on the stiffness and flexibility of various (GlcpA)Xylan molecules.


Instrument for near infrared emission spectroscopic probing of human fingertips in vivo.
We present instrumentation for probing of volar side fingertip capillary beds with free space coupled near infrared light while collecting Raman, Rayleigh, and Mie scattered light as well as fluorescence. Fingertip skin capillary beds are highly vascularized relative to other tissues and present a desirable target for noninvasive probing of blood. But human hands and fingers in particular are also highly idiosyncratic body parts requiring specific apparatus to allow careful and methodical spectroscopic probing. The apparatus includes means for precise and reproducible placement of the tissues relative to the optical aperture. Appropriate means are provided for applying and maintaining pressure to keep surface tissues immobile during experiments while obtaining the desired blood content and flow. Soft matter, e.g., skin, extrudes into the aperture in response to any applied pressure, e.g., to keep the tissue in registration with the optical system, so the position, contact area, pressure, and force are continuously measured and recorded to produce feedback for an actuator applying force and to discern the compliance of the test subject. The compliance strongly affects the reliability of the measurement and human factors must be adequately managed in the case of in vivo probing. The apparatus produces reproducible observations and measurements that allow consistent probing of the tissues of a wide range of skin types.


Cognitive-behavioural physical activity treatment in African-American pre-schoolers: effects of age, sex, and BMI.
Prevalence of overweight and obesity in children of 5 years and younger has greatly increased in countries including Australia, Canada, the UK and the USA, with African-Americans most affected in the USA. Low amounts of physical activity may be a primary cause. Interventions intended to increase physical activity during pre-school have had minimal effects. A physical activity intervention derived from self-efficacy and social cognitive theory administered by pre-school teachers in the USA (Start For Life) was contrasted with typical care over 8 weeks. The 30-min-per-day treatment incorporated structured gross motor skill physical activities and training in self-management and self-regulation skills. The African-American children in the treatment (n = 154, 21 classrooms) and control (n = 121, 11 classrooms) groups ranged in age from 3.5 to 5.6 years. Mixed-model repeated measures analysis of variances indicated significantly (P ≤ 0.05) greater increases in moderate-to-vigorous physical activity (MVPA) and vigorous physical activity (VPA) in the treatment group when both the children and classrooms were the unit of analysis. Time in sedentary activities was not affected. Together, age, sex and body mass index (BMI) percentile significantly predicted treatment-related changes in MVPA (R(2) = 0.11) and VPA (R(2) = 0.11), with age (β = -0.22 and β = -0.23, respectively) and BMI percentile (β = -0.24 and β = -0.23, respectively) contributing uniquely to the explained variances indicating greater treatment effects for participants who were younger and had a lower BMI percentile. The Start For Life treatment was associated with increased MVPA by approximately 1 h per week, with most of that change being in VPA. After sufficient replication, adjustments may be made to maximise treatment effects.


SPI-B activates transcription via a unique proline, serine, and threonine domain and exhibits DNA binding affinity differences from PU.1.
SPI-B is a B lymphocyte-specific Ets transcription factor that shares a high degree of similarity with PU.1/SPI-1. In direct contrast to PU.1(-/-) mice that die in utero and lack monocytes, neutrophils, B cells, and T cells, Spi-B-/- mice are viable and exhibit a severe B cell proliferation defect. Since PU.1 is expressed at wild type levels in Spi-B-/- B cells, the mutant mice provide genetic evidence that SPI-B and PU.1 have at least some non-redundant roles in B lymphocytes. To begin to understand the molecular basis for these defects, we delineated functional domains of SPI-B for comparison to those of PU.1. By using a heterologous co-transfection system, we identified two independent transactivation domains in the N terminus of SPI-B. Interestingly, only one of these domains (amino acids 31-61), a proline/serine/threonine-rich region, unique among Ets proteins, is necessary for transactivation of the immunoglobulin lambda light chain enhancer. This transactivation motif is in marked contrast to PU.1, which contains acidic and glutamine-rich domains. In addition, we describe a functional PU.1 site within the c-FES promoter which SPI-B fails to bind efficiently and transactivate. Finally, we show that SPI-B interacts with the PU.1 cofactors Pip, TBP, c-Jun and with lower affinity to nuclear factor interleukin-6beta and retinoblastoma. Taken together, these data suggest that SPI-B binds DNA with a different affinity for certain sites than PU.1 and harbors different transactivation domains. We conclude that SPI-B may activate unique target genes in B lymphocytes and interact with unique, although currently unidentified, cofactors.


Cellular-free magnesium depletion in brain and muscle of normal and preeclamptic pregnancy: a nuclear magnetic resonance spectroscopic study.
Preeclampsia is a pregnancy disorder of unknown origin, characterized by vasospasm, elevated blood pressure, and increased neuromuscular irritability, features common to syndromes of magnesium deficiency. Evidence of serum and ionized magnesium metabolism disturbances have been observed in women with preeclampsia. This and the therapeutic utility of magnesium in preeclampsia led us to investigate the extent to which an endogenous tissue magnesium deficiency might be present in and contribute to its pathophysiology. We used (31)P nuclear magnetic resonance spectroscopy to noninvasively measure in situ intracellular-free magnesium levels in brain and skeletal muscle of fasting nonpregnant women (n=12), and of third trimester women with uncomplicated pregnancies (n=11) and preeclampsia (n=7). Compared with nonpregnant controls (brain 519+/-59 micromol/L; muscle 604+/-34 micromol/L), brain and skeletal muscle intracellular magnesium levels were significantly lower in both normal pregnant (brain 342+/-23 micromol/L; muscle 482+/-40 micromol/L; P=0.05 for both tissues) and preeclamptic women (brain 229+/-17 micromol/L; muscle 433+/-46 micromol/L; P=0.05 for both tissues). Brain intracellular magnesium was further reduced in preeclamptics compared with normal pregnant subjects (P=0.05). For all pregnant subjects, blood pressure was significantly and inversely related to the concomitantly measured intracellular magnesium level in brain (systolic, r=-0.59, P=0.01; diastolic, r=-0.52, P=0.02) but not in muscle. Cellular magnesium depletion is characteristic of normal pregnancy and may be one factor contributing to the pathophysiology of preeclampsia. Furthermore, the influence of central nervous system factors on blood pressure may be mediated, at least in part, by ambient intracellular magnesium levels.


Evolutionary preferences for physical formidability in leaders.
This research uses evolutionary theory to evaluate followers' preferences for physically formidable leaders and to identify conditions that stimulate those preferences. It employs a population-based survey experiment (N ≥ 760), which offers the advantages to internal validity of experiments and external validity of a highly heterogeneous sample drawn from a nationally representative subject pool. The theoretical argument proffered here is followers tend to prefer leaders with greater physical formidability because of evolutionary adaptations derived from humans' violent ancestral environment. In this environment, individuals who allied with and ultimately followed physically powerful partners were more likely to acquire and retain important resources necessary for survival and reproduction because the presence of the physically powerful partner cued opponents to avoid a challenge for the resources or risk a costly confrontation. This argument suggests and the results indicate that threatening (war) and nonthreatening (peace, cooperation, and control) stimuli differentially motivate preferences for physically formidable leaders. In particular, the findings suggest threatening conditions lead to preferences for leaders with more powerful physical attributes, both anthropometric (i.e., weight, height, and body mass index) and perceptual (i.e., attributes of being "physically imposing or intimidating" and "physically strong"). Overall, this research offers a theoretical framework from which to understand this otherwise seemingly irrational phenomenon. Further, it advances the emerging but long-neglected investigation of biological effects on political behavior and has implications for a fundamental process in democratic society, leader selection.


Progressive neurovascular disturbances in the cerebral cortex of Alzheimer's disease-model mice: protection by atorvastatin and pitavastatin.
Structural and functional abnormalities in the neurovascular unit (NVU) have been recently observed in Alzheimer's disease (AD). Statins, which are used clinically for reducing cholesterol levels, can also exert beneficial vascular actions. Thus, we examined the protective effects of statins on NVU disturbances in a mouse AD model. Amyloid precursor protein (APP) transgenic (Tg) mice were used as a model of AD. Atorvastatin (30 mg/kg/day, p.o.) or pitavastatin (3 mg/kg/day, p.o.) were administered from 5 to 20 months of age. Changes in the NVU, including the endothelium and basement membrane, as well as astrogliosis and matrix metalloproteinase-9 (MMP-9) activation, were assessed. There was a reduction in immunopositive staining for N-acetyl glucosamine oligomer (NAGO) in the endothelium and in collagen IV in the APP vehicle (APP/Ve) group, with collagen IV staining most weakest near senile plaques (SPs). There was also an increase in intensity and number of glial fibrillary acidic protein (GFAP)-positive astrocytes, particularly around the SP, where MMP-9 was more strongly labeled. Double immunofluorescent analysis showed that astrocytic endfeet had detached from the capillary endothelium in the APP/Ve group. Treatment with atorvastatin or pitavastatin ameliorated the activation of MMP-9. Overall, these data suggest that statins may have therapeutic potential for AD by protecting NVU.


Hydroxide-bridged dicopper complexes: the influence of secondary coordination sphere on structure and catecholase activity.
Amide-based ligands (H2L1-6) with assorted functional groups appended to them have been used for the synthesis of dicopper(ii) complexes 1-6 having a Cu(μ-OH)Cu core. The crystal structures of 1-6 show that while every Cu(ii) ion is ligated within the N3 pincer cavity of a potentially multidentate ligand, two Cu(ii) centers are bridged by a hydroxide group. Notably, the Cu(μ-OH)Cu core is encased within the secondary coordination sphere intricately created by the appended groups. While complexes 1 and 2 exhibit the presence of an H-bond acceptor in the proximity of the Cu(μ-OH)Cu core, complexes 3 and 4 display the occurrence of both the H-bond donor as well as H-bond acceptor groups in the vicinity of the Cu(μ-OH)Cu core. In contrast, complexes 5 and 6 present modified secondary coordination spheres around the Cu(μ-OH)Cu core with limited H-bonding interacting groups in 5 and no such groups in 6. We show that the extent of H-bonding by the appended groups modulates not only the Cu-OH bond distance, Cu(μ-OH)Cu angle and Cu-Cu separation but also the Cu2+/Cu+ redox potential. All six complexes were utilized for their ability to oxidize 3,5-di-tert-butylcatechol, and the catecholase activity results have been correlated to the secondary coordination sphere created by the appended groups in all six complexes.


Evaluating dissociated optic nerve fiber layer appearance using en face layer imaging produced by optical coherence tomography.
To investigate the incidence of and risk factors for a dissociated optic nerve fiber layer (DONFL) appearance after pars plana vitrectomy (PPV). We retrospectively reviewed 189 eyes that underwent PPV with internal limiting membrane removal and judged the presence/absence of an apparent DONFL based on en face layer images produced by spectral-domain optical coherence tomography (SD-OCT). An apparent DONFL was observed in 47 (24.9%) eyes. The incidence of an apparent DONFL was significantly higher in the macular hole (MH) group (76.5%) than in the non-MH group (epiretinal membrane, diabetic macular edema, retinal vein occlusion, and others; 4.9%; p < 0.001). In the logistic regression analysis, surgical indication for MH was identified as the most significant DONFL risk factor (odds ratio 63.7; p = 1.05 × 10(-8)). Postoperative OCT en face layer imaging clarified that MH eyes are liable to have an apparent DONFL following PPV.


Sulfates in Martian layered terrains: the OMEGA/Mars Express view.
The OMEGA/Mars Express hyperspectral imager identified hydrated sulfates on light-toned layered terrains on Mars. Outcrops in Valles Marineris, Margaritifer Sinus, and Terra Meridiani show evidence for kieserite, gypsum, and polyhydrated sulfates. This identification has its basis in vibrational absorptions between 1.3 and 2.5 micrometers. These minerals constitute direct records of the past aqueous activity on Mars.


Prognostic and Predictive Biomarkers in Patients with Metastatic Colorectal Cancer Receiving Regorafenib.
Regorafenib is a tyrosine kinase inhibitor approved by the FDA for the treatment of patients with chemotherapy refractory metastatic colorectal cancer (mCRC). Regorafenib inhibits signaling through multiple receptors associated with angiogenesis, metastasis, and tumor immunity. Here, we report biomarker results from LCCC1029, a randomized, placebo-controlled, phase II trial of chemotherapy ± regorafenib in patients with second-line mCRC. A panel of 20 soluble protein biomarkers (termed the Angiome) was assessed in the plasma of 149 patients from the LCCC1029 trial both at baseline and along the treatment continuum. Baseline protein levels were analyzed for prognostic and predictive value for progression-free survival (PFS) and overall survival (OS). Changes in protein levels during treatment were analyzed for potential pharmacodynamic effects. Six markers (HGF, IL6, PlGF, VEGF-R1, OPN, and IL6R) were found to be prognostic for PFS. Nine markers (IL6, TIMP-1, PlGF, VCAM-1, ICAM-1, OPN, TSP-2, HGF, and VEGF-R1) were prognostic for OS. Higher baseline levels of OPN (P intx = 0.0167), VCAM-1 (P intx = 0.0216), and PDGF-AA (P intx = 0.0435) appeared to predict for PFS benefit from regorafenib compared with placebo. VCAM-1 was also potentially predictive of OS benefit from regorafenib compared with placebo (P intx = 0.0124). On-treatment changes of six markers reflected potential on-target effect of regorafenib. Consistent results were observed in an Italian cohort where 105 patients with late-stage mCRC received regorafenib monotherapy. The key findings of this study suggest that VCAM-1 may be a predictive biomarker for regorafenib benefit, while multiple protein markers may be prognostic of outcome in patients with mCRC.


Fuel-Driven Transient DNA Strand Displacement Circuitry with Self-Resetting Function.
Toehold-mediated DNA strand displacement (DSD) is a powerful strategy to engineer dynamics in DNA-based devices and for molecular computing. However, facile strategies for autonomously self-resettable DSD cascades with programmable lifetimes are still missing. Here, we concatenate an ATP-powered ligation/restriction network with toehold-mediated DSD reactions realizing ATP-driven transient DSD with self-resetting behavior. The ATP-fueled ligation biases strand displacement reactions by increasing the toehold length and increasing the local concentration by covalent fixation, while the concurrent endonuclease restriction eliminates this bias, allowing to reset the system. The lifetimes and adaptive dynamic steady states for the DSD are engineered by the ATP-fueled uphill-driven nonequilibrium ligation/restriction system. By programming the toeholds for downstream DSD reaction networks, we realize ATP-fueled transient DSD cascades. A higher level of fuel-driven automaton is achieved by combining two subsystems for the transient DSD, where the expelled strands are each other's input strands and the restriction-induced double-stranded DNA melting resets the systems.


Local inflammation is associated with aortic thrombus formation in abdominal aortic aneurysms. Relationship to clinical risk factors.
Intraluminal thrombus formation in aortic abdominal aneurysms (AAA) is associated with adverse clinical prognosis. Interplay between coagulation and inflammation, characterised by leukocyte infiltration and cytokine production, has been implicated in AAA thrombus formation. We studied leukocyte (CD45+) content by flow cytometry in AAA thrombi from 27 patients undergoing surgical repair. Luminal parts of thrombi were leukocyte-rich, while abluminal segments showed low leukocyte content. CD66b+ granulocytes were the most prevalent, but their content was similar to blood. Monocytes (CD14+) and T cells (CD3+) were also abundant, while content of B lymphocytes (CD19+) and NK cells (CD56+CD16+) were low. Thrombi showed comparable content of CD14highCD16- monocytes and lower CD14highCD16+ and CD14dimCD16+, than blood. Monocytes were activated with high CD11b, CD11c and HLA-DR expression. Total T cell content was decreased in AAA thrombus compared to peripheral blood but CD8 and CD3+CD4-CD8- (double negative T cell) contents were increased in thrombi. CD4+ cells were lower but highly activated (high CD69, CD25 and HLA-DR). No differences in T regulatory (CD4+CD25+FoxP3+) cell or pro-atherogenic CD4+CD28null lymphocyte content were observed between thrombi and blood. Thrombus T cells expressed high levels of CCR5 receptor for chemokine RANTES, commonly released from activated platelets. Leukocyte or T cell content in thrombi was not correlated with aneurysm size. However, CD3+ content was significantly associated with smoking in multivariate analysis taking into account major risk factors for atherosclerosis. In conclusion, intraluminal AAA thrombi are highly inflamed, predominantly with granulocytes, CD14highCD16- monocytes and activated T lymphocytes. Smoking is associated with T cell infiltration in AAA intraluminal thrombi.


[The importance of the wisdom of not knowing in clinical practice].
The theme of this Special issue is to investigate the relationship between pharmacotherapy and therapeutic relationships. In my paper, I first examine therapeutic relationships from a number of psychoanalytic perspectives. Specifically, I use concepts such as the building of therapeutic alliances, ego support, as well as autogenous and iatrogenous illnesses. A therapeutic relationship is a process in which a patient and his/her therapist build a relationship as collaborative therapists in the context of repeated interactions with each other. In this sense, a therapeutic relationship is not the premise for treatment, but its result. From the perspective of adherence and therapeutic effects, pharmacotherapy becomes a yardstick for measuring the quality of the therapeutic relationship. At the same time, pharmacotherapy is also a medium for building a therapeutic relationship. Lastly, I note that psychiatric knowledge and experience are factors that may impede these interactions. It is the wisdom of not knowing that helps a therapist avoid this pitfall and make therapeutic practice fruitful.


HLA-DQ-restricted CD4+ T cells specific to streptococcal antigen present in low but not in high responders.
We have found that the low immune response to streptococcal cell wall Ag (SCW) was inherited as a dominant trait and was linked to HLA, as deduced from family analysis. In the present report, HLA class II alleles of healthy donors were determined by serology and DNA typing to identify the HLA alleles controlling low or high immune responses to SCW. HLA-DR2-DQA1*0102-DQB1*0602(DQw6)-Dw2 haplotype or HLA-DR2-DQA1*0103-DQB1*0601(DQw6)-DW12 haplotype was increased in frequency in the low responders and the frequency of HLA-DR4-DRw53-DQA1*0301-DQB1*0401(DQw4)-Dw15 haplotype or HLA-DR9-DRw53-DQA1*0301-DQB1*0303(DQw3)-Dw23 haplotype was increased in the high responders to SCW. Homozygotes of either DQA1*0102 or DQA1*0103 exhibited a low responsiveness to SCW and those of DQA1*0301 were high responders. The heterozygotes of DQA1*0102 or 0103 and DQA1*0301 showed a low response to SCW, thereby confirming that the HLA-linked gene controls the low response to SCW, as a dominant trait. Using mouse L cell transfectants expressing a single class II molecule as the APC, we found that DQw6(DQA1*0103 DQB1*0601) from the low responder haplotype (DR2-DQA1*0103-DQB1*0601(DQw6)-Dw12) activated SCW-specific T cell lines whereas DQw4(DQA1*0301 DQB1*0401) from the high responder haplotype (DR4-DRw53-DQA1*0301-DQB1*0401(DQw4)-Dw15) did not activate T cell lines specific to SCW. However, DR4 and DR2 presented SCW to CD4+ T cells in both the high and low responders to SCW, hence the DR molecule even from the low responder haplotype functions as an restriction molecule in the low responders. Putative mechanisms linked to the association between the existence of DQ-restricted CD4+ T cells specific to SCW, and low responsiveness to SCW are discussed.


Implementation of C-reactive protein point of care testing to improve antibiotic targeting in respiratory illness in Vietnamese primary care (ICAT): a study protocol for a cluster randomised controlled trial.
C-reactive protein (CRP), a biomarker of infection, has been used widely in high-income settings to guide antibiotic treatment in patients presenting with respiratory illnesses in primary care. Recent trials in low- and middle-income countries showed that CRP testing could safely reduce antibiotic use in patients with non-severe acute respiratory infections (ARIs) and fever in primary care. The studies, however, were conducted in a research-oriented context, with research staff closely monitoring healthcare behaviour thus potentially influencing healthcare workers' prescribing practices. For policy-makers to consider wide-scale roll-out, a pragmatic implementation study of the impact of CRP point of care (POC) testing in routine care is needed. A pragmatic, cluster-randomised controlled trial, with two study arms, consisting of 24 commune health centres (CHC) in the intervention arm (provision of CRP tests with additional healthcare worker guidance) and 24 facilities acting as controls (routine care). Comparison between the treatment arms will be through logistic regression, with the treatment assignment as a fixed effect, and the CHC as a random effect. With 48 clusters, an average of 10 consultations per facility per week will result in approximately 520 over 1 year, and 24 960 in total (12 480 per arm). We will be able to detect a reduction of 12% to 23% or more in immediate antibiotic prescription as a result of the CRP POC intervention. The primary endpoint is the proportion of patient consultations for ARI resulting in immediate antibiotic prescription. Secondary endpoints include the proportion of all patients receiving an antibiotic prescription regardless of ARI diagnosis, frequency of re-consultation, subsequent antibiotic use when antibiotics are not prescribed, referral and hospitalisation. The study protocol was approved by the Oxford University Tropical Research Ethics Committee (OxTREC, Reference: 53-18), and the ethical committee of the National Hospital for Tropical Diseases in Vietnam (Reference:07/HDDD-NDTW/2019). Results from this study will be disseminated via meetings with stakeholders, conferences and publications in peer-reviewed journals. Authorship and reporting of this work will follow international guidelines. NCT03855215; Pre-results.


Maternal Antibody Response, Neutralizing Potency, and Placental Antibody Transfer After Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection.
To characterize maternal immune response after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection during pregnancy and quantify the efficiency of transplacental antibody transfer. We conducted a prospective cohort study of pregnant patients who tested positive for SARS CoV-2 infection at any point in pregnancy and collected paired maternal and cord blood samples at the time of delivery. An enzyme-linked immunosorbent assay (ELISA) and neutralization assays were performed to measure maternal plasma and cord blood concentrations and neutralizing potency of immunoglobulin (Ig)G, IgA, and IgM antibodies directed against the SARS-CoV-2 spike protein. Differences in concentrations according to symptomatic compared with asymptomatic infection and time from positive polymerase chain reaction (PCR) test result to delivery were analyzed using nonparametric tests of significance. The ratio of cord to maternal anti-receptor-binding domain IgG titers was analyzed to assess transplacental transfer efficiency. Thirty-two paired samples were analyzed. Detectable anti-receptor-binding domain IgG was detected in 100% (n=32) of maternal and 91% (n=29) of cord blood samples. Functional neutralizing antibody was present in 94% (n=30) of the maternal and 25% (n=8) of cord blood samples. Symptomatic infection was associated with a significant difference in median (interquartile range) maternal anti-receptor-binding domain IgG titers compared with asymptomatic infection (log 3.2 [3.5-2.4] vs log 2.7 [2.9-1.4], P=.03). Median (interquartile range) maternal anti-receptor-binding domain IgG titers were not significantly higher in patients who delivered more than 14 days after a positive PCR test result compared with those who delivered within 14 days (log 3.3 [3.5-2.4] vs log 2.67 [2.8-1.6], P=.05). Median (range) cord/maternal antibody ratio was 0.81 (0.67-0.88). These results demonstrate robust maternal neutralizing and anti-receptor-binding domain IgG response after SARS-CoV-2 infection, yet a lower-than-expected efficiency of transplacental antibody transfer and a significant reduction in neutralization between maternal blood and cord blood. Maternal infection does confer some degree of neonatal antibody protection, but the robustness and durability of protection require further study.


Association of ankle kinematics and performance on the y-balance test with inclinometer measurements on the weight-bearing-lunge test.
Ankle-dorsiflexion range of motion has often been measured in the weight-bearing condition in the clinical setting; however, little is known about the relationship between the weight-bearing-lunge test (WBLT) and both ankle kinematics and performance on dynamic postural-control tests. To examine whether ankle kinematics and performance on the Lower Quarter Y-Balance Test (YBT-LQ) are correlated with results of the WBLT using an inclinometer and tape measure. Cross-sectional. University motion-analysis laboratory. 30 physically active participants. None. The WBLT was evaluated using an inclinometer and a tape measure. The reach distances in the anterior, posteromedial, and posterolateral directions on the YBT-LQ were normalized by limb length. Ankle dorsiflexion during the YBT-LQ was recorded using a 3-dimensional motion-analysis system. Simple linear regression was used to examine the relationship between the WBLT results and both ankle dorsiflexion and the normalized reach distance in each direction on the YBT-LQ. The WBLT results were significantly correlated with ankle dorsiflexion in all directions on the YBT-LQ (P < .05). A strong correlation was found between the inclinometer measurement of the WBLT and ankle dorsiflexion (r = .74, r2 = .55), whereas the tape-measure results on the WBLT were moderately correlated with ankle dorsiflexion (r = .64, r2 = .40) during the anterior reach on the YBT-LQ. Only the normalized anterior reach distance was significantly correlated with the results for the inclinometer (r = .68, r2 = .46) and the tape measure (r = .64, r2 = .41) on the WBLT. Inclinometer measurements on the WBLT can be an appropriate tool for predicting the amount of ankle dorsiflexion during the YBT-LQ. Furthermore, WBLT should be measured in those who demonstrate poor dynamic balance.


Evidence for the regulation of left-right asymmetry in Ciona intestinalis by ion flux.
Vertebrate embryos develop distinct left-right asymmetry under the control of a conserved pathway involving left-sided deployment of the nodal and Pit x 2 genes. The mechanism that initiates asymmetric expression of these genes is less clear, with cilia, ion flux, and signalling molecules all implicated. Vertebrates share the chordate phylum with urochordates such as the sea squirt Ciona intestinalis. We have explored the role of ion flux in regulating left-right asymmetry in Ciona, using an assay in which perturbation of left-sided Ci-Pitx expression provides a read-out for the disruption of asymmetry. Our data show that omeprazole, which specifically inhibits H(+)K(+)ATPase activity, disrupts asymmetry in Ciona. The vertebrate H(+)K(+)ATPase is composed of two subunits, alpha and beta. We identified one Ciona beta ortholog and two Ciona alpha orthologs of the vertebrate H(+)K(+)ATPase genes, and show that one of these is expressed in dorsal and ventral embryonic midline cells shortly before the activation of left-sided Ci-Pitx expression. Furthermore, we show that omeprazole exerts its effect on asymmetry at this point in development, and additionally implicate K(+) channels in the regulation of asymmetry in Ciona. These experiments demonstrate a role for ion flux in the regulation of asymmetry in Ciona, and show a conserved, ancestral role for the H(+)K(+)ATPase ion pump in this process.


Lexical and sentential processing in British Sign Language.
Studies of spoken and written language suggest that the perception of sentences engages the left anterior and posterior temporal cortex and the left inferior frontal gyrus to a greater extent than non-sententially structured material, such as word lists. This study sought to determine whether the same is true when the language is gestural and perceived visually. Regional neural activity was measured using functional MRI while Deaf and hearing native signers of British Sign Language (BSL) detected semantic anomalies in well-formed BSL sentences and when they detected nonsense signs in lists of unconnected BSL signs. Processing BSL sentences, when contrasted with signed lists, was reliably associated with greater activation in the posterior portions of the left middle and superior temporal gyri and in the left inferior frontal cortex, but not in the anterior temporal cortex, which was activated to a similar extent whether lists or sentences were processed. Further support for the specificity of these areas for processing the linguistic-rather than visuospatial-features of signed sentences came from a contrast of hearing native signers and hearing sign-naïve participants. Hearing signers recruited the left posterior temporal and inferior frontal regions during BSL sentence processing to a greater extent than hearing non-signers. These data suggest that these left perisylvian regions are differentially associated with sentence processing, whatever the modality of the linguistic input.


A kaleidoscope of photosynthetic antenna proteins and their emerging roles.
Photosynthetic light-harvesting antennae are pigment-binding proteins that perform one of the most fundamental tasks on Earth, capturing light and transferring energy that enables life in our biosphere. Adaptation to different light environments led to the evolution of an astonishing diversity of light-harvesting systems. At the same time, several strategies have been developed to optimize the light energy input into photosynthetic membranes in response to fluctuating conditions. The basic feature of these prompt responses is the dynamic nature of antenna complexes, whose function readily adapts to the light available. High-resolution microscopy and spectroscopic studies on membrane dynamics demonstrate the crosstalk between antennae and other thylakoid membrane components. With the increased understanding of light-harvesting mechanisms and their regulation, efforts are focusing on the development of sustainable processes for effective conversion of sunlight into functional bio-products. The major challenge in this approach lies in the application of fundamental discoveries in light-harvesting systems for the improvement of plant or algal photosynthesis. Here, we underline some of the latest fundamental discoveries on the molecular mechanisms and regulation of light harvesting that can potentially be exploited for the optimization of photosynthesis.


PTOV1 is associated with UCH-L1 and in response to estrogen stimuli during the mouse oocyte development.
To investigate the biological significance of ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1) involvement in oocyte maturation, we screened for proteins that bound to UCH-L1 in mouse ovaries, and we found that the prostate tumor overexpressed-1 (PTOV1) protein was able to bind to UCH-L1. PTOV1 is highly expressed in prostate cancers and considered as a potential marker for carcinogenesis and the progress of prostate cancer. It was reported that PTOV1 plays an important role in cell cycle regulation, but its role in mammalian oocyte development and meiosis is still unclear. In this paper, it was found that the expression levels of PTOV1 in mouse ovaries progressively increased from prepubescence to adulthood. And we found by immunohistochemistry that PTOV1 spreaded in both the cytoplasm and nuclei of oocytes during prepuberty, but in normal adult mouse oocytes, it concentrated not only in nuclei but also on the plasma membrane, though in some oocytes with abnormal shapes, PTOV1 did not display the typical distribution patterns. In granulosa cells, however, it was found to locate in the cytoplasm at all the selected ages. In postnatal mouse ovaries (28 days), estradiol treatment induced the adult-specific distribution pattern of PTOV1 in oocytes. In addition, UCH-L1 was shown to be associated with CDK1, which participated in the regulation of cell cycle and oocyte maturation. Therefore, we propose that the distribution changes of PTOV1 are age-dependent, and significant for mouse oocyte development and maturation. Moreover, the discovery that PTOV1 is associated with UCH-L1 in mouse oocytes supports the explanations for that UCH-L1 is involved in oocyte development and maturation, especially under the regulation of estrogen.


A linear memory algorithm for Baum-Welch training.
Baum-Welch training is an expectation-maximisation algorithm for training the emission and transition probabilities of hidden Markov models in a fully automated way. It can be employed as long as a training set of annotated sequences is known, and provides a rigorous way to derive parameter values which are guaranteed to be at least locally optimal. For complex hidden Markov models such as pair hidden Markov models and very long training sequences, even the most efficient algorithms for Baum-Welch training are currently too memory-consuming. This has so far effectively prevented the automatic parameter training of hidden Markov models that are currently used for biological sequence analyses. We introduce the first linear space algorithm for Baum-Welch training. For a hidden Markov model with M states, T free transition and E free emission parameters, and an input sequence of length L, our new algorithm requires O(M) memory and O(LMTmax (T + E)) time for one Baum-Welch iteration, where Tmax is the maximum number of states that any state is connected to. The most memory efficient algorithm until now was the checkpointing algorithm with O(log(L)M) memory and O(log(L)LMTmax) time requirement. Our novel algorithm thus renders the memory requirement completely independent of the length of the training sequences. More generally, for an n-hidden Markov model and n input sequences of length L, the memory requirement of O(log(L)L(n-1) M) is reduced to O(L(n-1) M) memory while the running time is changed from O(log(L)Ln MTmax + Ln(T + E)) to O(Ln MTmax (T + E)). An added advantage of our new algorithm is that a reduced time requirement can be traded for an increased memory requirement and vice versa, such that for any c e {1, ..., (T + E)}, a time requirement of Ln MTmax c incurs a memory requirement of L(n-1) M(T + E - c). For the large class of hidden Markov models used for example in gene prediction, whose number of states does not scale with the length of the input sequence, our novel algorithm can thus be both faster and more memory-efficient than any of the existing algorithms.


Recommendations for the treatment of ulcerative colitis with infliximab: a gastroenterology expert group consensus.
Infliximab is currently the only biologic approved for treatment of adults with moderate to severe, active ulcerative colitis (UC) unresponsive to conventional therapies. It rapidly controls symptoms, induces and sustains steroid-free remission, stimulates mucosal healing, and reduces serious complications. Although infliximab tends to be reserved for patients with severe disease, it may be even more beneficial for moderate disease earlier in the disease course. Therefore, it is important to identify which patients are candidates for infliximab therapy. A collaborative Delphi survey was used to obtain consensus on use of biologic therapy in patients with UC from an expert panel of 12 gastroenterologists with substantial experience using infliximab in clinical practice and clinical trials. The panel also addressed issues that influence the use of infliximab in UC, including its potential as an alternative to surgery. The panel agreed that: (1) it is necessary to adopt additional treatment goals beyond symptom control, i.e., complete mucosal healing, steroid-free remission, improved QoL, and reduced long-term complications; (2) it may be possible to achieve these treatment goals with infliximab, especially if it is used earlier in the course of UC; and (3) infliximab should be offered as an alternative to surgery in patients being considered for colectomy. The panel also agreed on factors for identifying candidates for infliximab therapy (e.g., persistently active UC, steroid-dependent/refractory disease, and high C-reactive protein). This consensus statement provides useful and practical information on how to achieve evolving treatment goals with infliximab in moderate to severe UC.


Randomized controlled clinical trial on the antiseptic efficacy of polihexanide 0.04% on acute traumatic wounds.
Prevention of wound infections is a challenge in clinical practice. The aim of this study was to assess the efficacy of polyhexamethylene biguanide (PHMB, polihexanide) 0.04% on acute traumatic wounds. It was a randomized, double-blind, placebo-controlled prospective trial which included 61 patients. The polihexanide group showed a significant decrease in log10 colony-forming units (cfu) (P < 0.001) after 60 min treatment in comparison to baseline cfu, whereas the Ringer solution group did not show a significant change in cfu during 60 min treatment. Treatment of polihexanide 0.04% resulted in a significant reduction of bacterial load in acute traumatic wounds.


Heart failure in cardiomyopathies: a position paper from the Heart Failure Association of the European Society of Cardiology.
Cardiomyopathies are a heterogeneous group of heart muscle diseases and an important cause of heart failure (HF). Current knowledge on incidence, pathophysiology and natural history of HF in cardiomyopathies is limited, and distinct features of their therapeutic responses have not been systematically addressed. Therefore, this position paper focuses on epidemiology, pathophysiology, natural history and latest developments in treatment of HF in patients with dilated (DCM), hypertrophic (HCM) and restrictive (RCM) cardiomyopathies. In DCM, HF with reduced ejection fraction (HFrEF) has high incidence and prevalence and represents the most frequent cause of death, despite improvements in treatment. In addition, advanced HF in DCM is one of the leading indications for heart transplantation. In HCM, HF with preserved ejection (HFpEF) affects most patients with obstructive, and ∼10% of patients with non-obstructive HCM. A timely treatment is important, since development of advanced HF, although rare in HCM, portends a poor prognosis. In RCM, HFpEF is common, while HFrEF occurs later and more frequently in amyloidosis or iron overload/haemochromatosis. Irrespective of RCM aetiology, HF is a harbinger of a poor outcome. Recent advances in our understanding of the mechanisms underlying the development of HF in cardiomyopathies have significant implications for therapeutic decision-making. In addition, new aetiology-specific treatment options (e.g. enzyme replacement therapy, transthyretin stabilizers, immunoadsorption, immunotherapy, etc.) have shown a potential to improve outcomes. Still, causative therapies of many cardiomyopathies are lacking, highlighting the need for the development of effective strategies to prevent and treat HF in cardiomyopathies.


Matrix metalloproteinase circulating levels, genetic polymorphisms, and susceptibility to acute myocardial infarction among patients with coronary artery disease.
The aim of this study was to assess systematic differences between patients with acute myocardial infarction (MI) and patients with stable angina in matrix metalloproteinase (MMP) circulating levels and genetic polymorphisms. We identified adults in a large integrated health care delivery system whose initial clinical presentation of coronary disease was either an acute MI or stable exertional angina. A total of 909 patients with acute MI, 466 patients with stable angina, and 1023 healthy older control subjects were genotyped. Serum levels of pro-MMP1, MMP2, MMP3, MMP9, and MMP10 were measured in 199 randomly selected patients from each group. At a median of 15 weeks after initial clinical presentation, higher circulating levels of MMP2 and MMP9 were independently associated with acute MI after statistical adjustment for conventional risk factors, hs-CRP levels, and cardiac medications. By contrast, none of the polymorphisms in MMP1, MMP2, MMP3, MMP9, or MMP10 was significantly associated with either acute MI compared with angina, or with coronary disease compared with controls. Circulating levels of MMP2 and MMP9 are independently associated with development of an acute MI rather than stable angina as the initial clinical presentation of coronary artery disease.


Dimerization stabilizes the pore-forming toxin aerolysin in solution.
Aerolysin is a channel-forming protein secreted as a protoxin by Aeromonas hydrophila. Analytical centrifugation measurements showed that proaerolysin is a dimer in solution, and this was confirmed by chemical cross-linking with dimethyl suberimidate. Dissociation of proaerolysin with low concentrations of SDS resulted in the loss of tertiary structure, assessed by near ultraviolet circular dichroism. This was accompanied by an increase in the protein's ability to bind the hydrophobic dye 1-anilino-8-naphthalene sulfonate, as well as by increased sensitivity to proteolytic degradation. However, the monomer was not fully unfolded by the detergent, as the tryptophans remained in a hydrophobic environment, and the secondary structure measured by far ultraviolet circular dichroism did not seem to be affected. Aerolysin, the active form of the protein, was also shown to be a dimer, and its stability was found to be no different from the stability of the protoxin dimer. Substituting tryptophan 371 or tryptophan 373 with leucine greatly reduced the stability of dimeric proaerolysin. These substitutions are known to increase the protein's ability to oligomerize, supporting the conclusion that dimer dissociation is necessary for oligomerization to occur.


Inhibition of 5'-UTR RNA conformational switching in HIV-1 using antisense PNAs.
The genome of retroviruses, including HIV-1, is packaged as two homologous (+) strand RNA molecules, noncovalently associated close to their 5'-end in a region called dimer linkage structure (DLS). Retroviral HIV-1 genomic RNAs dimerize through complex interactions between dimerization initiation sites (DIS) within the (5'-UTR). Dimer formation is prevented by so calledLong Distance Interaction (LDI) conformation, whereas Branched Multiple Hairpin (BMH) conformation leads to spontaneous dimerization. We evaluated the role of SL1 (DIS), PolyA Hairpin signal and a long distance U5-AUG interaction by in-vitro dimerization, conformer assay and coupled dimerization and template-switching assays using antisense PNAs. Our data suggests evidence that PNAs targeted against SL1 produced severe inhibitory effect on dimerization and template-switching processes while PNAs targeted against U5 region do not show significant effect on dimerization and template switching, while PNAs targeted against AUG region showed strong inhibition of dimerization and template switching processes. Our results demonstrate that PNA can be used successfully as an antisense to inhibit dimerization and template switching process in HIV -1 and both of the processes are closely linked to each other. Different PNA oligomers have ability of switching between two thermodynamically stable forms. PNA targeted against DIS and SL1 switch, LDI conformer to more dimerization friendly BMH form. PNAs targeted against PolyA haipin configuration did not show a significant change in dimerization and template switching process. The PNA oligomer directed against the AUG strand of U5-AUG duplex structure also showed a significant reduction in RNA dimerization as well as template- switching efficiency.The antisense PNA oligomers can be used to regulate the shift in the LDI/BMH equilibrium.


Probing the structure, function, and interactions of the Escherichia coli H-NS and StpA proteins by using dominant negative derivatives.
Twelve different dominant negative mutants of the Escherichia coli nucleoid-associated protein, H-NS, have been selected and characterized in vivo. The mutants are all severely defective in promoter repression activity in a strain lacking H-NS, and they all disrupt the repression normally exerted by H-NS at two of its target promoters. From the locations of the alterations in these mutants, which result in both large truncations and amino acid substitutions, we propose that H-NAS contains at least two distinct domains. The in vitro protein-protein cross-linking data presented in this report indicate that the proposed N-terminal domain of H-NS has a role in H-NS multimerization. StpA is a protein with known structural and functional homologies to H-NS. We have analyzed the extent of these homologies by constructing and studying StpA mutants predicted to be dominant negative. Our data indicate that the substitutions and deletions found in dominant negative H-NS have similar effects in the context of StpA. We conclude that the domain organizations and functions in StpA and H-NS are closely related. Furthermore, dominant negative H-NS can disrupt the activity of native StpA, and reciprocally, dominant negative StpA can disrupt the activity of native H-NS. We demonstrate that the N-terminal domain of H-NS can be chemically cross-linked to both full-length H-NS and StpA. We account for these observations by proposing that H-NS and StpA have the ability to form hybrid species.


Analysis of Wnt signaling β-catenin spatial dynamics in HEK293T cells.
Wnt/β-catenin signaling is involved in different stages of mammalian development and implicated in various cancers (e.g. colorectal cancer). Recent experimental and computational studies have revealed characteristics of the pathway, however a cell-specific spatial perspective is lacking. In this study, a novel 3D confocal quantitation protocol is developed to acquire spatial (two cellular compartments: nucleus and cytosol-membrane) and temporal quantitative data on target protein (e.g. β-catenin) concentrations in Human Epithelial Kidney cells (HEK293T) during perturbation (with either cycloheximide or Wnt3A). Computational models of the Wnt pathway are constructed and interrogated based on this data. A single compartment Wnt pathway model is compared with a simple β-catenin two compartment model to investigate Wnt3A signaling in HEK293T cells. When protein synthesis is inhibited, β-catenin decreases at the same rate in both cellular compartments, suggesting diffusional transport is fast compared to β-catenin degradation in the cytosol. With Wnt3A stimulation, the total amount of β-catenin rises throughout the cell, however the increase is initially (~first hour) faster in the nuclear compartment. While both models were able to reproduce the whole cell changes in β-catenin, only the compartment model reproduced the Wnt3A induced changes in β-catenin distribution and it was also the best fit for the data obtained when active transport was included alongside passive diffusion transport. This integrated 3D quantitation imaging protocol and computational modeling approach allowed cell-specific compartment models of the signaling pathways to be constructed and analyzed. The Wnt models constructed in this study are the first for HEK293T and have suggested potential roles of inter-compartment transport to the dynamics of signaling.


Adrenocortical carcinoma and pulmonary embolism from tumoral extension.
Adrenococortical carcinoma (ACC) is a rare cancer, occurring at the rate of one case in two million person years. Cushing syndrome or a mixed picture of excess androgen and glucocorticoid production are the most common presentations of ACC. Other uncommon presentations include abdominal pain and adrenal incidentalomas. In the present report, a 71-year-old male presented with abdominal pain and was eventually diagnosed with ACC. He was found to have pulmonary thromboembolism following an investigation for hypoxemia, with the tumor thrombus extending upto the right atrium. This interesting case represents the unique presentation of a rare tumor, which if detected late or left untreated is associated with poor outcomes, highlighting the need for a low index of suspicion for ACC when similar presentations are encountered in clinical practice. ACC is a rare but aggressive tumor. ACC commonly presents with rapid onset of hypercortisolism, combined hyperandrogenism and hypercortisolism, or uncommonly with compressive symptoms. Clinicians should have a low index of suspicion for ACC in patients presenting with rapid onset of symptoms related to hypercortisolism and/or hyperandrogenism. Venous thromboembolism and extension of the tumor thrombus to the right side of the heart is a very rare but serious complication of ACC that clinicans should be wary of. The increased risk of venous thromboembolism in ACC could be explained by direct tumor invasion, tumor thrombi or hypercoagulability secondary to hypercortisolism. Early diagnosis and prompt treatment can improve the long-term survival of patients with ACC.


Intraoperative secondary insults during extracranial surgery in children with traumatic brain injury.
Data on intraoperative secondary insults in pediatric traumatic brain injury (TBI) are limited. We examined intraoperative secondary insults during extracranial surgery in children with moderate-severe TBI and polytrauma and their association with postoperative head computed tomography (CT) scans, intracranial pressure (ICP), and therapeutic intensity level (TIL) scores 24 h after surgery. After IRB approval, we reviewed the records of children <18 years with a Glasgow Coma Scale score <13 who underwent extracranial surgery within 72 h of TBI. Definitions of secondary insults were as follows: systemic hypotension (SBP <70 + 2 × age or 90 mmHg), cerebral hypotension (cerebral perfusion pressure <40 mmHg), intracranial hypertension (ICP >20 mmHg), hypoxia (oxygen saturation <90 %), hypercarbia (end-tidal CO2 >45 mmHg), hypocarbia (end-tidal CO2 <30 mmHg without hypotension and in the absence of intracranial hypertension), hyperglycemia (blood glucose >200 mg/dL), hyperthermia (temperature >38 °C), and hypothermia (temperature <35 °C). Data from 50 surgeries in 42 patients (median age 15.5 years, 25 males) revealed systemic hypotension during 78 %, hypocarbia during 46 %, and hypercarbia during 25 % surgeries. Intracranial hypertension occurred in 64 % and cerebral hypotension in 18 % surgeries with ICP monitoring (11/50). Hyperglycemia occurred during 17 % of the 29 surgeries with glucose monitoring. Cerebral hypotension and hypoxia were associated with postoperative intracranial hypertension (p = 0.02 and 0.03, respectively). We did not observe an association between intraoperative secondary insults and postoperative worsening of head CT scan or TIL score. Intraoperative secondary insults were common during extracranial surgery in pediatric TBI. Intraoperative cerebral hypotension and hypoxia were associated with postoperative intracranial hypertension. Strategies to prevent secondary insults during extracranial surgery in TBI are needed.


Anatomy of plantaris muscle: a study in adult Indians.
The plantaris muscle (PM) and its tendon is subject to considerable variation in both the points of origin and of insertion. The present study was carried out to fi nd the different types of origin, insertion and possible variations of the PM in the population of southern costal region of India. 52 embalmed (Formalin fixed) cadaver lower limbs of 26 males (age ranged 48-79 years, mean age 68 years) were dissected, to study the origin and insertion of PM. Various dimensions (length and width) of plantaris muscle belly and its tendon were also measured. Three types of origin and equal number of insertion were noticed in the present study. The PM took origin from type I: Lateral Supracondylar ridge, Capsule of Knee joint and Lateral head of gastrocnemius in 73.07% cases; type II: Capsule of Knee joint and Lateral head of gastronemius in 5.76% cases; type III: Lateral Supracondylar ridge , Capsule of Knee joint , Lateral head of gastrocnemius and fibular collateral ligament in 13.46% cases. The plantaris tendon was inserted into type I: to the flexor retinaculum of foot in 28.84% cases; type II: independently to the os calcaneum in 36.53% cases; type III: to the tendocalcaneus at various levels in 26.92% cases. In four lower limbs (7.69%) the plantaris muscle was completely absent. Additionally the length and width of the plantaris muscle and its tendon were measured to know any side difference. There were no statistically significant differences between the measurements of left and right side (p>0.05). Present study will help the surgeons while attempting various surgical procedures in and around the posterior aspect of knee involving plantaris.


Use of antidepressant medications and risk of fracture in older women.
Use of antidepressant medications has been associated with increased risk of fracture, but prior studies have been limited by incomplete control of confounders or a limited number of fractures. Use of antidepressant medications by 8,217 community-dwelling women aged 69 and older from a population-based prospective cohort study at four US clinical centers was assessed by interview at four examinations over a 10-year period, beginning in 1992-1994. Use was coded as a time-dependent variable. Incident fractures occurring after the initial medication assessment until July 2007 were confirmed by radiographic reports. Potential confounders were included in multivariable models and updated at each follow-up visit. Compared to nonusers of antidepressant medications, women using SSRIs experienced a higher risk of nonspine fracture in age-adjusted models (HR = 1.36, 95% CI 1.11-1.67) and in multivariable models controlling for potential confounders (HR = 1.30, 95% CI 1.04-1.62). SSRI use was not associated with an increased risk of first hip fracture (HR = 1.01, 95% CI 0.71-1.44) but was associated with an increased risk of wrist fracture (HR = 1.54, 95% CI 1.01-2.36). TCA use was associated with an increased risk of nonspine fracture in age-adjusted models, but in multivariable models this risk was attenuated. SSRI use was associated with a higher risk of any nonspine fracture, but not hip fracture, in this cohort of older women. TCA use was associated with a higher risk of nonspine fracture, but this association was in part explained by confounding factors.


Dynamic Causal Modelling suggests impaired effective connectivity in patients with schizophrenia spectrum disorders during gesture-speech integration.
Integrating visual and auditory information during gesture-speech integration (GSI) is important for successful social communication, which is often impaired in schizophrenia. Several studies suggested the posterior superior temporal sulcus (pSTS) to be a relevant multisensory integration site. However, intact STS activation patterns were often reported in patients. Thus, here we used Dynamic Causal Modelling (DCM) to analyze whether information processing in schizophrenia spectrum disorders (SSD) is impaired during GSI on network level. We investigated GSI in three different samples. First, we replicated a recently published connectivity model for GSI in a healthy subject group (n = 19). Second, we investigated differences between patients with SSD and a matched healthy control group (n = 17 each). Participants were presented videos of an actor performing intrinsically meaningful gestures accompanied by spoken sentences in German or Russian, or just telling a German sentence without gestures. Across all groups, fMRI analyses revealed similar activation patterns, and DCM analyses resulted in the same winning model for GSI. This finding directly replicates previous results. However, patients revealed significantly reduced connectivity in the verbal pathway (from left middle temporal gyrus (MTG) to left STS). The clinical significance of this connection is supported by its correlations with the severity of concretism and a subscale of negative symptoms (SANS). Our model confirms the importance of the pSTS as integration site during audio-visual integration. Patients showed generally intact connectivity during GSI, but revealed impaired information transfer via the verbal pathway. This might be the basis of interpersonal communication problems in patients with SSD.


Effect of enzyme dehydration on alcalase-catalyzed dipeptide synthesis in near-anhydrous organic media.
The effect of enzyme dehydration by molecular sieves on the coupling of phenylalanine amide and the carbamoylmethyl ester of N-protected phenylalanine in near-anhydrous tetrahydrofuran was investigated. This coupling was catalyzed by Alcalase covalently immobilized onto macroporous acrylic beads (Cov); these immobilized enzymes were hydrated prior to use. The dehydration kinetics of Cov by molecular sieve powder were determined by incubating Cov with different amounts of molecular sieve powder for different periods of time (0-80 h). Subsequently, the remaining coupling activity of Cov was measured. Dehydration-induced inactivation of Cov by molecular sieve powder was found to occur in three phases: (1) an initial, rapid, major dehydration-induced inactivation that takes place during the first activity measurement, (2) a phase of first-order inactivation, and (3) a plateau phase in activity. These dehydration kinetics were incorporated into a previously found reaction kinetics model. The resulting model was then used to fit progress curve data of the coupling in the presence of different amounts of molecular sieve powder. Upon establishment of parameter values, the model was used to predict independent data sets and found to work well.


Breast Cancer Cell Lines Exhibit Differential Sensitivities to Microtubule-targeting Drugs Independent of Doubling Time.
Microtubule-targeting agents (MTAs) are a mainstay in breast cancer treatment, yet patient responses differ. The underlying mechanisms of these differences are unknown. While MTAs are mitotic inhibitors, recent evidence highlights that non-mitotic effects of these drugs can contribute to their anticancer effects. It is critical to identify the non-mitotic mechanisms that could contribute to differences among MTAs. However, it is not clear whether rapidly dividing cells in culture are optimal tools to address these mechanistic questions in interphase cells. Detailed concentration response curves for five MTAs in a panel of diverse breast cancer cell lines were generated. Substantial differences among both drugs and cell lines, consistent with the clinical scenario, were observed. Importantly, these differences do not correlate with cell doubling time. The interphase actions of MTAs are critical to the full spectrum of their effects in cancer cells, even in cell culture models.


Inpatient Management of Acute Severe Ulcerative Colitis.
Acute severe ulcerative colitis (ASUC) is a potentially life-threatening presentation of ulcerative colitis that in nearly all cases requires inpatient management and coordinated care from hospitalists, gastroenterologists, and surgeons. Even with ideal care, a substantial proportion of patients will ultimately require colectomy, but most patients can avoid surgery with intravenous corticosteroid treatment and if needed, appropriate rescue therapy with infliximab or cyclosporine. In-hospital management requires not only therapies to reduce the inflammation at the heart of the disease process, but also to avoid complications of the disease and its treatment. Care for ASUC must be anticipatory, with patient education and evaluation starting at the time of admission in advance of the possible need for urgent medical or surgical rescue therapy. Here we outline a general approach to the treatment of patients hospitalized with ASUC, highlighting the common pitfalls and critical points in management.


Rapidly progressive polyneuropathy due to dry beriberi in a man: a case report.
We describe a case of rapidly progressive and severely debilitating polyneuropathy in a patient with confirmed hypovitaminosis B1, consistent with dry beriberi. Crucially, this is a treatable condition, although sometimes with incomplete recovery, but it is probably under-recognized yet increasingly common given increasing levels of alcohol abuse in the western world. A 49-year-old Caucasian British man presented with progressive weakness of both lower limbs of approximately seven months' duration. He noted difficulty climbing stairs. He also complained of lethargy, and loss of muscle bulk, including his thighs. He had a history of type 2 diabetes mellitus and admitted prior alcohol abuse but denied excessive alcohol intake in the five years prior to presentation. Initial clinical and neurophysiological examinations were consistent with a mild peripheral neuropathy and probable proximal myopathy. However, over the subsequent four months he evolved a marked tetraparesis, with profound sensory disturbance of all limbs. Repeat neurophysiology revealed a widespread polyneuropathy with extensive acute and sub-acute denervation changes in all four limbs, and reduced or absent sensory nerve action potentials. Hypovitaminosis B1 was confirmed (45 nmol/L, reference range 66-200 nmol/L). His rapid clinical deterioration was in keeping with dry beriberi. He was treated with thiamine. Subsequent follow-up revealed slow but significant improvement, such that by 15-16 months from the initial onset of symptoms, and approximately six months after the onset of his marked tetraparesis, he was able to stand independently and was gradually gaining confidence in walking pending a period of in-patient neurorehabilitation. A potentially wide differential diagnosis exists for this type of presentation. Confirming hypovitaminosis B1 by requesting the assay prior to vitamin replacement ensures accurate diagnosis and appropriate ongoing treatment. An increasingly high index of suspicion is likely to be required in the context of increasing levels of alcohol abuse in the western world and the possible increasing prevalence of dry beriberi.


Bayesian Inference and Online Learning in Poisson Neuronal Networks.
Motivated by the growing evidence for Bayesian computation in the brain, we show how a two-layer recurrent network of Poisson neurons can perform both approximate Bayesian inference and learning for any hidden Markov model. The lower-layer sensory neurons receive noisy measurements of hidden world states. The higher-layer neurons infer a posterior distribution over world states via Bayesian inference from inputs generated by sensory neurons. We demonstrate how such a neuronal network with synaptic plasticity can implement a form of Bayesian inference similar to Monte Carlo methods such as particle filtering. Each spike in a higher-layer neuron represents a sample of a particular hidden world state. The spiking activity across the neural population approximates the posterior distribution over hidden states. In this model, variability in spiking is regarded not as a nuisance but as an integral feature that provides the variability necessary for sampling during inference. We demonstrate how the network can learn the likelihood model, as well as the transition probabilities underlying the dynamics, using a Hebbian learning rule. We present results illustrating the ability of the network to perform inference and learning for arbitrary hidden Markov models.


Accounting for eXentricities: analysis of the X chromosome in GWAS reveals X-linked genes implicated in autoimmune diseases.
Many complex human diseases are highly sexually dimorphic, suggesting a potential contribution of the X chromosome to disease risk. However, the X chromosome has been neglected or incorrectly analyzed in most genome-wide association studies (GWAS). We present tailored analytical methods and software that facilitate X-wide association studies (XWAS), which we further applied to reanalyze data from 16 GWAS of different autoimmune and related diseases (AID). We associated several X-linked genes with disease risk, among which (1) ARHGEF6 is associated with Crohn's disease and replicated in a study of ulcerative colitis, another inflammatory bowel disease (IBD). Indeed, ARHGEF6 interacts with a gastric bacterium that has been implicated in IBD. (2) CENPI is associated with three different AID, which is compelling in light of known associations with AID of autosomal genes encoding centromere proteins, as well as established autosomal evidence of pleiotropy between autoimmune diseases. (3) We replicated a previous association of FOXP3, a transcription factor that regulates T-cell development and function, with vitiligo; and (4) we discovered that C1GALT1C1 exhibits sex-specific effect on disease risk in both IBDs. These and other X-linked genes that we associated with AID tend to be highly expressed in tissues related to immune response, participate in major immune pathways, and display differential gene expression between males and females. Combined, the results demonstrate the importance of the X chromosome in autoimmunity, reveal the potential of extensive XWAS, even based on existing data, and provide the tools and incentive to properly include the X chromosome in future studies.


Phenol removal from wastewater by surface imprinted bacterial cellulose nanofibres.
In this study, we have reported a novel wastewater treatment technique by phenol imprinted bacterial cellulose (BC-MIP) nanofibres with high specificity and adsorption capacity. N-methacryloyl-(L) phenylalanine methyl ester (MAPA) functional monomer was used to create specific binding sites for the template molecule phenol via electrostatic and hydrophobic interactions. BC-MIP nanofibres were synthesized by surface imprinting approach in the presence of different amounts of total monomer (% weight), monomer/template ratio and polymerization time. Then, the nanofibres were characterized by FTIR-ATR, surface area analysis (BET), elemental analysis, scanning electron microscopy (SEM) and contact angle measurements. Adsorption studies were performed with respect to pH, temperature and ionic strength, and the adsorption capacity was calculated by using the spectrophotometer. In order to desorb the adsorbed phenol from BC-MIP nanofibres, 0.1 M NaCl solution was used. Besides, BC-MIP nanofibres were applied to real wastewater samples from Ergene basin in Turkey. The suitable equilibrium isotherm was determined as Langmuir isotherm. To evaluate the selectivity of the BC-MIP nanofibres, similar molecules were utilized as competitor molecules, which were 2-chlorophenol, 4-chlorophenol and 2,4-dichlorophenol. Electrostatic interactions were found to contribute to the generation of specific recognition binding sites. The results have shown that imprinting of phenol was achieved successfully with high adsorption capacity. The phenol removal efficiency was reported up to 97%. BC-MIP nanofibres were used 10 times with a negligible decrease in adsorption capacity.


Intratumoral Comparison of Nanoparticle Entrapped Docetaxel (CPC634) with Conventional Docetaxel in Patients with Solid Tumors.
CPC634 is a novel nanoparticle entrapping docetaxel, developed to enhance the intratumoral chemotherapy exposure. This randomized cross-over study compared the intratumoral and plasma pharmacokinetics of CPC634 with conventional docetaxel. Adult patients with solid tumors were randomized to receive CPC634 (75 mg/m2) in cycle 1, and conventional docetaxel (75 mg/m2) in cycle 2 or vice versa. The study was powered to identify a 25% increase of intratumoral total docetaxel exposure after CPC634 infusion compared with conventional docetaxel. Four patients were allocated per tumor sampling time point, that is, 24, 48, 72, and 96 hours, 7 and 14 days after infusion during both cycles. Total docetaxel and released docetaxel from the nanoparticle were determined in tumor tissue derived from a metastatic lesion and in plasma. Pharmacokinetic data were analyzed using linear mixed modeling. In total, 24 evaluable patients were included. In the tumor, CPC634 exhibited a 461% higher total docetaxel (P < 0.001) and a comparable released docetaxel concentration (P = 0.43). Plasma AUCinf was 27% higher (P = 0.001) and C max was 91% lower (P < 0.001) for CPC634 released docetaxel. The median observed neutrophil count nadir after conventional docetaxel treatment was lower (0.50 × 109/L) compared with CPC634 (4.30 × 109/L; P < 0.001). Here, we demonstrated that CPC634 enhanced the intratumoral total docetaxel exposure compared with conventional docetaxel. The lower incidence of neutropenia during CPC634 treatment is presumably related to lower plasma C max of released docetaxel. The unique pharmacokinetic profile of CPC634 nanoparticles has the potential to improve docetaxel treatment. A phase II efficacy trial of CPC634 is currently ongoing.


Analysis of pressure, angle and temporal effects on tissue optical properties from polarization-gated spectroscopic probe measurements.
Noninvasive optical techniques for tissue characterization, in particular, light scattering properties and blood supply quantification of mucosa, is useful in a wide variety of applications. However, fiber-optic probes that require contact with the tissue surface can present a challenging problem in the variability of in vivo measurements due the nature of interactions, for example affects due to variations in pressure applied to the probe tip. We present an in vivo evaluation of pressure, angle, and temporal effects on tissue properties for polarization-gated spectroscopy at superficial depths (within 100 to 200 microns of tissue surface) for oral mucosa.


Nilotinib as front-line treatment for patients with chronic myeloid leukemia in early chronic phase.
Although most patients with chronic myeloid leukemia (CML) in chronic phase respond well to front-line therapy with imatinib, some patients do not achieve the desirable end point, and others may eventually lose response or are intolerant. Patients with newly diagnosed CML in chronic phase were treated with nilotinib 400 mg twice daily on an empty stomach as initial therapy. Among 51 patients in chronic phase observed for at least 3 months, 50 (98%) achieved a complete cytogenetic remission (CCyR), and 39 (76%) achieved a major molecular response (MMR). Responses occurred rapidly, with 96% of patients achieving CCyR by 3 months and 98% achieving CCyR by 6 months. The projected event-free survival at 24 months is 90%, and all patients are alive after a median follow-up time of 17 months. Grade >or= 3 neutropenia occurred in 12% of patients, and thrombocytopenia in occurred 11%. Nonhematologic toxicity was usually grade 1 to 2 and manageable. The actual median dose at 12 months was 800 mg (range, 200 to 800 mg). Nilotinib is an effective option for the initial management of CML in early chronic phase, producing high rates of CCyR and MMR, with most patients reaching these responses early during their therapy.


Different languages, similar encoding efficiency: Comparable information rates across the human communicative niche.
Language is universal, but it has few indisputably universal characteristics, with cross-linguistic variation being the norm. For example, languages differ greatly in the number of syllables they allow, resulting in large variation in the Shannon information per syllable. Nevertheless, all natural languages allow their speakers to efficiently encode and transmit information. We show here, using quantitative methods on a large cross-linguistic corpus of 17 languages, that the coupling between language-level (information per syllable) and speaker-level (speech rate) properties results in languages encoding similar information rates (~39 bits/s) despite wide differences in each property individually: Languages are more similar in information rates than in Shannon information or speech rate. These findings highlight the intimate feedback loops between languages' structural properties and their speakers' neurocognition and biology under communicative pressures. Thus, language is the product of a multiscale communicative niche construction process at the intersection of biology, environment, and culture.


Effects of solar flares on the ionosphere of Mars.
All planetary atmospheres respond to the enhanced x-rays and ultraviolet (UV) light emitted from the Sun during a flare. Yet only on Earth are observations so continuous that the consequences of these essentially unpredictable events can be measured reliably. Here, we report observations of solar flares, causing up to 200% enhancements to the ionosphere of Mars, as recorded by the Mars Global Surveyor in April 2001. Modeling the altitude dependence of these effects requires that relative enhancements in the soft x-ray fluxes far exceed those in the UV.