An interactive simulation and visualization tool for flood analysis usable for practitioners.
Developing strategies to mitigate or to adapt to the threats of floods is an important topic in the context of climate changes. Many of the world's cities are endangered due to rising ocean levels and changing precipitation patterns. It is therefore crucial to develop analytical tools that allow us to evaluate the threats of floods and to investigate the influence of mitigation and adaptation measures, such as stronger dikes, adaptive spatial planning, and flood disaster plans. Up until the present, analytical tools have only been accessible to domain experts, as the involved simulation processes are complex and rely on computational and data-intensive models. Outputs of these analytical tools are presented to practitioners (i.e., policy analysts and political decision-makers) on maps or in graphical user interfaces. In practice, this output is only used in limited measure because practitioners often have different information requirements or do not trust the direct outcome. Nonetheless, literature indicates that a closer collaboration between domain experts and practitioners can ensure that the information requirements of practitioners are better aligned with the opportunities and limitations of analytical tools. The objective of our work is to present a step forward in the effort to make analytical tools in flood management accessible for practitioners to support this collaboration between domain experts and practitioners. Our system allows the user to interactively control the simulation process (addition of water sources or influence of rainfall), while a realistic visualization allows the user to mentally map the results onto the real world. We have developed several novel algorithms to present and interact with flood data. We explain the technologies, discuss their necessity alongside test cases, and introduce a user study to analyze the reactions of practitioners to our system. We conclude that, despite the complexity of flood simulation models and the size of the involved data sets, our system is accessible for practitioners of flood management so that they can carry out flood simulations together with domain experts in interactive work sessions. Therefore, this work has the potential to significantly change the decision-making process and may become an important asset in choosing sustainable flood mitigations and adaptation strategies.


Limited cholesterol depletion causes aggregation of plasma membrane lipid rafts inducing T cell activation.
Acute cholesterol depletion is generally associated with decreased or abolished T cell signalling but it can also cause T cell activation. This anomaly has been addressed in Jurkat T cells using progressive cholesterol depletion with methyl-beta-cyclodextrin (MBCD). At depletion levels higher than 50% there is substantial cell death, which explains reports of signalling inhibition. At 10-20% depletion levels, tyrosine phosphorylation is increased, ERK is activated and there is a small increase in cytoplasmic Ca(2+). Peripheral actin polymerisation is also triggered by limited cholesterol depletion. Strikingly, the lipid raft marker GM1 aggregates upon cholesterol depletion and these aggregated domains concentrate the signalling proteins Lck and LAT, whereas the opposite is true for the non lipid raft marker the transferrin receptor. Using PP2, an inhibitor of Src family kinase activation, it is demonstrated that the lipid raft aggregation occurs independently of and thus upstream of the signalling response. Upon cholesterol depletion there is an increase in overall plasma membrane order, indicative of more ordered domains forming at the expense of disordered domains. That cholesterol depletion and not unspecific effects of MBCD was behind the reported results was confirmed by performing all experiments with MBCD-cholesterol, when no net cholesterol extraction took place. We conclude that non-lethal cholesterol depletion causes the aggregation of lipid rafts which then induces T cell signalling.


Adherence to endocrine therapy in breast cancer adjuvant and prevention settings.
Adherence to oral endocrine therapy in adjuvant breast cancer settings is a substantial clinical problem. To provide current perspective on adherence to oral endocrine therapies, a comprehensive literature review was conducted. In adjuvant trials, endocrine therapy adherence is relatively high with greater adherence for aromatase inhibitors compared with tamoxifen. In contrast, adherence to adjuvant therapy in clinical practice is relatively poor, with only about 50% of women successfully completing 5-year therapy. Importantly, good adherence (>80% use) has been associated with lower recurrence risk. Endocrine therapy adherence in primary breast cancer prevention trials parallels that seen in adjuvant trials. Factors associated with nonadherence include low recurrence risk perception, side effects, age extremes, medication cost, suboptimal patient-physician communication, and lack of social support. Few prospective studies have evaluated interventions designed to improve adherence. Interventions currently proposed reflect inferences from clinical trial procedures in which clinical contacts are commonly greater than in usual practice settings. In conclusion, for optimal breast cancer outcome, adherence to endocrine therapy must improve. Although general recommendations likely to improve adherence can be made based on clinical trial results and preliminary prospective trial findings, research specifically targeting this issue is needed to establish effective intervention strategies.


Atropisomerism in a thermally switchable, cyclometallated iridium complex.
Two stable diastereomeric atropisomers of a cyclometallated iridium complex containing a pyrene functionalized pyridine imine ligand have been isolated. These are the first fully characterized examples of metal containing atropisomers in which the rotational axis is not between two chelating atoms. The atropisomers can be converted thermally via a rocking motion of the pyrene moiety.


Plant-herbivore interactions in a North American mixed-grass prairie : III. Soil nematode populations and root biomass on Cynomys ludovicianus colonies and adjacent uncolonized areas.
Seasonal dynamics of soil nematodes and root biomass were examined from under western wheatgrass (Agropyron smithii) and little bluestem (Andropogon scoparius) from a heavily grazed prairie dog (Cynomys ludovicianus) colony occupied for 5 to 10 years and an adjacent lightly grazed, uncolonized area in Wind Cave National Park, South Dakota, USA. Nematodes were differentiated into classes of plant-parasitic Tylenchida and Dorylaimida and nonparasitic Dorylamida and Rhabditida. Root-feeding nematodes were generally more numerous from A. smithii than from A. scoparius, while nonparasitic populations were not different in soil from beneath the two plant species. Rhabditida, parasitic Dorylaimida and Tylenchida (from A. scoparius only) were more numerous on the prairie dog colony than from the uncolonized site, but nonparasitic Dorylaimida populations did not differ between the two areas. Mean total (live plus dead) root biomass beneath A. scoparius and A. smithii on the prairie dog colony averaged 71% and 81%, respectively, of values from the uncolonized area. Estimated consumption by root-feeding nematodes averaged 12.6% and 5.8% of annual net root production in the upper 10 cm from the prairie dog colony and uncolonized site, respectively. We conclude that, because of microhabitat modification or reductions in plant resistance to nematodes, heavy grazing by aboveground herbivores apparently facilitates grazing by belowground herbivores. Because heavily grazed plants have less roots than lightly grazed or ungrazed plants, the impact of root-feeding nematodes on primary producers is likely to be greatest in heavily grazed grasslands.


Direct metabolite detection with an n-type accumulation mode organic electrochemical transistor.
The inherent specificity and electrochemical reversibility of enzymes poise them as the biorecognition element of choice for a wide range of metabolites. To use enzymes efficiently in biosensors, the redox centers of the protein should have good electrical communication with the transducing electrode, which requires either the use of mediators or tedious biofunctionalization approaches. We report an all-polymer micrometer-scale transistor platform for the detection of lactate, a significant metabolite in cellular metabolic pathways associated with critical health care conditions. The device embodies a new concept in metabolite sensing where we take advantage of the ion-to-electron transducing qualities of an electron-transporting (n-type) organic semiconductor and the inherent amplification properties of an ion-to-electron converting device, the organic electrochemical transistor. The n-type polymer incorporates hydrophilic side chains to enhance ion transport/injection, as well as to facilitate enzyme conjugation. The material is capable of accepting electrons of the enzymatic reaction and acts as a series of redox centers capable of switching between the neutral and reduced state. The result is a fast, selective, and sensitive metabolite sensor. The advantage of this device compared to traditional amperometric sensors is the amplification of the input signal endowed by the electrochemical transistor circuit and the design simplicity obviating the need for a reference electrode. The combination of redox enzymes and electron-transporting polymers will open up an avenue not only for the field of biosensors but also for the development of enzyme-based electrocatalytic energy generation/storage devices.


The effect of scanning electrochemical potential on the short-term impedance of commercially pure titanium in simulated biological conditions.
The electrochemical history (voltage-time variations) of titanium oxide-solution interfaces can vary widely in vivo, particularly where oxide abrasion is present, and it is important to assess the effects of voltage on the impedance behavior of the interface. Potential step impedance analysis (PSIA) utilizes a time and frequency domain methodology to assess the electrochemical impedance of electrified interfaces over a range of voltages. The PSIA method was used to study the combined effects of scanning electrical potential and the presence of solution-born organic species (protein, amino acids, etc.) on the electrochemical properties of cpTi. The specific solutions used in these scanning PSIA experiments were phosphate buffered saline and cell culture medium supplemented with 10% fetal bovine serum. The results show that electrochemical impedance properties of cpTi are voltage-time history dependent and strongly influenced by electrical potential within the -1000 mV to +1000 mV range studied. Moreover, the presence of biologically relevant molecules in the electrolyte solution alters the impedance properties only at cathodic potentials. Specifically, at cathodic potentials, these organic species have been shown to suppress the cathodic current density, shift the zero current potential in the cathodic direction, and increase the interfacial capacitance, polarization resistance, and the distribution of surface relaxation times. At anodic potentials, the presence of the organic species does not alter any of the electrochemical properties examined. Overall, these results show the importance of understanding of the variation in electrochemical potentials achievable in vivo and the effects voltage history has on interfacial electrochemical behavior.


Growth differentiation factor-15 (GDF-15) levels are associated with cardiac and renal injury in patients undergoing coronary artery bypass grafting with cardiopulmonary bypass.
Growth differentiation factor-15 (GDF-15) has been identified as a strong marker of cardiovascular disease; however, no data are available concerning the role of GDF-15 in the occurrence of organ dysfunction during coronary artery bypass grafting (CABG) associated with cardiopulmonary bypass (CPB). Five arterial blood samples were taken sequentially in 34 patients from anesthesia induction (IND) until 24 h after arrival at the intensive care unit (ICU). Plasma levels of GDF-15, follistatin-like 1 (FLST1), myeloperoxidases (MPO), hydroperoxides and plasma antioxidant status (PAS) were measured at each time-point. Markers of cardiac (cardiac-troponin I, cTnI) and renal dysfunction (neutrophil gelatinase-associated lipocalin, NGAL) and other classical biological factors and clinical data were measured. Plasma GDF-15 levels increased gradually during and after surgery, reaching nearly three times the IND levels in the ICU (3,075±284 ng/L vs. 1,061±90 ng/L, p<0.001). Plasma MPO levels increased dramatically during surgery, attaining their highest level after unclamping (UNCLAMP) (49±11 ng/mL vs. 1,679±153 ng/mL, p<0.001) while PAS significantly decreased between IND and UNCLAMP (p<0.05), confirming the high oxidative status induced by this surgical procedure. ICU levels of GDF-15 correlated positively with cTnI and NGAL (p = 0.006 and p = 0.036, respectively), and also with hemoglobin and estimated glomerular filtration rate (eGFR). Among all the post-operative biomarkers available, only eGFR, NGAL and GDF-15 measured at ICU arrival were significantly associated with the onset of acute kidney injury (AKI). Patients with a EuroSCORE >3 were shown to have higher GDF-15 levels. During cardiac surgery associated with CPB, GDF-15 levels increased substantially and were associated with markers of cardiac injury and renal dysfunction.


Influenza virus-specific cytotoxic T lymphocytes recognize HLA-molecules. Blocking by monoclonal anti-HLA antibodies.
The effect of monoclonal anti-HLA antibodies on lysis of influenza virus-infected target cells by sensitized cytotoxic T lymphocytes was measured. Lysis was blocked, provided the antibody was present in a concentration sufficient to saturate the HLA determinants on the target cells. Antibodies to monomorphic HLA determinants and to beta 2-microglobulin inhibited. Antibody to HLA A2 and B17 blocked lysis of target cells that shared these antigens with the effector cell. It was concluded that the restriction elements for influenza virus-specific cytotoxic T cells are the HLA molecules themselves.


Saturating Splines and Feature Selection.
We extend the adaptive regression spline model by incorporating saturation, the natural requirement that a function extend as a constant outside a certain range. We fit saturating splines to data via a convex optimization problem over a space of measures, which we solve using an efficient algorithm based on the conditional gradient method. Unlike many existing approaches, our algorithm solves the original infinite-dimensional (for splines of degree at least two) optimization problem without pre-specified knot locations. We then adapt our algorithm to fit generalized additive models with saturating splines as coordinate functions and show that the saturation requirement allows our model to simultaneously perform feature selection and nonlinear function fitting. Finally, we briefly sketch how the method can be extended to higher order splines and to different requirements on the extension outside the data range.


An analysis of features of respiratory therapy departments that are avid for change.
Models of organizational change-readiness have been developed, but little attention has been given to features of change-avid health-care institutions, and, to our knowledge, no attention has been given to features of change-avid respiratory therapy (RT) departments. We conducted an exploratory study to compare RT departments we deemed change-avid or non-change-avid, to identify differentiating characteristics. Our assessments regarding change-readiness and avidity were based on structured, in-person interviews of the technical directors and/or medical directors of 8 RT departments. Based on a priori criteria, 4 of the 8 RT departments were deemed change-avid, based on the presence of > or = 2 of the following 3 criteria: (1) uses a management information system, (2) uses a comprehensive RT protocol program, (3) uses noninvasive ventilation in > 20% of patients with exacerbation of chronic obstructive pulmonary disease. Our ratings of the departments were based on 2 scales: one from Integrated Organizational Development Inc, and the 8-stage change model of Kotter. The ratings of the 4 change-avid departments differed significantly from those of the 4 non-change-avid departments, on both the Integrated Organizational Development Inc scale and the Kotter scale. We identified 11 highly desired features of a change-avid RT department: a close working relationship between the medical director and the RT staff; a strong and supportive hospital "champion" for change; using data to define problems and measure the effectiveness of solutions; using redundant types of communication; recognizing resistance and minimizing obstacles to change; being willing to tackle tough issues; maintaining a culture of ongoing education; consistently rewarding change-avid behavior; fostering ownership for change and involving stakeholders; attending to RT leadership succession planning; and having and communicating a vision for the department. In this first exploratory study we found that change-avid RT departments can be differentiated from non-change-avid RT departments with available assessment tools. Highly desired features of a change-avid RT department were identified but require further study, as does the relationship between change-avidity and clinical outcomes.


Intraocular tissue migration of silicone oil after silicone oil tamponade: a histopathological study of enucleated silicone oil-filled eyes.
Retrospective clinical and histopathological review of eight silicone oil-filled enucleated eyeballs using light microscopy was carried out in our department of ocular pathology during a period of six years. In all cases, silicone oil vacuoles, both free and incorporated within macrophages were seen in all the retinal layers. Silicone oil vacuoles were seen in the optic nerve, choroid, retinal pigment epithelium, corneal stroma, iris and ciliary body stroma, preretinal and subretinal membranes and retro-corneal membranes. Silicone oil migration could be seen in intraocular tissues as early as two months post surgery. There was no definite histopathological correlation between duration of tamponade and distribution of silicone oil vacuoles. Silicone oil vacuoles were seen in the optic nerve in eyes with neovascular glaucoma. Chronic inflammatory reaction was observed in the retinal tissue in the vicinity of silicone oil vacuoles.


A single cell transcriptome atlas of the developing zebrafish hindbrain.
Segmentation of the vertebrate hindbrain leads to the formation of rhombomeres, each with a distinct anteroposterior identity. Specialised boundary cells form at segment borders that act as a source or regulator of neuronal differentiation. In zebrafish, there is spatial patterning of neurogenesis in which non-neurogenic zones form at boundaries and segment centres, in part mediated by Fgf20 signalling. To further understand the control of neurogenesis, we have carried out single cell RNA sequencing of the zebrafish hindbrain at three different stages of patterning. Analyses of the data reveal known and novel markers of distinct hindbrain segments, of cell types along the dorsoventral axis, and of the transition of progenitors to neuronal differentiation. We find major shifts in the transcriptome of progenitors and of differentiating cells between the different stages analysed. Supervised clustering with markers of boundary cells and segment centres, together with RNA-seq analysis of Fgf-regulated genes, has revealed new candidate regulators of cell differentiation in the hindbrain. These data provide a valuable resource for functional investigations of the patterning of neurogenesis and the transition of progenitors to neuronal differentiation.


Enterococcus faecalis Infection and Reactive Oxygen Species Down-Regulates the miR-17-92 Cluster in Gastric Adenocarcinoma Cell Culture.
Chronic inflammation due to bacterial overgrowth of the stomach predisposes to the development of gastric cancer and is also associated with high levels of reactive oxygen species (ROS). In recent years increasing attention has been drawn to microRNAs (miRNAs) due to their role in the pathogenesis of many human diseases including gastric cancer. Here we studied the impact of infection by the gram-positive bacteria Enterococcus faecalis (E. faecalis) on global miRNA expression as well as the effect of ROS on selected miRNAs. Human gastric adenocarcinoma cell line MKN74 was infected with living E. faecalis for 24 h or for 5 days or with E. faecalis lysate for 5 days. The miRNA expression was examined by microarray analysis using Affymetrix GeneChip miRNA Arrays. To test the effect of ROS, MKN74 cells were treated with 100 mM tert-Butyl hydroperoxide (TBHP). Following 5 days of E. faecalis infection we found 91 differentially expressed miRNAs in response to living bacteria and 2 miRNAs responded to E. faecalis lysate. We verified the down-regulation of the miR-17-92 and miR-106-363 clusters and of other miRNAs involved in the oxidative stress-response by qRT-PCR. We conclude that only infection by living E. faecalis bacteria caused a significant global response in miRNA expression in the MKN74 cell culture. E. faecalis infection as well as ROS stimulation down-regulated the expression of the miR-17-92 cluster. We believe that these changes could reflect a general response of gastric epithelial cells to bacterial infections.


Ciliary neurotrophic factor stimulates muscle glucose uptake by a PI3-kinase-dependent pathway that is impaired with obesity.
Ciliary neurotrophic factor (CNTF) reverses muscle insulin resistance by increasing fatty acid oxidation through gp130-LIF receptor signaling to the AMP-activated protein kinase (AMPK). CNTF also increases Akt signaling in neurons and adipocytes. Because both Akt and AMPK regulate glucose uptake, we investigated muscle glucose uptake in response to CNTF signaling in lean and obese mice. Mice were injected intraperitoneally with saline or CNTF, and blood glucose was monitored. The effects of CNTF on skeletal muscle glucose uptake and AMPK/Akt signaling were investigated in incubated soleus and extensor digitorum longus (EDL) muscles from muscle-specific AMPKalpha2 kinase-dead, gp130(DeltaSTAT), and lean and obese ob/ob and high-fat-fed mice. The effect of C2-ceramide on glucose uptake and gp130 signaling was also examined. CNTF reduced blood glucose and increased glucose uptake in isolated muscles in a time- and dose-dependent manner with maximal effects after 30 min with 100 ng/ml. CNTF increased Akt-S473 phosphorylation in soleus and EDL; however, AMPK-T172 phosphorylation was only increased in soleus. Incubation of muscles from AMPK kinase dead (KD) and wild-type littermates with the PI3-kinase inhibitor LY-294002 demonstrated that PI3-kinase, but not AMPK, was essential for CNTF-stimulated glucose uptake. CNTF-stimulated glucose uptake and Akt phosphorylation were substantially reduced in obesity (high-fat diet and ob/ob) despite normal induction of gp130/AMPK signaling--effects also observed when treating myotubes with C2-ceramide. CNTF acutely increases muscle glucose uptake by a mechanism involving the PI3-kinase/Akt pathway that does not require AMPK. CNTF-stimulated glucose uptake is impaired in obesity-induced insulin resistance and by ceramide.


Quantitative analysis of immunological reactions on silicon surfaces by multiple-angle Brewster angle reflectometry.
An optical biosensing instrument has been developed for the quantitative analysis of immunological reactions on biochemically sensitized surfaces. It is based on the measurement of reflectance changes of polarized laser light incident on high refractive index substrates at angles close to the pseudo-Brewster angle. Multiple-angle Brewster angle reflectometry (MABAR) has been used to investigate the binding of anti-human serum albumin (a-HSA) to human serum albumin (HSA) coated silicon surfaces. The concentration dependence and reaction kinetics of antibody-antigen complex formation have been studied using red and green He-Ne laser light. A significant increase in sensitivity has been observed with green light.


Dynamic optical arbitrary waveform generation with amplitude controlled by interference of two FBG arrays.
In this paper, a novel structure of dynamic optical arbitrary waveform generation (O-AWG) with amplitude controlled by interference of two fiber Bragg grating (FBG) arrays is proposed. The FBG array consists of several FBGs and fiber stretchers (FSs). The amplitude is controlled by FSs through interference of two FBG arrays. The phase is controlled by FSs simultaneously. As a result, optical pulse trains with various waveforms as well as pulse trains with nonuniform pulse intensity, pulse spacing and pulse width in each period are obtained via FSs adjustment to change the phase shift of signal in each array.


The major phosphorylation site of the NADPH oxidase component p67phox is Thr233.
Phosphorylation of p67phox was shown to increase two- to three-fold upon stimulation by PMA, N-formylmethionyl-leucylphenylalanine or serum-opsonized zymosan. Phosphopeptide mapping showed one major tryptic peptide for p67phox immunoprecipitated from resting or stimulated cells. In vitro phosphorylation of p67phox by isolated cytosol or mitogen-activated protein kinase also generated the same phosphopeptide. Results of cyanogen bromide digestion and HPLC-MS suggested that Thr233 was the phosphorylated residue. Mutagenesis of Thr233 to alanine resulted in loss of phosphorylation in vitro. In the present work, Thr233 has been identified as the major phosphorylation site of p67phox, which is situated in a proline-rich domain.


Social determinants of ever initiating smoking differ from those of quitting: a cross-sectional study in Estonia.
To study the association of socioeconomic and demographic indicators with ever initiating regular smoking and quitting smoking among ever regular smokers in Estonia in order to identify target groups for equity-oriented tobacco control policies. Data for 4277 individuals in the 25-64 age group come from three cross-sectional studies conducted in 2000, 2002 and 2004. Age-standardized prevalence rates and odds ratios with 95% confidence intervals were calculated. High rates of ever initiation were observed for lower educated men and women after controlling for other socioeconomic indicators. This association was not observed for women above age 50. Independent, although weaker associations were found among men who were unemployed or with a low occupational status. Low cessation rates were observed among men who were unemployed, who had a lower occupational position or who had a low income. These associations remained after controlling for other socioeconomic variables. The effect of income became stronger in the older age groups among men. Rates of ever initiation and cessation also varied strongly in relationship to some demographic variables. The highest initiation rates were found among divorced women and among women living in the capital city. The lowest cessation rates were found among divorced women, and among Russian men. While educational level was the strongest predictor of ever initiating regular smoking, smoking cessation was related more directly to aspects of social disadvantage originating in adult life. To be effective, tobacco control interventions should not only target lower educated, but also those in material disadvantage.


The effect of raloxifene on risk of breast cancer in postmenopausal women: results from the MORE randomized trial. Multiple Outcomes of Raloxifene Evaluation.
Raloxifene hydrochloride is a selective estrogen receptor modulator that has antiestrogenic effects on breast and endometrial tissue and estrogenic effects on bone, lipid metabolism, and blood clotting. To determine whether women taking raloxifene have a lower risk of invasive breast cancer. The Multiple Outcomes of Raloxifene Evaluation (MORE), a multicenter, randomized, double-blind trial, in which women taking raloxifene or placebo were followed up for a median of 40 months (SD, 3 years), from 1994 through 1998, at 180 clinical centers composed of community settings and medical practices in 25 countries, mainly in the United States and Europe. A total of 7705 postmenopausal women, younger than 81 (mean age, 66.5) years, with osteoporosis, defined by the presence of vertebral fractures or a femoral neck or spine T-score of at least 2.5 SDs below the mean for young healthy women. Almost all participants (96%) were white. Women who had a history of breast cancer or who were taking estrogen were excluded. Raloxifene, 60 mg, 2 tablets daily; or raloxifene, 60 mg, 1 tablet daily and 1 placebo tablet; or 2 placebo tablets. New cases of breast cancer, confirmed by histopathology. Transvaginal ultrasonography was used to assess the endometrial effects of raloxifene in 1781 women. Deep vein thrombosis or pulmonary embolism were determined by chart review. Thirteen cases of breast cancer were confirmed among the 5129 women assigned to raloxifene vs 27 among the 2576 women assigned to placebo (relative risk [RR], 0.24; 95% confidence interval [CI], 0.13-0.44; P<.001). To prevent 1 case of breast cancer, 126 women would need to be treated. Raloxifene decreased the risk of estrogen receptor-positive breast cancer by 90% (RR, 0.10; 95% CI, 0.04-0.24), but not estrogen receptor-negative invasive breast cancer (RR, 0.88; 95% CI, 0.26-3.0). Raloxifene increased the risk of venous thromboembolic disease (RR, 3.1; 95% CI, 1.5-6.2), but did not increase the risk of endometrial cancer (RR, 0.8; 95% CI, 0.2-2.7). Among postmenopausal women with osteoporosis, the risk of invasive breast cancer was decreased by 76% during 3 years of treatment with raloxifene.


Reconstruction of the genome origins and evolution of the hybrid lager yeast Saccharomyces pastorianus.
Inter-specific hybridization leading to abrupt speciation is a well-known, common mechanism in angiosperm evolution; only recently, however, have similar hybridization and speciation mechanisms been documented to occur frequently among the closely related group of sensu stricto Saccharomyces yeasts. The economically important lager beer yeast Saccharomyces pastorianus is such a hybrid, formed by the union of Saccharomyces cerevisiae and Saccharomyces bayanus-related yeasts; efforts to understand its complex genome, searching for both biological and brewing-related insights, have been underway since its hybrid nature was first discovered. It had been generally thought that a single hybridization event resulted in a unique S. pastorianus species, but it has been recently postulated that there have been two or more hybridization events. Here, we show that there may have been two independent origins of S. pastorianus strains, and that each independent group--defined by characteristic genome rearrangements, copy number variations, ploidy differences, and DNA sequence polymorphisms--is correlated with specific breweries and/or geographic locations. Finally, by reconstructing common ancestral genomes via array-CGH data analysis and by comparing representative DNA sequences of the S. pastorianus strains with those of many different S. cerevisiae isolates, we have determined that the most likely S. cerevisiae ancestral parent for each of the independent S. pastorianus groups was an ale yeast, with different, but closely related ale strains contributing to each group's parentage.


Mating system variation and morph fluctuations in a polymorphic lizard.
In polymorphic male painted dragon lizards (Ctenophorus pictus), red males win staged contests for females over yellow males, and yellow males have greater success in staged sperm competition trials than red males. This predicts different reproductive strategies in the wild with red males being more coercive or better mate guarders than yellow males. Yellow males would be expected to sire more offspring per copulation and have a greater proportion of offspring from clutches with mixed paternity. However, here we show using microsatellites that the frequency of mixed paternity in the wild is low (< 20% on average across years), that all morphs on average have the same number of offspring sired per year, and that mating system variation (polyandry vs. monandry) is strongly correlated with perch density on male territories. Furthermore, a logistic regression on male successful vs. unsuccessful mate acquisition showed that red males were under negative selection when they dominated the population, which suggests ongoing frequency dependent selection on male colouration.


Knee Osteoarthritis after Arthroscopic Partial Meniscectomy: Prevalence and Progression of Radiographic Changes after 5 to 12 Years Compared with Contralateral Knee.
The purpose of this study was to study the clinical and radiographic changes in the knee after arthroscopic partial meniscectomy (APM) at a long-term follow-up compared with the contralateral knee. We assessed 57 patients (38 males and 19 females) with pre- and postoperative weight-bearing radiography with a follow-up ranging from 5.1 to 12.1 years (mean: 8.1) to analyze prevalence and progression of knee osteoarthritis (OA) after APM. We stratified patients according to body mass index (BMI), type of lesion (degenerative vs. traumatic), and side of meniscectomy (medial, lateral, and medial plus lateral). Patients were evaluated both clinically with Knee Osteoarthritis Outcome Score (KOOS) and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score and radiographically with the Kellgren and Lawrence (K/L) score. Radiographic OA was defined as K/L grade 2 or worse. The prevalence of knee OA was 62.69% in the tibiofemoral compartment. The progression of knee OA was statistically significant, ranging from 17.2% preoperatively to 65.95% postoperatively (p = 0.001) in the medial compartment and from 17.64% preoperatively to 58.82% postoperatively (p = 0.0324) in the lateral compartment. The progression of knee OA in the patellofemoral compartment ranged from 5.26 to 42.10% (p = 0.001). The OA progression regarding BMI was higher into the obese group than the normal-weight group and greater in the degenerative group than the traumatic one. The mean KOOS was 72.01 and the mean WOMAC was 73.84. The Spearman's test showed a statistical significance between clinical and radiographic results. Patients in the obese, overweight, and degenerative tear group had a greater predisposition to OA in the tibiofemoral and patellofemoral compartments after meniscectomy. The level of evidence is III, retrospective study.


Paradigm Shift for Radical S-Adenosyl-l-methionine Reactions: The Organometallic Intermediate Ω Is Central to Catalysis.
Radical S-adenosyl-l-methionine (SAM) enzymes comprise a vast superfamily catalyzing diverse reactions essential to all life through homolytic SAM cleavage to liberate the highly reactive 5'-deoxyadenosyl radical (5'-dAdo·). Our recent observation of a catalytically competent organometallic intermediate Ω that forms during reaction of the radical SAM (RS) enzyme pyruvate formate-lyase activating-enzyme (PFL-AE) was therefore quite surprising, and led to the question of its broad relevance in the superfamily. We now show that Ω in PFL-AE forms as an intermediate under a variety of mixing order conditions, suggesting it is central to catalysis in this enzyme. We further demonstrate that Ω forms in a suite of RS enzymes chosen to span the totality of superfamily reaction types, implicating Ω as essential in catalysis across the RS superfamily. Finally, EPR and electron nuclear double resonance spectroscopy establish that Ω involves an Fe-C5' bond between 5'-dAdo· and the [4Fe-4S] cluster. An analogous organometallic bond is found in the well-known adenosylcobalamin (coenzyme B12) cofactor used to initiate radical reactions via a 5'-dAdo· intermediate. Liberation of a reactive 5'-dAdo· intermediate via homolytic metal-carbon bond cleavage thus appears to be similar for Ω and coenzyme B12. However, coenzyme B12 is involved in enzymes catalyzing only a small number (∼12) of distinct reactions, whereas the RS superfamily has more than 100 000 distinct sequences and over 80 reaction types characterized to date. The appearance of Ω across the RS superfamily therefore dramatically enlarges the sphere of bio-organometallic chemistry in Nature.


The effect of balanced protein energy supplementation in undernourished pregnant women and child physical growth in low- and middle-income countries: a systematic review and meta-analysis.
The beneficial effect of balanced protein energy supplementation during pregnancy on subsequent child growth is unclear and may depend upon the mother entering pregnancy adequately nourished or undernourished. Systematic reviews to-date have included studies from high-, middle- and low-income countries. However, the effect of balanced protein energy supplementation should not be generalised. This review assesses the effect of balanced protein energy supplementation in undernourished pregnant women from low- and middle-income countries on child growth. A systematic review of articles published in English (1970-2015) was conducted via MEDLINE, Scopus, the Cochrane Register and hand searching. Only peer-reviewed experimental studies analysing the effects of balanced protein energy supplementation in undernourished pregnant women from low- and middle-income countries with measures of physical growth as the primary outcome were included. Two reviewers independently assessed full-text articles against inclusion criteria. Validity of eligible studies was ascertained using the Quality Assessment Tool for Quantitative Studies (EPHPP QAT). In total, seven studies met the inclusion criteria. All studies reported on birthweight, five on birth length, three on birth head circumference, and one on longer-term growth. Standardised mean differences were calculated using a random-effects meta-analysis. Balanced protein energy supplementation significantly improved birthweight (seven randomised controlled trials, n = 2367; d = 0.20, 95% confidence interval, 0.03-0.38, P = 0.02). No significant benefit was observed on birth length or birth head circumference. Impact of intervention could not be determined for longer-term physical growth due to limited evidence. Additional research is required in low- and middle-income countries to identify impacts on longer-term infant growth.


Molecular cloning of the cDNA for the catalytic subunit of plant DNA polymerase alpha and its cell-cycle dependent expression.
DNA polymerase alpha has been studied in considerable detail in yeast and animals. Genetic and biochemical analyses reveal that this enzyme is composed of a heterotetramer and is necessary for replicon initiation and primer synthesis in lagging strand synthesis. In spite of the fact that modes of DNA replication in plants seem to be similar to those in other eukaryotes, very little is known about the biochemical components that participate in DNA replication of plants, including DNA polymerases. Using a 561-base pair DNA fragment, obtained by polymerase chain reaction amplification from a rice cDNA library as a probe, we isolated and sequenced a cDNA homologous to the cDNA for the catalytic subunit of rice DNA polymerase alpha. The encoded polypeptide has extensive homology with the catalytic subunit of DNA polymerase alpha from several species. Furthermore, when the cDNA was expressed in eukaryotic transcription/translation systems, the protein products showed DNA polymerase activity which was inhibited by a monoclonal antibody specific for DNA polymerase alpha. Using RNA gel blot analysis, we found that the levels of mRNA of the catalytic subunit of this enzyme is regulated during the cell-cycle in plant cells. This is the first report which describes the cDNA cloning of plant DNA polymerase. We conclude that the principal features of the DNA polymerase alpha catalytic subunit are conserved in plants.


Observations, Meteorites, and Models: A Preflight Assessment of the Composition and Formation of (16) Psyche.
Some years ago, the consensus was that asteroid (16) Psyche was almost entirely metal. New data on density, radar properties, and spectral signatures indicate that the asteroid is something perhaps even more enigmatic: a mixed metal and silicate world. Here we combine observations of Psyche with data from meteorites and models for planetesimal formation to produce the best current hypotheses for Psyche's properties and provenance. Psyche's bulk density appears to be between 3,400 and 4,100 kg m-3. Psyche is thus predicted to have between ~30 and ~60 vol% metal, with the remainder likely low-iron silicate rock and not more than ~20% porosity. Though their density is similar, mesosiderites are an unlikely analog to bulk Psyche because mesosiderites have far more iron-rich silicates than Psyche appears to have. CB chondrites match both Psyche's density and spectral properties, as can some pallasites, although typical pallasitic olivine contains too much iron to be consistent with the reflectance spectra. Final answers, as well as resolution of contradictions in the data set of Psyche physical properties, for example, the thermal inertia measurements, may not be resolved until the NASA Psyche mission arrives in orbit at the asteroid. Despite the range of compositions and formation processes for Psyche allowed by the current data, the science payload of the Psyche mission (magnetometers, multispectral imagers, neutron spectrometer, and a gamma-ray spectrometer) will produce data sets that distinguish among the models.


4-hydroxynonenal protein adducts: Key mediator in Rett syndrome oxinflammation.
In the last 15 years a strong correlation between oxidative stress (OxS) and Rett syndrome (RTT), a rare neurodevelopmental disorder known to be caused in 95% of the cases, by a mutation in the methyl-CpG-binding protein 2 (MECP2) gene, has been well documented. Here, we revised, summarized and discussed the current knowledge on the role of lipid peroxidation byproducts, with special emphasis on 4-hydroxynonenal (4HNE), in RTT pathophysiology. The posttranslational modifications of proteins via 4HNE, known as 4HNE protein adducts (4NHE-PAs), causing detrimental effects on protein functions, appear to contribute to the clinical severity of the syndrome, since their levels increase significantly during the subsequent 4 clinical stages, reaching the maximum degree at stage 4, represented by a late motor deterioration. In addition, 4HNE-PA are only partially removed due to the compromised functionality of the proteasome activity, contributing therefore to the cellular damage in RTT. All this will lead to a characteristic subclinical inflammation, defined "OxInflammation", derived by a positive feedback loop between OxS byproducts and inflammatory mediators that in a long run further aggravates the clinical features of RTT patients. Therefore, in a pathology completely orphan of any therapy, aiming 4HNE as a therapeutic target could represent a coadjuvant treatment with some beneficial impact in these patients..


New data on the Late Cretaceous lizard Dicothodon bajaensis (Squamata, Borioteiioidea) from Baja California, Mexico reveals an unusual tooth replacement pattern in squamates.
Borioteiioids comprise an extinct family of squamates that inhabited the Northern Hemisphere during the Cretaceous and were characterized by varying patterns of tooth replacement and dental morphology. Understanding the evolution of these tooth replacement patterns has, however, been largely hampered by an extremely fragmentary fossil record. Here we present new information on Dicothodon bajaensisfrom the Campanian of Baja California (Mexico), so far known only from isolated teeth and jaw fragments. Among abundant new materials there are ten maxillae and five dentaries belonging to distinct ontogenetic stages. Whereas juveniles display active tooth replacement, older specimens show no evidence of replacement. Dicothodon bajaensis is therefore inferred to have had arrested tooth replacement later in ontogeny. This provides the first evidence of cessation of tooth replacement during late ontogeny in lizards (living or extinct). This replacement type is also an evolutionary intermediate between the typical lizard replacement pattern, observed in some borioteiioids (e.g., Bicuspidon) and the complete absence of tooth replacement since early ontogeny as observed in other borioteiioids (e.g., Polyglyphanodon).


Preoperative cross-sectional mapping for deep inferior epigastric and profunda artery perforator flaps.
Perforator flap-based breast reconstruction in a post mastectomy patient requires dissection of the artery-vein bundle (perforators) responsible for perfusion of the subcutaneous fat and skin of the flap. Traditionally, these reconstructions were performed with the transverse rectus abdominis myocutaneous (TRAM) flap, but autologous breast reconstruction using muscle sparing free flaps has become steadily more popular in recent years. Preoperative imaging to locate and evaluate candidate perforators has become an essential step before patients undergo the microsurgical procedure. Preoperative mapping assists with operative planning, reduces operating times, and brings anatomical variations to their attention. Pre-operative imaging also assists in choosing the appropriate donor site for harvesting flaps. Computed tomography angiography (CTA) and magnetic resonance angiography (MRA) have been widely used for this type of preoperative imaging. Both MRA and CTA have their inherent advantages and disadvantages, and the preferred modality for this purpose varies by institution based on factors such as scanner availability, radiologist and surgeon experience, and comfort in interpreting the images. Concerns over excessive exposure to ionizing radiation and poor iodinated contrast agent enhancement of the intramuscular perforator course has made MRA the first-choice imaging modality in many centers. The purpose of the article is to review technique and protocols for the pre-operative CTA/MRA in patients who are being considered for a deep inferior epigastric artery perforator (DIEP) or profunda artery perforator (PAP) flap and to familiarize the reader with the normal and variant anatomic features of the deep inferior epigastric and PAP vessels along with the anatomic and surgical considerations used in the selection of perforator flap donor site for breast reconstruction post mastectomy.


Timely Diagnosis and Successful Treatment of Intravascular Large B-Cell Lymphoma in an Elderly Patient with Poor Performance Status.
BACKGROUND Intravascular large B-cell lymphoma (IVLBCL) is a rare type of extranodal large B-cell lymphoma characterized by involvement of lymphoma cells in the lumina of small blood vessels in various organs. Although many studies have claimed that timely diagnosis and early initiation of chemotherapy are important, the literature on the successful treatment of IVLBCL in elderly patients over the age of 80 years is scarce. CASE REPORT An 82-year-old man presented with abnormal elevation of lactate dehydrogenase at 1605 IU/L and altered mental status, which manifested as forgetfulness, abnormal behavior, and worsening performance status for 2 days. There was no evidence of lymphadenopathy or skin lesions, but a computed tomography scan of the chest showed bilateral diffuse ground-glass opacities. With a primary consideration of IVLBCL, random skin biopsy and transbronchial lung biopsy were performed. Immediately after the pathologic findings on hematoxylin-eosin staining alone revealed abnormal large cells in the small vessels, chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) at half the usual dose was started; later on, immunostaining revealed CD20 expression in the abnormal lymphoid cells. Immediately after CHOP administration, his mental and physical symptoms rapidly resolved. After 8 cycles of dose-reduced CHOP with rituximab, he remained free from disease progression 2 years after the diagnosis. CONCLUSIONS We presented a case of successful early chemotherapy for IVLBCL in an elderly patient with poor performance status. Early chemotherapy with CHOP, even before obtaining a definitive diagnosis based on immunostaining, may contribute to good outcomes.


Population pharmacokinetics and pharmacodynamics of rivaroxaban in patients with non-valvular atrial fibrillation: results from ROCKET AF.
Two once-daily rivaroxaban dosing regimens were compared with warfarin for stroke prevention in patients with non-valvular atrial fibrillation in ROCKET AF: 20 mg for patients with normal/mildly impaired renal function and 15 mg for patients with moderate renal impairment. Rivaroxaban population pharmacokinetic (PK)/pharmacodynamic (PD) modeling data from ROCKET AF patients (n = 161) are reported and are used to confirm established rivaroxaban PK and PK/PD models and to re-estimate values of the models' parameters for the current AF population. An oral one-compartment model with first-order absorption adequately described rivaroxaban PK. Age, renal function, and lean body mass influenced the PK model. Prothrombin time and prothrombinase-induced clotting time exhibited a near-linear relationship with rivaroxaban plasma concentration; inhibitory effects were observed through to 24 hours post-dose. Rivaroxaban plasma concentration and factor Xa activity had an inhibitory maximum-effect (Emax ) relationship. Renal function (on prothrombin time; prothrombinase-induced clotting time) and age (on factor Xa activity) had moderate effects on PK/PD models. PK and PK/PD models were shown to be adequate for describing the current dataset. These findings confirm the modeling and empirical results that led to the selection of doses tested against warfarin in ROCKET AF.


Dim light in the evening causes coordinated realignment of circadian rhythms, sleep, and short-term memory.
Light provides the primary signal for entraining circadian rhythms to the day/night cycle. In addition to rods and cones, the retina contains a small population of photosensitive retinal ganglion cells (pRGCs) expressing the photopigment melanopsin (OPN4). Concerns have been raised that exposure to dim artificial lighting in the evening (DLE) may perturb circadian rhythms and sleep patterns, and OPN4 is presumed to mediate these effects. Here, we examine the effects of 4-h, 20-lux DLE on circadian physiology and behavior in mice and the role of OPN4 in these responses. We show that 2 wk of DLE induces a phase delay of ∼2 to 3 h in mice, comparable to that reported in humans. DLE-induced phase shifts are unaffected in Opn4-/- mice, indicating that rods and cones are capable of driving these responses in the absence of melanopsin. DLE delays molecular clock rhythms in the heart, liver, adrenal gland, and dorsal hippocampus. It also reverses short-term recognition memory performance, which is associated with changes in preceding sleep history. In addition, DLE modifies patterns of hypothalamic and cortical cFos signals, a molecular correlate of recent neuronal activity. Together, our data show that DLE causes coordinated realignment of circadian rhythms, sleep patterns, and short-term memory process in mice. These effects are particularly relevant as DLE conditions-due to artificial light exposure-are experienced by the majority of the populace on a daily basis.


Short dental implants in reduced alveolar bone height.
Reduced alveolar bone height is very common in the posterior jaws. The current treatment modality to replace the missing teeth with an implant-retained fixed partial denture includes sinus bone grafting in the maxilla and onlay bone graft in the mandible. These procedures are invasive and require more time and cost. Short dental implants are used as an alternative treatment modality to bone grafting procedures. To enhance success rate, certain principles should apply. Short implants could provide comparable results to those of longer implants. This article reviews the current literature on the use of short implants, discusses the biomechanical considerations when utilizing short implants, and presents a case.


Role of outer-membrane proteins and lipopolysaccharide in conjugation between Neisseria gonorrhoeae and Neisseria cinerea.
Little is known concerning the mechanism involved in cell contact between the donor and recipient during conjugation in Neisseria gonorrhoeae. The formation of stable mating pairs during conjugation in Escherichia coli appears to require a specific protein as well as LPS in the outer membrane of the recipient cell. To attempt to identify the cell surface components necessary for conjugation in the neisseriae, we began a comparison of the outer membrane of Neisseria cinerea strains that can (Con+) and cannot (Con-) serve as recipients in conjugation with N. gonorrhoeae. There were no differences in outer-membrane protein profiles on SDS-polyacrylamide gel electrophoresis between Con+ and Con- strains that could be correlated with the ability to conjugate. However, whole outer membrane isolated from Con+ strains specifically inhibited conjugation while those from Con- strains did not. Proteolytic cleavage of outer-membrane proteins by trypsin, pronase or alpha-chymotrypsin abolished the inhibitory effect of Con+ outer membranes, suggesting that these outer membranes contained a protease-sensitive protein(s) involved in conjugation. Although periodate oxidation of Con+ outer-membrane carbohydrates did not abolish the inhibitory action of these membranes, purified LPS from both Con+ and Con- strains inhibited conjugation when added at low concentrations. These results suggest that conjugation requires the presence of a specific conjugal receptor that consists of both LPS and one or more outer-membrane proteins. Both Con+ and Con- strains contain the necessary LPS, but only Con+ strains contain the required protein(s).


Carotenoids Inhibit Fructose-Induced Inflammatory Response in Human Endothelial Cells and Monocytes.
This research is aimed at determining the vascular health characteristics of carotenoids by evaluating their effect on excessive inflammatory response in endothelial and monocyte cells, the main factors of atherosclerosis. Human umbilical vein endothelial cells (HUVECs) or U937 monocytes were treated with escalating concentrations (0.1, 0.5, and 1 μM) of five most common carotenoids in human plasma, i.e., α-carotene, β-carotene, β-cryptoxanthin, lutein, and lycopene prior to stimulation with 2 mM fructose. We examined the monocyte adhesion to endothelial cells (ECs) and relevant endothelial adhesion molecules. Chemokine and proinflammatory cytokine production as well as intracellular oxidative stress were also assessed in fructose-stimulated ECs and monocytes. Carotenoids repressed monocyte adhesion to fructose-stimulated ECs dose dependently via decreasing primarily the expression of endothelial VCAM-1. In ECs and monocytes, three carotenoids, i.e., β-cryptoxanthin, lutein, and lycopene, suppressed the fructose-induced expression of chemokines MCP-1, M-CSF, and CXCL-10 and inflammatory cytokines TNF-α and IL-1β, with CXCL-10 being the most repressed inflammatory mediator. β-Cryptoxanthin, lutein, and lycopene dramatically downregulated the fructose-induced CXCL-10 expression in vascular cells. The reduction in the inflammatory response was associated with a slight but significant decrease of intracellular oxidative stress. Our results show that carotenoids have a variety of anti-inflammatory and antiatherosclerosis activities, which can help prevent or reduce fructose-induced inflammatory vascular diseases.


Failure to detect IL-3-binding sites on human mast cells.
IL-3, a pleiotropic lymphokine, has been termed mast cell growth factor because it promotes growth and differentiation of murine mast cells. Murine mast cells, in turn, express cell surface receptors for IL-3. Human rIL-3 has been shown to induce proliferation and differentiation of human basophils and to activate basophils via high affinity binding sites. To investigate whether human mast cells express IL-3R, binding studies with 125I-radiolabeled human rIL-3 were performed on HMC-1, a novel human mast cell line, and on pure populations (i.e., 93 to 99% purity) of human tissue mast cells obtained with mAb and C from dispersed lung (n = 2). Unexpectedly, neither enriched human lung mast cells nor HMC-1 cells bound radiolabeled human rIL-3 specifically. Moreover, human rIL-3 failed to promote uptake of [3H]thymidine, synthesis of histamine, histamine releasability, or changes in expression of mast cell differentiation Ag (YB5B8, CD54/ICAM-1, CD9/p24, CD33/gp67) on either human lung mast cells or HMC-1 cells. It is hypothesized that the fundamental difference in the biologic response to IL-3 between human and murine mast cells is due to a loss during evolution of mast cell high affinity IL-3 binding sites.


A preliminary experience of moderate-intensity stereotactic body radiation therapy for ultra-central lung tumor.
Purpose: Administration of stereotactic body radiation therapy (SBRT) to ultra-central (UC) lung tumors, generally defined as those abutting the proximal bronchial trees, is difficult due to concerns about serious toxicities. Therefore, our institution has performed moderate-intensity SBRT. Patients and methods: Patients with UC tumors underwent SBRT at a dose of 50-60 Gy in 10 fractions, with Dmax in the target volume not exceeding 110% of the prescribed dose. The primary outcomes were tumor response and overall survival (OS). Results: From January 2017 to September 2018, we treated eight patients who had been diagnosed with UC tumors. The median follow-up time was 8.6 months (range: 2.7-14.9). Five of the eight patients (62.5%) showed a complete response (CR), two (25%) had a partial response (PR), and one (12.5%) had stable disease (SD); the response and disease control rates were 87.5% and 100%, respectively. Seven patients were alive with no evidence of disease or with controlled disease until the last follow-ups, except for one patient who died due to a non-RT cause at 3 months after SBRT. One patient experienced grade 2 esophageal pain and another had grade 1 cough. No grade 3 or higher toxicities were reported. Conclusion: Moderate-intensity SBRT might aid in achieving good control of UC tumors without excessive toxicities. Future studies involving larger numbers of patients and longer follow-up times are warranted to confirm the efficacy and feasibility.


Baseline predictors of treatment gains in peak propulsive force in individuals poststroke.
Current rehabilitation for individuals poststroke focuses on increasing walking speed because it is an indicator of community walking ability and quality of life. Propulsive force generated from the paretic limb is critical to walking speed and may reflect actual neural recovery that restores the affected neural systems. A wide variation across individuals in the improvements in paretic propulsive force was observed following an intervention that targeted paretic propulsive force. This study aimed to determine if specific baseline characteristics can be used to predict patients who would respond to the intervention. Participants (N = 19) with chronic poststroke hemiparesis walked at their self-selected and maximal walking speeds on a treadmill before and after a 12-week gait training program. Propulsive forces from the paretic limb were analyzed. Pearson correlation coefficient was used to determine the relationships between (1) treatment gains in walking speed and propulsive force following intervention, and (2) treatment gains in propulsive force and baseline propulsive forces. Treatment gains in self-selected walking speed were correlated to treatment gains in paretic propulsive force following intervention. In addition, changes in paretic propulsive force between self-selected and maximal walking speeds at baseline were strongly correlated to treatment gains in paretic propulsive force. The capacity to modulate paretic propulsive force, rather than the absolute propulsive force during self-selected or maximal walking speed, predicted treatment gains in propulsive force following the intervention. Findings from this research could help to inform clinicians and researchers to target the appropriate patient population for rehabilitation interventions.


Respiratory health effects of industrial air pollution: a study in east Lancashire, UK.
To determine whether there was a higher incidence of respiratory ill health in children living near to a cement works than in those from a different area, and if so whether the higher incidence was due to the use of a hazardous waste-derived fuel at the works. A sample of the population of children living near the cement works (the study area) was compared with a sample of children living between 9 and 19 km away from the site (the control area). The cement works is located on the north eastern edge of a small rural town in east Lancashire. Data were collected via the use of a health questionnaire. This was distributed through selected primary schools to families who had one or more children of primary school age (5-11 years). The study and control populations were comparable in terms of response rates, gender, and socioeconomic indicators. There was no significant difference in the incidence of asthma (as diagnosed by a general practitioner) between the two areas when adjustment for hayfever was made. The incidence of sore throat was significantly higher in the case area, a difference not explained by other factors. For two other non-specific indicators of respiratory health (blocked nose and sore eyes) there was a significantly higher incidence in the study area, although hayfever and mould were also significant influences. The results indicated that certain non-specific health indicators were more common in the children living near a cement works. This excess may be due to exposure to emissions from the site. However, it is not possible to draw firm conclusions because there are no epidemiological data predating the use of the hazardous waste derived fuel.


Proliferation zones in adult medaka (Oryzias latipes) brain.
Cell proliferation in the adult mammalian brain is maintained at a low rate, but cell proliferation in the adult fish brain is prominent. To compare the distribution of proliferating cells among fish species, mutants, and under different growing environments, we mapped the zones of cell proliferation in the adult medaka (Oryzias latipes) brain and identified 17 proliferation zones in both male and female brains. These zones were distributed in the telencephalon (4 zones), preoptic area (2 zones), pineal body (1 zone), hypophysis (1 zone), habenular nucleus (1 zone), optic tectum (2 zones), third ventricular zone (1 zone), ventromedial nucleus (1 zone), hypothalamus (1 zone), and cerebellum (3 zones). Of the 17 zones, 16 corresponded to brain regions where cells proliferate in the zebrafish brain, suggesting that the persistence of the generation of new cells, at least in these zones, might be conserved among some fish species. We then compared the distribution of proliferation zones using two body-color mutant medaka, the T5 and Quintet, the latter of which is an albino mutant that completely lacks pigmentation. There was no apparent difference in the distribution pattern among these mutant strains. Finally, we compared these proliferation zones in the brains of isolated- and group-reared fish and detected no significant difference between the two groups. These findings demonstrate that there is persistent cell proliferation in at least these 16 zones of the adult medaka brain, irrespective of sex, body-color, and growth environment, suggesting that proliferation capacity in the 16 zones is maintained robustly in the adult medaka brain.


Utilization of Palliative Care for Patients Undergoing Hematopoietic Stem Cell Transplantation During Hospitalization: A Population-Based National Study.
Patients undergoing hematopoietic stem cell transplantation (HSCT) have substantial physical and psychological symptoms. This study aimed to investigate the utilization of palliative care (PC) in patients undergoing HSCT during hospitalization. The 2008-2014 National Inpatient Sample was queried for eligible participants. Demographics, hospital characteristics, comorbidities, posttransplantation complications, and inpatient procedures were compared between patients with and without PC. Multivariate logistic regression was performed to identify predictors associated with PC use. Among 21 458 patients undergoing HSCT during hospitalization, 278 (1.30%) received PC. The rate of PC use has significantly increased from 0.64% in 2008 to 1.95% in 2014. Patients receiving PC had more co-comorbidities, posttransplantation complications, inpatient procedures, and were more likely to carry a diagnosis of leukemia. In allogeneic HSCT, large bed size (odds ratio [OR] =2.80; 95% confidence interval [CI]: 1.17-6.70), stem cell source from cord blood (OR = 1.93; 95% CI: 1.15-3.24), and graft-versus-host disease (OR = 2.04; 95% CI: 1.36-3.06) were predictors of PC use. In a subset analysis of 783 patients who died during hospitalization, 166 (21.20%) received PC. Among the decedents, Hispanic race had lower odds of PC use (OR = 0.20; 95% CI: 0.05-0.82) in allogeneic HSCT and women had higher odds of PC (OR = 2.70; 95% CI: 1.35-5.41) in autologous HSCT. The rate of PC use has significantly increased among patients undergoing HSCT during hospitalization from 2008 to 2014 but still remains very low. Further investigation is warranted to verify and better understand the barriers toward PC use for HSCT patients.


Congenital portal vein aneurysm associated with peliosis hepatis and intestinal lymphangiectasia.
Portal vein aneurisym (PVA), peliosis hepatis (PH) and intestinal lymphangiectasia (IL) all are very uncommon entities. Herein, we presented a unique patient with these three rare entities who was admitted to our hospital because of portal hypertensive ascites rich in protein and lymphocyte. PVA was extrahepatic and associated with coronary vein aneurysm. Peliosis hepatis was of microscopic form. Lymphangiectasia was present in peritoneum and small intestine. Diagnoses of these rare entities were made by imaging techniques and histopathological findings. Patient also had hydronephrosis caused by ureteropelvic junction narrowing. Best of our knowledge, there is no such a case reported previously with the association of PVA, PH and IL. Therefore, we propose PVAPHIL syndrome to define this novel association.


Understanding the parietal lobe syndrome from a neurophysiological and evolutionary perspective.
In human and nonhuman primates parietal cortex is formed by a multiplicity of areas. For those of the superior parietal lobule (SPL) there exists a certain homology between man and macaques. As a consequence, optic ataxia, a disturbed visual control of hand reaching, has similar features in man and monkeys. Establishing such correspondence has proven difficult for the areas of the inferior parietal lobule (IPL). This difficulty depends on many factors. First, no physiological information is available in man on the dynamic properties of cells in the IPL. Second, the number of IPL areas identified in the monkey is paradoxically higher than that so far described in man, although this issue will probably be reconsidered in future years, thanks to comparative imaging studies. Third, the consequences of parietal lesions in monkeys do not always match those observed in humans. This is another paradox if one considers that, in certain cases, the functional properties of neurons in the monkey's IPL would predict the presence of behavioral skills, such as construction capacity, that however do not seem to emerge in the wild. Therefore, constructional apraxia, which is well characterized in man, has never been described in monkeys and apes. Finally, only certain aspects, i.e. hand directional hypokinesia and gaze apraxia (Balint's psychic paralysis of gaze), of the multifaceted syndrome hemispatial neglect have been described in monkeys. These similarities, differences and paradoxes, among many others, make the study of the evolution and function of parietal cortex a challenging case.


Linkage of a marker in intron D of the estrogen synthase locus to rheumatoid arthritis.
To test for the presence of linkage of the estrogen synthase (CYP19) locus to rheumatoid arthritis (RA) in affected sibling pair (ASP) families. Two data sets of RA ASPs (225 ASPs and 107 ASPs) were genotyped for a polymorphic tetranucleotide marker at the CYP19 locus using fluorescence-based semiautomated genotyping technology. Evidence of linkage was assessed by estimating allele sharing (identical by descent) in affected sibling pairs. The effect of this locus was also examined in patient subgroups stratified by sex and by age at disease onset. An increase in allele sharing at the CYP19 locus was observed in the first data set of 225 ASPs (logarithm of odds [LOD] 0.8; P = 0.04). There was also an increase in allele sharing in a second data set, but this did not reach statistical significance (LOD 0.34; P = 0.1). The highest increase in allele sharing was seen in patients with an age at disease onset that was >50 years (LOD 1.1; P = 0.02). An increase in allele sharing at the CYP19 locus has been demonstrated in 2 large samples of RA ASPs. The evidence for linkage was strongest in patients with an age at onset that was >50 years, which suggests that this locus may be a susceptibility locus for developing RA later in life. These data provide preliminary evidence that CYP19 may have a role in RA susceptibility.


Pyk2 phosphorylation of VE-PTP downstream of STIM1-induced Ca2+ entry regulates disassembly of adherens junctions.
Vascular endothelial protein tyrosine phosphatase (VE-PTP) stabilizes endothelial adherens junctions (AJs) through constitutive dephosphorylation of VE-cadherin. Here we investigated the role of stromal interaction molecule 1 (STIM1) activation of store-operated Ca2+ entry (SOCE) in regulating AJ assembly. We observed that SOCE induced by STIM1 activated Pyk2 in human lung microvascular endothelial cells (ECs) and induced tyrosine phosphorylation of VE-PTP at Y1981. Pyk2-induced tyrosine phosphorylation of VE-PTP promoted Src binding to VE-PTP, Src activation, and subsequent VE-cadherin phosphorylation and thereby increased the endothelial permeability response. The increase in permeability was secondary to disassembly of AJs. Pyk2-mediated responses were blocked in EC-restricted Stim1 knockout mice, indicating the requirement for STIM1 in initiating the signaling cascade. A peptide derived from the Pyk2 phosphorylation site on VE-PTP abolished the STIM1/SOCE-activated permeability response. Thus Pyk2 activation secondary to STIM1-induced SOCE causes tyrosine phosphorylation of VE-PTP, and VE-PTP, in turn, binds to and activates Src, thereby phosphorylating VE-cadherin to increase endothelial permeability through disassembly of AJs. Our results thus identify a novel signaling mechanism by which STIM1-induced Ca2+ signaling activates Pyk2 to inhibit the interaction of VE-PTP and VE-cadherin and hence increase endothelial permeability. Therefore, targeting the Pyk2 activation pathway may be a potentially important anti-inflammatory strategy.


MSSP, a protein binding to an origin of replication in the c-myc gene, interacts with a catalytic subunit of DNA polymerase alpha and stimulates its polymerase activity.
MSSP has been identified as a protein that binds to both single- and double-stranded sequences of a putative DNA replication origin sequence in the human c-myc gene. MSSP possesses versatile functions, including stimulation of DNA replication, transcriptional regulation, apoptosis induction, and cell transformation coordinated by c-Myc. MSSP contains two RNP domains, RNP1-A and RNP1-B, both of which are necessary for all of the functions of MSSP. In this study, we found that MSSP binds to the N-terminal region of a catalytic subunit of a human DNA polymerase alpha via its RNP domains both in vitro and in human cells. Furthermore, MSSP was released from the putative DNA replication origin of the c-myc gene after it complexed with DNA polymerase alpha, and MSSP stimulated DNA polymerase activity in vitro.


Neopterin is a cerebrospinal fluid marker for treatment outcome evaluation in patients affected by Trypanosoma brucei gambiense sleeping sickness.
Post-therapeutic follow-up is essential to confirm cure and to detect early treatment failures in patients affected by sleeping sickness (HAT). Current methods, based on finding of parasites in blood and cerebrospinal fluid (CSF) and counting of white blood cells (WBC) in CSF, are imperfect. New markers for treatment outcome evaluation are needed. We hypothesized that alternative CSF markers, able to diagnose the meningo-encephalitic stage of the disease, could also be useful for the evaluation of treatment outcome. Cerebrospinal fluid from patients affected by Trypanosoma brucei gambiense HAT and followed for two years after treatment was investigated. The population comprised stage 2 (S2) patients either cured or experiencing treatment failure during the follow-up. IgM, neopterin, B2MG, MMP-9, ICAM-1, VCAM-1, CXCL10 and CXCL13 were first screened on a small number of HAT patients (n = 97). Neopterin and CXCL13 showed the highest accuracy in discriminating between S2 cured and S2 relapsed patients (AUC 99% and 94%, respectively). When verified on a larger cohort (n = 242), neopterin resulted to be the most efficient predictor of outcome. High levels of this molecule before treatment were already associated with an increased risk of treatment failure. At six months after treatment, neopterin discriminated between cured and relapsed S2 patients with 87% specificity and 92% sensitivity, showing a higher accuracy than white blood cell numbers. In the present study, neopterin was highlighted as a useful marker for the evaluation of the post-therapeutic outcome in patients suffering from sleeping sickness. Detectable levels of this marker in the CSF have the potential to shorten the follow-up for HAT patients to six months after the end of the treatment.


Studies of hematopoietic stem cells spared by 5-fluorouracil.
Mouse marrow cells were exposed to 5-fluorouracil (FU) either in vivo or in vitro and the effects on the hematopoietic stem cell compartment were studied. The drug was highly toxic to bone marrow cells including the spleen colony-forming unit (CFU-S) population. The small population of stem cells surviving FU, however, caused a different pattern of spleen colony growth when injected into lethally irradiated mice. Whereas numbers of spleen colonies caused by normal marrow cells remained constant during an 8-14 d period after transplantation, spleen colonies derived from FU-treated marrow cells increased by as much as 100-fold during this time. This effect on stem cells was dose dependent both in vitro and in vivo. When FU was given in vivo, the day 14/day 8 ratio of colonies was greatest 1 d after injection and, over the next 7 d, returned to a near-normal value, that is, unity. A number of studies have shown that the stem cell compartment is heterogeneous with respect to self-replicative capacity and developmental potential. An age structure for the stem cell compartment has been proposed wherein cells with a short mitotic history are more likely to self-replicate than they are to differentiate; hence they are more primitive. 'Older' stem cells with a longer mitotic history are, according to the hypothesis, more likely to differentiate. 5-fluorouracil may be toxic to the older stem cells and selectively spare the more primitive subpopulation. Although the surviving cells may not themselves be able to form spleen colonies, they may give rise to an older cohort of cells more likely to differentiate and form spleen colonies. It is the requisite developmental maturation within the stem cell compartment that may be responsible for the delay in appearance of spleen colonies derived from FU-treated marrow. Our results support this explanation and identify the locus of at least part of this activity as the bone marrow. We found that the FU-treated marrow did not cause an increase in spleen colony numbers between 8 and 14 d in hosts with a long-standing marrow aplasia, due to the incorporation of 89Sr into bone. I propose that the delayed spleen colony appearance in normal hosts is the result of developmental maturation of the primitive stem cell compartment that survives FU and is responsible for spleen colonies arising around day 14. This maturation, at least initially, occurs in the marrow and leads to the replenishment of the more differentiated CFU-S subsets ablated by FU, which are normally responsible for spleen colonies appearing earlier after transplantation.


Beyond the Barriers of Light Penetration: Strategies, Perspectives and Possibilities for Photodynamic Therapy.
Photodynamic therapy (PDT) is a photochemistry based treatment modality that involves the generation of cytotoxic species through the interactions of a photosensitizer molecule with light irradiation of an appropriate wavelength. PDT is an approved therapeutic modality for several cancers globally and in several cases has proved to be effective where traditional treatments have failed. The key parameters that determine PDT efficacy are 1. the photosensitizer (nature of the molecules, selectivity, and macroscopic and microscopic localization etc.), 2. light application (wavelength, fluence, fluence rate, irradiation regimes etc.) and 3. the microenvironment (vascularity, hypoxic regions, stromal tissue density, molecular heterogeneity etc.). Over the years, several groups aimed to monitor and manipulate the components of these critical parameters to improve the effectiveness of PDT treatments. However, PDT is still misconstrued to be a surface treatment primarily due to the limited depths of light penetration. In this review, we present the recent advances, strategies and perspectives in PDT approaches, particularly in cancer treatment, that focus on increasing the 'damage zone' beyond the reach of light in the body. This is enabled by a spectrum of approaches that range from innovative photosensitizer excitation strategies, increased specificity of phototoxicity, and biomodulatory approaches that amplify the biotherapeutic effects induced by photodynamic action. Along with the increasing depth of understanding of the underlying physical, chemical and physiological mechanisms, it is anticipated that with the convergence of these strategies, the clinical utility of PDT will be expanded to a powerful modality in the armamentarium for the management of cancer.


Amelioration of alloxan induced diabetes mellitus and oxidative stress in rats by oil of Eruca sativa seeds.
Clinical research has confirmed the efficacy of several plant extracts in the modulation of oxidative stress associated with diabetes mellitus (DM). Oil of Eruca sativa seeds (ESS) is tried for prevention and treatment of DM induced experimentally by alloxan injection. A single dose of alloxan (100 mg/kg) produced a decrease in insulin level, hyperglycemia, elevated total lipids, triglycerides and cholesterol, decreased high-density lipoprotein and hepatic glycogen contents and elevated hepatic glucose-6-phosphatase activity. Concurrent with these changes, there was an increase in the concentration of malondialdehyde and 4-hydroxynonenal in the liver. This oxidative stress was related to a decreased glutathione (GSH) content and superoxide dismutase activity in the liver of alloxan-diabetic rats. ESS oil (0.06 ml/kg) on its own increased significantly hepatic GSH. Daily oral administration of ESS oil 2 weeks before or after diabetes induction ameliorated hyperglycemia, improved lipid profile, blunted the increase in malondialdehyde and 4-hydroxynonenal and stimulated the GSH production in the liver of alloxan-treated rats. We suggested that ESS oil could be used as antidiabetic complement in case of DM. This may be related to its antioxidative properties and to the increase in hepatic GSH.


3-M syndrome: a novel CUL7 mutation associated with respiratory distress and a good response to GH therapy.
3-M syndrome is a rare autosomal recessive disorder caused by mutations in the CUL7, OBSL1 and CCDC8 genes. It is characterised by growth failure, dysmorphic features and skeletal abnormalities. Data in the literature show variable efficacy of GH in the treatment of short stature. We report four Emirati siblings with the condition. The index case is a 10-year-old boy with characteristic features, including prenatal and postnatal growth failure, a triangular face, a long philtrum, full lips and prominent heels. Genetic testing confirmed a novel mutation (p.val88Ala) in the CUL7 gene. The parents are healthy, first-degree cousins with nine children, of whom two died in the first year of life with respiratory failure. Both had low birth weight and growth retardation. The boy's older sibling reached an adult height of 117 cm (-6.71 SDS). She was never treated with GH. He was started on GH treatment at 7 years of age, when his height was 94 cm (-5.3 SDS). 3-M syndrome should be considered in children with short stature who have associated dysmorphism and skeletal abnormalities. The diagnosis is more likely to occur in families that have a history of consanguinity and more than one affected sibling. Death in early infancy due to respiratory failure is another clue to the diagnosis, which might have a variable phenotype within a family. Genetic testing is important for confirming the diagnosis and for genetic counselling. GH treatment might be beneficial in improving stature in affected children. 3-M syndrome should be considered in families that have more than one sibling with short stature, particularly if there is consanguinity.Syndrome phenotype might be variable within a family with the same mutation.Genetic analysis is helpful in confirming diagnosis in the presence of variable siblings' phenotype.GH treatment might be useful in improving stature in 3-M syndrome.


Sleep-Related Electrophysiology and Behavior of Tinamous (Eudromia elegans): Tinamous Do Not Sleep Like Ostriches.
The functions of slow wave sleep (SWS) and rapid eye movement (REM) sleep, distinct sleep substates present in both mammals and birds, remain unresolved. One approach to gaining insight into their function is to trace the evolution of these states through examining sleep in as many taxonomic groups as possible. The mammalian and avian clades are each composed of two extant groups, i.e., the monotremes (echidna and platypus) and therian (marsupial and eutherian [or placental]) mammals, and Palaeognaths (cassowaries, emus, kiwi, ostriches, rheas, and tinamous) and Neognaths (all other birds) among birds. Previous electrophysiological studies of monotremes and ostriches have identified a unique "mixed" sleep state combining features of SWS and REM sleep unlike the well-delineated sleep states observed in all therian mammals and Neognath birds. In the platypus this state is characterized by periods of REM sleep-related myoclonic twitching, relaxed skeletal musculature, and rapid eye movements, occurring in conjunction with SWS-related slow waves in the forebrain electroencephalogram (EEG). A similar mixed state was also observed in ostriches; although in addition to occurring during periods with EEG slow waves, reduced muscle tone and rapid eye movements also occurred in conjunction with EEG activation, a pattern typical of REM sleep in Neognath birds. Collectively, these studies suggested that REM sleep occurring exclusively as an integrated state with forebrain activation might have evolved independently in the therian and Neognath lineages. To test this hypothesis, we examined sleep in the elegant crested tinamou (Eudromia elegans), a small Palaeognath bird that more closely resembles Neognath birds in size and their ability to fly. A 24-h period was scored for sleep state based on electrophysiology and behavior. Unlike ostriches, but like all of the Neognath birds examined, all indicators of REM sleep usually occurred in conjunction with forebrain activation in tinamous. The absence of a mixed REM sleep state in tinamous calls into question the idea that this state is primitive among Palaeognath birds and therefore birds in general.


Southern Ocean frontal structure and sea-ice formation rates revealed by elephant seals.
Polar regions are particularly sensitive to climate change, with the potential for significant feedbacks between ocean circulation, sea ice, and the ocean carbon cycle. However, the difficulty in obtaining in situ data means that our ability to detect and interpret change is very limited, especially in the Southern Ocean, where the ocean beneath the sea ice remains almost entirely unobserved and the rate of sea-ice formation is poorly known. Here, we show that southern elephant seals (Mirounga leonina) equipped with oceanographic sensors can measure ocean structure and water mass changes in regions and seasons rarely observed with traditional oceanographic platforms. In particular, seals provided a 30-fold increase in hydrographic profiles from the sea-ice zone, allowing the major fronts to be mapped south of 60 degrees S and sea-ice formation rates to be inferred from changes in upper ocean salinity. Sea-ice production rates peaked in early winter (April-May) during the rapid northward expansion of the pack ice and declined by a factor of 2 to 3 between May and August, in agreement with a three-dimensional coupled ocean-sea-ice model. By measuring the high-latitude ocean during winter, elephant seals fill a "blind spot" in our sampling coverage, enabling the establishment of a truly global ocean-observing system.


The Phaeodactylum genome reveals the evolutionary history of diatom genomes.
Diatoms are photosynthetic secondary endosymbionts found throughout marine and freshwater environments, and are believed to be responsible for around one-fifth of the primary productivity on Earth. The genome sequence of the marine centric diatom Thalassiosira pseudonana was recently reported, revealing a wealth of information about diatom biology. Here we report the complete genome sequence of the pennate diatom Phaeodactylum tricornutum and compare it with that of T. pseudonana to clarify evolutionary origins, functional significance and ubiquity of these features throughout diatoms. In spite of the fact that the pennate and centric lineages have only been diverging for 90 million years, their genome structures are dramatically different and a substantial fraction of genes ( approximately 40%) are not shared by these representatives of the two lineages. Analysis of molecular divergence compared with yeasts and metazoans reveals rapid rates of gene diversification in diatoms. Contributing factors include selective gene family expansions, differential losses and gains of genes and introns, and differential mobilization of transposable elements. Most significantly, we document the presence of hundreds of genes from bacteria. More than 300 of these gene transfers are found in both diatoms, attesting to their ancient origins, and many are likely to provide novel possibilities for metabolite management and for perception of environmental signals. These findings go a long way towards explaining the incredible diversity and success of the diatoms in contemporary oceans.


Haplotypes and gene expression implicate the MAPT region for Parkinson disease: the GenePD Study.
Microtubule-associated protein tau (MAPT) has been associated with several neurodegenerative disorders including forms of parkinsonism and Parkinson disease (PD). We evaluated the association of the MAPT region with PD in a large cohort of familial PD cases recruited by the GenePD Study. In addition, postmortem brain samples from patients with PD and neurologically normal controls were used to evaluate whether the expression of the 3-repeat and 4-repeat isoforms of MAPT, and neighboring genes Saitohin (STH) and KIAA1267, are altered in PD cerebellum. Twenty-one single-nucleotide polymorphisms (SNPs) in the region of MAPT on chromosome 17q21 were genotyped in the GenePD Study. Single SNPs and haplotypes, including the H1 haplotype, were evaluated for association to PD. Relative quantification of gene expression was performed using real-time RT-PCR. After adjusting for multiple comparisons, SNP rs1800547 was significantly associated with PD affection. While the H1 haplotype was associated with a significantly increased risk for PD, a novel H1 subhaplotype was identified that predicted a greater increased risk for PD. The expression of 4-repeat MAPT, STH, and KIAA1267 was significantly increased in PD brains relative to controls. No difference in expression was observed for 3-repeat MAPT. This study supports a role for MAPT in the pathogenesis of familial and idiopathic Parkinson disease (PD). Interestingly, the results of the gene expression studies suggest that other genes in the vicinity of MAPT, specifically STH and KIAA1267, may also have a role in PD and suggest complex effects for the genes in this region on PD risk.


The need for a revised version of the Benton judgment of line orientation test.
The Judgment of Line Orientation Test (JLOT) is considered a valid task for the assessment of visuospatial perception, and, for this reason, it is also considered to be a sensitive tool able to discriminate between right-hemisphere-damaged (RHD) patients and left-hemisphere-damaged (LHD) patients. In contrast with this view, we report evidence that the greater impairment in JLOT usually shown by RHD patients is unrelated to the supposed JLOT effectiveness in measuring visuospatial judgment ability and to the putative dominant role of the right hemisphere in visuospatial processing. JLOT is characterized by a left-right structural asymmetry (i.e., left-side lines are easier to judge) that seriously undermines the test validity: This asymmetry interacts with ipsilesional attentional biases of brain-damaged patients and affects their performance. Results obtained with a JLOT version composed of both the original items and their mirror-reversed versions clearly indicate that the cognitive functions tested by the JLOT are distributed across the two hemispheres: LHD and RHD patients did not differ from each other or from their matched controls when their performances were compared on this balanced JLOT version. Impaired performances of either RHD or LHD patients were found only when performances in original and mirror-reversed items were considered separately. This suggests that the original JLOT cannot assess visuospatial perception independently from attentional biases. The test can be a powerful clinical tool, as long as both original and mirror-reversed items are used, and the standard scoring method is replaced by the evaluation of the individual lines of stimulus pairs.


Correcting for multivariate measurement error by regression calibration in meta-analyses of epidemiological studies.
Within-person variability in measured values of multiple risk factors can bias their associations with disease. The multivariate regression calibration (RC) approach can correct for such measurement error and has been applied to studies in which true values or independent repeat measurements of the risk factors are observed on a subsample. We extend the multivariate RC techniques to a meta-analysis framework where multiple studies provide independent repeat measurements and information on disease outcome. We consider the cases where some or all studies have repeat measurements, and compare study-specific, averaged and empirical Bayes estimates of RC parameters. Additionally, we allow for binary covariates (e.g. smoking status) and for uncertainty and time trends in the measurement error corrections. Our methods are illustrated using a subset of individual participant data from prospective long-term studies in the Fibrinogen Studies Collaboration to assess the relationship between usual levels of plasma fibrinogen and the risk of coronary heart disease, allowing for measurement error in plasma fibrinogen and several confounders.


PDGF signalling is required for gastrulation of Xenopus laevis.
During Xenopus gastrulation, platelet-derived growth factor (PDGF) receptor-alpha is expressed in involuting marginal zone cells which migrate over ectodermal cells expressing PDGF-A. To investigate the role of PDGF signalling during this process, we have generated a novel point mutant of PDGF receptor-alpha analogous to the W37 mutation of c-kit. This molecule is a specific, potent, dominant inhibitor of PDGF signalling in vivo. Injection of RNA encoding this protein into Xenopus embryos prevents closure of the blastopore, leads to abnormal gastrulation and a loss of anterior structures. Convergent extension is not inhibited in these embryos, but rather, involuting mesodermal cells fail to adhere to the overlying ectoderm. PDGF may therefore be required for mesodermal cell-substratum interaction.


African 2, a clonal complex of Mycobacterium bovis epidemiologically important in East Africa.
We have identified a clonal complex of Mycobacterium bovis isolated at high frequency from cattle in Uganda, Burundi, Tanzania, and Ethiopia. We have named this related group of M. bovis strains the African 2 (Af2) clonal complex of M. bovis. Af2 strains are defined by a specific chromosomal deletion (RDAf2) and can be identified by the absence of spacers 3 to 7 in their spoligotype patterns. Deletion analysis of M. bovis isolates from Algeria, Mali, Chad, Nigeria, Cameroon, South Africa, and Mozambique did not identify any strains of the Af2 clonal complex, suggesting that this clonal complex of M. bovis is localized in East Africa. The specific spoligotype pattern of the Af2 clonal complex was rarely identified among isolates from outside Africa, and the few isolates that were found and tested were intact at the RDAf2 locus. We conclude that the Af2 clonal complex is localized to cattle in East Africa. We found that strains of the Af2 clonal complex of M. bovis have, in general, four or more copies of the insertion sequence IS6110, in contrast to the majority of M. bovis strains isolated from cattle, which are thought to carry only one or a few copies.


Intermolecular dissociation energies of hydrogen-bonded 1-naphthol complexes.
We have measured the intermolecular dissociation energies D 0 of supersonically cooled 1-naphthol (1NpOH) complexes with solvents S = furan, thiophene, 2,5-dimethylfuran, and tetrahydrofuran. The naphthol OH forms non-classical H-bonds with the aromatic π-electrons of furan, thiophene, and 2,5-dimethylfuran and a classical H-bond with the tetrahydrofuran O atom. Using the stimulated-emission pumping resonant two-photon ionization method, the ground-state D 0(S 0) values were bracketed as 21.8 ± 0.3 kJ/mol for furan, 26.6 ± 0.6 kJ/mol for thiophene, 36.5 ± 2.3 kJ/mol for 2,5-dimethylfuran, and 37.6 ± 1.3 kJ/mol for tetrahydrofuran. The dispersion-corrected density functional theory methods B97-D3, B3LYP-D3 (using the def2-TZVPP basis set), and ωB97X-D [using the 6-311++G(d,p) basis set] predict that the H-bonded (edge) isomers are more stable than the face isomers bound by dispersion; experimentally, we only observe edge isomers. We compare the calculated and experimental D 0 values and extend the comparison to the previously measured 1NpOH complexes with cyclopropane, benzene, water, alcohols, and cyclic ethers. The dissociation energies of the nonclassically H-bonded complexes increase roughly linearly with the average polarizability of the solvent, α ¯ (S). By contrast, the D 0 values of the classically H-bonded complexes are larger, increase more rapidly at low α ¯ (S), but saturate for large α ¯ (S). The calculated D 0(S 0) values for the cyclopropane, benzene, furan, and tetrahydrofuran complexes agree with experiment to within 1 kJ/mol and those of thiophene and 2,5-dimethylfuran are ∼3 kJ/mol smaller than experiment. The B3LYP-D3 calculated D 0 values exhibit the lowest mean absolute deviation (MAD) relative to experiment (MAD = 1.7 kJ/mol), and the B97-D3 and ωB97X-D MADs are 2.2 and 2.6 kJ/mol, respectively.


Management of myelodysplastic syndromes after failure of response to hypomethylating agents.
Hypomethylating agents (HMAs) are the standard of care for patients with myelodysplastic syndrome (MDS). However, only around 50% of patients respond to these agents, and responses tend to be transient, with loss of response frequently happening within 2 years and being associated with very poor prognosis and limited therapeutic options. Identification of patients who will respond to HMAs is challenging. Mechanisms underlying resistance to HMAs are not clear yet. Recently, absence of response has been associated with increased cell-cycle quiescence among the hematopoietic progenitor cells. There are no standard-of-care options for patients after HMA failure. However, the increasing knowledge of MDS pathogenesis has led to the development of new potential therapies, including HMAs with longer half-life and exposure, inhibition of the antiapoptotic BCL2 protein with venetoclax or inhibition of immune-checkpoint regulatory proteins such as PD-1 or CTLA-4, innate immunity and targeting of CD33/CD3 with multiple monoclonal antibodies. In addition, multiple targeted agents are opening opportunities to treat subgroups of patients whose disease harbors mutations in TP53, IDH, FLT3, and genes involved in splicing machinery. Newer formulations of intensive chemotherapy and its different combinations may be considered a valid option in selected patients after HMA failure. Finally, decision making at the time of failure of response to HMAs should be personalized, taking into account that allogenic stem-cell transplantation remains the only therapeutic approach with curative potential in these patients. In the current review, we will focus on all the above aspects.