Differential transcriptome analysis between Paulownia fortunei and its synthesized autopolyploid.
Paulownia fortunei is an ecologically and economically important tree species that is widely used as timber and chemical pulp. Its autotetraploid, which carries a number of valuable traits, was successfully induced with colchicine. To identify differences in gene expression between P. fortunei and its synthesized autotetraploid, we performed transcriptome sequencing using an Illumina Genome Analyzer IIx (GAIIx). About 94.8 million reads were generated and assembled into 383,056 transcripts, including 18,984 transcripts with a complete open reading frame. A conducted Basic Local Alignment Search Tool (BLAST) search indicated that 16,004 complete transcripts had significant hits in the National Center for Biotechnology Information (NCBI) non-redundant database. The complete transcripts were given functional assignments using three public protein databases. One thousand one hundred fifty eight differentially expressed complete transcripts were screened through a digital abundance analysis, including transcripts involved in energy metabolism and epigenetic regulation. Finally, the expression levels of several transcripts were confirmed by quantitative real-time PCR. Our results suggested that polyploidization caused epigenetic-related changes, which subsequently resulted in gene expression variation between diploid and autotetraploid P. fortunei. This might be the main mechanism affected by the polyploidization. Our results represent an extensive survey of the P. fortunei transcriptome and will facilitate subsequent functional genomics research in P. fortunei. Moreover, the gene expression profiles of P. fortunei and its autopolyploid will provide a valuable resource for the study of polyploidization.


Evidence-based practice in child and adolescent mental health services.
The authors review the status, strength, and quality of evidence-based practice in child and adolescent mental health services. The definitional criteria that have been applied to the evidence base differ considerably across treatments, and these definitions circumscribe the range, depth, and extensionality of the evidence. The authors describe major dimensions that differentiate evidence-based practices for children from those for adults and summarize the status of the scientific literature on a range of service practices. The readiness of the child and adolescent evidence base for large-scale dissemination should be viewed with healthy skepticism until studies of the fit between empirically based treatments and the context of service delivery have been undertaken. Acceleration of the pace at which evidence-based practices can be more readily disseminated will require new models of development of clinical services that consider the practice setting in which the service is ultimately to be delivered.


In utero exposure to endocrine disrupting chemicals, micro-RNA profiles, and fetal growth: a pilot study protocol.
Background: The developing fetus is particularly vulnerable to the effects of endocrine disrupting chemicals (EDCs). Molecular fingerprints of EDCs can be identified via microRNA (miRNA) expression profiles and may be etiologically implicated in the developmental origin of disease (DOHaD). Methods/design: This pilot study includes pregnant women at high risk (smoking at conception), and low risk (non-smoking at conception) for SGA birth (birthweight<10th percentile for gestational age). We have randomly selected 12 mothers (3 high-risk SGA birth, 3 low-risk SGA birth, 3 high-risk non-SGA birth, 3 low-risk non-SGA birth), with EDC measurements from gestational week 17. All offspring are female. We aim to test the stability of our samples (maternal serum, cord blood, placenta tissue), observe the differential expression of miRNA profiles over time (gestational weeks 17, 25, 33, 37, birth), and study the consistency between maternal EDC measures and miRNA expression profiles across our repeated measures. Expected impact of the study for Public Health: Results from this pilot study will inform the development of a larger cohort wide analysis, and will impact the current state of knowledge in the fields of public health, epigenetics, and the DOHaD.


Understanding the genetics of survival in dairy cows.
Premature mortality and culling causes great wastage in the dairy industry, as a large number of heifers born never become productive or are culled before their full lactation potential is reached. The objectives of this study were to characterize survival and estimate genetic parameters for alternative longevity traits that considered (1) the survival of replacement heifers and (2) functional longevity of milking cows in the UK Holstein Friesian population, using combined information from the British Cattle Movement Service and milk recording organizations. Mortality of heifers was highest in the first month of life and was proportionately highest in calves born during winter months. Heifer mortality tended to decrease with age until about 16 mo onward; it then gradually increased, expected to be associated with culls due to reproductive failure or problems during pregnancy and calving. In milking cows, days of productive life (DPL) was analyzed as an alternative to the current trait lifespan score. Cows that died in 2009 on average lived for 6.8 yr with an average production of 4.3 yr. Heritability estimates were low for both heifer and cow survival and were ~0.01 and ~0.06, respectively. The positive genetic correlation between heifer survival with lifespan score (0.31) indicates that bulls that sire daughters with longer productive lives are also likely to have calves that survive and become replacement heifers. However, the magnitude of the genetic correlation suggests that survival in the rearing period and the milking herd are different traits. Genetic correlations were favorable between DPL with somatic cell count and fertility traits indicating that animals with a longer productive life tend to have lower somatic cell count, a shorter calving interval, fewer days to first service, and require fewer inseminations. However, an antagonistic relationship existed between DPL with milk and fat yield traits.


Inhibitory Effect of the Noncamptothecin Topoisomerase I Inhibitor LMP-400 on Female Mice Models and Human Pheochromocytoma Cells.
Metastatic pheochromocytoma continues to be an incurable disease, and treatment with conventional cytotoxic chemotherapy offers limited efficacy. In the present study, we evaluated a novel topoisomerase I inhibitor, LMP-400, as a potential treatment for this devastating disease. We found a high expression of topoisomerase I in human metastatic pheochromocytoma, providing a basis for the evaluation of a topoisomerase 1 inhibitor as a therapeutic strategy. LMP-400 inhibited the cell growth of established mouse pheochromocytoma cell lines and primary human tumor tissue cultures. In a study performed in athymic female mice, LMP-400 demonstrated a significant inhibitory effect on tumor growth with two drug administration regimens. Furthermore, low doses of LMP-400 decreased the protein levels of hypoxia-inducible factor 1 (HIF-1α), one of a family of factors studied as potential metastatic drivers in these tumors. The HIF-1α decrease resulted in changes in the mRNA levels of HIF-1 transcriptional targets. In vitro, LMP-400 showed an increase in the growth-inhibitory effects in combination with other chemotherapeutic drugs that are currently used for the treatment of pheochromocytoma. We conclude that LMP-400 has promising antitumor activity in preclinical models of metastatic pheochromocytoma and its use should be considered in future clinical trials.


A combination of transanal minimally invasive surgery and transanal technique to facilitate suturing during transanal minimally invasive surgery.
Transanal minimally invasive surgery (TAMIS) is an effective option for the local excision of benign, non-invasive rectal lesions, or selected early stage rectal cancers. However, the suturing encountered in TAMIS remains technically challenging. A combination of TAMIS and transanal approach to suturing is demonstrated to address this challenge. A 64-year-old female with a T1N0 adenocarcinoma located in the anterior mid-rectum underwent TAMIS for resection of the lesion. Total operative time was 91 minutes. Free peritoneal defect was closed in two layers. The patient was discharged on postoperative day 1. Final pathology revealed a 0.7 cm T1 well-differentiated adenocarcinoma 0.8 cm from the closest resection margin. The patient remains free of systemic or local recurrence at 24 months. TAMIS is a safe and effective option for removal of benign rectal lesions or selected low grade T1 adenocarcinomas of the rectum. A hybrid TAMIS and transanal approach to suturing may often easily address the technical challenge of pure laparoscopic suturing in TAMIS.


Depression in youth recovering from concussion: Correlates and predictors.
Although depression can be a serious consequence of concussion, little is known about the factors that predict depression and concussion recovery outcomes in children. The purpose of this study was to explore the risk and possible predictors of developing significant depressive symptoms in children recovering from concussion. A prospective cohort study was conducted in a paediatric tertiary care clinic. Depression data were collected from 92 children using the Children's Depression Inventory-2 (CDI-2) screening tool. Correlations, t-tests and logistic regression were used to examine the associations between depression scores and demographic as well as injury-related factors. Depressive symptoms were found in 22% of the children (T score on CDI-2 >65). Children with evidence of depressive symptomatology had significantly higher mean post-concussive symptom inventory (PCSI) scores in recovery (p = 0.004) than children who were not depressed. Variables of i) Sex; ii) hospital admission; iii) number of head injuries; iv) post-concussion symptom score and v) experience of prolonged symptoms were predictive of clinically significant CDI T scores, explaining 36% of the variation in the binary logistic model. Depression is commonly reported in this subset of children. High post-concussive symptom scores and hospital admission were strong predictors of depression. Screening for depression should be standard practice in concussion management in children and youth.


Antigen-binding properties of monoclonal antibodies reactive with EBNA1 and use in immunoaffinity chromatography.
Epstein-Barr virus (EBV) nuclear antigen 1 (EBNA1) was overexpressed and purified from Escherichia coli. Mouse monoclonal antibodies (mAbs) were prepared that react with EBNA1. Eleven high affinity mAbs were recovered. Nine mAbs are isotype IgG (all subisotype IgG(1)) and two mAbs are isotype IgM. All mAbs react strongly with EBNA1 in an ELISA assay while only one mAb (designated 1EB6) fails to react in a Western blot assay. The epitopes for these mAbs were mapped to seven different regions, providing good coverage of the entire EBNA1 protein. The mAbs had differing affinity for an EBNA1/DNA complex with four mAbs able to supershift the complex completely. All mAbs can immunoprecipitate EBNA1 from E. coli overexpressing EBNA1. A modified ELISA assay, termed ELISA-elution assay, was used to screen for mAbs that release EBNA1 in the presence of a low molecular weight polyhydroxylated compound (polyol) and a nonchaotropic salt. MAbs with this property, termed polyol-responsive (PR)-mAbs, allow gentle elution of labile proteins and protein complexes. Four mAbs are polyol-responsive with two showing usefulness in gentle immunoaffinity chromatography. Purification with these PR-mAbs may be useful in purifying EBNA1 complexes and elucidating EBNA1-associated proteins. This panel of anti-EBNA1 mAbs will advance the study of EBV by providing new tools to detect and purify EBNA1.


Effect of physical education and activity levels on academic achievement in children.
This study was conducted to determine the effect of physical education class enrollment and physical activity on academic achievement in middle school children. Participants were 214 sixth-grade students randomly assigned to physical education during either first or second semesters. Moderate and vigorous physical activity (MVPA) (number of 30-min time blocks) outside of school was assessed using the 3-d physical activity recall (3DPAR). The 3DPAR time blocks were converted to ordinal data with scores of 1 (no activity), 2 (some activity), or 3 (activity meeting Healthy People 2010 guidelines). Academic achievement was assessed using grades from four core academic classes and standardized test scores (Terra Nova percentiles). Grades were similar regardless of whether students were enrolled in physical education during first or second semesters. Physical education classes averaged only 19 min of MVPA. Students who either performed some or met Healthy People 2010 guidelines for vigorous activity had significantly higher grades (P < 0.05) than students who performed no vigorous activity in both semesters. Moderate physical activity did not affect grades. Standardized test scores were not significantly related to physical education class enrollment or physical activity levels. Although academic achievement was not significantly related to physical education enrollment, higher grades were associated with vigorous physical activity, particularly activity meeting recommended Healthy People 2010 levels.


Mixed polymer brush as a functional ligand of silica beads for temperature-modulated hydrophobic and electrostatic interactions.
We developed a mixed polymer brush, which consists of temperature-responsive polymer and cationic polymer modified beads as functional chromatographic matrices, for temperature-modulated multiple hydrophobic and electrostatic interactions. The mixed polymer brush was modified on silica beads through the combination of reversible addition-fragmentation chain transfer (RAFT) polymerization of N,N-dimethylaminopropyl acrylamide (DMAPAAm) and surface initiated atom transfer radical polymerization (ATRP) of N-isopropylacrylamide (NIPAAm). Zeta potential measurement of the mixed polymer brush revealed that the zeta potential increased with increasing temperature, which was attributed to the exposed PDMAPAAm on the beads arising from the shrinking of PNIPAAm upon increasing the temperature. The prepared beads were used as the packing material of high performance liquid chromatography (HPLC) columns, and the elution behavior of steroids, adenosine nucleotides, and proteins through the column was observed. The retention time of steroids increased with increasing the column temperature because of the dehydration of PNIPAAm in the mixed polymer brush. Adenosine nucleotides were also retained by the columns, which was attributed to the electrostatic interaction with PDMAPAAm in the mixed polymer brush. Several proteins were adsorbed on the column at elevated temperatures because of the enhanced electrostatic interaction of exposed PDMAPAAm and the enhanced hydrophobic interaction resulting from the dehydration of PNIPAAm. By exploiting this unique property, mixtures of proteins could be separated by simply changing the column temperature. These results indicate that the developed mixed polymer brush modified beads would be useful as functional chromatographic packing matrices for thermally-modulated multiple hydrophobic and electrostatic interactions.


Biochemical and redox characterization of the mediator complex and its associated transcription factor GeBPL, a GLABROUS1 enhancer binding protein.
The eukaryotic mediator integrates regulatory signals from promoter-bound transcription factors (TFs) and transmits them to RNA polymerase II (Pol II) machinery. Although redox signalling is important in adjusting plant metabolism and development, nothing is known about a possible redox regulation of mediator. In the present study, using pull-down and yeast two-hybrid assays, we demonstrate the association of mediator (MED) subunits MED10a, MED28 and MED32 with the GLABROUS1 (GL1) enhancer-binding protein-like (GeBPL), a plant-specific TF that binds a promoter containing cryptochrome 1 response element 2 (CryR2) element. All the corresponding recombinant proteins form various types of covalent oligomers linked by intermolecular disulfide bonds that are reduced in vitro by the thioredoxin (TRX) and/or glutathione/glutaredoxin (GRX) systems. The presence of recombinant MED10a, MED28 and MED32 subunits or changes of its redox state affect the DNA-binding capacity of GeBPL suggesting that redox-driven conformational changes might modulate its activity. Overall, these results advance our understanding of how redox signalling affects transcription and identify mediator as a novel actor in redox signalling pathways, relaying or integrating redox changes in combination with specific TFs as GeBPL.


Liability of commercial and social hosts for alcohol-related injuries: a national survey of accountability norms and judgments.
Legal standards for liability of commercial sellers and social providers of alcoholic beverages are affected by social norms concerning accountability and responsibility. Using a nationwide probability sample telephone survey of 7,021 U.S. residents, we conducted a randomized experiment in which each subject was asked to respond to multiple vignettes. The vignettes told stories of drinking situations, systematically varying dimensions concerning age of drinker, commercial versus social settings, amount of alcohol consumed, history of previous behavior, and seriousness of damage or injury following drinking. Analyses involved linear mixed (i.e., random effects) model regressions, using responses to vignettes as the outcome variable, controlling for a series of sociodemographic, behavioral, and attitudinal measures. Results showed that age of drinker (young), setting (bar), and previous behavior (history of irresponsibility) were most strongly associated with harsher judgments of civil liability. Citizens' multiple standards for assigning legal liability and implications for public policy are discussed.


[Evaluation of insulin resistance and lipid profile in turner syndrome].
To evaluate the presence of insulin resistance (IR) and changes in lipid profile in Turner Syndrome (TS), and to check the influence of age, karyotype, systemic arterial hypertension (SAH), height, weight, body mass index (BMI), and pubertal development. A transversal study of 35 TS patients, confirmed with karyotype (5 to 43 years), without previous use of anabolic steroid or hGH, with evaluation of blood pressure, pubertal development, anthropometric data, measurement of waist (W), hip (H), W to H ratio, total cholesterol, HDL, triglycerides (TGC), LDL, insulin and glucose. HOMA and QUICKI indexes were calculated, as well as glucose to insulin ratio (G/I). Data were examined by the Mann-Whitney and Spearman tests. Ten patients were >20 years. Seventeen had a 45,X karyotype and 6 structural aberrations; differences of the variables in relation to the karyotypes were not observed; 15 were nonpubertal and 20 pubertal; TGC and HOMA were significantly higher in puberty, while G/I was lower. Seven had normal height, 8 had BMI >25 Kg/m2 (6 between 25 and 30, and 2 >30), and 19 W/H >0.85. Cholesterol levels were 180 +/- 42mg% (4 >240); HDL 57 +/- 16mg%; LDL 99 +/- 34 mg%; TGC 108 +/- 96 mg% (2 >200); HOMA 1.01 +/- 0.71; QUICKI 0.4 +/- 0.04 and G/I 23.5 +/- 12.1 (2 <7.0). Changes were observed in lipid profile independent of age, karyotype, SAH and obesity, but associated with IR. The frequency of IR was lower than described in literature, and seems to be directly linked to chronological age, obesity and estrogen therapy.


Primate hippocampus size and organization are predicted by sociality but not diet.
The hippocampus is well known for its roles in spatial navigation and memory, but it is organized into regions that have different connections and functional specializations. Notably, the region CA2 has a role in social and not spatial cognition, as is the case for the regions CA1 and CA3 that surround it. Here, we investigated the evolution of the hippocampus in terms of its size and organization in relation to the evolution of social and ecological variables in primates, namely home range, diet and different measures of group size. We found that the volumes within the whole cornu ammonis coevolve with group size, while only the volume of CA1 and subiculum can also be predicted by home range. On the other hand, diet, expressed as a shift from folivory towards frugivory, was shown to not be related to hippocampal volume. Interestingly, CA2 was shown to exhibit phylogenetic signal only against certain measures of group size, but not with ecological factors. We also found that sex differences in the hippocampus are related to body size sex dimorphism. This is in line with reports of sex differences in hippocampal volume in non-primates that are related to social structure and sex differences in behaviour. Our findings support the notion that in primates, the hippocampus is a mosaic structure evolving in line with social pressures, where certain subsections evolve in line with spatial ability too.


Regeneration of the immunoglobulin heavy-chain repertoire after transient B-cell depletion with an anti-CD20 antibody.
B-cell depletive therapies have beneficial effects in patients suffering from rheumatoid arthritis. Nevertheless, the role of B cells in the pathogenesis of the disease is not clear. In particular, it is not known how the regeneration of the B-cell repertoire takes place. Two patients with active rheumatoid arthritis were treated with rituximab, and the rearranged immunoglobulin heavy-chain genes (Ig-VH) were analysed to follow the B-cell regeneration. Patient A was treated with two courses of rituximab, and B-cell regeneration was followed over 27 months by analysing more than 680 Ig-VH sequences. Peripheral B-cell depletion lasted 7 months and 10 months, respectively, and each time was accompanied by a clinical improvement. Patient B received one treatment course. B-cell depletion lasted 5 months and was accompanied by a good clinical response. B cells regenerated well in both patients, and the repopulated B-cell repertoire was characterised by a polyclonal and diverse use of Ig-VH genes, as expected in adult individuals. During the early phase of B-cell regeneration we observed the expansion and recirculation of a highly mutated B-cell population. These cells expressed very different Ig-VH genes. They were class-switched and could be detected for a short period only. Patient A was followed long term, whereby some characteristic changes in the VH2 family as well as in specific mini-genes like VH3-23, VH 4-34 or VH 1-69 were observed. In addition, rituximab therapy resulted in the loss of clonal B cells for the whole period. Our data show that therapeutic transient B-cell depletion by anti-CD20 antibodies results in the regeneration of a diverse and polyclonal heavy-chain repertoire. During the early phase of B-cell regeneration, highly mutated B cells recirculate for a short time period in both the patients analysed. The longitudinal observation of a single patient up to 27 months shows subtle intraindividual changes, which may indicate repertoire modulation.


Siderophore production by uropathogenic Escherichia coli.
Urinary tract infection (UTI) is one of the most frequently encountered problems in ambulatory medicine. The present study was designed to determine siderophore production as the urovirulence factor of Escherichia coli isolated from the patients of UTI. A total of 160 strains of E. coli isolated from urine of patients with clinically diagnosed UTI were included in the study and 50 fecal isolates of E. coli, siderophore production was seen in 156 (97.5%). In 50 fecal isolates, siderophore production was seen in 2 (4%). Siderophore production has been shown to be more frequent in E. coli from patients with UTI, than in fecal isolates. The results suggest that siderophore production positive strains can be considered as UPEC. Thus, although a great deal has been learned regarding E. coli virulence mechanisms in UTI, much remains to be learned and the practical application of our growing understanding of E. coli virulence factors to the prevention and treatment of UTI has to be continued.


Transformation of coffee-growing landscapes across Latin America. A review.
In Latin America, the cultivation of Arabica coffee (Coffea arabica) plays a critical role in rural livelihoods, biodiversity conservation, and sustainable development. Over the last 20 years, coffee farms and landscapes across the region have undergone rapid and profound biophysical changes in response to low coffee prices, changing climatic conditions, severe plant pathogen outbreaks, and other drivers. Although these biophysical transformations are pervasive and affect millions of rural livelihoods, there is limited information on the types, location, and extent of landscape changes and their socioeconomic and ecological consequences. Here we review the state of knowledge on the ongoing biophysical changes in coffee-growing regions, explore the potential socioeconomic and ecological impacts of these changes, and highlight key research gaps. We identify seven major land-use trends which are affecting the sustainability of coffee-growing regions across Latin America in different ways. These trends include (1) the widespread shift to disease-resistant cultivars, (2) the conventional intensification of coffee management with greater planting densities, greater use of agrochemicals and less shade, (3) the conversion of coffee to other agricultural land uses, (4) the introduction of Robusta coffee (Coffea canephora) into areas not previously cultivated with coffee, (5) the expansion of coffee into forested areas, (6) the urbanization of coffee landscapes, and (7) the increase in the area of coffee produced under voluntary sustainability standards. Our review highlights the incomplete and scattered information on the drivers, patterns, and outcomes of biophysical changes in coffee landscapes, and lays out a detailed research agenda to address these research gaps and elucidate the effects of different landscape trajectories on rural livelihoods, biodiversity conservation, and other aspects of sustainable development. A better understanding of the drivers, patterns, and consequences of changes in coffee landscapes is vital for informing the design of policies, programs, and incentives for sustainable coffee production. The online version contains supplementary material available at 10.1007/s13593-021-00712-0.


HIV-1 capsid uncoating initiates after the first strand transfer of reverse transcription.
Correct disassembly of the HIV-1 capsid shell, called uncoating, is increasingly recognised as central for multiple steps during retroviral replication. However, the timing, localisation and mechanism of uncoating are poorly understood and progress in this area is hampered by difficulties in measuring the process. Previous work suggested that uncoating occurs soon after entry of the viral core into the cell, but recent studies report later uncoating, at or in the nucleus. Furthermore, inhibiting reverse transcription delays uncoating, linking these processes. Here, we have used a combined approach of experimental interrogation of viral mutants and mathematical modelling to investigate the timing of uncoating with respect to reverse transcription. By developing a minimal, testable, model and employing multiple uncoating assays to overcome the disadvantages of each single assay, we find that uncoating is not concomitant with the initiation of reverse transcription. Instead, uncoating appears to be triggered once reverse transcription reaches a certain stage, namely shortly after first strand transfer. Using multiple approaches, we have identified a point during reverse transcription that induces uncoating of the HIV-1 CA shell. We propose that uncoating initiates after the first strand transfer of reverse transcription.


Synthetic lethal screening with small-molecule inhibitors provides a pathway to rational combination therapies for melanoma.
Recent data show that extracellular signals are transmitted through a network of proteins rather than hierarchical signaling pathways, suggesting that the inhibition of a single component of a canonical pathway is insufficient for the treatment of cancer. The biologic outcome of signaling through a network is inherently more robust and resistant to inhibition of a single network component. In this study, we conducted a functional chemical genetic screen to identify novel interactions between signaling inhibitors that would not be predicted on the basis of our current understanding of signaling networks. We screened over 300 drug combinations in nine melanoma cell lines and have identified pairs of compounds that show synergistic cytotoxicity. The synergistic cytotoxicities identified did not correlate with the known RAS and BRAF mutational status of the melanoma cell lines. Among the most robust results was synergy between sorafenib, a multikinase inhibitor with activity against RAF, and diclofenac, a nonsteroidal anti-inflammatory drug (NSAID). Drug substitution experiments using the NSAIDs celecoxib and ibuprofen or the MAP-ERK kinase inhibitor PD325901 and the RAF inhibitor RAF265 suggest that inhibition of COX and mitogen-activated protein kinase signaling are targets for the synergistic cytotoxicity of sorafenib and diclofenac. Cotreatment with sorafenib and diclofenac interrupts a positive feedback signaling loop involving extracellular signal-regulated kinase, cellular phospholipase A2, and COX. Genome-wide expression profiling shows synergy-specific downregulation of survival-related genes. This study has uncovered novel functional drug combinations and suggests that the underlying signaling networks that control responses to targeted agents can vary substantially, depending on unexplored components of the cell genotype.


The evolution of compositionally and functionally distinct actin filaments.
The actin filament is astonishingly well conserved across a diverse set of eukaryotic species. It has essentially remained unchanged in the billion years that separate yeast, Arabidopsis and man. In contrast, bacterial actin-like proteins have diverged to the extreme, and many of them are not readily identified from sequence-based homology searches. Here, we present phylogenetic analyses that point to an evolutionary drive to diversify actin filament composition across kingdoms. Bacteria use a one-filament-one-function system to create distinct filament systems within a single cell. In contrast, eukaryotic actin is a universal force provider in a wide range of processes. In plants, there has been an expansion of the number of closely related actin genes, whereas in fungi and metazoa diversification in tropomyosins has increased the compositional variety in actin filament systems. Both mechanisms dictate the subset of actin-binding proteins that interact with each filament type, leading to specialization in function. In this Hypothesis, we thus propose that different mechanisms were selected in bacteria, plants and metazoa, which achieved actin filament compositional variation leading to the expansion of their functional diversity.


The Role of Walking Experience in the Emergence of Gait Harmony in Typically Developing Toddlers.
The ability to walk without support usually develops in the first year of a typically developing toddler's life and matures further in the following years. Mature walking is characterized by the correct timing of the different gait phases that make up a full gait cycle formed by stance, swing, and double support phases. The harmony of mature walking is given by a specific self-similar structure of the ratios between the durations of these phases (stride/stance, stance/swing, swing/double support), that in adults all converge to the golden ratio (phi, about 1.618). The aim of this longitudinal, prospective, experimental study was to investigate the evolution of this gait harmonic structure in the transition from supported to independent walking. In total, 27 children were recruited and recorded at various stages of locomotor development, ranging from neonatal stepping up to an independent walking experience of about six months. Differently from walking speed that progressively increased with age, the gait phase ratios started to converge to golden value only after the first independent steps, suggesting a relation to the maturation of the walking experience. The independent walking experience seems to represent a trigger for the evolution of a locomotor harmonic pattern in toddlers learning to walk.


Clinical effect of treating secondary asthma attacks of children Mycoplasma pneumoniae with combined therapy of montelukast and azithromycin.
To discuss the clinical effects of treating secondary asthma attacks of children Mycoplasma pneumoniae with combined therapy of montelukast and azithromycin. 96 children patients diagnosed with secondary asthma attacks of Mycoplasma pneumonia were enrolled in this study. They were randomly divided into two groups: the control group (n=49) and the observation group (n=47). Patients in the control group received combined therapy using azithromycin and bronchodilators or glucocorticoid, and patients in the observation group received a combined therapy of montelukast, azithromycin and bronchodilators or glucocorticoid. The lung function indexes, T lymphocyte subpopulation, cytokines levels, positive rate of lgG and lgM, asthma control rate and recurrence rate were compared between groups before and after treatment. The levels of V-T, t-PTEF/t-E, MTIF/MTEF and TEF25/PTEF in both groups increased after treatment, but we observed a more significant improvement in the observation group. The CD4+ and CD4+/CD8+ levels in both groups also increased after the intervention, while the level of CD8+ decreased. The IL-10, IL-17 and TGF-β levels decreased more intensely in the observation group. The positive rate of lgG and lgM in both groups decreased significantly after the intervention. In the observation group, the asthma control rate was higher while the recurrence rate was lower. Although montelukast had little effect on improving the immune function, it was certainly beneficial for controlling the symptoms of asthma and improving the prognosis. Using combined therapy of montelukast and azithromycin for treating the secondary asthma attacks of children mycoplasma pneumonia can relieve immunological and inflammatory reactions and improve the lung function.


Single-crystal nanopyramidal BGaN by nanoselective area growth on AlN/Si(111) and GaN templates.
We report nano-selective area growth (NSAG) of BGaN by MOCVD on AlN/Si(111) and GaN templates resulting in 150 nm single crystalline nanopyramids. This is in contrast to unmasked or micro-selective area growth, which results in a multi-crystalline structure on both substrates. Various characterization techniques were used to evaluate NSAG as a viable technique to improve BGaN material quality on AlN/Si(111) using results of GaN NSAG and unmasked BGaN growth for comparison. Evaluation of BGaN nanopyramid quality, shape and size uniformity revealed that the growth mechanism is the same on both the templates. Further STEM analysis of BGaN nanopyramids on AlN/Si (111) templates confirmed that these are single-crystalline structures without any dislocations, likely due to single nucleation occurring in the 80 nm mask opening. CL results correspond to boron content between 1.7% and 2.0% in the nanopyramids. We conclude that NSAG is promising for growth of high-quality BGaN nanostructures and complex nano-heterostructures, especially for low-cost silicon substrates.


Changes in trends and outcomes of eclampsia: a success story from Qatar.
Background: Preeclampsia and eclampsia are two hypertensive disorders of pregnancy that significantly contribute to higher morbidity and mortality rates. Eclampsia is the occurrence of seizures in patients with preeclampsia without any previous history of seizure disorders. The incidence and prevalence of eclampsia varies, and there is scarce literature about the prevalence and trends of eclampsia in the Arabian Gulf countries. This study aimed to identify the incidence and changing trends of eclampsia in Qatar. Patients and Methods: This retrospective study was conducted at Hamad Medical Corporation, the only tertiary heathcare center in Qatar, and included all patients admitted with eclampsia from 1979 to 2017. The demographic data, maternal age, parity, gestational age, antenatal visits, timing of seizures, mode of delivery, treatment, maternal morbidity, and mortality were recorded. The study period was divided into the initial period of 1979-1988, 1991-2009, and the recent period of 2010-2017. Data analysis was performed using chi-square tests to identify trends among the three different periods. A p value of ≤ 0.05 (two-tailed) was considered statistically significant. Results: A total of 151 patients with eclampsia were admitted with an increasing incidence of eclampsia over time. There was a statistically significant improvement in antenatal follow-up and an increase in the maternal age of patients with eclampsia (p = 0.001). The incidence of eclampsia without proteinuria increased significantly over time (p = 0.03). Postpartum eclampsia was more common (p = 0.002). Labetalol was the most frequently used antihypertensive agent (p = 0.001), and magnesium sulfate has been increasingly used as an anticonvulsant agent (p = 0.001). The rate of maternal morbidity was decreasing, and in the recent period, posterior reversible encephalopathy syndrome was becoming a common comorbidity in patients with eclampsia. Maternal mortality displayed significant improvement, reaching 0% in the recent study period (p = 0.02). Perinatal mortality likewise displayed a decreasing trend and reached 3.17% in the recent period. Conclusion: The incidence of eclampsia is increasing in Qatar. The antenatal care of patients with eclampsia has improved significantly. The medical management of patients with eclampsia has also drastically improved, leading to a significant decrease in maternal mortality and improvement in perinatal outcomes.


Initial nitrous oxide, carbon dioxide, and methane costs of converting conservation reserve program grassland to row crops under no-till vs. conventional tillage.
Around 4.4 million ha of land in USDA Conservation Reserve Program (CRP) contracts will expire between 2013 and 2018 and some will likely return to crop production. No-till (NT) management offers the potential to reduce the global warming costs of CO2 , CH4 , and N2 O emissions during CRP conversion, but to date there have been no CRP conversion tillage comparisons. In 2009, we converted portions of three 9-21 ha CRP fields in Michigan to conventional tillage (CT) or NT soybean production and reserved a fourth field for reference. Both CO2 and N2 O fluxes increased following herbicide application in all converted fields, but in the CT treatment substantial and immediate N2 O and CO2 fluxes occurred after tillage. For the initial 201-day conversion period, average daily N2 O fluxes (g N2 O-N ha(-1) d(-1) ) were significantly different in the order: CT (47.5 ± 6.31, n = 6) ≫ NT (16.7 ± 2.45, n = 6) ≫ reference (2.51 ± 0.73, n = 4). Similarly, soil CO2 fluxes in CT were 1.2 times those in NT and 3.1 times those in the unconverted CRP reference field. All treatments were minor sinks for CH4 (-0.69 ± 0.42 to -1.86 ± 0.37 g CH4 -C ha(-1) d(-1) ) with no significant differences among treatments. The positive global warming impact (GWI) of converted soybean fields under both CT (11.5 Mg CO2 e ha(-1) ) and NT (2.87 Mg CO2 e ha(-1) ) was in contrast to the negative GWI of the unconverted reference field (-3.5 Mg CO2 e ha(-1) ) with on-going greenhouse gas (GHG) mitigation. N2 O contributed 39.3% and 55.0% of the GWI under CT and NT systems with the remainder contributed by CO2 (60.7% and 45.0%, respectively). Including foregone mitigation, we conclude that NT management can reduce GHG costs by ~60% compared to CT during initial CRP conversion.


A functional magnetic resonance imaging technique based on nulling extravascular gray matter signal.
A new functional magnetic resonance imaging (fMRI) technique is proposed based on nulling the extravascular gray matter (GM) signal, using a spatially nonselective inversion pulse. The remaining MR signal provides cerebral blood volume (CBV) information from brain activation. A theoretical framework is provided to characterize the sources of GM-nulled (GMN) fMRI signal, effects of partial voluming of cerebrospinal fluid (CSF) and white matter, and behaviors of GMN fMRI signal during brain activation. Visual stimulation paradigm was used to explore the GMN fMRI signal behavior in the human brain at 3T. It is shown that the GMN fMRI signal increases by 7.2%+/-1.5%, which is two to three times more than that obtained with vascular space occupancy (VASO)-dependent fMRI (-3.2%+/-0.2%) or blood oxygenation level-dependent (BOLD) fMRI (2.9%+/-0.7%), using a TR of 3,000 ms and a resolution of 2 x 2 x 5 mm(3). Under these conditions the fMRI signal-to-noise ratio (SNR(fMRI)) for BOLD, GMN, and VASO images was 4.97+/-0.76, 4.56+/-0.86, and 2.43+/-1.06, respectively. Our study shows that both signal intensity and activation volume in GMN fMRI depend on spatial resolution because of partial voluming from CSF. It is shown that GMN fMRI is a convenient tool to assess CBV changes associated with brain activation.


Loss or duplication of key regulatory genes coincides with environmental adaptation of the stomatal complex in Nymphaea colorata and Kalanchoe laxiflora.
The stomatal complex is critical for gas and water exchange between plants and the atmosphere. Originating over 400 million years ago, the structure of the stomata has evolved to facilitate the adaptation of plants to various environments. Although the molecular mechanism of stomatal development in Arabidopsis has been widely studied, the evolution of stomatal structure and its molecular regulators in different species remains to be answered. In this study, we examined stomatal development and the orthologues of Arabidopsis stomatal genes in a basal angiosperm plant, Nymphaea colorata, and a member of the eudicot CAM family, Kalanchoe laxiflora, which represent the adaptation to aquatic and drought environments, respectively. Our results showed that despite the conservation of core stomatal regulators, a number of critical genes were lost in the N. colorata genome, including EPF2, MPK6, and AP2C3 and the polarity regulators BASL and POLAR. Interestingly, this is coincident with the loss of asymmetric divisions during the stomatal development of N. colorata. In addition, we found that the guard cell in K. laxiflora is surrounded by three or four small subsidiary cells in adaxial leaf surfaces. This type of stomatal complex is formed via repeated asymmetric cell divisions and cell state transitions. This may result from the doubled or quadrupled key genes controlling stomatal development in K. laxiflora. Our results show that loss or duplication of key regulatory genes is associated with environmental adaptation of the stomatal complex.


Aerosol Absorption: Progress Towards Global and Regional Constraints.
Some aerosols absorb solar radiation, altering cloud properties, atmospheric stability and circulation dynamics, and the water cycle. Here we review recent progress towards global and regional constraints on aerosol absorption from observations and modeling, considering physical properties and combined approaches crucial for understanding the total (natural and anthropogenic) influences of aerosols on the climate. We emphasize developments in black carbon absorption alteration due to coating and ageing, brown carbon characterization, dust composition, absorbing aerosol above cloud, source modeling and size distributions, and validation of high-resolution modeling against a range of observations. Both observations and modeling of total aerosol absorption, absorbing aerosol optical depths and single scattering albedo, as well as the vertical distribution of atmospheric absorption, still suffer from uncertainties and unknowns significant for climate applications. We offer a roadmap of developments needed to bring the field substantially forward.


Heat acclimation responses of an ultra-endurance running group preparing for hot desert-based competition.
Heat acclimation induces adaptations that improve exercise tolerance in hot conditions. Here we report novel findings into the effects of ultra-marathon specific exercise load in increasing hot ambient conditions on indices of heat acclimation. Six male ultra-endurance runners completed a standard pre-acclimation protocol at 20°C ambient temperature (T amb), followed by a heat acclimation protocol consisting of six 2 h running exercise-heat exposures (EH) at 60% VO2max on a motorised treadmill in an environmental chamber. Three EH were performed at 30°C T amb, followed by another three EH at 35°C T amb. EH were separated by 48 h within T amb and 72 h between T amb. Nude body mass (NBM), blood and urine samples were collected pre-exercise; while NBM and urine were collected post-exercise. Rectal temperature (T re), heart rate (HR), thermal comfort rating (TCR) and rating of perceived exertion were measured pre-exercise and monitored every 5 min during exercise. Water was provided ad libitum during exercise. Data were analysed using a repeated measures and one-way analysis of variance (ANOVA), with post hoc Tukey's HSD. Significance was accepted as P< 0.05. Overall mean T re was significantly lower during 30°C EH3 and 35°C EH3 compared with their respective EH1 (-0.20 and-0.23°C, respectively; P<0.05). Similarly, overall mean HR was significantly lower during 30°C EH3 and 35°C EH3 compared with their respective EH1 (8 and 7 bpm respectively; P<0.05). A significant decrease in overall mean TCR was observed during 35°C EH3, compared with 35°C EH1 (P< 0.05). Significant increases in resting pre-exercise plasma volume (estimated from Hb and Hct) were observed by 30°C EH3 (7.9%; P< 0.05). Thereafter, plasma volume remained above baseline throughout the experimental protocol. Two EH of 2 h at 60% VO2max at 30°C T amb was sufficient to initiate heat acclimation in all ultra-endurance runners. Further, heat acclimation responses occurred with increasing EH to 35°C T amb. Preventing exertional heat illnesses and optimising performance outcomes in ultra-endurance runners may occur with exposure to at least 2 h of exercise-heat stress on at least two occasions in the days leading up to multi-stage ultra-marathon competition in the heat.


Pharmacokinetics of oral methamphetamine and effects of repeated daily dosing in humans.
The pharmacokinetics of orally administered S-(+)-methamphetamine-d3 were investigated in human male volunteers before and after a 13-day course of a slow release form of S-methamphetamine hydrochloride. A one-compartment pharmacokinetic model incorporating a lag time fits the data best. The average elimination half-life was 10.1 hr (range of 6.4-15.1 hr). There were no statistically significant differences in pharmacokinetic parameters when a low dose (0.125 mg/kg) was given before and after the 13-day oral regimen. When a higher challenge dose (0.250 mg/kg) was used, the maximum plasma concentration of methamphetamine-d3 was slightly but significantly greater when the test dose was given at the end of the oral dosing period than when it was given at the beginning. Although minor differences in pharmacokinetics occur after subchronic treatment with low doses of methamphetamine, their result would be to increase plasma concentration of the drug. Therefore, development of pharmacodynamic tolerance to methamphetamine could not be explained on the grounds of a change in pharmacokinetics.


M680I/M694V Heterozygous Mutation in Early Onset Familial Mediterranean Fever.
Familial Mediterranean fever (FMF) is a hereditary autoinflammatory disorder affecting individuals with biallelic pathogenic mutations in the MEFV gene. The disease is characterized by recurrent attacks of fever and serosal inflammation as manifested by abdominal and chest pain. This case report presents an FMF case with a 3-year history of pain crises consisting of severe abdominal pain and fever, lasting up to 72 h. Genetic investigation identified an uncommon heterozygous mutation in the MEFV gene. This mutation is associated with a more severe phenotype of FMF and may lead to an early onset of the disease.


Cardiomyocyte-enriched protein CIP protects against pathophysiological stresses and regulates cardiac homeostasis.
Cardiomyopathy is a common human disorder that is characterized by contractile dysfunction and cardiac remodeling. Genetic mutations and altered expression of genes encoding many signaling molecules and contractile proteins are associated with cardiomyopathy; however, how cardiomyocytes sense pathophysiological stresses in order to then modulate cardiac remodeling remains poorly understood. Here, we have described a regulator in the heart that harmonizes the progression of cardiac hypertrophy and dilation. We determined that expression of the myocyte-enriched protein cardiac ISL1-interacting protein (CIP, also known as MLIP) is reduced in patients with dilated cardiomyopathy. As CIP is highly conserved between human and mouse, we evaluated the effects of CIP deficiency on cardiac remodeling in mice. Deletion of the CIP-encoding gene accelerated progress from hypertrophy to heart failure in several cardiomyopathy models. Conversely, transgenic and AAV-mediated CIP overexpression prevented pathologic remodeling and preserved cardiac function. CIP deficiency combined with lamin A/C deletion resulted in severe dilated cardiomyopathy and cardiac dysfunction in the absence of stress. Transcriptome analyses of CIP-deficient hearts revealed that the p53- and FOXO1-mediated gene networks related to homeostasis are disturbed upon pressure overload stress. Moreover, FOXO1 overexpression suppressed stress-induced cardiomyocyte hypertrophy in CIP-deficient cardiomyocytes. Our studies identify CIP as a key regulator of cardiomyopathy that has potential as a therapeutic target to attenuate heart failure progression.


Effects of the endocrine-disrupting chemical DDT on self-renewal and differentiation of human mesenchymal stem cells.
Although the global use of the endocrine-disrupting chemical DDT has decreased, its persistence in the environment has resulted in continued human exposure. Accumulating evidence suggests that DDT exposure has long-term adverse effects on development, yet the impact on growth and differentiation of adult stem cells remains unclear. Human mesenchymal stem cells (MSCs) exposed to DDT were used to evaluate the impact on stem cell biology. We assessed DDT-treated MSCs for self-renewal, proliferation, and differentiation potential. Whole genome RNA sequencing was performed to assess gene expression in DDT-treated MSCs. MSCs exposed to DDT formed fewer colonies, suggesting a reduction in self-renewal potential. DDT enhanced both adipogenic and osteogenic differentiation, which was confirmed by increased mRNA expression of glucose transporter type 4 (GLUT4), lipoprotein lipase (LpL), peroxisome proliferator-activated receptor gamma (PPARγ), leptin, osteonectin, core binding factor 1 (CBFA1), and FBJ murine osteosarcoma viral oncogene homolog (c-Fos). Expression of factors in DDT-treated cells was similar to that in estrogen-treated MSCs, suggesting that DDT may function via the estrogen receptor (ER)-mediated pathway. The coadministration of ICI 182,780 blocked the effects of DDT. RNA sequencing revealed 121 genes and noncoding RNAs to be differentially expressed in DDT-treated MSCs compared with controls cells. Human MSCs provide a powerful biological system to investigate and identify the molecular mechanisms underlying the effects of environmental agents on stem cells and human health. MSCs exposed to DDT demonstrated profound alterations in self-renewal, proliferation, differentiation, and gene expression, which may partially explain the homeostatic imbalance and increased cancer incidence among those exposed to long-term EDCs.


Cost-effectiveness of anti-retroviral therapy at a district hospital in southern Ethiopia.
As the resource implications of expanding anti-retroviral therapy (ART) are likely to be large, there is a need to explore its cost-effectiveness. So far, there is no such information available from Ethiopia. To assess the cost-effectiveness of ART for routine clinical practice in a district hospital setting in Ethiopia. We estimated the unit cost of HIV-related care from the 2004/5 fiscal year expenditure of Arba Minch Hospital in southern Ethiopia. We estimated outpatient and inpatient service use from HIV-infected patients who received care and treatment at the hospital between January 2003 and March 2006. We measured the health effect as life years gained (LYG) for patients receiving ART compared with those not receiving such treatment. The study adopted a health care provider perspective and included both direct and overhead costs. We used Markov model to estimate the lifetime costs, health benefits and cost-effectiveness of ART. ART yielded an undiscounted 9.4 years expected survival, and resulted in 7.1 extra LYG compared to patients not receiving ART. The lifetime incremental cost is US$2,215 and the undiscounted incremental cost per LYG is US$314. When discounted at 3%, the additional LYG decreases to 5.5 years and the incremental cost per LYG increases to US$325. The undiscounted and discounted incremental costs per LYG from introducing ART were less than the per capita GDP threshold at the base year. Thus, ART could be regarded as cost-effective in a district hospital setting in Ethiopia.


Electrically Controllable Single-Point Covalent Functionalization of Spin-Cast Carbon-Nanotube Field-Effect Transistor Arrays.
Single-point-functionalized carbon-nanotube field-effect transistors (CNTFETs) have been used to sense conformational changes and binding events in protein and nucleic acid structures from intrinsic molecular charge. The key to utilizing these devices as single-molecule sensors is the ability to attach a single probe molecule to an individual device. In contrast, with noncovalent attachment approaches such as those based on van der Waals interactions, covalent attachment approaches generally deliver higher stability but have traditionally been more difficult to control, resulting in low yield. Here, we present a single-point-functionalization method for CNTFET arrays based on electrochemical control of a diazonium reaction to create sp3 defects, combined with a scalable spin-casting method for fabricating large arrays of devices on arbitrary substrates. Attachment of probe DNA to the functionalized device enables single-molecule detection of DNA hybridization with complementary target, verifying the single-point functionalization. Overall, this method enables single-point defect generation with 80% yield.


Metagenomics and Bioinformatics in Microbial Ecology: Current Status and Beyond.
Metagenomic approaches are now commonly used in microbial ecology to study microbial communities in more detail, including many strains that cannot be cultivated in the laboratory. Bioinformatic analyses make it possible to mine huge metagenomic datasets and discover general patterns that govern microbial ecosystems. However, the findings of typical metagenomic and bioinformatic analyses still do not completely describe the ecology and evolution of microbes in their environments. Most analyses still depend on straightforward sequence similarity searches against reference databases. We herein review the current state of metagenomics and bioinformatics in microbial ecology and discuss future directions for the field. New techniques will allow us to go beyond routine analyses and broaden our knowledge of microbial ecosystems. We need to enrich reference databases, promote platforms that enable meta- or comprehensive analyses of diverse metagenomic datasets, devise methods that utilize long-read sequence information, and develop more powerful bioinformatic methods to analyze data from diverse perspectives.


Social factors matter in cancer risk and survivorship.
Greater attention to social factors, such as race/ethnicity, socioeconomic position, and others, are needed across the cancer continuum, including breast cancer, given differences in tumor biology and genetic variants have not completely explained the persistent Black/White breast cancer mortality disparity. In this commentary, we use examples in breast cancer risk assessment and survivorship to demonstrate how the failure to appropriately incorporate social factors into the design, recruitment, and analysis of research studies has resulted in missed opportunities to reduce persistent cancer disparities. The conclusion offers recommendations for how to better document and use information on social factors in cancer research and care by (1) increasing education and awareness about the importance of inclusion of social factors in clinical research; (2) improving testing and documentation of social factors by incorporating them into journal guidelines and reporting stratified results; and (3) including social factors to refine extant tools that assess cancer risk and assign cancer care. Implementing the recommended changes would enable more effective design and implementation of interventions and work toward eliminating cancer disparities by accounting for the social and environmental contexts in which cancer patients live and are treated.


Glutamate: its role in learning, memory, and the aging brain.
L-Glutamate is the most abundant of a group of endogenous amino acids in the mammalian central nervous system which presumably function as excitatory neurotransmitters and under abnormal conditions may behave as neurotoxins. As neurotransmitters, these compounds are thought to play an important role in functions of learning and memory. As neurotoxins, they are believed to be involved in the pathogenesis of a variety of neurodegenerative disorders in which cognition is impaired. Moreover, brain structures which are considered anatomical substrata for learning and memory may be particularly vulnerable to the neurotoxic actions of these excitatory amino acids, especially in the elderly who are also the segment of the population most susceptible to impairments of mnemonic function. This paper is a review of data concerning the role of excitatory amino acids in the processes of learning and memory and in the pathogenesis and treatment of disorders thereof.


Synthesis and characterization of a flexible metal organic framework generated from MnIII and the 4,4'-bipyrazolate-ligand.
The synthesis and crystal structure of a novel metal organic framework, constructed from MnIII, the 4,4'-bipyrazolate (BPZ) ligand and bridging hydroxyl groups is presented in this work. The network topology is identical to M-CFA-6 (M = Fe, Ga), but in the case of Mn-CFA-6, the structure crystallizes in the monoclinic crystal system due to the Jahn-Teller effect of the high spin d4 manganese(iii) centers. Thermal treatment of Mn-CFA-6 leads to decomposition of the framework above 150 °C. The porosity of Mn-CFA-6 was measured by carbon dioxide sorption, since solvent exchange and removal of the occluded solvent molecules leads to a compression of the pores. Electronic spectra of Mn-CFA-6 reveal two distinct absorption bands that are assigned to the two different manganese(iii) centers as revealed by the single crystal structure analysis. Furthermore, SQUID measurements exhibit ferromagnetic behaviour of Mn-CFA-6 below the magnetic ordering at 45 K and antiferromagnetic coupling above this temperature. Evaluation of the paramagnetic region by the Curie-Weiß formula reveals an effective moment of 4.8μB, which is very close to the spin-only value of MnIII centers.


Safety, tolerability, and efficacy of cyclosporine microemulsion in heart transplant recipients: a randomized, multicenter, double-blind comparison with the oil-based formulation of cyclosporine--results at 24 months after transplantation.
The widespread use of cyclosporine has improved the survival of cardiac transplant patients as a result of reduced morbidity and mortality from rejection and infection. The original oil-based form of cyclosporine demonstrated unpredictable absorption resulting in an increased frequency of acute and chronic rejection in patients with poor bioavailability. The primary end. points of the present, prospective, randomized multicenter, double-blind trial were to compare the efficacy of the micro-emulsion form of cycolsporine (CsA-NL) with the oil-based formulation as determined by cardiac allograft and recipient survival and the incidence and severity of the acute rejection episodes and to determine the safety and tolerability of CsA-NL compared with Sandimmune CsA-(SM) in the study population. The 6-month analysis of the study showed reduced number of CsA-NL patients requiring antilymphocyte antibody therapy for rejection, fewer International Society of Heart and Lung Transplantation grade > or =3A rejections in female patients and fewer infections. Our report represents the final analysis of the results 24 months after transplantation. A total of 380 patients undergoing de novo cardiac transplants at 24 centers in the United States, Canada, and Europe were enrolled in this double-blind, randomized trial evaluating the efficacy and safety of CsA-NL versus CsA-SM. Acute allograft rejection was diagnosed by endomyocardial biopsy and graded according to the International Society of Heart and Lung Transplantation nomenclature. Kaplan-Meier analysis and Fisher's exact test were used for comparisons between groups. After 24 months, allograft and recipient survival were identical in both groups. There were fewer CsA-NL patients (6.9%) requiring antilymphocyte antibody therapy for rejection than in the CsA-SM-treated patient group (17.7%, P=0.002). There were fewer discontinuations of study drug for treatment failures in the CsA-NL groups (7; 3.7%) compared with the CsA-SM group (18; 9.4%, P=0.037). The average corticosteroid dose was lower in the CsA-NL group (0.37 mg/kg/day) compared with the CsA-SM group (0.48 mg/kg/day, P=0.034) over the 24-month study period. Overall, there was no difference in blood pressure or creatinine between the two study groups. The final results of this multi-center, randomized study of two forms of cyclosporine confirmed that there were fewer episodes of rejection requiring antilymphocyte antibodies and fewer study discontinuations for treatment failures in CsA-NL-treated patients compared to those treated with CsA-SM. The use of CsA-NL did not predispose these patients to a higher risk of adverse events.


Desulfovibrio profundus sp. nov., a novel barophilic sulfate-reducing bacterium from deep sediment layers in the Japan Sea.
Several strains of a strictly anaerobic, vibrio-shaped or sigmoid, sulfate-reducing bacterium were isolated from deep marine sediments (depth, 80 and 500 m) obtained from the Japan Sea (Ocean Drilling Program Leg 128, site 798B). This bacterium was identified as a member of the genus Desulfovibrio on the basis of the presence of desulfoviridin and characteristic phospholipid fatty acids (iso 17:1 omega 7 and iso 15:0), the small number of growth substrates utilized (lactate, pyruvate, and hydrogen), and 16S rRNA gene sequence analysis data. Based on data for 16S rRNA sequences (1,369 bp), all of the Japan Sea strains were identical to each other and were most closely related to Desulfovibrio salexigens and less closely related to Desulfovibrio desulfuricans (levels of similarity, 91 and 89.6%, respectively). There were, however, considerable phenotypic differences (in temperatures, pressures, and salinities tolerated, growth substrates, and electron donors) between the Japan Sea isolates and the type strains of previously described desulfovibrios, as well as important differences among the Japan Sea isolates. The Japan Sea isolates were active (with sulfide production) over a wide temperature range (15 to 65 degrees C) and a wide sodium chloride concentration range (0.2 to 10%) (moderate halophile), and they were barophiles that were active at pressures up to about 40 MPa (400 atm). The optimum pressures for activity corresponded to the calculated pressures at the depths from which the organisms were isolated (for isolates obtained at depths of 80 and 500 m the optimum activities occurred at 10 and 15 MPa, respectively [100 and 150 atm, respectively]). This confirms that the organisms came from deep sediments and indicates that they are well-adapted for deep sediment conditions, which is consistent with other characteristics (utilization of hydrogen, fermentation, and utilization of ferric iron and organic sulfonates as electron acceptors). We propose that Japan Sea isolate 500-1 is the type strain of a new species, Desulfovibrio profundus.


The nuclear factor-kappaB pathway controls the progression of prostate cancer to androgen-independent growth.
Typically, the initial response of a prostate cancer patient to androgen ablation therapy is regression of the disease. However, the tumor will progress to an "androgen-independent" stage that results in renewed growth and spread of the cancer. Both nuclear factor-kappaB (NF-kappaB) expression and neuroendocrine differentiation predict poor prognosis, but their precise contribution to prostate cancer progression is unknown. This report shows that secretory proteins from neuroendocrine cells will activate the NF-kappaB pathway in LNCaP cells, resulting in increased levels of active androgen receptor (AR). By blocking NF-kappaB signaling in vitro, AR activation is inhibited. In addition, the continuous activation of NF-kappaB signaling in vivo by the absence of the IkappaBalpha inhibitor prevents regression of the prostate after castration by sustaining high levels of nuclear AR and maintaining differentiated function and continued proliferation of the epithelium. Furthermore, the NF-kappaB pathway was activated in the ARR(2)PB-myc-PAI (Hi-myc) mouse prostate by cross-breeding into a IkappaBalpha(+/-) haploid insufficient line. After castration, the mouse prostate cancer continued to proliferate. These results indicate that activation of NF-kappaB is sufficient to maintain androgen-independent growth of prostate and prostate cancer by regulating AR action. Thus, the NF-kappaB pathway may be a potential target for therapy against androgen-independent prostate cancer.


In vitro and in vivo anticancer action of Saquinavir-NO, a novel nitric oxide-derivative of the protease inhibitor saquinavir, on hormone resistant prostate cancer cells.
The NO-derivative of the HIV protease inhibitor saquinavir (Saq-NO) is a nontoxic variant of the parental drug with enhanced anticancer activity on several cell lines. However, it is still unclear whether the p53 status of the target cell might influence the sensitivity to Saq-NO. In this study we evaluated the in vitro and in vivo activity of Saq-NO on the p53-deficient hormone resistant prostate cancer PC-3 cells. We demonstrate that the absence of functional p53 is not essential for the capacity of Saq-NO to reduce prostate cancer cell growth. In contrast to its previously described cytostatic action in B16 and C6 cell lines, Saq-NO exerted cytotoxic effects in PC-3 cells leading to dominant induction of apoptosis and enhanced production of proapoptotic Bim. In addition, differently from saquinavir, Saq-NO restored TRAIL sensitivity that was correlated with increased expression of DR5 independent from ROS/RNS production and YY1 repression. NF-κB activation may be responsible of the Saq-NO induced DR5 expression. Moreover, Saq-NO but not saquinavir, exerted synergistic activity with conventional cytostatic therapy. In agreement with these in vitro studies, Saq-NO inhibited the in vivo growth of PC-3 cells xenotransplants to a greater extent than the parental compound. Taken together, these data indicate that Saq-NO possesses powerful and suitable in vitro and in vivo chemotherapeutic potential to be further studied as a novel drug for the treatment of prostate cancer in the clinical setting.


Hybrid neuromusculoskeletal modeling to best track joint moments using a balance between muscle excitations derived from electromyograms and optimization.
Current electromyography (EMG)-driven musculoskeletal models are used to estimate joint moments measured from an individual׳s extremities during dynamic movement with varying levels of accuracy. The main benefit is the underlying musculoskeletal dynamics is simulated as a function of realistic, subject-specific, neural-excitation patterns provided by the EMG data. The main disadvantage is surface EMG cannot provide information on deeply located muscles. Furthermore, EMG data may be affected by cross-talk, recording and post-processing artifacts that could adversely influence the EMG׳s information content. This limits the EMG-driven model׳s ability to calculate the multi-muscle dynamics and the resulting joint moments about multiple degrees of freedom. We present a hybrid neuromusculoskeletal model that combines calibration, subject-specificity, EMG-driven and static optimization methods together. In this, the joint moment tracking errors are minimized by balancing the information content extracted from the experimental EMG data and from that generated by a static optimization method. Using movement data from five healthy male subjects during walking and running we explored the hybrid model׳s best configuration to minimally adjust recorded EMGs and predict missing EMGs while attaining the best tracking of joint moments. Minimally adjusted and predicted excitations substantially improved the experimental joint moment tracking accuracy than current EMG-driven models. The ability of the hybrid model to predict missing muscle EMGs was also examined. The proposed hybrid model enables muscle-driven simulations of human movement while enforcing physiological constraints on muscle excitation patterns. This might have important implications for studying pathological movement for which EMG recordings are limited.


Oral contraceptive use: implications for cognitive and emotional functioning.
This study investigated the role of oral contraception use versus nonuse as a moderator variable differentially influencing cognitive-emotional processes. Seventy-six healthy women (29 users and 47 nonusers; 18 to 48 years old), completed the State-Trait Anger Expression Inventory, the Clinical Analysis Questionnaire, the Rotter Scale of locus of control, the Daily Hassles Scale, and a Repertory Grid. A subsample (N = 33) also volunteered for a blood draw. Hormonal levels of progesterone and estrogen mostly were unrelated to cognitive and emotional measures, and contraindicated the "chemical suppression" proposition. Alternatively, when cognitive-emotional functioning was examined separately for users and nonusers, cognitive factors including the appraisal of stress, loci of control, and self-integration were implicated with specific patterns of negative affect and much more so for users than for nonusers. For the most part, oral contraceptive use versus nonuse seemed to influence the saliency rather than the nature of cognitive-emotional patterns. Discussion focused on oral contraceptive use as a moderator variable and the need for longitudinal research to clarify the evolving, biopsychosocial influence of hormonal regulatory treatment.


Staphylococcus aureus Colonization: Modulation of Host Immune Response and Impact on Human Vaccine Design.
In apparent contrast to its invasive potential Staphylococcus aureus colonizes the anterior nares of 20-80% of the human population. The relationship between host and microbe appears particularly individualized and colonization status seems somehow predetermined. After decolonization, persistent carriers often become re-colonized with their prior S. aureus strain, whereas non-carriers resist experimental colonization. Efforts to identify factors facilitating colonization have thus far largely focused on the microorganism rather than on the human host. The host responds to S. aureus nasal colonization via local expression of anti-microbial peptides, lipids, and cytokines. Interplay with the co-existing microbiota also influences colonization and immune regulation. Transient or persistent S. aureus colonization induces specific systemic immune responses. Humoral responses are the most studied of these and little is known of cellular responses induced by colonization. Intriguingly, colonized patients who develop bacteremia may have a lower S. aureus-attributable mortality than their non-colonized counterparts. This could imply a staphylococcal-specific immune "priming" or immunomodulation occurring as a consequence of colonization and impacting on the outcome of infection. This has yet to be fully explored. An effective vaccine remains elusive. Anti-S. aureus vaccine strategies may need to drive both humoral and cellular immune responses to confer efficient protection. Understanding the influence of colonization on adaptive response is essential to intelligent vaccine design, and may determine the efficacy of vaccine-mediated immunity. Clinical trials should consider colonization status and the resulting impact of this on individual patient responses. We urgently need an increased appreciation of colonization and its modulation of host immunity.


Population Genomics Analysis of Legume Host Preference for Specific Rhizobial Genotypes in the Rhizobium leguminosarum bv. viciae Symbioses.
Rhizobium leguminosarum bv. viciae establishes root nodule symbioses with several legume genera. Although most isolates are equally effective in establishing symbioses with all host genera, previous evidence suggests that hosts select specific rhizobial genotypes among those present in the soil. We have used population genomics to further investigate this observation. Pisum sativum, Lens culinaris, Vicia sativa, and V. faba plants were used to trap rhizobia from a well-characterized soil, and pooled genomic DNA from 100 isolates from each plant were sequenced. Sequence reads were aligned to the R. leguminosarum bv. viciae 3841 reference genome. High overall conservation of sequences was observed in all subpopulations, although several multigenic regions were absent from the soil population. A large fraction (16 to 22%) of sequence reads could not be recruited to the reference genome, suggesting that they represent sequences specific to that particular soil population. Although highly conserved, the 16S to 23S ribosomal RNA gene region presented single nucleotide polymorphisms (SNP) regarding the reference genome, but no striking differences could be found among plant-selected subpopulations. Plant-specific SNP patterns were, however, clearly observed within the nod gene cluster, supporting the existence of a plant preference for specific rhizobial genotypes. This was also shown after genome-wide analysis of SNP patterns.


Receptor-mediated transport of IgG.
The intestinal epithelium of the neonatal rat is a model system for the study of receptor-mediated endocytosis in which large amounts of IgG are transferred intact across polarized cells. This review summarizes the ultrastructural pathway followed by IgG during cellular transit and several important properties of the membrane receptor that recognizes the IgG.


Genome-wide association study identifies a new locus for coronary artery disease on chromosome 10p11.23.
Recent genome-wide association (GWA) studies identified 10 chromosomal loci for coronary artery disease (CAD) or myocardial infarction (MI). However, these loci explain only a small proportion of the genetic variability of these pertinent diseases. We sought to identify additional CAD/MI loci by applying a three-stage approach. We genotyped n = 1157 MI cases and n = 1748 controls from a population-based study population [German MI Family Study (GerMIFS) III (KORA)] with genome-wide SNP arrays. At this first stage, n = 462 SNPs showed association with MI at P<1 × 10(-3) in two-sided logistic regression. In a second stage, 415 of these SNPs were evaluated in silico in two independent GWA samples, the GerMIFS I (875 cases/1644 controls) and GerMIFS II (1222 cases/1298 controls). Nine SNPs, representing three regions, displayed consistent replication in this in silico analysis (P<0.05 for each GWA sample): five SNPs at 9p21.3, a well-known CAD/MI locus, two SNPs at 10p11.21, and two SNPs at 2p24.3. Wet-lab replication, i.e. the third stage, of SNP rs3739998 (representing the novel locus at 10p11.21, p.S1002T in the KIAA1462 gene) in additional 5790 cases and 5302 controls confirmed the association (P=9.54 × 10(-4)), but not for the 2p24.3 locus. The combined P-value across all stages for SNP rs3739998 is P=1.27 × 10(-11) [odds ratio (OR) = 1.15 (1.11-1.20)]. Analysis of a GWA study followed by in silico and wet-lab replication steps identified the KIAA1462 gene, encoding a yet uncharacterized protein, on chromosome 10p11.23 with genome-wide significant association for CAD/MI. Further studies are needed to characterize the functional role of this locus in the aetiology of these diseases.


A cross-sectional study examining factors related to critical thinking in nursing.
The purpose of this study was to examine critical thinking skills among registered nurses who work in a military hospital. Sixty-five nurses were administered the Health Sciences Reasoning Test to obtain scores in inductive reasoning, deductive reasoning, interpretation, analysis, and evaluation skills. Results showed no significant association between critical thinking skills and years of experience; however, differences were identified among racial/ethnic groups. It is hoped that findings from this study create a platform for dialogue among staff development nurses who are best situated to develop strategies that address these issues.


Coordinated lumen contraction and expansion during vulval tube morphogenesis in Caenorhabditis elegans.
Morphogenesis is a developmental phase during which cell fates are executed. Mechanical forces shaping individual cells play a key role during tissue morphogenesis. By investigating morphogenesis of the Caenorhabditis elegans hermaphrodite vulva, we show that the force-generating actomyosin network is differentially regulated by NOTCH and EGFR/RAS/MAPK signaling to shape the vulval tube. NOTCH signaling activates expression of the RHO kinase LET-502 in the secondary cell lineage through the ETS-family transcription factor LIN-1. LET-502 induces actomyosin-mediated contraction of the apical lumen in the secondary toroids, thereby generating a dorsal pushing force. In contrast, MAPK signaling in the primary lineage downregulates LET-502 RHO kinase expression to prevent toroid contraction and allow the gonadal anchor cell to expand the dorsal lumen of the primary toroids. The antagonistic action of the MAPK and NOTCH pathways thus controls vulval tube morphogenesis linking cell fate specification to morphogenesis.


The room temperature crystal structure of a bacterial phytochrome determined by serial femtosecond crystallography.
Phytochromes are a family of photoreceptors that control light responses of plants, fungi and bacteria. A sequence of structural changes, which is not yet fully understood, leads to activation of an output domain. Time-resolved serial femtosecond crystallography (SFX) can potentially shine light on these conformational changes. Here we report the room temperature crystal structure of the chromophore-binding domains of the Deinococcus radiodurans phytochrome at 2.1 Å resolution. The structure was obtained by serial femtosecond X-ray crystallography from microcrystals at an X-ray free electron laser. We find overall good agreement compared to a crystal structure at 1.35 Å resolution derived from conventional crystallography at cryogenic temperatures, which we also report here. The thioether linkage between chromophore and protein is subject to positional ambiguity at the synchrotron, but is fully resolved with SFX. The study paves the way for time-resolved structural investigations of the phytochrome photocycle with time-resolved SFX.


Drive decay: the cause of fast "extinction" of habits learned for brain stimulation.
According to Deutsch's theory of intracranial self-stimulation, cessation of responding after the withdrawal of the stimulus should be a simple function of time without stimulation. To test this prediction, the lever was withdrawn from a Skinner box for varying times, then replaced and normal extinction completed. The number of extinction trials was a simple function of the time the lever was out of the box, thus confirming Deutsch's hypothesis that cessation of responding in this instance is due to a decay of a motivational excitation produced by the electrical stimulation, and not a function of the number of unreinforced trials as in normal extinction.


Implementing therapist-guided internet-delivered cognitive behaviour therapy for obsessive-compulsive disorder in the UK's IAPT programme: A pilot trial.
Digital therapies such as internet-delivered cognitive behaviour therapy (ICBT) can improve treatment access for patients with common mental disorders, but are rarely used in the Improving Access to Psychological Therapies (IAPT) programme in the United Kingdom. The objective of this study was to evaluate an evidence-based ICBT intervention for obsessive-compulsive disorder (OCD-NET) in three IAPT services in an open trial. Consecutively referred patients with a primary diagnosis of OCD (n = 474) were offered OCD-NET. Symptoms of OCD, depression, anxiety, and level of functioning were measured weekly throughout treatment. In the full intention to treat sample (n = 474), the intervention was associated with large reductions in self-reported OCD symptoms (d = 1.77), anxiety (d = 1.55) and depression (d = 0.8), as well as improvements in functional impairment (d = 0.51 to 0.72). Further, 35% of participants were in recovery at their last assessment, 25% achieved reliable improvement and 15% met criteria for both recovery and improvement. Among participants completing at least 4 modules (n = 261), corresponding to an adequate 'dose' of treatment, the rates of recovery (44%), reliable improvement (34%) and reliable recovery (21%) were higher. A majority of participants were satisfied with the online treatment and found the online materials helpful. OCD-NET is an effective treatment when delivered in regular care within the IAPT system. Challenges associated with implementing ICBT in regular health care are discussed.


Autonomic function testing in Friedreich's ataxia.
Friedreich ataxia (FRDA) is an inherited movement disorder which manifests with progressive gait instability, sensory loss and cardiomyopathy. Peripheral neuropathy is an established feature of FRDA. At neuropathological examination, a depletion of large, myelinated axons is evident, but also unmyelinated fibers are affected which may result in a variety of sensory and autonomic signs and symptoms. Impaired temperature perception, vasomotor disturbances of lower extremities and a high prevalence of urinary symptoms have been documented in FRDA, but data from autonomic function testing in genetically confirmed cases are lacking. Genetically confirmed FRDAs were recruited in an outpatient setting. In a screening visit, general and neurological examination, laboratory testing, ECG and echocardiography were performed. Autonomic functions were evaluated by means of systematic questionnaires (SCOPA-Aut, OHQ), skin sympathetic reflex and cardiovascular autonomic function testing (CAFT). For the latter, a comparison with matched healthy controls was performed. 20 patients were recruited and 13 underwent CAFT. Symptoms referred to multiple autonomic domains, particularly bladder function, thermoregulation and sweating were reported. SCOPA-Aut scores were significantly predicted by disease severity. At CAFT, FRDAs did not differ from controls except for increased heart rate at rest and during orthostatic challenge. Two patients had non-neurogenic orthostatic hypotension (14%). Skin sympathetic responses were pathologic in 3 out of 10 patients (of whom 2 aged > 50). FRDA patients may experience several autonomic symptoms and overall their burden correlates with disease severity. Nonetheless, clinical testing shows no major involvement of sudomotor and cardiovascular autonomic function.


Induction of inhibitory central nervous system-derived and stimulatory blood-derived dendritic cells suggests a dual role for granulocyte-macrophage colony-stimulating factor in central nervous system inflammation.
The mononuclear phagocyte system, particularly dendritic cells, plays several pivotal roles in the development of multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis. Here, we demonstrate that functionally distinct dendritic cell subpopulations are present in the central nervous system during experimental autoimmune encephalomyelitis. At peak experimental autoimmune encephalomyelitis, the majority of dendritic cells consisted of a CD11b(+)F4/80(+) inflammatory dendritic cell subtype. Both granulocyte-macrophage colony-stimulating factor and chemokine (C-C motif) ligand 2 were previously suggested to recruit 'inflammatory' monocyte-derived dendritic cells to the central nervous system during experimental autoimmune encephalomyelitis. We show that intra-cerebral production of granulocyte-macrophage colony-stimulating factor leading to chemokine (C-C motif) ligand 2 induction and attraction of chemokine (C-C motif) receptor 2-positive precursors suffices to recruit dendritic cell populations identical to those observed in experimental autoimmune encephalomyelitis into the central nervous system of healthy mice. This does not occur with fms-like tyrosine kinase-3-ligand treatment. Both during experimental autoimmune encephalomyelitis and upon intra-cerebral granulocyte-macrophage colony-stimulating factor production, all myeloid dendritic cells, lymphoid dendritic cells and periphery-derived inflammatory dendritic cells stimulated T cell proliferation, whereas inflammatory dendritic cells that differentiated from central nervous system precursors inhibited T cell activation and pro-inflammatory cytokine production. Despite the capacity of granulocyte-macrophage colony-stimulating factor to induce central nervous system-derived inhibitory inflammatory dendritic cells, the administration of granulocyte-macrophage colony-stimulating factor into mice with experimental autoimmune encephalomyelitis resulted in exacerbated disease. Granulocyte-macrophage colony-stimulating factor thus has a dual role in the central nervous system: it directs both central nervous system-derived dendritic cells towards an inhibitory phenotype and recruits peripheral dendritic cells exhibiting pro-inflammatory functions.


A role for polymodal C-fiber afferents in nonhistaminergic itch.
Recent psychophysical and electrophysiological studies in humans suggest the existence of two peripheral pathways for itch, one that is responsive to histamine and a second pathway that can be activated by nonhistaminergic pruritogens (e.g., cowhage spicules). To explore the peripheral neuronal pathway for nonhistaminergic itch, behavioral responses and neuronal activity in unmyelinated afferent fibers were assessed in monkey after topical application of cowhage spicules or intradermal injection of histamine and capsaicin. Cowhage and histamine, but not capsaicin, evoked scratching behavior indicating the presence of itch. In single-fiber recordings, cowhage, histamine and/or capsaicin were applied to the cutaneous receptive field of 43 mechano-heat-sensitive C-fiber (CMH) nociceptors. The majority of CMHs exhibited a prolonged response to cowhage (39 of 43) or histamine (29 of 38), but not to capsaicin (3 of 34). Seven CMHs were activated by cowhage but not histamine. The average response to cowhage was more than twice the response to histamine, and responses were not correlated. The response of the CMHs to a stepped heat stimulus (49 degrees C, 3 s) was either quickly adapting (QC) or slowly adapting (SC). In contrast, the cowhage response was characterized by bursts of two or more action potentials (at approximately 1 Hz). The total cowhage response of the QC fibers (97 action potentials/5 min) was twice that of the SC fibers (49 action potentials/5 min). A subset of QC fibers exhibited high-frequency intraburst discharges ( approximately 30 Hz). These results suggest multiple mechanisms by which CMHs may encode itch to cowhage as well as pain to mechanical and heat stimuli.


A Comparison of Two Strategies for Building an Exposure Prediction Model.
Cost-efficient assessments of job exposures in large populations may be obtained from models in which 'true' exposures assessed by expensive measurement methods are estimated from easily accessible and cheap predictors. Typically, the models are built on the basis of a validation study comprising 'true' exposure data as well as an extensive collection of candidate predictors from questionnaires or company data, which cannot all be included in the models due to restrictions in the degrees of freedom available for modeling. In these situations, predictors need to be selected using procedures that can identify the best possible subset of predictors among the candidates. The present study compares two strategies for selecting a set of predictor variables. One strategy relies on stepwise hypothesis testing of associations between predictors and exposure, while the other uses cluster analysis to reduce the number of predictors without relying on empirical information about the measured exposure. Both strategies were applied to the same dataset on biomechanical exposure and candidate predictors among computer users, and they were compared in terms of identified predictors of exposure as well as the resulting model fit using bootstrapped resamples of the original data. The identified predictors were, to a large part, different between the two strategies, and the initial model fit was better for the stepwise testing strategy than for the clustering approach. Internal validation of the models using bootstrap resampling with fixed predictors revealed an equally reduced model fit in resampled datasets for both strategies. However, when predictor selection was incorporated in the validation procedure for the stepwise testing strategy, the model fit was reduced to the extent that both strategies showed similar model fit. Thus, the two strategies would both be expected to perform poorly with respect to predicting biomechanical exposure in other samples of computer users.


Rationale and design of the PREFERS (Preserved and Reduced Ejection Fraction Epidemiological Regional Study) Stockholm heart failure study: an epidemiological regional study in Stockholm county of 2.1 million inhabitants.
Heart failure (HF) with preserved (HFpEF) or reduced (HFrEF) ejection fraction is associated with poor prognosis and quality of life. While the incidence of HFrEF is declining and HF treatment is effective, HFpEF is increasing, with no established therapy. PREFERS Stockholm is an epidemiological study with the aim of improving clinical care and research in HF and to find new targets for drug treatment in HFpEF (https://internwebben.ki.se/sites/default/files/20150605_4d_research_appendix_final.pdf). Patients with new-onset HF (n = 2000) will be characterized at baseline and after 1-year follow-up by standardized protocols for clinical evaluation, echocardiography, and ECG. In one subset undergoing elective coronary bypass surgery (n = 100) and classified according to LV function, myocardial biopsies will be collected during surgery, and cardiac magnetic resonance (CMR) imaging will be performed at baseline and after 1 year. Blood and tissue samples will be stored in a biobank. We will characterize and compare new-onset HFpEF and HFrEF patients regarding clinical findings and cardiac imaging, genomics, proteomics, and transcriptomics from blood and cardiac biopsies, and by established biomarkers of fibrosis, inflammation, haemodynamics, haemostasis, and thrombosis. The data will be explored by state-of-the-art bioinformatics methods to investigate gene expression patterns, sequence variation, DNA methylation, and post-translational modifications, and using systems biology approaches including pathway and network analysis. In this epidemiological HF study with biopsy studies in a subset of patients, we aim to identify new biomarkers of disease progression and to find pathophysiological mechanisms to support explorations of new treatment regimens for HFpEF.


Recognizing specific characteristics of nonspecific low back pain.
A retrospective review of 1293 cases of low back pain treated over a 12-year period revealed that sacroiliac joint syndrome and posterior joint syndromes were the most common referred-pain syndromes, whereas herniated nucleus pulposus and lateral spinal stenosis were the most common nerve root compression lesions. Referred pain syndromes occur nearly twice as often and frequently mimic the clinical presentation of nerve root compression syndromes. Combined lesions occurred in 33.5% of cases. Lateral spinal stenosis and herniated nucleus pulposus coexisted in 17.7%. In 30% of the cases of spondylolisthesis, the radiographic findings were incidental and the source of pain was the sacroiliac joint. Distinguishing radicular from referred pain, recognition of coexisting lesions, and correlation of diagnostic imaging with the overall clinical presentation facilities formulation of a rational plan of therapy. The above-outlined approach to managing low back pain evolved over a 12-year period. Designed to establish a specific diagnosis, it should yield excellent or good results in 84% of patients.


Reticulospinal systems mediate atonia with short and long latencies.
The pontomedullary region is responsible for both the tonic and phasic reduction of muscle activity in rapid-eye-movement sleep and contributes to the control of muscle tone in waking. This study focused on determining the time course of activity in the pontomedullary systems mediating atonia. Short-train stimulations (3 0.2-ms pulses at 330 Hz) of the pons and medulla suppressed neck and hindlimb muscle activity in decerebrate cats. We identified two distinct phases of suppression, early and late. The anatomic sites that produced each suppression were intermixed. We estimated the dividing value of the conduction velocity for reticulospinal projections responsible for early and late phases of hindlimb muscle tone suppression to be 22.8 m/s. In the medial medulla, 238 reticulospinal units, which send axons to the L1 level of the spinal cord, were identified. Pontine stimulation that suppressed hindlimb muscle tone increased the firing rate of 138 units (type I). Sixteen type I units showed a delayed response to the pontine stimulation with a latency of 10 ms or longer (type Id), whereas 122 type I units exhibited an earlier response (type Ie). Seven type Ie units had an axonal conduction velocity of <22.8 m/s, whereas the remaining 115 conducted at faster than 22.8 m/s. Early and late hindlimb muscle tone suppressions were hypothesized to be mediated through fast and slow conducting type Ie reticulospinal units. The activity of type Id neurons may contribute to the cessation of the early-phase suppression as well as to the induction, maintenance, or cessation of the late-phase suppression.


Tracing problem solving in real time: fMRI analysis of the subject-paced Tower of Hanoi.
Previous research has found three brain regions for tracking components of the ACT-R cognitive architecture: a posterior parietal region that tracks changes in problem representation, a prefrontal region that tracks retrieval of task-relevant information, and a motor region that tracks the programming of manual responses. This prior research has used relatively simple tasks to incorporate a slow event-related procedure, allowing the blood oxygen level-dependent (BOLD) response to go back to baseline after each trial. The research described here attempts to extend these methods to tracking problem solving in a complex task, the Tower of Hanoi, which involves many complex steps of cognition and motor actions in rapid succession. By tracking the activation patterns in these regions, it is possible to predict with intermediate accuracy when participants are planning a future sequence of moves. The article describes a cognitive model in the ACT-R architecture that is capable of explaining both the latency data in move generation and the BOLD responses in these three regions.


Young carers and young adult carers in Switzerland: Caring roles, ways into care and the meaning of communication.
Although there is already general recognition of the fact that many relatives provide unpaid care for family members, there is still little awareness that children, adolescents and young adults under 25 also provide such care. Until recently, the situation of young carers and young adult carers, as those young persons are referred to in international research, has not been in the focus of professionals, research and the public in Switzerland. Between September 2015 and October 2016, 30 interviews in seven cantons were conducted with 16 young carers aged 10-17 and 14 young adult carers aged 18-25. The interviews were recorded, transcribed and analysed following a grounded theory approach. This paper now presents the first qualitative data on Swiss young carers and young adult carers. It explores their sociodemographic backgrounds, the nature and intensity of caring tasks they carry out, their pathways into caring as well as the role of communication with family members, extended family, professionals and peers. Our findings provide a first insight in the lives of young carers and young adult carers in Switzerland and illustrate, as well, the challenges they face.