Prospective study of incident age-related macular degeneration in relation to vigorous physical activity during a 7-year follow-up.
To test whether the risk of age-related macular degeneration (AMD) decreases with vigorous physical activity. This was a prospective study of self-reported clinically diagnosed macular degeneration in male (n = 29,532) and female (n = 12,176) runners followed prospectively for 7.7 years. Survival analyses of incident AMD versus average running distance (kilometers per day), cardiorespiratory fitness (10-km footrace performance), body mass index (BMI), cigarette use, and diet at baseline. The 110 men and 42 women reporting incident AMD were older than those unaffected (mean +/- SE: 54.81 +/- 0.97 vs. 44.86 +/- 0.06 years), and the men were significantly more likely to have once smoked cigarettes (50.6 vs. 41.2%, P = 0.04 when adjusted for age). Age- and sex-adjusted AMD risk was greater in the men and women who consumed more meat (3.17 +/- 0.20 vs. 2.55 +/- 0.02 servings/wk) and less fruit (9.41 +/- 0.70 vs. 10.92 +/- 0.05 pieces/wk). The men and women reporting incident AMD ran for exercise significantly less than those who remained unaffected, when adjustment was made for age and sex (4.57 +/- 0.30 vs. 5.34 +/- 0.02 km/d, P < or = 0.01). When adjusted for age, sex, diet, and smoking history, the relative risk for AMD decreased 10% per km/d increment in running distance. Moreover, compared with the men and women who averaged less than 2 km/d, those averaging 2 to 4 km/d had 19% lower adjusted risk, and those averaging > or = 4 km/d had 42% to 54% lower adjusted AMD risk. Higher doses of vigorous exercise (running) are associated with lower incident AMD risk independent of weight, cardiorespiratory fitness, and cigarette use. Limitations of the analyses include the select nature of the sample and reliance on self-report of both running history and clinically diagnosed AMD.


Viral load dynamics and disease severity in patients infected with SARS-CoV-2 in Zhejiang province, China, January-March 2020: retrospective cohort study.
To evaluate viral loads at different stages of disease progression in patients infected with the 2019 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) during the first four months of the epidemic in Zhejiang province, China. Retrospective cohort study. A designated hospital for patients with covid-19 in Zhejiang province, China. 96 consecutively admitted patients with laboratory confirmed SARS-CoV-2 infection: 22 with mild disease and 74 with severe disease. Data were collected from 19 January 2020 to 20 March 2020. Ribonucleic acid (RNA) viral load measured in respiratory, stool, serum, and urine samples. Cycle threshold values, a measure of nucleic acid concentration, were plotted onto the standard curve constructed on the basis of the standard product. Epidemiological, clinical, and laboratory characteristics and treatment and outcomes data were obtained through data collection forms from electronic medical records, and the relation between clinical data and disease severity was analysed. 3497 respiratory, stool, serum, and urine samples were collected from patients after admission and evaluated for SARS-CoV-2 RNA viral load. Infection was confirmed in all patients by testing sputum and saliva samples. RNA was detected in the stool of 55 (59%) patients and in the serum of 39 (41%) patients. The urine sample from one patient was positive for SARS-CoV-2. The median duration of virus in stool (22 days, interquartile range 17-31 days) was significantly longer than in respiratory (18 days, 13-29 days; P=0.02) and serum samples (16 days, 11-21 days; P<0.001). The median duration of virus in the respiratory samples of patients with severe disease (21 days, 14-30 days) was significantly longer than in patients with mild disease (14 days, 10-21 days; P=0.04). In the mild group, the viral loads peaked in respiratory samples in the second week from disease onset, whereas viral load continued to be high during the third week in the severe group. Virus duration was longer in patients older than 60 years and in male patients. The duration of SARS-CoV-2 is significantly longer in stool samples than in respiratory and serum samples, highlighting the need to strengthen the management of stool samples in the prevention and control of the epidemic, and the virus persists longer with higher load and peaks later in the respiratory tissue of patients with severe disease.


Transforming growth factor beta receptors and p27kip in thyroid carcinoma.
To investigate the role of cell cycle regulators in the pathogenesis of papillary carcinoma of the thyroid. Resistance to transforming growth factor beta-mediated inhibition is a well-known pathogenic mechanism in epithelial neoplasias. In a retrospective study, the expression of transforming growth factor beta receptors types I and II, cyclin D1, and the cyclin-dependent inhibitor p27kip, was analyzed by immunohistochemistry. Results were interpreted in the context of clinicopathological data. Patient follow-up ranged from 1 to 18 years, with a mean of 4 years. Twenty conventional primary papillary carcinomas and their metastases were selected according to current pathologic criteria. Nonconventional papillary carcinomas (eg, tall-cell, columnar) were excluded from the analysis. Cyclin D1 was expressed more intensely in the tumor than in adjacent nonneoplastic parenchyma. Within a given tumor, however, there was significant heterogeneity in expression intensity and percentage of positive cells, particularly in metastases. Type I receptors were strongly expressed in 90% of tumors, while 80% of the tumors revealed low to no expression of type II receptors. In 10% of tumors, type I receptors were absent and type II receptors expressed. Simultaneous absence of both receptors was not observed. While p27kip was strongly expressed in nonneoplastic thyroid, it was not detected in any of the primary tumors or their metastases. The results strongly suggest that functional abnormalities in type II receptors result in increased levels of cyclin D1 and down-regulation of p27kip. This would maintain cells in a proliferative state and would promote tumor progression.


Hereditary spherocytosis in zebrafish riesling illustrates evolution of erythroid beta-spectrin structure, and function in red cell morphogenesis and membrane stability.
Spectrins are key cytoskeleton proteins with roles in membrane integrity, cell morphology, organelle transport and cell polarity of varied cell types during development. Defects in erythroid spectrins in humans result in congenital hemolytic anemias with altered red cell morphology. Although well characterized in mammals and invertebrates, analysis of the structure and function of non-mammalian vertebrate spectrins has been lacking. The zebrafish riesling (ris) suffers from profound anemia, where the developing red cells fail to assume terminally differentiated erythroid morphology. Using comparative genomics, erythroid beta-spectrin (sptb) was identified as the gene mutated in ris. Zebrafish Sptb shares 62.3% overall identity with the human ortholog and phylogenetic comparisons suggest intragenic duplication and divergence during evolution. Unlike the human and murine orthologs, the pleckstrin homology domain of zebrafish Sptb is not removed in red cells by alternative splicing. In addition, apoptosis and abnormal microtubule marginal band aggregation contribute to hemolysis of mutant erythrocytes, which are features not present in mammalian red cells with sptb defects. This study presents the first genetic characterization of a non-mammalian vertebrate sptb and demonstrates novel features of red cell hemolysis in non-mammalian red cells. Further, we propose that the distinct mammalian erythroid morphology may have evolved from specific modifications of Sptb structure and function.


Astaxanthin protects neuronal cells against oxidative damage and is a potent candidate for brain food.
Astaxanthin (AST) is a powerful antioxidant that occurs naturally in a wide variety of living organisms. Based on the report claiming that AST could cross the brain-blood barrier, the aim of this study was to investigate the neuroprotective effect of AST by using an oxidative stress-induced neuronal cell damage system. The treatment with DHA hydroperoxide (DHA-OOH) or 6-hydroxydopamine (6-OHDA), either of which is a reactive oxygen species (ROS)-inducing neurotoxin, led to a significant decrease in viable dopaminergic SH-SY5Y cells by the MTT assay, whereas a significant protection was shown when the cells were pretreated with AST. Moreover, 100 nM AST pretreatment significantly inhibited intracellular ROS generation that occurred in either DHA-OOH- or 6-OHDA-treated cells. The neuroprotective effect of AST is suggested to be dependent upon its antioxidant potential and mitochondria protection; therefore, it is strongly suggested that treatment with AST may be effective for oxidative stress-associated neurodegeneration and a potential candidate for natural brain food.


An ecologic study of prostate-specific antigen screening and prostate cancer mortality in nine geographic areas of the United States.
Ecologic studies of cancer screening examine cancer mortality rates in relation to use of population screening. These studies can be confounded by treatment patterns or influenced by choice of outcome and time horizon. Interpretation can be complicated by uncertainty about when mortality differences might be expected. The authors examined these issues in an ecologic analysis of prostate-specific antigen (PSA) screening and prostate cancer mortality across nine cancer registries in the United States. Results suggested a weak trend for areas with greater PSA screening rates to have greater declines in prostate cancer mortality; however, the magnitude of this trend varied considerably with the time horizon and outcome measure. A computer model was used to determine whether divergence of mortality declines would be expected under an assumption of a clinically significant survival benefit due to screening. Given a mean lead time of 5 years, the model projected that differences in mortality between high- and low-use areas should be apparent by 1999 in the absence of other factors affecting mortality. The authors concluded that modest differences in PSA screening rates across areas, together with additional sources of variation, could have produced a negative ecologic result. Ecologic analyses of the effectiveness of PSA testing should be interpreted with caution.


Leptin restores euglycemia and normalizes glucose turnover in insulin-deficient diabetes in the rat.
Leptin has been shown to improve insulin sensitivity and glucose metabolism in normoinsulinemic healthy or obese rodents. It has not been determined whether leptin may act independently of insulin in regulating energy metabolism in vivo. The present study was designed to examine the effects of leptin treatment alone on glucose metabolism in insulin-deficient streptozotocin (STZ)-induced diabetic rats. Four groups of STZ-induced diabetic rats were studied: 1) rats treated with recombinant methionine murine leptin subcutaneous infusion with osmotic pumps for 12-14 days (LEP; 4 mg x kg(-1) x day(-1), n = 10); 2) control rats infused with vehicle (phosphate-buffered saline) for 12-14 days (VEH; n = 10); 3) pair-fed control rats given a daily food ration matching that of LEP rats for 12-14 days (PF; n = 8); and 4) rats treated with subcutaneous phloridzin for 4 days (PLZ; 0.4 g/kg twice daily, n = 10). Phloridzin treatment normalizes blood glucose without insulin and was used as a control for the effect of leptin in correcting hyperglycemia. All animals were then studied with a hyperinsulinemic-euglycemic clamp (6 mU x kg(-1) x min(-1). Our study demonstrates that leptin treatment in the insulin-deficient diabetic rats restored euglycemia, minimized body weight loss due to food restriction, substantially improved glucose metabolic rates during the postabsorptive state, and restored insulin sensitivities at the levels of the liver and the peripheral tissues during the glucose clamp. The effects on glucose turnover are largely independent of food restriction and changes in blood glucose concentration, as evidenced by the minimal improvement of insulin action and glucose turnover parameters in the PF and PLZ groups. Our results suggest that the antidiabetic effects of leptin are achieved through both an insulin-independent and an insulin-sensitizing mechanism.


Epicardium-derived cells: a new source of regenerative capacity.
Cardiovascular regenerative medicine aims to counter muscle loss post ischaemic disease with the identification of new cellular sources for cardiomyocyte replacement. A number of embryonic and adult cell models have been explored preclinically and in patient trials, but modest outcome, coupled with issues with impaired graft survival and limited/immature (trans-) differentiation alongside host rejection, has left the door open for more therapeutically efficacious sources of myocardial regeneration. Due to its fundamental role in heart development, the epicardium emerges as an obvious candidate. Here, recent findings are reviewed that show adult epicardium-derived cells as a new source of regenerative capacity for heart repair.


Can GPS be used to detect deleterious progression in training volume among runners?
There is a need to ascertain if an association exists between excessive progression in weekly volume and development of running-related injuries (RRI). The purpose of this study was to investigate if GPS can be used to detect deleterious progression in weekly training volume among 60 novice runners included in a 10-week prospective study. All participants used GPS to quantify training volume while running. In case of injury, participants attended a clinical examination. The 13 runners who sustained injuries during follow-up had a significantly higher weekly progression in total training volume in the week before the injury origin (86% [95% confidence interval: 12.9-159.9], p = 0.026) compared with other weeks. Although not significant, participants with injuries had an increase in weekly training volume of 31.6% compared with a 22.1% increase among the healthy participants. The error of the GPS measurements in open landscape, forest, and urban area of volume was ≤6.2%. To conclude, no clinically relevant measurement errors of the GPS devices were found for training volume. Based on this, GPS has a potential to detect errors in training volume, which may be associated with development of RRI. Based on the results from the current study, increases in weekly training progression may become deleterious at a weekly increase above 30%, which is more than the 10% rule currently used as a guideline for correct progression in weekly volume by runners and coaches. Still, no clear evidence for safe progression of weekly volume exists. But it seems likely that some individuals may tolerate weekly progressions around 20-25%, at least for a short period of time.


Isolation and characterization of a regulated form of actin depolymerizing factor.
Actin depolymerizing factor (ADF) is an 18.5-kD protein with pH-dependent reciprocal F-actin binding and severing/depolymerizing activities. We previously showed developing muscle down-regulates ADF (J. R. Bamburg and D. Bray. 1987. J. Cell Biol. 105: 2817-2825). To further study this process, we examined ADF expression in chick myocytes cultured in vitro. Surprisingly, ADF immunoreactivity increases during the first 7-10 d in culture. This increase is due to the presence of a new ADF species with higher relative molecular weight which reacts identically to brain ADF with antisera raised against either brain ADF or recombinant ADF. We have purified both ADF isoforms from myocytes and have shown by peptide mapping and partial sequence analysis that the new isoform is structurally related to ADF. Immunoprecipitation of both isoforms from extracts of cells prelabeled with [32P]orthophosphate showed that the new isoform is radiolabeled, predominantly on a serine residue, and hence is called pADF. pADF can be converted into a form which comigrates with ADF on 1-D and 2-D gels by treatment with alkaline phosphatase. pADF has been quantified in a number of cells and tissues where it is present from approximately 18% to 150% of the amount of unphosphorylated ADF. pADF, unlike ADF, does not bind to G-actin, or affect the rate or extent of actin assembly. Four ubiquitous protein kinases failed to phosphorylate ADF in vitro suggesting that ADF phosphorylation in vivo is catalyzed by a more specific kinase. We conclude that the ability to regulate ADF activity is important to muscle development since myocytes have both pre- and posttranslational mechanisms for regulating ADF activity. The latter mechanism is apparently a general one for cell regulation of ADF activity.


The effects of short-term fluoride ingestion on bone formation and resorption in the rat femur.
The femurs from rats given 120 ppm fluoride in their drinking water for 4 weeks were examined with histological, histochemical, and radiographic methods. Blood removed from the rats prior to sacrifice was analyzed for calcium, phosphorus, and alkaline phosphatase. Results of this study indicated that the ingestion of fluoride produced wide osteoid seams on the periosteal surface of the femoral diaphysis within 4 weeks. The increase in osteoid appeared to be due to an increase in the number of osteoid-producing cells (osteoblasts) along with a subsequent delay in the mineralization of this tissue. The metabolic activity of osteoblasts did not appear to be affected since the intracellular production of acid and alkaline phosphatase was not inhibited. However, due to the high concentration of fluoride ingested, abnormal collagen deposition and a change in bone mineral may have combined to cause a delay in osteoid mineralization. Mineralization was also delayed in the distal femoral epiphyseal plate resulting in an increase in the number of hypertrophied cells. Resorption of metaphyseal trabecular bone, presumably formed prior to fluoride administration, was increased causing a reduction in the amount of trabeculae extending into the shaft of the femur. Concurrent with these changes in bone, the serum levels of calcium, phosphorus, and alkaline phosphatase remained within normal ranges.


Josef Klingler's models of white matter tracts: influences on neuroanatomy, neurosurgery, and neuroimaging.
During the 1930s, white matter tracts began to assume relevance for neurosurgery, especially after Cajal's work. In many reviews of white matter neurobiology, the seminal contributions of Josef Klingler (1888-1963) and their neurological applications have been overlooked. In 1934 at the University of Basel under Eugen Ludwig, Klingler developed a new method of dissection based on a freezing technique for brain tissue that eloquently revealed the white matter tracts. Klingler worked with anatomists, surgeons, and other scientists, and his models and dissections of white matter tracts remain arguably the most elegant ever created. He stressed 3-dimensional anatomic relationships and laid the foundation for defining mesial temporal, limbic, insular, and thalamic fiber and functional relationships and contributed to the potential of stereotactic neurosurgery. Around 1947, Klingler was part of a Swiss-German group that independently performed the first stereotactic thalamotomies, basing their targeting and logic on Klingler's white matter studies, describing various applications of stereotaxy and showing Klingler's work integrated into a craniocerebral topographic system for targeting with external localization of eloquent brain structures and stimulation of deep thalamic nuclei. Klingler's work has received renewed interest because it is applicable for correlating the results of the fiber-mapping paradigms from diffusion tensor imaging to actual anatomic evidence. Although others have described white matter tracts, none have had as much practical impact on neuroscience as Klinger's work. More importantly, Josef Klingler was an encouraging mentor, influencing neurosurgeons, neuroscientists, and brain imaging for more than three quarters of a century.


The value of the Rehabilitation Activities Profile (RAP) as a quality sub-system in rehabilitation medicine.
To determine whether interdisciplinary team care, using the Rehabilitation Activities Profile (RAP) as a team tool, results in a better rehabilitation outcome. A multilevel prospective cohort study, with a controlled before and after design. Eighteen rehabilitation teams in eight rehabilitation centres in the Netherlands and Belgium participated. Based on the level of implementation of the RAP, we compared three study groups. Consecutive adult patients (n = 933) with stroke, amputation of the lower limb, spinal cord injury, multiple sclerosis, or other neuromuscular disorders, were followed during inpatient or outpatient rehabilitation. Main outcome measures were Barthel Index, RAP-CPM (sum score of the domains communication, personal care and mobility), Nottingham Health Profile (NHP), length of rehabilitation (LOR) and discharge destination (home vs elsewhere). Overall results show that scores on the Barthel Index, the RAP-CPM and the NHP improved, on average, by 18.4%, 12.7%, and 6.7%, respectively. However, treatment from a rehabilitation team that uses the RAP was associated with a significantly lower Barthel score, and small, non-significant effects on the RAP-CPM and the NHP. Partial use of the RAP resulted in non-significant, lower scores on these measures. With respect to discharge destination and LOR, there were also no significant differences between the three study groups, with the exception of a shorter outpatient rehabilitation period for the group in which partial use was made of the RAP. The RAP, at the current level of implementation, does not improve rehabilitation outcome.


Symptoms and sources of Yersinia enterocolitica-infection: a case-control study.
Yersinia enterocolitica (YE) is the causative agent of yersiniosis. YE encompass strains of diverse pathogenicity: YE biotypes 1B and 2-5 are considered pathogenic, whereas biotype 1A is in general considered nonvirulent. Also YE-like species, which can sometimes be misidentified as YE, are considered nonvirulent. In order to study differences in clinical picture caused by different YE types and their possible sources a case-control study was conducted in 2006. In this case-control study, 295 case-patients with YE or YE-like finding and their 758 controls responded to the questionnaire about symptoms and possible sources of infection. Strains of pathogenic YE bio/serotypes 3-4/O:3 or 2/O:9 were found in 18%, YE biotype 1A in 65% and YE -like strains of 17% of the patients. Patients infected with the strains of pathogenic YE bio/serotypes were younger and had fever more often than those with BT 1A who suffered more from vomiting. Symptoms of reactive arthritis were reported by 10% of pathogenic YE infections, 3% of YE BT 1A, and 0.3% of the controls. Eating or tasting raw or medium done pork was a significant risk factor for pathogenic YE bio/serotype infection (OR 6.6; 95% CI 1.7-24.9) as well as eating in a canteen (OR 3.5; 95% CI 1.6-7.9). Imported fruits and berries were associated with increased risk of YE BT 1A finding. The symptoms of the patients with YE BT 1A differed from yersiniosis caused by the classic pathogenic YE bio/serotypes. In addition, the patients with YE BT 1A had more protracted gastrointestinal disorders and unspecific complaints. Small children were overrepresented in classic pathogenic bio/serotypes while in BT 1A or YE-like species were not found among children younger than two years. This suggests the lacking virulence of the BT 1A strains. We can not, however, rule out the possibility that some strains of genetically heterogeneous group of BT 1A may cause an illness.


Glow discharge in microfluidic chips for visible analog computing.
Here we present a novel visible analog computing approach for solving a wide class of shortest path problems. Using a microfluidic chip for computation, based on the lighting up of a glow discharge, the solution to maze search problems, the solution of a network shortest path and k-shortest paths problems and the practical application of finding the shortest paths between several landmarks from a street map are presented. The solution and visible display (in real time) for these problems shows only a small difference in practical problem solving time among problems with varying differences in size.


The preventive effect of fish oil on abdominal aortic aneurysm development.
Abdominal aortic aneurysm (AAA) is a vascular disease involving gradual dilation of the abdominal aorta and high rupture-related mortality rates. AAA is histologically characterized by oxidative stress, chronic inflammation, and extracellular matrix degradation in the vascular wall. We previously demonstrated that aortic hypoperfusion could cause the vascular inflammation and AAA formation. However, the preventive method for hypoperfusion-induced AAA remains unknown. In this study, we evaluated the effect of fish oil on AAA development using a hypoperfusion-induced AAA animal model. Dilation of the abdominal aorta in the fish oil administration group was smaller than in the control group. Collagen destruction and oxidative stress were suppressed in the fish oil administration group than in the control group. These results suggested that fish oil could prevent the development of AAA induced by hypoperfusion.


Genes and hepatitis C: susceptibility, fibrosis progression and response to treatment.
Hepatitis C virus contact and infection show three different phenotypes: spontaneous viral clearance (SVC), chronic hepatitis C (CHC) and sustained virological response (SVR) following antiviral treatment. Many factors, including genetics, influence the evolution of these three phenotypes. We performed a literature search (PubMed) up to 31 January 2010 without language restriction to identify relevant studies on genes and hepatitis C. Additional studies were sought by reviewing the reference lists of the identified articles. Meta-analysis (using Meta-disk 1.4) was conducted to evaluate the association of single nucleotide polymorphism (SNP) in the IL28B region and SVR. The candidate gene approach showed strong relationships between human leucocyte antigen class II (DQB1(*) 0301 and DRB1(*) 1101) and SVC. A cirrhosis risk score involving 7 SNPs has been validated recently. The set of odds ratios of studies demonstrated an association between SNP (rs12987960/rs8099917) in the IL28B and SVR in CHC treated with peginterferon plus ribavirin (OR: 4.6; 95% CI: 2.9-7.3). The overall distribution of protective allele correlated with ethnic differences in SVR (Asians, Europeans, Hispanic and Afro-Americans) together with SVC, but not with fibrosis stage or viral load. These polymorphisms did not influence SVR in very-easy-to-treat patients such as genotype 2/3, rapid virological responders or patients with acute hepatitis C. While the genetic fingerprint for fibrosis progression remains elusive, IL28b polymorphism predicts SVC and SVR. However, nearly half of patients achieving SVR did not show favourable genotype. Further genetic signals are warranted to complete the puzzle of factors influencing hepatitis C.


The physical activity preferences of gynecologic cancer survivors.
To identify physical activity (PA) preferences of gynecologic cancer survivors (GCSs) and to understand the reasons for them. Population-based, cross-sectional mailed survey and semistructured interviews with a subsample. Nova Scotia, Canada. 239 GCSs completed the survey, and 16 participated in an interview. GCSs identified from a provincial cancer registry completed a questionnaire assessing PA preferences. Survey respondents were asked to participate in a substudy exploring PA preferences through a semistructured interview. Self-reported PA and PA preferences. Analyses indicated that participants were interested in a PA program. Interviews highlighted that PA counseling was highly desired and should include discussions about the benefits and appropriate amounts of PA, as well as available opportunities for PA. GCSs have preferences regarding characteristics of PA discussions and programs. Oncology nurses are integral to the promotion of PA in GCSs. Providing oncology nurses with training opportunities to learn about PA for cancer survivors is an important consideration for cancer centers in ensuring a satisfactory experience for cancer survivors.


The bHLH Rac Immunity1 (RAI1) Is Activated by OsRac1 via OsMAPK3 and OsMAPK6 in Rice Immunity.
The Rac/Rop GTPase OsRac1 plays an essential role in rice immunity. However, the regulatory genes acting downstream of OsRac1 are largely unknown. We focused on the RAI1 gene, which is up-regulated in suspension cells expressing a constitutively active form of OsRac1. RAI1 encodes a putative basic helix-loop-helix transcription factor. A microarray analysis of cells transformed with an inducible RAI1 construct showed increased expression of PAL1 and OsWRKY19 genes after induction, suggesting that these genes are regulated by RAI1. This was confirmed using RAI1 T-DNA activation-tagged and RNA interference lines. The PAL1 and OsWRKY19 genes were also up-regulated by sphingolipid and chitin elicitors, and the RAI1 activation-tagged plants had increased resistance to a rice blast fungus. These results indicated that RAI1 is involved in defense responses in rice. RAI1 interacted with OsMAPK3 and OsMAPK6 proteins in vivo and in vitro. Also, RAI1 was phosphorylated by OsMAPK3/6 and OsMKK4-dd in vitro. Overexpression of OsMAPK6 and/or OsMAPK3 together with OsMKK4-dd increased PAL1 and OsWRKY19 expression in rice protoplasts. Therefore, the regulation of PAL1 and OsWRKY19 expression by RAI1 could be controlled via an OsMKK4-OsMAPK3/6 cascade. Co-immunoprecipitation assays indicated that OsMAPK3 and OsRac1 occur in the same complex as OsMAPK6. Taken together, our results indicate that RAI1 could be regulated by OsRac1 through an OsMAPK3/6 cascade. In this study, we have identified RAI1 as the first transcription factor acting downstream of OsRac1. This work will help us to understand the immune system regulated by OsRac1 in rice and its orthologs in other plant species.


Site-specific orientation of an α-helical peptide ovispirin-1 from isotope-labeled SFG spectroscopy.
Sum-frequency generation (SFG) vibrational spectroscopy is often used to probe the backbone structures and orientations of polypeptides at surfaces. Using the ovispirin-1 polypeptide at the solid/liquid interface of polystyrene, we demonstrate for the first time that SFG can probe the polarization response of a single-isotope-labeled residue. To interpret the spectral intensities, we simulated the spectra using an excitonic Hamiltonian approach. We show that the polarization dependence of either the label or the unlabeled amide I band alone does not provide sufficient structural constraints to obtain both the tilt and the twist of the ovispirin helix at a solid/liquid interface, but that both can be determined from the polarization dependence of the complete spectrum. For ovispirin, the detailed analysis of the polarized SFG experimental data shows that the helix axis is tilted at roughly 138° from the surface normal, and the transition dipole of the isotope-labeled C═O group is tilted at 23° from the surface normal, with the hydrophobic region facing the polystyrene surface. We further demonstrate that the Hamiltonian approach is able to address the coupling effect and the structural disorder. For comparison, we also collected the FTIR spectrum of ovispirin under similar conditions, which reveals the enhanced sensitivity of SFG for structural studies of single monolayer peptide surfaces. Our study provides insight into how structural and environmental effects appear in SFG spectra of the amide I band and establishes that SFG of isotope-labeled peptides will be a powerful technique for elucidating secondary structures with residue-by-residue resolution.


Aptamers: Promising Tools for the Detection of Circulating Tumor Cells.
Circulating tumor cells (CTCs) are cells that shed from a primary tumor and freely circulate in the blood, retaining the ability to initiate metastasis and form a secondary tumor in distant organs in the body. CTCs reflect the molecular profile of the primary tumor, therefore studying CTCs can allow for an understanding of the mechanism of metastasis, and an opportunity to monitor the prognosis of cancer. Unfortunately, the detection of CTCs is a considerable challenge due to their low abundance in the bloodstream and the lack of consistent markers present to recognize these cells. The aim of this review is to summarize some of the aptamer-based affinity methods for the detection of CTCs. The basic biological concept of how metastasis occurs and the role of CTCs in this process are presented. Some methods of CTC detection employing antibodies or peptides are mentioned here for comparison. The review of present literature suggests that aptamers are emerging as competitive technology in the detection of CTCs, especially due to their unique properties, but there still remain several challenges to be met, including the need to improve the throughput and sensitivity of such methods.


Using outgroup comfort to predict Black students' college experiences.
This study investigated whether Black students' social comfort with Whites, termed outgroup comfort (OC), predicted outcomes related to academics and mental health. Surveys administered to Black college students near the beginning and end of their first year showed OC measured in the fall predicted outcomes assessed in the spring, including contact with other races, academic concerns among men, and psychological well-being among women. A subsample selected on the basis of high or low OC scores participated in two weeks of experience sampling, revealing students high in OC reported less state anxiety than those low in OC when in academic settings; in nonacademic settings, anxiety did not differ by OC. System-justifying ideology favoring the outgroup was controlled, thus OC is distinct from internalized oppression. Results are discussed in relation to gender differences in racial identity and college student development.


Stratified Care vs Stepped Care for Depression: A Cluster Randomized Clinical Trial.
Depression is a major cause of disability worldwide. Although empirically supported treatments are available, there is scarce evidence on how to effectively personalize psychological treatment selection. To compare the clinical effectiveness and cost-effectiveness of 2 treatment selection strategies: stepped care and stratified care. This multisite, cluster randomized clinical trial recruited participants from the English National Health Service from July 5, 2018, to February 1, 2019. Thirty clinicians working across 4 psychological therapy services were randomly assigned to provide stratified (n = 15) or stepped (n = 15) care. In stepped care, patients sequentially access low-intensity guided self-help followed by high-intensity psychotherapy. In stratified care, patients are matched with either low- or high-intensity treatments at initial assessment. Data were analyzed from May 18, 2020, to October 13, 2021, using intention-to-treat principles. All clinicians used the same interview schedule to conduct initial assessments with patients seeking psychological treatment for common mental disorders, but those in the stratified care group received a personalized treatment recommendation for each patient generated by a machine learning algorithm. Eligible patients received either stratified or stepped care (ie, treatment as usual). The preregistered outcome was posttreatment reliable and clinically significant improvement (RCSI) of depression symptoms (measured using the 9-item Patient Health Questionnaire). The RCSI outcome was compared between groups using logistic regression adjusted for baseline severity. Cost-effectiveness analyses compared incremental costs and health outcomes of the 2 treatment pathways. A total of 951 patients were included (618 women among 950 with data available [65.1%]; mean [SD] age, 38.27 [14.53] years). The proportion of cases of RCSI was significantly higher in the stratified care arm compared with the stepped care arm (264 of 505 [52.3%] vs 134 of 297 [45.1%]; odds ratio, 1.40 [95% CI, 1.04-1.87]; P = .03). Stratified care was associated with a higher mean additional cost per patient (£104.5 [95% CI, £67.5-£141.6] [$139.83 (95% CI, $90.32-$189.48)]; P < .001) because more patients accessed high-intensity treatments (332 of 583 [56.9%] vs 107 of 368 [29.1%]; χ2 = 70.51; P < .001), but this additional cost resulted in an approximately 7% increase in the probability of RCSI. In this cluster randomized clinical trial of adults with common mental disorders, stratified care was efficacious and cost-effective for the treatment of depression symptoms compared with stepped care. Stratified care can improve depression treatment outcomes at a modest additional cost. isrctn.org Identifier: ISRCTN11106183.


B cell abnormalities in Wegener's granulomatosis and microscopic polyangiitis: role of CD25+-expressing B cells.
The use of rituximab in vasculitis has increased interest in B cell biology. A subpopulation of B cells expressing CD25 shows antigen-presenting properties and may have regulatory functions. We assessed subpopulations of B cell maturation (Bm) and markers related to activity and antigen presentation, and related the findings to disease activity. Multiparameter flow cytometry was used to assess numbers and proportions of circulating lymphocytes from 34 patients with vasculitis (16 remission, 18 active) and 20 controls. Active vasculitis samples showed decreased proportions of Bm1 (7.8% vs 11%; p = 0.041), Bm2' (0.2% vs 0.7%; p = 0.002), and Bm3/Bm4 (0.1% vs 0.3%; p = 0.006), compared with controls; Bm2 cells were the most frequently occurring B cells but they were not significantly different in active vasculitis (74% vs 62%; p = 0.083). In patients with remission the proportion of CD25+ B cells was increased compared to controls (48% vs 29%, respectively; p = 0.006) and also compared to active vasculitis (23%; p = 0.006). The proportion of CD86+ B cells was also increased (31%) compared to active vasculitis (8%; p = 0.001), and to controls (6%; p = 0.0003). In multivariate analysis, Bm2' cells and CD25+27- B cells were independently influencing the patient group. In active vasculitis, a lower proportion of Bm1 cells may indicate activated B cells. Patients in remission had higher proportions of CD25+ (α-chain of interleukin 2 receptor) and CD86+ (costimulatory molecule) B cells. We suggest that these B cells may have a regulatory role, or alternatively may result from previous treatment.


Biological Robots: Perspectives on an Emerging Interdisciplinary Field.
Advances in science and engineering often reveal the limitations of classical approaches initially used to understand, predict, and control phenomena. With progress, conceptual categories must often be re-evaluated to better track recently discovered invariants across disciplines. It is essential to refine frameworks and resolve conflicting boundaries between disciplines such that they better facilitate, not restrict, experimental approaches and capabilities. In this essay, we address specific questions and critiques which have arisen in response to our research program, which lies at the intersection of developmental biology, computer science, and robotics. In the context of biological machines and robots, we explore changes across concepts and previously distinct fields that are driven by recent advances in materials, information, and life sciences. Herein, each author provides their own perspective on the subject, framed by their own disciplinary training. We argue that as with computation, certain aspects of developmental biology and robotics are not tied to specific materials; rather, the consilience of these fields can help to shed light on issues of multiscale control, self-assembly, and relationships between form and function. We hope new fields can emerge as boundaries arising from technological limitations are overcome, furthering practical applications from regenerative medicine to useful synthetic living machines.


Associations between inverted repeats and the structural evolution of bacterial genomes.
The stability of the structure of bacterial genomes is challenged by recombination events. Since major rearrangements (i.e., inversions) are thought to frequently operate by homologous recombination between inverted repeats, we analyzed the presence and distribution of such repeats in bacterial genomes and their relation to the conservation of chromosomal structure. First, we show that there is a strong under-representation of inverted repeats, relative to direct repeats, in most chromosomes, especially among the ones regarded as most stable. Second, we show that the avoidance of repeats is frequently associated with the stability of the genomes. Closely related genomes reported to differ in terms of stability are also found to differ in the number of inverted repeats. Third, when using replication strand bias as a proxy for genome stability, we find a significant negative correlation between this strand bias and the abundance of inverted repeats. Fourth, when measuring the recombining potential of inverted repeats and their eventual impact on different features of the chromosomal structure, we observe a tendency of repeats to be located in the chromosome in such a way that rearrangements produce a smaller strand switch and smaller asymmetries than expected by chance. Finally, we discuss the limitations of our analysis and the influence of factors such as the nature of repeats, e.g., transposases, or the differences in the recombination machinery among bacteria. These results shed light on the challenges imposed on the genome structure by the presence of inverted repeats.


Transcriptome Analysis of Post-Mortem Brain Tissue Reveals Up-Regulation of the Complement Cascade in a Subgroup of Schizophrenia Patients.
Schizophrenia is a genetically complex neuropsychiatric disorder with largely unresolved mechanisms of pathology. Identification of genes and pathways associated with schizophrenia is important for understanding the development, progression and treatment of schizophrenia. In this study, pathways associated with schizophrenia were explored at the level of gene expression. The study included post-mortem brain tissue samples from 68 schizophrenia patients and 44 age and sex-matched control subjects. Whole transcriptome poly-A selected paired-end RNA sequencing was performed on tissue from the prefrontal cortex and orbitofrontal cortex. RNA expression differences were detected between case and control individuals, focusing both on single genes and pathways. The results were validated with RT-qPCR. Significant differential expression between patient and controls groups was found for 71 genes. Gene ontology analysis of differentially expressed genes revealed an up-regulation of multiple genes in immune response among the patients (corrected p-value = 0.004). Several genes in the category belong to the complement system, including C1R, C1S, C7, FCN3, SERPING1, C4A and CFI. The increased complement expression is primarily driven by a subgroup of patients with increased expression of immune/inflammatory response genes, pointing to important differences in disease etiology within the patient group. Weighted gene co-expression network analysis highlighted networks associated with both synaptic transmission and activation of the immune response. Our results demonstrate the importance of immune-related pathways in schizophrenia and provide evidence for elevated expression of the complement cascade as an important pathway in schizophrenia pathology.


The impact of augmented information on visuo-motor adaptation in younger and older adults.
Adjustment to a visuo-motor rotation is known to be affected by ageing. According to previous studies, the age-related differences primarily pertain to the use of strategic corrections and the generation of explicit knowledge on which strategic corrections are based, whereas the acquisition of an (implicit) internal model of the novel visuo-motor transformation is unaffected. The present study aimed to assess the impact of augmented information on the age-related variation of visuo-motor adjustments. Participants performed aiming movements controlling a cursor on a computer screen. Visual feedback of direction of cursor motion was rotated 75 degrees relative to the direction of hand motion. Participants had to adjust to this rotation in the presence and absence of an additional hand-movement target that explicitly depicted the input-output relations of the visuo-motor transformation. An extensive set of tests was employed in order to disentangle the contributions of different processes to visuo-motor adjustment. Results show that the augmented information failed to affect the age-related variations of explicit knowledge, adaptive shifts, and aftereffects in a substantial way, whereas it clearly affected initial direction errors during practice and proprioceptive realignment. Contrary to expectations, older participants apparently made no use of the augmented information, whereas younger participants used the additional movement target to reduce initial direction errors early during practice. However, after a first block of trials errors increased, indicating a neglect of the augmented information, and only slowly declined thereafter. A hypothetical dual-task account of these findings is discussed. The use of the augmented information also led to a selective impairment of proprioceptive realignment in the younger group. The mere finding of proprioceptive realignment in adaptation to a visuo-motor rotation in a computer-controlled setup is noteworthy since visual and proprioceptive information pertain to different objects.


Effects of sodium depletion on inactive and active renin from dog kidney and plasma.
The relationship of active renin and inactive renin (trypsin-activated angiotensin-I-forming enzyme) to sodium depletion was examined in renal and peripheral plasma and at the subcellular level in the kidneys of dogs. Subcellular fractionation was carried out by discontinuous sucrose density (1.5 and 1.6 M) centrifugation. Sodium depletion selectively caused a six- to sevenfold increase in the renal content of inactive and active renins in the original homogenate, while the subcellular distribution patterns of these enzymes were little changed. Of the total granule fractions of 1.5 M sucrose (F1), 1.6 M sucrose (F2), and sediment (F3), approximately 80% of inactive renin was recovered in F1, which was rich in microsomes, while about 50% of active renin was in F2. The ratio of inactive to active renin was 0.02 in F1 and 0.003 to 0.004 in F2. Sodium depletion also caused a 20-fold increase in active renin and a twofold increase in inactive renin in peripheral plasma. The renal venous-arterial concentration difference of inactive renin was statistically significant in low-sodium dogs, although it was not significant in controls. The ratio of inactive to active renin was 0.2 to 0.4 in plasma from low-sodium dogs, while it was 1.5 to 3 in plasma from control dogs. These results suggest that plasma inactive renin originates, at least in part, in the kidney.


Treatment Considerations for the Cardiometabolic Signs of Polycystic Ovary Syndrome: A Review of the Literature Since the 2013 Endocrine Society Clinical Practice Guidelines.
Polycystic ovary syndrome is characterized by an excess in androgen levels, ovarian dysfunction, and polycystic ovarian morphology but is also associated with metabolic dysfunction and risk factors for cardiovascular disease. To our knowledge, there are few therapeutic recommendations for these cardiometabolic risk factors and little evidence of their long-term clinical relevance to cardiovascular health. To determine metabolic and/or cardiovascular outcomes in polycystic ovary syndrome treatment literature since the publication of the most recent Endocrine Society clinical practice guidelines in 2013. We searched PubMed using a string of variations of polycystic ovary syndrome, therapy/treatment, and adolescence, and we included English-language original research articles published while the 2013 clinical practice guidelines were disseminated (ie, articles published from January 1, 2011, to June 1, 2015). Articles that appeared relevant based on a review of titles and abstracts were read in full to determine relevancy. References from relevant articles were reviewed for additional studies. Four topic areas emerged: (1) lifestyle modification, (2) metformin vs placebo or estrogen-progestin oral contraceptives, (3) insulin-sensitizing agents, and (4) estrogen-progestin formulations. Most studies assessed the role of metformin as a monotherapy or dual therapy supplement and found significant benefit when including metformin in polycystic ovary syndrome treatment regimens. Studies showed improvements in cardiometabolic risk factors and, in several, androgen excess and cutaneous and menstrual symptoms. Studies were limited by sample size (range, 22-171), few adolescent participants, and short-term outcomes. Findings show potential for metformin and estrogen-progestin dual therapy but warrant longitudinal studies examining outcomes from adolescence through middle age to determine the effect on long-term cardiovascular health.


Epilepsy and Electroencephalographic Abnormalities in SATB2-Associated Syndrome.
Seizures are an under-reported feature of the SATB2-associated syndrome phenotype. We describe the electroencephalographic findings and seizure semiology and treatment in a population of individuals with SATB2-associated syndrome. We performed a retrospective review of 101 individuals with SATB2-associated syndrome who were reported to have had a previous electroencephalographic study to identify those who had at least one reported abnormal result. For completeness, a supplemental survey was distributed to the caregivers and input from the treating neurologist was obtained whenever possible. Forty-one subjects were identified as having at least one prior abnormal electroencephalography. Thirty-eight individuals (93%) had epileptiform discharges, 28 (74%) with central localization. Sleep stages were included as part of the electroencephalographies performed in 31 individuals (76%), and epileptiform activity was recorded during sleep in all instances (100%). Definite clinical seizures were diagnosed in 17 individuals (42%) with a mean age of onset of 3.2 years (four months to six years), and focal seizures were the most common type of seizure observed (42%). Six subjects with definite clinical seizures needed polytherapy (35%). Delayed myelination and/or abnormal white matter hyperintensities were seen on neuroimaging in 19 individuals (61%). Epileptiform abnormalities are commonly seen in individuals with SATB2-associated syndrome. A baseline electroencephalography that preferably includes sleep stages is recommended during the initial evaluation of all individuals with SATB2-associated syndrome, regardless of clinical suspicion of epilepsy.


Hemoglobin-albumin cross-linking with disuccinimidyl suberate (DSS) and/or glutaraldehyde for blood substitutes.
Hemoglobin (Hb) derivatization for blood substitute purposes often involves multi-step processes including redox reagents such as borohydride and periodate, with possible subsequent side effects. Disuccinimidyl suberate (DSS) allows protein cross-linking without toxic side-products, forming one-step peptide bonds with the lysine residues. Here, we report that Hb polymers were obtained using DSS, making this the first report of a single-step polymerization for blood substitutes. The increase in autooxidation rate incurred by this polymerization is completely reversed when BSA is copolymerized with Hb. Copolymerization of Hb with BSA appears to be beneficial for alleviating pro-oxidant effects, regardless of the polymerizing agent employed.


Incidence of breast-feeding in a low socioeconomic group of mothers in the United States: ethnic patterns.
Breast-feeding has been shown to have increased in incidence during recent years in the United States. However, this increase is not particularly evident in lower socioeconomic groups. Factors associated with the decision to breast-feed or not were investigated in a population of 379 mothers. Self-completed questionnaires were obtained from 94.5% of these mothers. Data with respect to demographics, reproductive history, prenatal care, and education were collected. Only 27.2% of the study population indicated that they intended to breast-feed. Using the chi2 test for equality of proportions, marital status, head of household, maternal and paternal ethnicity, maternal education, income, and number of pregnancy were found to be the most important variables associated with breast-feeding. The effect of ethnicity predominated over that of the other demographic variables when they were examined jointly within ethnic groups. The effect of ethnicity was apparent when the number of each ethnic group in the study population was compared with the percent of that group that intended to breast-feed: 145 Anglo-Americans, 43.5% breast-feeding; 131 black Americans, 9.2%; 62 Mexican Americans, 22.6%; 19 others, 42.1%. The importance of ethnicity in the decision to breast-feed has probably been underestimated. Efforts to increase breast-feeding in the United States ought to be designed with full consideration of this factor.


Improving PMTCT uptake and retention services through novel approaches in peer-based family-supported care in the clinic and community: a 3-arm cluster randomized trial (PURE Malawi).
In July 2011, Malawi introduced an ambitious public health program known as "Option B+," which provides all HIV-infected pregnant and breastfeeding women with lifelong combination antiretroviral therapy, regardless of clinical stage or CD4 count. Option B+ is expected to have benefits for HIV-infected women, their HIV-exposed infants, and their HIV-uninfected male sex partners. However, these benefits hinge on early uptake of prevention of mother-to-child transmission, good adherence, and long-term retention in care. The Prevention of mother-to-child transmission Uptake and REtention (PURE) study is a 3-arm cluster randomized controlled trial to evaluate whether clinic- or community-based peer support will improve care-seeking and retention in care by HIV-infected pregnant and breastfeeding women, their HIV-exposed infants, and their male sex partners, and ultimately improve health outcomes in all 3 populations. We describe the PURE Malawi Consortium, the initial work conducted to inform the trial and interventions, the trial design, and the analysis plan. We then discuss concerns and expected contributions to Malawi and the region.


Custodial Parole Sanctions and Earnings after Release from Prison.
Although the labor market consequences of incarceration in prison have been central to the literature on mass incarceration, punishment, and inequality, other components of the growing criminal justice system have received less attention from sociologists. In particular, the rise of mass incarceration was accompanied by an even larger increase in community supervision. In this paper, we examine the labor market effects of one frequently experienced aspect of post-prison parole, short-term custody for parole violations. Although such sanctions are viewed as an alternative to returning parole violators to prison, they have the potential to affect labor market outcomes in ways similar to imprisonment, including both adverse and positive effects on earnings. We estimate that parolees lost approximately 37 percent of their earnings in quarters during which they were in short-term custody. Although their earnings tended to increase in the quarter immediately following short-term custody-consistent with the stated intentions of such sanctions-parolees experienced further earnings loss over the longer term after such sanctions. In the third quarter following a short-term custody sanction, earnings are lowered by about 13 percent. These associations are larger for those who were employed in the formal labor market before their initial incarceration.


Analogical processes in children's understanding of spatial representations.
We propose that map reading can be construed as a form of analogical mapping. We tested 2 predictions that follow from this claim: First, young children's patterns of performance in map reading tasks should parallel those found in analogical mapping tasks; and, second, children will benefit from guided alignment instructions that help them see the relational correspondences between the map and the space. In 4 experiments, 3-year-olds completed a map reading task in which they were asked to find hidden objects in a miniature room, using a corresponding map. We manipulated the availability of guided alignment (showing children the analogical mapping between maps and spaces; Experiments 1, 2, and 3a), the format of guided alignment (gesture or relational language; Experiment 2), and the iconicity of maps (Experiments 3a and 3b). We found that (a) young children's difficulties in map reading follow from known patterns of analogical development-for example, focusing on object similarity over relational similarity; and (b) guided alignment based on analogical reasoning led to substantially better performance. Results also indicated that children's map reading performance was affected by the format of guided alignment, the iconicity of the maps, and the order of tasks. The results bear on the developmental mechanisms underlying young children's learning of spatial representations and also suggest ways to support this learning. (PsycINFO Database Record


A new species of Chromis damselfish from the tropical western Atlantic (Teleostei, Pomacentridae).
Initially described in 1882, Chromis enchrysurus, the Yellowtail Reeffish, was redescribed in 1982 to account for an observed color morph that possesses a white tail instead of a yellow one, but morphological and geographic boundaries between the two color morphs were not well understood. Taking advantage of newly collected material from submersible studies of deep reefs and photographs from rebreather dives, this study sought to determine whether the white-tailed Chromis is actually a color morph of Chromis enchrysurus or a distinct species. Phylogenetic analyses of mitochondrial genes cytochrome b and cytochrome c oxidase subunit I separated Chromis enchrysurus and the white-tailed Chromis into two reciprocally monophyletic clades. A principal component analysis based on 27 morphological characters separated the two groups into clusters that correspond with caudal-fin coloration, which was either known or presumed based on the specimen's collection site according to biogeographic data on species boundaries in the Greater Caribbean. Genetic, morphological, and biogeographic data all indicate that the white-tailed Chromis is a distinct species, herein described as Chromis vanbebberae sp. nov. The discovery of a new species within a conspicuous group such as damselfishes in a well-studied region of the world highlights the importance of deep-reef exploration in documenting undiscovered biodiversity.


Can I trust you? Negative affective priming influences social judgments in schizophrenia.
Successful social interactions rely on the ability to make accurate judgments based on social cues as well as the ability to control the influence of internal or external affective information on those judgments. Prior research suggests that individuals with schizophrenia misinterpret social stimuli and this misinterpretation contributes to impaired social functioning. We tested the hypothesis that for people with schizophrenia, social judgments are abnormally influenced by affective information. Twenty-three patients with schizophrenia and 35 healthy control participants rated the trustworthiness of faces following the presentation of neutral, negative (threat-related), or positive affective primes. Results showed that all participants rated faces following negative affective primes as less trustworthy than faces following neutral or positive primes. Importantly, this effect was significantly more pronounced for participants with schizophrenia, suggesting that schizophrenia may be characterized by an exaggerated influence of negative affective information on social judgment. Furthermore, the extent that the negative affective prime influenced trustworthiness judgments was significantly associated with patients' severity of positive symptoms, particularly feelings of persecution. These findings suggest that for people with schizophrenia, negative affective information contributes to an interpretive bias, consistent with paranoid ideation, when judging the trustworthiness of others. This bias may contribute to social impairments in schizophrenia.


Distinct host species correlate with Anaplasma phagocytophilum ankA gene clusters.
Anaplasma phagocytophilum is a gram-negative, tick-transmitted, obligate intracellular bacterium that elicits acute febrile diseases in humans and domestic animals. In contrast to the United States, human granulocytic anaplasmosis seems to be a rare disease in Europe despite the initial recognition of A. phagocytophilum as the causative agent of tick-borne fever in European sheep and cattle. Considerable strain variation has been suggested to occur within this species, because isolates from humans and animals differed in their pathogenicity for heterologous hosts. In order to explain host preference and epidemiological diversity, molecular characterization of A. phagocytophilum strains has been undertaken. Most often the 16S rRNA gene was used, but it might be not informative enough to delineate distinct genotypes of A. phagocytophilum. Previously, we have shown that A. phagocytophilum strains infecting Ixodes ricinus ticks are highly diverse in their ankA genes. Therefore, we sequenced the 16S rRNA and ankA genes of 194 A. phagocytophilum strains from humans and several animal species. Whereas the phylogenetic analysis using 16S rRNA gene sequences was not meaningful, we showed that distinct host species correlate with A. phagocytophilum ankA gene clusters.


Immunization with purified protein antigens from Streptococcus mutans against dental caries in rhesus monkeys.
Protein antigens I, I/II, II, and III were prepared from Streptococcus mutans (serotype c). Their immunogenicities and protective effects against dental caries were investigated in 40 rhesus monkeys kept entirely on a human-type diet, containing about 15% sucrose. Antigens I, I/II and, to a lesser extent, antigen II induced significant reductions in dental caries, as compared with sham-immunized monkeys. This was achieved with 1 or 2 doses of antigen, the first of which was administered with adjuvant (Freund incomplete adjuvant or aluminum hydroxide). There was no reduction in caries in monkeys immunized with antigen III. The reduction in caries in the animals immunized with antigens I or I/II was comparable to that in monkeys immunized with whole cells. Protection against caries was associated predominantly with serum and gingival crevicular fluid immunoglobulin G antibodies, which appeared to be directed against the antigen I determinant, but antibodies to antigen II, though not to antigen III, were also protective.


The vascular endothelial growth factor receptor inhibitor sunitinib causes a preeclampsia-like syndrome with activation of the endothelin system.
Angiogenesis inhibition is an established treatment for several tumor types. Unfortunately, this therapy is associated with adverse effects, including hypertension and renal toxicity, referred to as "preeclampsia." Recently, we demonstrated in patients and in rats that the multitarget tyrosine kinase inhibitor sunitinib induces a rise in blood pressure (BP), renal dysfunction, and proteinuria associated with activation of the endothelin system. In the current study we investigated the effects of sunitinib on rat renal histology, including the resemblance with preeclampsia, as well as the roles of endothelin 1, decreased nitric oxide (NO) bioavailability, and increased oxidative stress in the development of sunitinib-induced hypertension and renal toxicity. In rats on sunitinib, light and electron microscopic examination revealed marked glomerular endotheliosis, a characteristic histological feature of preeclampsia, which was partly reversible after sunitinib discontinuation. The histological abnormalities were accompanied by an increase in urinary excretion of endothelin 1 and diminished NO metabolite excretion. In rats on sunitinib alone, BP increased (ΔBP: 31.6±0.9 mm Hg). This rise could largely be prevented with the endothelin receptor antagonist macitentan (ΔBP: 12.3±1.5 mm Hg) and only mildly with Tempol, a superoxide dismutase mimetic (ΔBP: 25.9±2.3 mm Hg). Both compounds could not prevent the sunitinib-induced rise in serum creatinine or renal histological abnormalities and had no effect on urine nitrates but decreased proteinuria and urinary endothelin 1 excretion. Our findings indicate that both the endothelin system and oxidative stress play important roles in the development of sunitinib-induced proteinuria and that the endothelin system rather than oxidative stress is important for the development of sunitinib-induced hypertension.


KEAP1 loss modulates sensitivity to kinase targeted therapy in lung cancer.
Inhibitors that target the receptor tyrosine kinase (RTK)/Ras/mitogen-activated protein kinase (MAPK) pathway have led to clinical responses in lung and other cancers, but some patients fail to respond and in those that do resistance inevitably occurs (Balak et al., 2006; Kosaka et al., 2006; Rudin et al., 2013; Wagle et al., 2011). To understand intrinsic and acquired resistance to inhibition of MAPK signaling, we performed CRISPR-Cas9 gene deletion screens in the setting of BRAF, MEK, EGFR, and ALK inhibition. Loss of KEAP1, a negative regulator of NFE2L2/NRF2, modulated the response to BRAF, MEK, EGFR, and ALK inhibition in BRAF-, NRAS-, KRAS-, EGFR-, and ALK-mutant lung cancer cells. Treatment with inhibitors targeting the RTK/MAPK pathway increased reactive oxygen species (ROS) in cells with intact KEAP1, and loss of KEAP1 abrogated this increase. In addition, loss of KEAP1 altered cell metabolism to allow cells to proliferate in the absence of MAPK signaling. These observations suggest that alterations in the KEAP1/NRF2 pathway may promote survival in the presence of multiple inhibitors targeting the RTK/Ras/MAPK pathway.


Influence of vitamin C and vitamin E on redox signaling: Implications for exercise adaptations.
The exogenous antioxidants vitamin C (ascorbate) and vitamin E (α-tocopherol) often blunt favorable cell signaling responses to exercise, suggesting that redox signaling contributes to exercise adaptations. Current theories posit that this antioxidant paradigm interferes with redox signaling by attenuating exercise-induced reactive oxygen species (ROS) and reactive nitrogen species (RNS) generation. The well-documented in vitro antioxidant actions of ascorbate and α-tocopherol and characterization of the type and source of the ROS/RNS produced during exercise theoretically enable identification of redox-dependent mechanisms responsible for the blunting of favorable cell signaling responses to exercise. This review aimed to apply this reasoning to determine how the aforementioned antioxidants might attenuate exercise-induced ROS/RNS production. The principal outcomes of this analysis are (1) neither antioxidant is likely to attenuate nitric oxide signaling either directly (reaction with nitric oxide) or indirectly (reaction with derivatives, e.g., peroxynitrite); (2) neither antioxidant reacts appreciably with hydrogen peroxide, a key effector of redox signaling; (3) ascorbate but not α-tocopherol has the capacity to attenuate exercise-induced superoxide generation; and (4) alternate mechanisms, namely pro-oxidant side reactions and/or reduction of bioactive oxidized macromolecule adducts, are unlikely to interfere with exercise-induced redox signaling. Out of all the possibilities considered, ascorbate-mediated suppression of superoxide generation with attendant implications for hydrogen peroxide signaling is arguably the most cogent explanation for blunting of favorable cell signaling responses to exercise. However, this mechanism is dependent on ascorbate accumulating at sites rich in NADPH oxidases, principal contributors to contraction-mediated superoxide generation, and outcompeting nitric oxide and superoxide dismutase isoforms. The major conclusions of this review are: (1) direct evidence for interference of ascorbate and α-tocopherol with exercise-induced ROS/RNS production is lacking; (2) theoretical analysis reveals that both antioxidants are unlikely to have a major impact on exercise-induced redox signaling; and (3) it is worth considering alternate redox-independent mechanisms.


pySBOL: A Python Package for Genetic Design Automation and Standardization.
This paper presents pySBOL, a software library for computer-aided design of synthetic biological systems in the Python scripting language. This library provides an easy-to-use, object-oriented, application programming interface (API) with low barrier of entry for synthetic biology application developers. The pySBOL library enables reuse of genetic parts and designs through standardized data exchange with biological parts repositories and software tools that communicate using the Synthetic Biology Open Language (SBOL). In addition, pySBOL supports data management of design-build-test-learn workflows for individual laboratories as well as large, distributed teams of synthetic biologists. PySBOL also lets users add custom data to SBOL files to support the specific data requirements of their research. This extensibility helps users integrate software tool chains and develop workflows for new applications. These features and others make the pySBOL library a valuable tool for supporting engineering practices in synthetic biology. Documentation and installation instructions can be found at pysbol2.readthedocs.io .


Detection of pulmonary congestion by chest ultrasound in dialysis patients.
This study sought to investigate clinical and echocardiographic correlates of the lung comets score. Early detection of pulmonary congestion is a fundamental goal for the prevention of congestive heart failure in high-risk patients. We undertook an inclusive survey by a validated ultrasound (US) technique in a hemodialysis center to estimate the prevalence of pulmonary congestion and its reversibility after dialysis in a population of 75 hemodialysis patients. Chest US examinations were successfully completed in all patients (N = 75). Before dialysis, 47 patients (63%) exhibited moderate to severe lung congestion. This alteration was commonly observed in patients with heart failure but also in the majority of asymptomatic (32 of 56, 57%) and normohydrated (19 of 38, 50%) patients. Lung water excess was unrelated with hydration status but it was strongly associated with New York Heart Association functional class (p < 0.0001), left ventricular ejection fraction (r = -0.55, p < 0.001), early filling to early diastolic mitral annular velocity (r = 0.48, p < 0.001), left atrial volume (r = 0.39, p = 0.001), and pulmonary pressure (r = 0.36, p = 0.002). Lung water reduced after dialysis, but 23 patients (31%) still had pulmonary congestion of moderate to severe degree. Lung water after dialysis maintained a strong association with left ventricular ejection fraction (r = -0.59, p < 0.001), left atrial volume (r = 0.30, p = 0.01), and pulmonary pressure (r = 0.32, p = 0.006) denoting the critical role of cardiac performance in the control of this water compartment in end-stage renal disease. In a multiple regression model including traditional and nontraditional risk factors only left ventricular ejection fraction maintained an independent link with lung water excess (beta = -0.61, p < 0.001). Repeatability studies of the chest US technique (Bland-Altman plots) showed good interobserver and inter-US probes reproducibility. Pulmonary congestion is highly prevalent in symptomatic (New York Heart Association functional class III to IV) and asymptomatic dialysis patients. Chest ultrasound is a reliable technique that detects pulmonary congestion at a pre-clinical stage in end-stage renal disease.


A comparative analysis of the encapsulated end-organs of mammalian skeletal muscles and of their sensory nerve endings.
The encapsulated sensory endings of mammalian skeletal muscles are all mechanoreceptors. At the most basic functional level they serve as length sensors (muscle spindle primary and secondary endings), tension sensors (tendon organs), and pressure or vibration sensors (lamellated corpuscles). At a higher functional level, the differing roles of individual muscles in, for example, postural adjustment and locomotion might be expected to be reflected in characteristic complements of the various end-organs, their sensory endings and afferent nerve fibres. This has previously been demonstrated with regard to the number of muscle-spindle capsules; however, information on the other types of end-organ, as well as the complements of primary and secondary endings of the spindles themselves, is sporadic and inconclusive regarding their comparative provision in different muscles. Our general conclusion that muscle-specific variability in the provision of encapsulated sensory endings does exist demonstrates the necessity for the acquisition of more data of this type if we are to understand the underlying adaptive relationships between motor control and the structure and function of skeletal muscle. The present quantitative and comparative analysis of encapsulated muscle afferents is based on teased, silver-impregnated preparations. We begin with a statistical analysis of the number and distribution of muscle-spindle afferents in hind-limb muscles of the cat, particularly tenuissimus. We show that: (i) taking account of the necessity for at least one primary ending to be present, muscles differ significantly in the mean number of additional afferents per spindle capsule; (ii) the frequency of occurrence of spindles with different sensory complements is consistent with a stochastic, rather than deterministic, developmental process; and (iii) notwithstanding the previous finding, there is a differential distribution of spindles intramuscularly such that the more complex ones tend to be located closer to the main divisions of the nerve. Next, based on a sample of tendon organs from several hind-foot muscles of the cat, we demonstrate the existence in at least a large proportion of tendon organs of a structural substrate to account for multiple spike-initiation sites and pacemaker switching, namely the distribution of sensory terminals supplied by the different first-order branches of the Ib afferent to separate, parallel, tendinous compartments of individual tendon organs. We then show that the numbers of spindles, tendon organs and paciniform corpuscles vary independently in a sample of (mainly) hind-foot muscles of the cat. Grouping muscles by anatomical region in the cat indicated the existence of a gradual proximo-distal decline in the overall average size of the afferent complement of muscle spindles from axial through hind limb to intrinsic foot muscles, but with considerable muscle-specific variability. Finally, we present some comparative data on muscle-spindle afferent complements of rat, rabbit and guinea pig, one particularly notable feature being the high incidence of multiple primary endings in the rat.


Rituximab or Cyclosporine in the Treatment of Membranous Nephropathy.
B-cell anomalies play a role in the pathogenesis of membranous nephropathy. B-cell depletion with rituximab may therefore be noninferior to treatment with cyclosporine for inducing and maintaining a complete or partial remission of proteinuria in patients with this condition. We randomly assigned patients who had membranous nephropathy, proteinuria of at least 5 g per 24 hours, and a quantified creatinine clearance of at least 40 ml per minute per 1.73 m2 of body-surface area and had been receiving angiotensin-system blockade for at least 3 months to receive intravenous rituximab (two infusions, 1000 mg each, administered 14 days apart; repeated at 6 months in case of partial response) or oral cyclosporine (starting at a dose of 3.5 mg per kilogram of body weight per day for 12 months). Patients were followed for 24 months. The primary outcome was a composite of complete or partial remission of proteinuria at 24 months. Laboratory variables and safety were also assessed. A total of 130 patients underwent randomization. At 12 months, 39 of 65 patients (60%) in the rituximab group and 34 of 65 (52%) in the cyclosporine group had a complete or partial remission (risk difference, 8 percentage points; 95% confidence interval [CI], -9 to 25; P = 0.004 for noninferiority). At 24 months, 39 patients (60%) in the rituximab group and 13 (20%) in the cyclosporine group had a complete or partial remission (risk difference, 40 percentage points; 95% CI, 25 to 55; P<0.001 for both noninferiority and superiority). Among patients in remission who tested positive for anti-phospholipase A2 receptor (PLA2R) antibodies, the decline in autoantibodies to anti-PLA2R was faster and of greater magnitude and duration in the rituximab group than in the cyclosporine group. Serious adverse events occurred in 11 patients (17%) in the rituximab group and in 20 (31%) in the cyclosporine group (P = 0.06). Rituximab was noninferior to cyclosporine in inducing complete or partial remission of proteinuria at 12 months and was superior in maintaining proteinuria remission up to 24 months. (Funded by Genentech and the Fulk Family Foundation; MENTOR ClinicalTrials.gov number, NCT01180036.).


The novel Hsp90 inhibitor NXD30001 induces tumor regression in a genetically engineered mouse model of glioblastoma multiforme.
Glioblastoma multiforme (GBM) has an abysmal prognosis. We now know that the epidermal growth factor receptor (EGFR) signaling pathway and the loss of function of the tumor suppressor genes p16Ink4a/p19ARF and PTEN play a crucial role in GBM pathogenesis: initiating the early stages of tumor development, sustaining tumor growth, promoting infiltration, and mediating resistance to therapy. We have recently shown that this genetic combination is sufficient to promote the development of GBM in adult mice. Therapeutic agents raised against single targets of the EGFR signaling pathway have proven rather inefficient in GBM therapy, showing the need for combinatorial therapeutic approaches. An effective strategy for concurrent disruption of multiple signaling pathways is via the inhibition of the molecular chaperone heat shock protein 90 (Hsp90). Hsp90 inhibition leads to the degradation of so-called client proteins, many of which are key effectors of GBM pathogenesis. NXD30001 is a novel second generation Hsp90 inhibitor that shows improved pharmacokinetic parameters. Here we show that NXD30001 is a potent inhibitor of GBM cell growth in vitro consistent with its capacity to inhibit several key targets and regulators of GBM biology. We also show the efficacy of NXD30001 in vivo in an EGFR-driven genetically engineered mouse model of GBM. Our findings establish that the Hsp90 inhibitor NXD30001 is a therapeutically multivalent molecule, whose actions strike GBM at the core of its drivers of tumorigenesis and represent a compelling rationale for its use in GBM treatment.


A Remote Collaborative Care Program for Patients with Depression Living in Rural Areas: Open-Label Trial.
In the treatment of depression, primary care teams have an essential role, but they are most effective when inserted into a collaborative care model for disease management. In rural areas, the shortage of specialized mental health resources may hamper management of depressed patients. The aim was to test the feasibility, acceptability, and effectiveness of a remote collaborative care program for patients with depression living in rural areas. In a nonrandomized, open-label (blinded outcome assessor), two-arm clinical trial, physicians from 15 rural community hospitals recruited 250 patients aged 18 to 70 years with a major depressive episode (DSM-IV criteria). Patients were assigned to the remote collaborative care program (n=111) or to usual care (n=139). The remote collaborative care program used Web-based shared clinical records between rural primary care teams and a specialized/centralized mental health team, telephone monitoring of patients, and remote supervision by psychiatrists through the Web-based shared clinical records and/or telephone. Depressive symptoms, health-related quality of life, service use, and patient satisfaction were measured 3 and 6 months after baseline assessment. Six-month follow-up assessments were completed by 84.4% (221/250) of patients. The remote collaborative care program achieved higher user satisfaction (odds ratio [OR] 1.94, 95% CI 1.25-3.00) and better treatment adherence rates (OR 1.81, 95% CI 1.02-3.19) at 6 months compared to usual care. There were no statically significant differences in depressive symptoms between the remote collaborative care program and usual care. Significant differences between groups in favor of remote collaborative care program were observed at 3 months for mental health-related quality of life (beta 3.11, 95% CI 0.19-6.02). Higher rates of treatment adherence in the remote collaborative care program suggest that technology-assisted interventions may help rural primary care teams in the management of depressive patients. Future cost-effectiveness studies are needed. Clinicaltrials.gov NCT02200367; https://clinicaltrials.gov/ct2/show/NCT02200367 (Archived by WebCite at http://www.webcitation.org/6xtZ7OijZ).


New energy geographies: a case study of yoga, meditation and healthfulness.
Beginning with a routine day in the life of a practitioner of yoga and meditation and emphasising the importance of nurturing, maintaining and preventing the dissipation of diverse 'energies', this paper explores the possibilities for geographical health studies which take seriously 'new energy geographies'. It is explained how this account is derived from in-depth fieldwork tracing how practitioners of yoga and meditation find times and spaces for these practices, often in the face of busy urban lifestyles. Attention is paid to the 'energy talk' featuring heavily in how practitioners describe the benefits that they perceive themselves to derive from these practices, and to claims made about 'energies' generated during the time-spaces of these practices which seemingly flow, usually with positive effects, into other domains of their lives. The paper then discusses the implications of this energy talk in the context of: (a) critically reviewing conventional approaches to studying 'energy geographies'; (b) identifying an alertness to the likes of 'affective energies' surfacing in recent theoretically-attuned works of human geography (and cognate disciplines); and (c) exploring differing understandings of energy/energies extant in geographical studies of health and in step with the empirical research materials presented about yoga, meditation and healthfulness. While orientated towards explicitly geographical inquiries, the paper is intended as a statement of interest to the wider medical humanities.


Canine distemper virus: in vivo virulence of in vitro-passaged persistent virus strains.
Groups of ferrets were inoculated intraperitoneally with cell lysates or equivalent doses of whole cells from 9 different cell lines persistently infected with canine distemper virus. Viral persistence in these cell lines was characterized by noncytolytic infection and restricted release of cell-free infectious virus. In vivo replication competency of the various viruses in ferrets ranged from nil to virulent and did not correlate with in vitro titers of inocula. Ferret virulence (cell lysates only) for one cell line (CCL64-RCDV) was associated with morphologic absence of virion assembly, failure to interfere with lytic virus replication after superinfection, and in vitro infectivity restricted to canine macrophage-like tumor cells. Virion protein production in the CCL64-RCDV virulent inoculum and in the CCL64-Ly avirulent inoculum was evaluated by use of the immunoblot technique. All major virion proteins were produced by infected cells. Virulence was not associated with obvious changes in electrophoretic mobility of virion proteins when profiles of ferret-virulent CCL64-RCDV were compared with those of avirulent CCL64-Ly.


C-reactive protein as a potential biomarker for disease progression in dengue: a multi-country observational study.
Dengue infection can cause a wide spectrum of clinical outcomes. The severe clinical manifestations occur sufficiently late in the disease course, during day 4-6 of illness, to allow a window of opportunity for risk stratification. Markers of inflammation may be useful biomarkers. We investigated the value of C-reactive protein (CRP) measured early on illness days 1-3 to predict dengue disease outcome and the difference in CRP levels between dengue and other febrile illnesses (OFI). We performed a nested case-control study using the clinical data and samples collected from the IDAMS-consortium multi-country study. This was a prospective multi-center observational study that enrolled almost 8000 participants presenting with a dengue-like illness to outpatient facilities in 8 countries across Asia and Latin America. Predefined severity definitions of severe and intermediate dengue were used as the primary outcomes. A total of 281 cases with severe/intermediate dengue were compared to 836 uncomplicated dengue patients as controls (ratio 1:3), and also 394 patients with OFI. In patients with confirmed dengue, median (interquartile range) of CRP level within the first 3 days was 30.2 mg/L (12.4-61.2 mg/L) (uncomplicated dengue, 28.6 (10.5-58.9); severe or intermediate dengue, 34.0 (17.4-71.8)). Higher CRP levels in the first 3 days of illness were associated with a higher risk of severe or intermediate outcome (OR 1.17, 95% CI 1.07-1.29), especially in children. Higher CRP levels, exceeding 30 mg/L, also associated with hospitalization (OR 1.37, 95% CI 1.14-1.64) and longer fever clearance time (HR 0.84, 95% CI 0.76-0.93), especially in adults. CRP levels in patients with dengue were higher than patients with potential viral infection but lower than patients with potential bacterial infection, resulting in a quadratic association between dengue diagnosis and CRP, with levels of approximately 30 mg/L associated with the highest risk of having dengue. CRP had a positive correlation with total white cell count and neutrophils and negative correlation with lymphocytes, but did not correlate with liver transaminases, albumin, or platelet nadir. In summary, CRP measured in the first 3 days of illness could be a useful biomarker for early dengue risk prediction and may assist differentiating dengue from other febrile illnesses.


Patient-specific generation of the Purkinje network driven by clinical measurements of a normal propagation.
The propagation of the electrical signal in the Purkinje network is the starting point for the activation of the ventricular muscular cells leading to the contraction of the ventricle. In the computational models, describing the electrical activity of the ventricle is therefore important to account for the Purkinje fibers. Until now, the inclusion of such fibers has been obtained either by using surrogates such as space-dependent conduction properties or by generating a network based on an a priori anatomical knowledge. The aim of this work was to propose a new method for the generation of the Purkinje network using clinical measures of the activation times on the endocardium related to a normal electrical propagation, allowing to generate a patient-specific network. The measures were acquired by means of the EnSite NavX system. This system allows to measure for each point of the ventricular endocardium the time at which the activation front, that spreads through the ventricle, has reached the subjacent muscle. We compared the accuracy of the proposed method with the one of other strategies proposed so far in the literature for three subjects with a normal electrical propagation. The results showed that with our method we were able to reduce the absolute errors, intended as the difference between the measured and the computed data, by a factor in the range 9-25 %, with respect to the best of the other strategies. This highlighted the reliability of the proposed method and the importance of including a patient-specific Purkinje network in computational models.


The Force at the Tip--Modelling Tension and Proliferation in Sprouting Angiogenesis.
Sprouting angiogenesis, where new blood vessels grow from pre-existing ones, is a complex process where biochemical and mechanical signals regulate endothelial cell proliferation and movement. Therefore, a mathematical description of sprouting angiogenesis has to take into consideration biological signals as well as relevant physical processes, in particular the mechanical interplay between adjacent endothelial cells and the extracellular microenvironment. In this work, we introduce the first phase-field continuous model of sprouting angiogenesis capable of predicting sprout morphology as a function of the elastic properties of the tissues and the traction forces exerted by the cells. The model is very compact, only consisting of three coupled partial differential equations, and has the clear advantage of a reduced number of parameters. This model allows us to describe sprout growth as a function of the cell-cell adhesion forces and the traction force exerted by the sprout tip cell. In the absence of proliferation, we observe that the sprout either achieves a maximum length or, when the traction and adhesion are very large, it breaks. Endothelial cell proliferation alters significantly sprout morphology, and we explore how different types of endothelial cell proliferation regulation are able to determine the shape of the growing sprout. The largest region in parameter space with well formed long and straight sprouts is obtained always when the proliferation is triggered by endothelial cell strain and its rate grows with angiogenic factor concentration. We conclude that in this scenario the tip cell has the role of creating a tension in the cells that follow its lead. On those first stalk cells, this tension produces strain and/or empty spaces, inevitably triggering cell proliferation. The new cells occupy the space behind the tip, the tension decreases, and the process restarts. Our results highlight the ability of mathematical models to suggest relevant hypotheses with respect to the role of forces in sprouting, hence underlining the necessary collaboration between modelling and molecular biology techniques to improve the current state-of-the-art.


Electron transfer reactions between copper(II) porphyrin complexes and various oxidizing reagents in acetonitrile.
Homogeneous electron transfer reactions of the Cu(II) complexes of 5,10,15,20-tetraphenylporphyrin (TPP) and 2,3,7,8,12,13,17,18-octaethylporphyrin (OEP) with various oxidizing reagents were spectrophotometrically investigated in acetonitrile. The reaction products were confirmed to be the pi-cation radicals of the corresponding Cu(II)-porphyrin complexes on the basis of the electronic spectra and the redox potentials of the complexes. The rate of the electron transfer reaction between the Cu(II)-porphyrin complex and solvated Cu(2+) was determined as a function of the water concentration under the pseudo first-order conditions where Cu(2+) is in large excess over the Cu(II)-porphyrin complex. The decrease in the pseudo first-order rate constant with increasing the water concentration was attributed to the stepwise displacement of acetonitrile in [Cu(AN)(6)](2+)(AN = acetonitrile) by water, and it was concluded that only the Cu(2+) species fully solvated by acetonitrile, [Cu(AN)(6)](2+), possesses sufficiently high redox potential for the oxidation of Cu(ii)-OEP and Cu(ii)-TPP. The reactions of the Cu(II)-porphyrin complexes with other oxidizing reagents such as [Ni(tacn)(2)](3+)(tacn = 1,4,7-triazacyclononane) and [Ru(bpy)(3)](3+)(bpy = 2,2'-bipyridine) were too fast to be followed by a conventional stopped-flow technique. Marcus cross relation for the outer-sphere electron transfer reaction was used to estimate the rate constants of the electron self-exchange reaction between Cu(II)-porphyrin and its pi-cation radical: log(k/M(-1) s(-1))= 9.5 +/- 0.5 for TPP and log(k/M(-1) s(-1))= 11.1 +/- 0.5 for OEP at 25.0 degrees C. Such large electron self-exchange rate constants are typical for the porphyrin-centered redox reactions for which very small inner- and outer-sphere reorganization energies are required.


Prognostic significance of CD83 positive, mature dendritic cells in the gallbladder carcinoma.
Dendritic cells (DCs) are very potent antigen-presenting cells that play an essential role in the primary immune response to carcinoma. Tumor-infiltrating DCs have been found to be clinically significant in many human malignancies such as colon, stomach, lung, breast and hepatic carcinoma. However, clinical significance of activated and/or immature DCs in gallbladder carcinoma has not been reported yet. Thus, we immunohistochemically evaluated CD83+ DCs and CD1a+ DCs of cancerous and peritumoral area in 29 cases of resected gallbladder. In the results, CD83(+) DCs were significantly fewer in cancerous area than that in peritumoral area (1.55/hpf vs. 4.26/hpf, p=0.0047), but the numbers of CD1a(+) DCs did not differ (p=0.075). In addition, we defined a CD83 index as CD83(+) DCs/(CD83(+) DCs plus CD1a(+) DCs), and analyzed the relationship between CD83 index and clinicopathological factors. The group with a higher CD83 index (index >0.316) showed significantly better prognosis than the group with a lower CD83 index (index < or =0.316) in cancerous and peritumoral areas. In conclusion, we suggest the importance of tumor-infiltrating CD83(+) DCs as a useful prognostic factor for patients with gallbladder carcinoma.


Cancer-specific and other-cause mortality after radical prostatectomy versus observation in patients with prostate cancer: competing-risks analysis of a large North American population-based cohort.
Initial treatment options for low-risk clinically localized prostate cancer (PCa) include radical prostatectomy (RP) or observation. To examine cancer-specific mortality (CSM) after accounting for other-cause mortality (OCM) in PCa patients treated with either RP or observation. Using the Surveillance Epidemiology and End Results Medicare-linked database, a total of 44 694 patients ≥65 yr with localized (T1/2) PCa were identified (1992-2005). RP and observation. Propensity-score matching was used to adjust for potential selection biases associated with treatment type. The matched cohort was randomly divided into the development and validation sets. Competing-risks regression models were fitted and a competing-risks nomogram was developed and externally validated. Overall, 22,244 (49.8%) patients were treated with RP versus 22450 (50.2%) with observation. Propensity score-matched analyses derived 11,669 matched pairs. In the development cohort, the 10-yr CSM rate was 2.8% (2.3-3.5%) for RP versus 5.8% (5.0-6.6%) for observation (absolute risk reduction: 3.0%; relative risk reduction: 0.5%; p<0.001). In multivariable analyses, the CSM hazard ratio for RP was 0.48 (0.38-0.59) relative to observation (p<0.001). The competing-risks nomogram discrimination was 73% and 69% for prediction of CSM and OCM, respectively, in external validation. The nature of observational data may have introduced a selection bias. On average RP reduces the risk of CSM by half in patients aged ≥65 yr, relative to observation. The individualized protective effect of RP relative to observation may be quantified with our nomogram.


The Eya1 Phosphatase Mediates Shh-Driven Symmetric Cell Division of Cerebellar Granule Cell Precursors.
During neural development, stem and precursor cells can divide either symmetrically or asymmetrically. The transition between symmetric and asymmetric cell divisions is a major determinant of precursor cell expansion and neural differentiation, but the underlying mechanisms that regulate this transition are not well understood. Here, we identify the Sonic hedgehog (Shh) pathway as a critical determinant regulating the mode of division of cerebellar granule cell precursors (GCPs). Using partial gain and loss of function mutations within the Shh pathway, we show that pathway activation determines spindle orientation of GCPs, and that mitotic spindle orientation correlates with the mode of division. Mechanistically, we show that the phosphatase Eya1 is essential for implementing Shh-dependent GCP spindle orientation. We identify atypical protein kinase C (aPKC) as a direct target of Eya1 activity and show that Eya1 dephosphorylates a critical threonine (T410) in the activation loop. Thus, Eya1 inactivates aPKC, resulting in reduced phosphorylation of Numb and other components that regulate the mode of division. This Eya1-dependent cascade is critical in linking spindle orientation, cell cycle exit and terminal differentiation. Together these findings demonstrate that a Shh-Eya1 regulatory axis selectively promotes symmetric cell divisions during cerebellar development by coordinating spindle orientation and cell fate determinants.