Individual versus collective fibroblast spreading and migration: regulation by matrix composition in 3D culture.
Extracellular matrix (ECM) supplies both physical and chemical signals to cells and provides a substrate through which fibroblasts migrate during wound repair. To directly assess how ECM composition regulates this process, we used a nested 3D matrix model in which cell-populated collagen buttons were embedded in cell-free collagen or fibrin matrices. Time-lapse microscopy was used to record the dynamic pattern of cell migration into the outer matrices, and 3D confocal imaging was used to assess cell connectivity and cytoskeletal organization. Corneal fibroblasts stimulated with PDGF migrated more rapidly into collagen as compared to fibrin. In addition, the pattern of fibroblast migration into fibrin and collagen ECMs was strikingly different. Corneal fibroblasts migrating into collagen matrices developed dendritic processes and moved independently, whereas cells migrating into fibrin matrices had a more fusiform morphology and formed an interconnected meshwork. A similar pattern was observed when using dermal fibroblasts, suggesting that this response is not unique to corneal cells. We next cultured corneal fibroblasts within and on top of standard collagen and fibrin matrices to assess the impact of ECM composition on the cell spreading response. Similar differences in cell morphology and connectivity were observed – cells remained separated on collagen but coalesced into clusters on fibrin. Cadherin was localized to junctions between interconnected cells, whereas fibronectin was present both between cells and at the tips of extending cell processes. Cells on fibrin matrices also developed more prominent stress fibers than those on collagen matrices. Importantly, these spreading and migration patterns were consistently observed on both rigid and compliant substrates, thus differences in ECM mechanical stiffness were not the underlying cause. Overall, these results demonstrate for the first time that ECM protein composition alone (collagen vs. fibrin) can induce a switch from individual to collective fibroblast spreading and migration in 3D culture. Similar processes may also influence cell behavior during wound healing, development, tumor invasion and repopulation of engineered tissues.


Cost-effectiveness of fusion with and without instrumentation for patients with degenerative spondylolisthesis and spinal stenosis.
A cost-effectiveness study was performed from the societal perspective. To evaluate the costs and benefits of laminectomy alone and laminectomy with concomitant lumbar fusion for patients with degenerative lumbar spondylolisthesis and spinal stenosis. Costs, probabilities, and utilities were estimated from the literature. Short-term risks considered were perioperative complications, the probability of the fusion healing, and the probability that surgery will relieve symptoms. Long-term risks considered were recurrence of symptoms and reoperation. The 10-year costs, quality-adjusted life years, and incremental cost-effectiveness ratios (reported as dollars per quality-adjusted year of life gained) were calculated using a Markov model. Sensitivity analysis was performed on all variables using clinically plausible ranges. Laminectomy with noninstrumented fusion costs $56,500 per quality-adjusted year of life versuslaminectomy without fusion. The cost-effectiveness of laminectomy with noninstrumented fusion was most sensitive to the increase in quality-of-life associated with relief of severe stenosis symptoms. The cost-effectiveness ratio of instrumented fusion compared with noninstrumented fusion was $3,112,800 per quality-adjusted year of life. However, if the proportion of patients experiencing symptom relief after instrumented fusion was 90% as compared with 80% for patients with noninstrumented fusion, then the cost-effectiveness ratio of instrumented fusion compared with noninstrumented fusion would be $82,400 per quality-adjusted year of life. The cost-effectiveness of laminectomy with noninstrumented fusion compares favorably with other surgical interventions, although it depends greatly on the true effectiveness of these surgeries to alleviatesymptoms and on how patients value the quality-of-life effect of relieving severe stenosis symptoms. Instrumented fusion was very expensive compared with the incremental gain in health outcome. Better data on the effectiveness of these alternative procedures are needed.


Some New Aspects of Genetic Variability in Patients with Cutaneous T-Cell Lymphoma.
Cutaneous T-cell lymphoma (CTCL) is a group of T-cell malignancies that develop in the skin. Though studied intensively, the etiology and pathogenesis of CTCL remain elusive. This study evaluated the survival of CTCL patients in the 1st Department of Dermatovenereology of St. Anne's University Hospital Brno. It included analysis of 19 polymorphic gene variants based on their expected involvement in CTCL severity. 75 patients with CTCL, evaluated and treated at the 1st Department of Dermatovenereology of St. Anne´s University Hospital Brno, Faculty of Medicine, Masaryk University, were recruited for the study over the last 28 years (44 men and 31 women, average age 58 years, range 20-82 years). All patients were genotyped for 19 chosen gene polymorphisms by the conventional PCR method with restriction analysis. A multivariate Cox regression model was calculated to reveal genetic polymorphisms and other risk factors for survival. The model identified MDR Ex21 2677 (rs2032582) as a significant genetic factor influencing the survival of the patients, with the T-allele playing a protective role. A multivariate stepwise Cox regression model confirmed the following as significant independent risk factors for overall survival: increased age at admission, clinical staging of the tumor, and male sex. We showed that the TT genotype at position 2677 of the MDR1 gene exhibited statistically significant longer survival in CTCL patients. As such, the TT genotype of MDR1 confers a significant advantage for the CTCL patients who respond to treatment.


Urinary symptoms and sexual dysfunction among Italian men: The results of the #Controllati survey.
Prevention may improve the quality of life and sexual and reproductive health. To improve prevention require a comprehensive research approach that examines the frequency and risk factors for urologic conditions. In June 2016 the Italian Urologic Society coordinated a preventive initiative : the 1st Week of Male Urologic Prevention "#Controllati". During the 1st Week of Male Urologic Prevention "#Controllati", men aged 18 years or more were invited to attend participating urologic centers for a free of charge visit for counseling about urologic or andrologic conditions. Each participating man underwent a physical examination. Further he was asked about his a medical history and about his urologic symptoms, sexual activity and possible related problems. Data were collected in 81 centers: 2380 men answered the questionnaire. A total of 1226 subjects participating in the study reported one or more urinary symptom [51.5% (IC 95% 48.9%-54.5%)]. The risk of any urinary symptoms increased with age: in comparison with men aged < = 30 years or less the risk of any urinary symptoms was 2.31, 2.92, 5.12, 7.82 and 17.02 respectively in the class age 31-40, 41-50, 51-60, 61-70 and > = 71. Overweight/obese men were at increased risk of any urinary symptoms [OR1.35 (95% CI 1.12-1.64)]. 27.2% (IC 95% overall 25.2% -29.3%) of the subjects had at least a sexual disorder (erectile dysfunction, premature ejaculation, hypoactive sexual desire). The erectile dysfunction and hypoactive sexual desire increased with age, but premature ejaculation tended to be higher among younger aged men aged 40 years or more. Current any urinary symptoms [OR 1.85 (CI 1.40-2.43)], hypertension [OR 1.66 (95% CI 1.21-2.26) and diabetes (OR 2.37 (95% CI 1.45-3.88)] increased the risk of erectile dysfunction. This large survey gives a picture of the burden of the more frequent urologic conditions offering useful information in order to focus preventive campaign.


Nonsurgical scar management of the face: does early versus late intervention affect outcome?
Special emphasis is placed on the clinical management of facial scarring because of the profound physical and psychological impact of facial burns. Noninvasive methods of facial scar management include pressure therapy, silicone, massage, and facial exercises. Early implementation of these scar management techniques after a burn injury is typically accepted as standard burn rehabilitation practice, however, little data exist to support this practice. This study evaluated the timing of common noninvasive scar management interventions after facial skin grafting in children and the impact on outcome, as measured by scar assessment and need for facial reconstructive surgery. A retrospective review of 138 patients who underwent excision and grafting of the face and subsequent noninvasive scar management during a 10-year time frame was conducted. Regression analyses were used to show that earlier application of silicone was significantly related to lower Modified Vancouver Scar Scale scores, specifically in the subscales of vascularity and pigmentation. Early use of pressure therapy and implementation of facial exercises were also related to lower Modified Vancouver Scar Scale vascularity scores. No relationship was found between timing of the interventions and facial reconstructive outcome. Early use of silicone, pressure therapy, and exercise may improve scar outcome and accelerate time to scar maturity.


On the genetic architecture of cytoplasmic incompatibility: inference from phenotypic data.
Numerous insects carry intracellular bacteria that manipulate the insects' reproduction and thus facilitate their own spread. Cytoplasmic incompatibility (CI) is a common form of such manipulation, where a (currently uncharacterized) bacterial modification of male sperm induces the early death of embryos unless the fertilized eggs carry the same bacteria, inherited from the mother. The death of uninfected embryos provides an indirect selective advantage to infected ones, thus enabling the spread of the bacteria. Here we use and expand recently developed algorithms to infer the genetic architecture underlying the complex incompatibility data from the mosquito Culex pipiens. We show that CI requires more genetic determinants than previously believed and that quantitative variation in gene products potentially contributes to the observed CI patterns. In line with population genetic theory of CI, our analysis suggests that toxin factors (those inducing embryo death) are present in fewer copies in the bacterial genomes than antitoxin factors (those ensuring that infected embryos survive). In combination with comparative genomics, our approach will provide helpful guidance to identify the genetic basis of CI and more generally of other toxin/antitoxin systems that can be conceptualized under the same framework.


Application of Edwards' statistical mechanics to high-dimensional jammed sphere packings.
The isostatic jamming limit of frictionless spherical particles from Edwards' statistical mechanics [Song et al., Nature (London) 453, 629 (2008)] is generalized to arbitrary dimension d using a liquid-state description. The asymptotic high-dimensional behavior of the self-consistent relation is obtained by saddle-point evaluation and checked numerically. The resulting random close packing density scaling ϕ∼d2(-d) is consistent with that of other approaches, such as replica theory and density-functional theory. The validity of various structural approximations is assessed by comparing with three- to six-dimensional isostatic packings obtained from simulations. These numerical results support a growing accuracy of the theoretical approach with dimension. The approach could thus serve as a starting point to obtain a geometrical understanding of the higher-order correlations present in jammed packings.


Rodents and risk in the Mekong Delta of Vietnam: seroprevalence of selected zoonotic viruses in rodents and humans.
In the Mekong Delta in southern Vietnam, rats are commonly traded in wet markets and sold live for food consumption. We investigated seroprevalence to selected groups of rodent-borne viruses among human populations with high levels of animal exposure and among co-located rodent populations. The indirect fluorescence antibody test (IFAT) was used to determine seropositivity to representative reference strains of hantaviruses (Dobrava virus [DOBV], Seoul virus [SEOV]), cowpox virus, arenaviruses (lymphocytic choriomeningitis virus [LCMV]), flaviviruses (tick-borne encephalitis virus [TBEV]), and rodent parechoviruses (Ljungan virus), using sera from 245 humans living in Dong Thap Province and 275 rodents representing the five common rodent species sold in wet markets and present in peridomestic and farm settings. Combined seropositivity to DOBV and SEOV among the rodents and humans was 6.9% (19/275) and 3.7% (9/245), respectively; 1.1% (3/275) and 4.5% (11/245) to cowpox virus; 5.4% (15/275) and 47.3% (116/245) for TBEV; and exposure to Ljungan virus was 18.8% (46/245) in humans, but 0% in rodents. Very little seroreactivity was observed to LCMV in either rodents (1/275, 0.4%) or humans (2/245, 0.8%). Molecular screening of rodent liver tissues using consensus primers for flaviviruses did not yield any amplicons, whereas molecular screening of rodent lung tissues for hantavirus yielded one hantavirus sequence (SEOV). In summary, these results indicate low to moderate levels of endemic hantavirus circulation, possible circulation of a flavivirus in rodent reservoirs, and the first available data on human exposures to parechoviruses in Vietnam. Although the current evidence suggests only limited exposure of humans to known rodent-borne diseases, further research is warranted to assess public health implications of the rodent trade.


Papillary muscle discoordination rather than increased annular area facilitates mitral regurgitation after acute posterior myocardial infarction.
Acute posterior myocardial infarction that produces immediate mitral regurgitation alters the mitral annulus and its spatial relationship with both papillary muscles. The precise deformations that cause valve insufficiency are not understood and impair efforts to repair the valve. In six Dorsett hybrid sheep, sonomicrometry transducers were placed around the mitral annulus (6) and at the tips and bases of both papillary muscles (4). Two weeks later, three branches of the circumflex coronary artery were occluded to infarct approximately 32% of the posterior left ventricle. This infarction produced acute 2 to 3+ mitral regurgitation in all animals, as determined by color flow Doppler velocity mapping. Before and after infarction, distance measurements between sonomicrometry transducers were used to produce the three-dimensional coordinates of each transducer every 5 ms. After infarction, the area of the annulus increased only 9.2+/-6.3% at end systole (ES). In addition, the normal shortening of the posterior papillary muscle was obliterated to allow its tip to move 1.4+/-0.6 mm closer to the centroid of the annulus at ES. After infarction, the anterior papillary muscle continued to shorten normally, but at ES, its tip and base were 0.9+/-0.7 mm and 1.3+/-0.7 mm farther from the centroid, respectively. These deformations tend to produce a relative prolapse of leaflet tissue attached to the posterior papillary muscle and restriction of leaflet tissue attached to the anterior papillary muscle. This papillary muscle discoordination with minimal annular dilatation distorts leaflet coaptation sufficiently to produce severe mitral regurgitation.


Appetite, energy intake, and PYY3-36 responses to energy-matched continuous exercise and submaximal high-intensity exercise.
High-intensity intermittent exercise induces physiological adaptations similar to energy-matched continuous exercise, but the comparative appetite and energy balance responses are unknown. Twelve healthy males (mean ± SD: age, 22 ± 3 years; body mass index, 23.7 ± 3.0 kg·m(-2); maximum oxygen uptake, 52.4 ± 7.1 mL·kg(-1)·min(-1)) completed three 8 h trials (control, steady-state exercise (SSE), high-intensity intermittent exercise (HIIE)) separated by 1 week. Trials commenced upon completion of a standardized breakfast. Exercise was performed from hour 2 to hour 3. In SSE, 60 min of cycling at 59.5% ± 1.6% of maximum oxygen uptake was performed. In HIIE, ten 4-min cycling intervals were completed at 85.8% ± 4.0% of maximum oxygen uptake, with a 2-min rest between each interval. A standardized lunch and an ad libitum afternoon meal were provided at hours 3.75 and 7, respectively. Appetite ratings and peptide YY3-36 concentrations were measured throughout each trial. Appetite was acutely suppressed during exercise, but more so during HIIE (p < 0.05). Peptide YY3-36 concentrations increased significantly upon cessation of exercise in SSE (p = 0.002), but were highest in the hours after exercise in HIIE (p = 0.05). Exercise energy expenditure was not different between HIIE and SSE (p = 0.649), but perceived exertion was higher in HIIE (p < 0.0005). Ad libitum energy intake did not differ between trials (p = 0.833). Therefore, relative energy intake (energy intake minus the net energy expenditure of exercise) was lower in the SSE and HIIE trials than in the control trial (control, 4759 ± 1268 kJ; SSE, 2362 ± 1224 kJ; HIIE, 2523 ± 1402 kJ; p < 0.0005). An acute bout of energy-matched continuous exercise and HIIE were equally effective at inducing an energy deficit without stimulating compensatory increases in appetite.


An isoleucine zipper peptide forms a native-like triple stranded coiled coil in solution.
Recent studies in the field of de novo protein design have focused on the construction of native-like structures. Here we describe the design and characterization of an isoleucine zipper peptide intended to form a parallel triple-stranded coiled coil. To obtain the native-like structural uniqueness, the hydrophobic interface of the peptide consists of beta-branched Ile residues for complementary side chain packing. The peptide forms a stable triple-stranded coiled coil, as determined by circular dichroism and sedimentation equilibrium analyses. A fluorescence quenching assay after the incorporation of acridine revealed a parallel orientation of the peptides. The structural uniqueness of the coiled coil was confirmed by proton-deuterium amide hydrogen exchange and hydrophobic dye binding. The peptide contains amide protons with hydrogen exchange rates that are approximately an order of magnitude slower than those expected if the exchange occurred via global unfolding. A hydrophobic dye does not bind to the peptide. These results strongly suggest that the peptide folds into a well-packed structure that is very similar to the native state of a natural protein. Thus, Ile residues in the hydrophobic interface can improve the side chain packing, which can impart native-like structural uniqueness to the designed coiled coil.


Evaluation of Duraflo II heparin immobilized cardiopulmonary bypass circuits.
Cardiopulmonary bypass (CPB) involves extensive contact between blood and synthetic surfaces and may result in blood cell activation and plasma protein alterations. This study determines the effect of Duraflo II heparin treated CPB circuits (Bentley Laboratories, Irvine, CA) on calves under simulated clinical conditions. Calves were placed on CPB for 4 hr, and activated clotting times were maintained above 480 sec with systemic heparin. Better preserved platelet number and function, lower fibrinopeptide A levels, and lack of thrombus deposition were observed in the Duraflo II treated group, relative to the untreated control group, during the entire bypass period. The results suggest that despite high doses of circulating heparin in calves during CPB, the use of extracorporeal circuits with improved blood compatibility still provides measurable benefit.


Potency on lowering serum uric acid in gout patients: a pooled analysis of registrative studies comparing febuxostat vs. allopurinol.
Hyperuricemia leading to urate crystal formation in tissues represents the pathophysiological mechanism of gout. Guidelines recommend a therapeutic target of serum urate concentration (sUA) <6 mg/dL, or even lower (≤5 mg/dL) in patients with large deposits. We conducted an analysis with the aim to achieve additional insights into the urate-lowering efficacy of two xanthine oxidase inhibitors, allopurinol and febuxostat. This was a pooled analysis of phase III trials on allopurinol and febuxostat, including 4101 patients with gout and hyperuricemia. The efficacy outcomes were: mean reduction of sUA concentration from baseline; number of patients with target sUA levels (<6.0 mg/dL or ≤5 mgdL); time to reach target sUA levels. Three registrative, phase III, randomized, multicenter, placebo-controlled/allopurinol-controlled trials assessing the efficacy of febuxostat, were included. The mean reduction of sUA concentration with any dose of febuxostat was higher (-2.92±2.87 mg/dL; -27%), with respect to placebo- (-0.62±1.84 mg/dL; -5%) and allopurinol-pooled groups (-2.41±2.20 mg/dL; -24%). Moreover, febuxostat showed a higher probability to achieve the recommended target sUA concentration than allopurinol [odds ratio: 2.43 (95% CI: 2.119-2.789) and 4.05 (95% CI: 3.41-4.82) for sUA levels <6 mg/dL and ≤5 mg/dL, respectively]. Patients on any-dose febuxostat reached target sUA faster than allopurinol-treated patients (86.04±71.47 vs. 98.76±70.88 days and 52.08±49.97 vs. 90.42±68.03 days for reaching sUA levels <6 mg/dL and ≤5 mg/dL, respectively; p <0.001 for both comparisons). In patients with gout and hyperuricemia, febuxostat was significantly more effective and faster than allopurinol in obtaining the recommended target sUA levels, which were reached by a higher number of patients. Therefore, febuxostat was confirmed as an effective option for the treatment of hyperuricemia in gout.


Central Venous-to-Arterial CO2 Difference-Assisted Goal-Directed Hemodynamic Management During Major Surgery-A Randomized Controlled Trial.
Different goals have guided goal-directed therapy (GDT). Protocols aiming for central venous-to-arterial carbon dioxide gap (DCO2) <6 mm Hg have improved organ function in septic shock. Evidence for use of DCO2 in the perioperative period is scarce. We aimed to determine if a GDT protocol using central venous saturation of oxygen (SCvo2) and DCO2 reduced organ dysfunction and intensive care unit (ICU) stay in American Society of Anesthesiologist (ASA) I and II patients undergoing major surgeries compared to pragmatic goal-directed care. One hundred patients were randomized. Arterial and venous blood-gas values were recorded every 2 hours perioperatively for all patients. Intervention group (GrI) with access to both values was managed per protocol based on DCO2 and SCvo2. Dobutamine infusion 3 to 5 µg/kg/min started if DCO2 >6 mm Hg after correcting all macrocirculatory end points. Control group (GrC) had access only to arterial-gas values and managed per "conventional" goals without DCO2 or SCvo2. Patients were followed for 48 hours after surgery. Organ dysfunction, sequential organ failure assessment (SOFA) scores-primary outcome, length of stay in ICU, and duration of postoperative mechanical ventilation and hospital stay were recorded. The patient, surgeons, ICU team, and analyzer were blinded to group allocation. The groups (44 each) did not significantly differ with respect to baseline characteristics. Perioperative fluids, blood products, and vasopressors used did not significantly differ. The GrI had less organ dysfunction although not significant (79% vs 66%; P = .2). Length of ICU stay in the GrI was significantly less (1.52; standard deviation [SD], 0.82 vs 2.18; SD, 1.08 days; P = .002). Mechanical ventilation duration (0.9 days in intervention versus 0.6 days in control; P = .06) and length of hospital stay did not significantly differ between the groups. Perioperative DCO2 (5.8 vs 8.4 mm Hg; P < .001) and SCvo2 (73.5 vs 68.4 mm Hg; P < .001) were significantly better in the GrI. GDT guided by DCO2 did not improve organ function in our cohort. It resulted in greater use of dobutamine, improved tissue oxygen parameters, and decreased length of ICU stay. More evidence is needed for the routine use of DCO2 in sicker patients. In the absence of cardiac output monitors, it may be a readily available, less-expensive, and underutilized parameter for major surgical procedures.


Patterns of postnatal growth in HIV-infected and HIV-exposed children.
HIV infection can contribute to disturbances in both linear growth and weight gain in early childhood, with disturbances often apparent as early as 3 months of age. There is little evidence for a difference in the early growth of HIV-exposed but uninfected children compared to healthy controls. Owing to the close association of growth with immune function and clinical progression, an understanding of growth patterns may be an important tool to ensure the provision of appropriate care to HIV-infected and exposed children. Timely growth monitoring may be used to improve the clinical course and quality of life of these children.


Understanding Waste Management Behavior Among University Students in China: Environmental Knowledge, Personal Norms, and the Theory of Planned Behavior.
Previous studies have confirmed that individual waste management behavior is influenced by both rational-based and altruistic-oriented beliefs and attitudes. Scholars incorporated personal norms in Ajzen's theory of planned behavior and confirmed its usefulness in predicting waste management behavior. However, limited attention has been paid to the interactions between the variables in the model. Scholars also commented that the cognitive dimension was largely neglected in the current socio-psychological framework of waste management behavior. This study intends to address this issue by incorporating environmental concern and environmental knowledge in the model and examining the psychological paths linking these variables to waste management behavior within the expanded model of planned behavior. Based on a cross-sectional survey among 434 university students in China, the results showed that subjective norms, perceived behavioral control, personal norms, and environmental knowledge were essential predictors of waste management behavior, whereas the direct effect of attitude was not statistically significant. Environmental concern and subjective norms could influence waste management behavior through personal norms. Environmental knowledge could influence waste management behavior indirectly through environmental concern, personal norms, and perceived behavioral control. Moreover, perceived behavioral control served as a mediator between the relationship of personal norms and waste management behavior.


Effect of water on overbased sulfonate engine oil additives.
The presence and effect of water on calcium carbonate nanoparticles used in engine additives, stabilized with a sulfonate surfactant, is investigated using small-angle neutron scattering, dynamic light scattering, Fourier transform infrared spectroscopy, and rheometry. These techniques provide complementary data that suggests the formation of a layer of water around the core of the particles ensuring continued colloidal stability yet increasing the dispersion viscosity. Through the use of small-angle neutron scattering, the dimensions of this layer have been quantified to effectively one or two water molecules in thickness. The lack of a significant electrostatic repulsion is evidence that the water layer is insufficient to cause major dissociation of surface ions.


Recent Advances in Photosensitizers as Multifunctional Theranostic Agents for Imaging-Guided Photodynamic Therapy of Cancer.
In recent years tremendous effort has been invested in the field of cancer diagnosis and treatment with an overall goal of improving cancer management, therapeutic outcome, patient survival, and quality of life. Photodynamic Therapy (PDT), which works on the principle of light-induced activation of photosensitizers (PS) leading to Reactive Oxygen Species (ROS) mediated cancer cell killing has received increased attention as a promising alternative to overcome several limitations of conventional cancer therapies. Compared to conventional therapies, PDT offers the advantages of selectivity, minimal invasiveness, localized treatment, and spatio-temporal control which minimizes the overall therapeutic side effects and can be repeated as needed without interfering with other treatments and inducing treatment resistance. Overall PDT efficacy requires proper planning of various parameters like localization and concentration of PS at the tumor site, light dose, oxygen concentration and heterogeneity of the tumor microenvironment, which can be achieved with advanced imaging techniques. Consequently, there has been tremendous interest in the rationale design of PS formulations to exploit their theranostic potential to unleash the imperative contribution of medical imaging in the context of successful PDT outcomes. Further, recent advances in PS formulations as activatable phototheranostic agents have shown promising potential for finely controlled imaging-guided PDT due to their propensity to specifically turning on diagnostic signals simultaneously with photodynamic effects in response to the tumor-specific stimuli. In this review, we have summarized the recent progress in the development of PS-based multifunctional theranostic agents for biomedical applications in multimodal imaging combined with PDT. We also present the role of different imaging modalities; magnetic resonance, optical, nuclear, acoustic, and photoacoustic in improving the pre-and post-PDT effects. We anticipate that the information presented in this review will encourage future development and design of PSs for improved image-guided PDT for cancer treatment.


[Role of children physical development in radiation hygienic monitoring system].
The article deals with longstanding work on studies of physical development parameters among preschoolers aged 4-7 and dwelling on territories near to objects with potential radiation danger, also on radiation-connected anxiety in parents of the examined children. The stated objects when exploited in normal mode were proved to cause no influence on the children's development. Social and economical factors appeared to play leading role in developmental parameters formation. Increased level of radiation-connected anxiety in parents of the children examined appeared to be out of proportion to real favorable radiation background of the territories examined.


Supramolecular organization of photosystem II and its light-harvesting antenna in partially solubilized photosystem II membranes.
We present an extended analysis of the organization of green plant photosystem II and its associated light-harvesting antenna using electron microscopy and image analysis. The analysis is based on a large dataset of 16 600 projections of negatively stained PSII-LHCII supercomplexes and megacomplexes prepared by means of three different pretreatments. In addition to our previous work on this system [Boekema, E.J., van Roon, H., Calkoen, F., Bassi, R. and Dekker, J.P. (1999) Biochemistry 38, 2233-2239], the following results were obtained. The rotational orientation of trimeric LHCII at the S, M and L binding positions was determined. It was found that compared to the S trimer, the M and L trimers are rotationally shifted by about -20 degrees and -50 degrees, respectively. The number of projections with empty CP29, CP26 and CP24 binding sites was found to be about 0, 18 and 4%, respectively. We suggest that CP26 and CP24 are not required for the binding of trimeric LHCII at any of the three binding positions. A new type of megacomplex was observed with a characteristic windmill-like shape. This type III megacomplex consists of two C2S2 supercomplexes connected at their CP26 tips. Structural variation in the region of the central dimeric photosystem II complex was found to occur at one specific position near the periphery of the complex. We attribute this variation to the partial absence of an extrinsic polypeptide or one or more small intrinsic membrane proteins.


Patient Safety Culture, Infection Prevention, and Patient Safety in the Operating Room: Health Workers' Perspective.
A hospital's patient safety culture affects surgical outcomes. Operating room safety culture has been overlooked despite the importance of patient safety. The AHRQ's Hospital Survey on Patient Safety Culture (HSOPSC) has been used worldwide to assess and enhance patient safety culture. This study examined how patient safety culture and infection prevention effect patient safety in the Operating Room (OR). This observational study used an online survey and included 143 OR workers. Descriptive statistics and multilinear regression were used to examine how patient safety culture and infection prevention affects level of patient safety. Most responders worked in excellent-accredited general hospitals. Most responders were male, aged between 26 to 40 years old, and had bachelor's degrees. Most were hospital-experienced nurses. Less than half had worked in units for over ten years. Organizational Learning - Continuous Improvement; Teamwork and Handoffs; and Information Exchange had the most positive responses in the OR. However, Staffing, Work Pace, and Patient Safety ranked lowest. Organizational Learning - Continuous Improvement and Hospital Management Support for Infection Prevention Efforts were found to affect OR patient safety level perceptions. According to the findings of our study, the overall patient safety culture in the operating room remains weak which highlights the importance of continuing efforts to improve patient safety in the OR. Further study could be directed to identify organizational learning in infection prevention to enhance the patient safety in the OR.


Diffusion of water in zeolites.
The self-diffusion coefficient D of water occluded in samples of near-faujasite has been determined by pulsed field-gradient spin-echo nuclear magnetic resonance. The value of D in square centimeters per second x 10(5) at 30 degrees C is 1.34, 1.65, and 1.88 in the following zeolites, respectively: Na X, Ca X, and Ca Y (X and Y being an indication of ratio of silicon to aluminum in the zeolites). By comparison, the value of D in pure water at 30 degrees C is 2.5 x 10(-5) cm(2)/sec. Arrhenius activation energies for D are 6.9, 6.8, and 5.6 kilocalories per mole, respectively, for the three faujasites and 5.0 kcal/mole for pure water. Thus, there appears to be little difference in diffusion behavior between free water and water occluded in faujasite.


Changes in the placental glucocorticoid barrier during rat pregnancy: impact on placental corticosterone levels and regulation by progesterone.
Glucocorticoid excess in utero inhibits fetal growth and programs adverse outcomes in adult offspring. Access of maternal glucocorticoid to the glucocorticoid receptor (NR3C1) in the placenta and fetus is regulated by metabolism via the 11beta-hydroxysteroid dehydrogenase (HSD11B) enzymes, as well as multidrug resistance P-glycoprotein (ABCB1)-mediated efflux of glucocorticoids from the syncytiotrophoblast. This study determined expression of genes encoding the two HSD11B isoforms (Hsd11b1 and Hsd11b2), the two ABCB1 isoforms (Abcb1a and Abcb1b), and Nr3c1 in the junctional and labyrinth zones of rat placentas at Days 16 and 22 of normal gestation (Day 23 is term). To assess possible regulation of the Hsd11b and Abcb1 isoforms by glucocorticoids and progesterone, their placental expression was also measured at Day 22 after partial progesterone withdrawal from Day 16 (maternal ovariectomy plus full estrogen and partial progesterone replacement) or after treatment with dexamethasone acetate (1 microg/ml of drinking water from Day 13). Expression of Hsd11b1 mRNA increased in the labyrinth zone (the site of maternal-fetal exchange) from Day 16 to Day 22, whereas that of Hsd11b2 fell dramatically. Consistent with these changes, corticosterone levels increased 10-fold in the labyrinth zone over this period. Expression of both Abcb1a and Abcb1b was markedly higher in the labyrinth zone compared with the junctional zone on both days, consistent with the proposed barrier role of ABCB1 in the placenta. Nr3c1 mRNA expression was similar in the two placental zones at Day 16 but increased 3-fold in the labyrinth zone by Day 22. Partial progesterone withdrawal increased Hsd11b1 mRNA and protein expression in the labyrinth zone but decreased Nr3c1 mRNA expression. These data show that the dynamic expression patterns of the placental HSD11Bs in late gestation are associated with dramatic shifts in placental corticosterone. Moreover, the late gestational rise in labyrinthine Hsd11b1 seems to be driven by the normal prepartum fall in progesterone level.


[Endocrine cells in the rabbit colon mucosal epithelium].
The epithelium of the rabbit colon was studied by light and electron microscopy. The highest number of endocrinocytes in colon are observed in terminal parts of colon, i.e. in a distal part of appendix (135 +/- 15 cells/mm2) and in rectum (142 +/- 20), to decrease in the ileocaeal region (caecum proxinmal part--39 +/- 9, colon proximal part--56 +/- 9), where the least number of cells was marked. Agrentaffin cells (EC) number the same way, however, with a weaker difference in the number of cells between terminal departments and ileocaeal region. An electron microscope study of mucosal epithelium of the colon enabled us to identify 5 types of endocrinocytes. I-III types: EC-, D- and L-cells. IV and V are seldom met types, the same way as the "mixed" cells have been indentified. Whose cytoplasm simultaneously contained both mucous and endocrine granules. The received data show a certain degree of similarity in the endocrine apparatus of the rabbit with that of humans, although essential differences exists in regards of the appendix pattern.


Using natural language processing to characterize and predict homeopathic product-associated adverse events in consumer reviews: comparison to reports to FDA Adverse Event Reporting System (FAERS).
Apply natural language processing (NLP) to Amazon consumer reviews to identify adverse events (AEs) associated with unapproved over the counter (OTC) homeopathic drugs and compare findings with reports to the US Food and Drug Administration Adverse Event Reporting System (FAERS). Data were extracted from publicly available Amazon reviews and analyzed using JMP 16 Pro Text Explorer. Topic modeling identified themes. Sentiment analysis (SA) explored consumer perceptions. A machine learning model optimized prediction of AEs in reviews. Reports for the same time interval and product class were obtained from the FAERS public dashboard and analyzed. Homeopathic cough/cold products were the largest category common to both data sources (Amazon = 616, FAERS = 445) and were analyzed further. Oral symptoms and unpleasant taste were described in both datasets. Amazon reviews describing an AE had lower Amazon ratings (X2 = 224.28, P < .0001). The optimal model for predicting AEs was Neural Boosted 5-fold combining topic modeling and Amazon ratings as predictors (mean AUC = 0.927). Topic modeling and SA of Amazon reviews provided information about consumers' perceptions and opinions of homeopathic OTC cough and cold products. Amazon ratings appear to be a good indicator of the presence or absence of AEs, and identified events were similar to FAERS. Amazon reviews may complement traditional data sources to identify AEs associated with unapproved OTC homeopathic products. This study is the first to use NLP in this context and lays the groundwork for future larger scale efforts.


Ehd1, a B-type response regulator in rice, confers short-day promotion of flowering and controls FT-like gene expression independently of Hd1.
Two evolutionarily distant plant species, rice (Oryza sativa L.), a short-day (SD) plant, and Arabidopsis thaliana, a long-day plant, share a conserved genetic network controlling photoperiodic flowering. The orthologous floral regulators-rice Heading date 1 (Hd1) and Arabidopsis CONSTANS (CO)-integrate circadian clock and external light signals into mRNA expression of the FLOWERING LOCUS T (FT) group floral inducer. Here, we report that the rice Early heading date 1 (Ehd1) gene, which confers SD promotion of flowering in the absence of a functional allele of Hd1, encodes a B-type response regulator that might not have an ortholog in the Arabidopsis genome. Ehd1 mRNA was induced by 1-wk SD treatment, and Ehd1 may promote flowering by inducing FT-like gene expression only under SD conditions. Microarray analysis further revealed a few MADS box genes downstream of Ehd1. Our results indicate that a novel two-component signaling cascade is integrated into the conserved pathway in the photoperiodic control of flowering in rice.


A novel subgroup 16SrVII-D phytoplasma identified in association with Erigeron witches' broom.
Erigeron sp. plants showing symptoms of witches' broom and stunting were found near orchards of passion fruit in São Paulo state, Brazil. These symptoms were indicative of infection by phytoplasmas. Thus, the aim of this study was to detect and identify possible phytoplasmas associated with diseased plants. Total DNA was extracted from symptomatic and asymptomatic plants and used in nested PCR conducted with the primer pairs P1/Tint and R16F2n/16R2. Amplification of genomic fragments of 1.2 kb from the 16S rRNA gene confirmed the presence of phytoplasma in all symptomatic samples. The sequence identity scores between the 16S rRNA gene of the phytoplasma strain identified in the current study and those of previously reported 'Candidatus Phytoplasma fraxini'-related strains ranged from 98% to 99% indicating the phytoplasma to be a strain affiliated with 'Candidatus Phytoplasma fraxini'. The results from a phylogenetic analysis and virtual RFLP analysis of the 16S rRNA gene sequence with 17 restriction enzymes revealed that the phytoplasma strain belongs to the ash yellows phytoplasma group (16SrVII); the similarity coefficient of RFLP patterns further suggested that the phytoplasma represents a novel subgroup, designated 16SrVII-D. The representative of this new subgroup was named EboWB phytoplasma (Erigeron bonariensis Witches' Broom).


Are variations in cuticular hydrocarbons of queens and workers a reliable signal of fertility in the ant Harpegnathos saltator?
One of the key features of insect societies is the division of labor in reproduction between one or a few fertile individuals and many sterile nestmates that function as helpers. The behavioral and physiological mechanisms regulating reproduction in ant societies are still not very well understood, especially in species in which all colony members are reproductively totipotent. In the ponerine ant Harpegnathos saltator, queen-worker dimorphism is very limited, and a few mated workers reproduce ("gamergates") once the founding queen becomes senescent. Worker oviposition is regulated by highly directed aggressive interactions among nestmates, who can recognize different levels of ovarian activity. We show that variations in cuticular hydrocarbons (CHC) correlate with oogenesis, both for queens and workers. 13,23-Dimethylheptatriacontane is present in egg-layers, but not in infertile workers and queens. Proportions of other CHCs vary as well, resulting in clear separation of the ants in a multivariate analysis. Egg-layers are characterized by an elongation of the chain length of CHCs. We used solid-phase microextraction to measure CHCs in live ants that were experimentally induced to start producing eggs. Over a period of 118 days, CHC profiles of infertile workers changed completely to that of reproductives. The effect of age can be excluded in this modification. This striking correlation of ovarian activity with CHC variation and its correspondence with the observed recognition behavior exhibited by the workers toward egg-laying nestmates suggests that CHCs serve as a fertility signal in the ant H. saltator, a reliable basis for regulating reproduction.


Commentary on the management of total laryngectomy patients during the COVID-19 pandemic.
The coronavirus disease-2019 (COVID-19) pandemic has rapidly spread across the world, placing unprecedented strain on the health care system. Health care resources including hospital beds, ICUs, as well as personal protective equipment are becoming increasingly rationed and scare commodities. In this environment, the laryngectomee (patient having previously undergone a total laryngectomy) continues to represent a unique patient with unique needs. Given their surgically altered airway, they pose a challenge to manage for the otolaryngologist within the current COVID-19 pandemic. In this brief report, we present special considerations and best practice recommendations in the management of total laryngectomy patients. We also discuss recommendations for laryngectomy patients and minimizing community exposures.


Lattice thermal conductivity of Janus MoSSe and WSSe monolayers.
In this work, the heat transport properties of Janus MoSSe and WSSe monolayers are systematically investigated using non-equilibrium molecular dynamics simulations. Strong size dependence of the thermal conductivity is found in the Janus MoSSe and WSSe monolayers. In the two-dimensional limit, the Mo-based Janus MoSSe monolayer shows a higher thermal conductivity but similar phonon mean free path as MoS2, while the W-based Janus WSSe monolayer shows a similar thermal conductivity but longer phonon mean free path than WSe2. These two Janus monolayers also present quite different temperature dependencies. With temperature increasing from 100 K to 350 K, the reduction in thermal conductivity of MoSSe is up to 28.4%, but only 12.75% in WSSe, because of the weak temperature dependence in the phonon density of states. With 2% vacancy density, the thermal conductivity of defective MoSSe is only 16.03% that of pristine MoSSe, while for defective WSSe, the thermal conductivity is 14.04% that of pristine WSSe. The strong dependence on vacancy is explained by atomic heat flux vector analysis. The present study demonstrates rich physical phenomena in the thermal transport properties of Janus transition metal dichalcogenide monolayers, which may offer a new degree of freedom for manipulating their thermal conductivity for applications including thermal management and thermoelectric devices.


A determinant of odorant specificity is located at the extracellular loop 2-transmembrane domain 4 interface of an Anopheles gambiae odorant receptor subunit.
To explore the structural basis for odorant specificity in odorant receptors of the human malaria vector mosquito, Anopheles gambiae, odorant-binding subunits (Agam\Ors) expressed in Xenopus oocytes in combination with Agam\Orco (coreceptor subunit) were assayed by 2-electrode voltage clamp against 25 structurally related odorants. Agam\Or13 and Agam\Or15 display 82% amino acid identity and had similar, but somewhat distinct odorant response profiles. The ratio of acetophenone to 4-methylphenol responses was used in a mutation-based analysis of Agam\Or15, interchanging 37 disparate residues between Agam\Or15 and Agam\Or13. Eleven mutations caused significant changes in odorant responsiveness. Mutation of alanine 195 resulted in the largest shift in response ratio from Agam\Or15 toward Agam\Or13. Concentration-response analysis for a series of mutations of residue 195 revealed a large effect on acetophenone sensitivity, with EC50 values varying by >1800-fold and correlating with residue side chain length. Similar results were obtained for propiophenone and benzaldehyde. But, for other odorants, such as 4-methylphenol, 4-methylbenzaldehyde, and 4-methylpropiophenone, the effect of mutation was much smaller (EC50 values varied by ≤16-fold). These results show that alanine 195, putatively located at the second extracellular loop/fourth transmembrane domain interface, plays a critical role in determining the odorant response specificity of Agam\Or15.


Myeloperoxidase oxidizes mitoxantrone to metabolites which bind covalently to DNA and RNA.
The anticancer agent mitoxantrone is readily oxidized by the human haem enzyme myeloperoxidase and hydrogen peroxide. Intercalation of mitoxantrone with DNA inhibited oxidation of the drug by myeloperoxidase. However, at a physiological ionic strength, significant oxidation of the drug was evident. At a H2O2:mitoxantrone ratio of 1.0, myeloperoxidase oxidized mitoxantrone to a metabolite (product B) which associated reversibly with DNA. At greater hydrogen peroxide concentrations, two further metabolites were produced (products C and D), neither of which associated reversibly with DNA, as indicated by the absence of any spectral change in the presence of DNA. Long exposure of the products derived from the oxidation of [14C]mitoxantrone by myeloperoxidase resulted in a time-dependent covalent binding of the activated drug to both DNA and RNA. The amount of DNA adduct increased linearly with the extent of oxidation of mitoxantrone (up to a H2O2:mitoxantrone ratio of 5.0). No adducts resulted from exposure of the oxidized product B to DNA, but adducts formed following further oxidation of B by myeloperoxidase. The myeloperoxidase-catalysed oxidation of mitoxantrone to products capable of interacting covalently and non-covalently with nucleic acids may represent an important mode of action of mitoxantrone against acute myeloid leukemias since these cells (including neutrophils, monocytes and their precursors) contain high levels of myeloperoxidase.


A Mobile Phone Intervention to Improve Obesity-Related Health Behaviors of Adolescents Across Europe: Iterative Co-Design and Feasibility Study.
Promotion of physical activity, healthy eating, adequate sleep, and reduced sedentary behavior in adolescents is a major priority globally given the current increase in population health challenges of noncommunicable diseases and risk factors such as obesity. Adolescents are highly engaged with mobile technology, but the challenge is to engage them with mobile health (mHealth) technology. Recent innovations in mobile technology provide opportunities to promote a healthy lifestyle in adolescents. An increasingly utilized approach to facilitate increased engagement with mHealth technology is to involve potential users in the creation of the technology. This study aimed to describe the process of and findings from co-designing and prototyping components of the PEGASO Fit for Future (F4F) mHealth intervention for adolescents from different cultural backgrounds. A total of 74 adolescents aged 13 to 16 years from Spain, Italy, and the United Kingdom participated in the co-design of the PEGASO F4F technology. In 3 iterative cycles over 12 months, participants were involved in the co-design, refinement, and feasibility testing of a system consisting of diverse mobile apps with a variety of functions and facilities to encourage healthy weight-promoting behaviors. In the first iteration, participants attended a single workshop session and were presented with mock-ups or early-version prototypes of different apps for user requirements assessment and review. During the second iteration, prototypes of all apps were tested by participants for 1 week at home or school. In the third iteration, further developed prototypes were tested for 2 weeks. Participants' user experience feedback and development ideas were collected through focus groups and completion of questionnaires. For the PEGASO F4F technology to be motivating and engaging, participants suggested that it should (1) allow personalization of the interface, (2) have age-appropriate and easy-to-understand language (of icons, labels, instructions, and notifications), (3) provide easily accessible tutorials on how to use the app or navigate through a game, (4) present a clear purpose and end goal, (5) have an appealing and self-explanatory reward system, (6) offer variation in gamified activities within apps and the serious game, and (7) allow to seek peer support and connect with peers for competitive activities within the technology. Incorporating adolescents' preferences, the PEGASO F4F technology combines the functions of a self-monitoring, entertainment, advisory, and social support tool. This was the first study demonstrating that it is possible to develop a complex mobile phone-based technological system applying the principles of co-design to mHealth technology with adolescents across 3 countries. The findings from this study informed the development of an mHealth system for healthy weight promotion to be tested in a controlled multinational pilot trial.


[Seven theses on health education for community participation]
This article attempts to establish some postulates to orient health education aimed at promoting community participation. Theories on human action serve as the point of departure for establishing two currents of thought explaining action or non-action by people. Two working principles are proposed, i.e., that it is necessary to both know and rely on human beings. These two principles are expressed in two premises: "Only by knowing individuals and their living circumstances is it possible to take efficient and on-going action in health," and "No one can care for someone else's health if that person does not wish to do so himself/herself." The author goes on to raise seven theses: 1. There is no such thing as one person knowing and another not knowing; rather, there are two people who know distinct things. 2. Education is imparted not only through educational programs, but in all health-related action. 3. Ignorance is not a void to be filled, but a plenitude to be changed. 4. Education should be dialogical and participatory. 5. Education should reinforce people's self-confidence. 6. Education should seek to reinforce the effort-achievement model of knowledge. 7. Education should promote individual responsibility and collective cooperation.


Prediction of contrast-induced nephropathy by the serum creatinine level on the day following cardiac catheterization.
The majority of patients who undergo coronary arteriography are discharged from the hospital on the day of the procedure or on the following day. The aim of this study is to investigate whether the change in serum creatinine (SCr) and estimated glomerular filtration rate (eGFR) on the day following cardiac catheterization can predict the development of contrast-induced nephropathy (CIN). This is a multicenter prospective observational study, which consists of 860 patients who underwent cardiac catheterization. We measured SCr and eGFR before cardiac catheterization, on the following day, and 48-72h post-procedure. Definition of CIN is changes in SCr ≥0.5mg/dL or ≥25% from baseline 48-72h after contrast exposure. CIN occurred in 40 patients. SCr levels significantly increased from a baseline of 1.55±1.08mg/dL to 1.79±1.26mg/dL on the following day in patients with CIN (p<0.0001), but significantly decreased from a baseline of 1.21±0.65mg/dL to 1.18±0.61mg/dL on the following day in those without CIN (p<0.0001). eGFR significantly decreased from a baseline of 47.3±28.3mL/min/1.73m2 to 40.6±26.7mL/min/1.73m2 on the following day in patients with CIN (p<0.0001), but significantly increased from a baseline of 53.1±22.0mg/dL to 53.6±21.2mg/dL on the following day in those without CIN (p=0.0236). Receiver operating characteristic curve analysis indicated that SCr change ≥0.1mg/dL [area under the curve (AUC)=0.852, sensitivity 72.5%, specificity 86.1%] and eGFR change ≤-1.1mL/min/1.73m2 (AUC=0.789, sensitivity 85.0%, specificity 64.9%) were the best cut-off values for predicting CIN. Multivariate logistic regression showed that a change in SCr ≥0.1mg/dL [odds ratio (OR), 29.3; 95% confidence interval (CI), 10.8-96.2] and change in eGFR ≤-1.1mL/min/1.73m2 (OR, 69.7; 95% CI, 13.3-952) were powerful independent predictors of CIN. Changes in SCr and eGFR on the day following cardiac catheterization predict the development of CIN.


[Parenting stress, maternal feeding styles related to preschooler body mass index].
Introduction: excess weight in childhood is influenced by multiple factors; parenting could contribute to this problem, given that during the infant stage the parents, and mainly the mother, are responsible for providing food and feeding their children. Objective: to explore the relationship of parenting stress and maternal feeding styles with preschool BMI. Materials and methods: a cross-sectional study. A total of 382 dyads, mother and child (3-5 years of age) participated. The children attended public preschool institutions. Participating mothers completed the Parenting Stress Scale and the Caregiver Feeding Styles Questionnaire. Weight and height were measured, and the child's BMI was calculated. Results: 34 % of the mothers more frequently used an indulgent style, 28.2 % of the preschool children had overweight-obese. Mothers with an authoritative style had the highest mean range of parenting stress compared to other categories (H = 15.302, gl = 3, p = 0.002). Maternal schooling, responsibility and demand dimensions were identified as contributing to preschooler BMI. Conclusion: parenting stress and feeding styles are variables that contribute to the risk of overweight-obesity in prescho.


The forkhead transcription factor Fkh2 regulates the cell division cycle of Schizosaccharomyces pombe.
In eukaryotes the regulation of gene expression plays a key role in controlling cell cycle progression. Here, we demonstrate that a forkhead transcription factor, Fkh2, regulates the periodic expression of cdc15(+) and spo12(+) in the M and G(1) phases of the cell division cycle in the fission yeast Schizosaccharomyces pombe. We also show that Fkh2 is important for several cell cycle processes, including cell morphology and cell separation, nuclear structure and migration, and mitotic spindle function. We find that the expression of fkh2(+) is itself regulated in a cell cycle-dependent manner in G(1) coincident with the expression of cdc18(+), a Cdc10-regulated gene. However, fkh2(+) expression is independent of Cdc10 function. Fkh2 was found to be phosphorylated during the cell division cycle, with a timing that suggests that this posttranslational modification is important for cdc15(+) and spo12(+) expression. Related forkhead proteins regulate G(2) and M phase-specific gene expression in the evolutionarily distant Saccharomyces cerevisiae, suggesting that these proteins play conserved roles in regulating cell cycle processes in eukaryotes.


Exploring injury severity measures and in-hospital mortality: A multi-hospital study in Kenya.
Low- and middle-income countries (LMICs) have a disproportionately high burden of injuries. Most injury severity measures were developed in high-income settings and there have been limited studies on their application and validity in low-resource settings. In this study, we compared the performance of seven injury severity measures: estimated Injury Severity Score (eISS), Glasgow Coma Score (GCS), Mechanism, GCS, Age, Pressure score (MGAP), GCS, Age, Pressure score (GAP), Revised Trauma Score (RTS), Trauma and Injury Severity Score (TRISS) and Kampala Trauma Score (KTS), in predicting in-hospital mortality in a multi-hospital cohort of adult patients in Kenya. This study was performed using data from trauma registries implemented in four public hospitals in Kenya. Estimated ISS, MGAP, GAP, RTS, TRISS and KTS were computed according to algorithms described in the literature. All seven measures were compared for discrimination by computing area under curve (AUC) for the receiver operating characteristics (ROC), model fit information using Akaike information criterion (AIC), and model calibration curves. Sensitivity analysis was conducted to include all trauma patients during the study period who had missing information on any of the injury severity measure(s) through multiple imputations. A total of 16,548 patients were included in the study. Complete data analysis included 14,762 (90.2%) patients for the seven injury severity measures. TRISS (complete case AUC: 0.889, 95% CI: 0.866-0.907) and KTS (complete case AUC: 0.873, 95% CI: 0.852-0.892) demonstrated similarly better discrimination measured by AUC on in-hospital deaths overall in both complete case analysis and multiple imputations. Estimated ISS had lower AUC (0.764, 95% CI: 0.736-0.787) than some injury severity measures. Calibration plots showed eISS and RTS had lower calibration than models from other injury severity measures. This multi-hospital study in Kenya found statistical significant higher performance of KTS and TRISS than other injury severity measures. The KTS, is however, an easier score to compute as compared to the TRISS and has stable good performance across several hospital settings and robust to missing values. It is therefore a practical and robust option for use in low-resource settings, and is applicable to settings similar to Kenya.


FJ5002: a potent telomerase inhibitor identified by exploiting the disease-oriented screening program with COMPARE analysis.
To facilitate the search for candidate telomerase inhibitors, we exploited the database of the disease-oriented screening program (DOS) available in our facility by using COMPARE analysis. In primary and arbitrary screening, we were able to identify the alkaloid berberine as a moderate inhibitor with 50% inhibition at approximately 35 microM. Using this alkaloid as a seed compound in COMPARE resulted in the identification of other berberine-like compounds and mitochondria-accumulating agents as highly related to berberine. Among these compounds, MKT077, a rhodacyanine derivative currently under Phase I clinical trials, showed a potent inhibitory effect with 50% inhibition at approximately 5 microM. With MKT077 as an upgraded seed for a new round of COMPARE analysis, we identified rhodacyanine FJ5002, a close derivative of MKT077, as the most potent telomerase inhibitor with 50% inhibition at approximately 2 microM. Long-term cultivation of U937, a human leukemia cell line, with subacute concentrations of FJ5002 resulted in population-doubling dependent changes characterized by progressive telomere erosion (from approximately 10 to approximately 4.0 kb), increased chromosome abnormalities, and senescence/crisis-like features. These results indicated that FJ5002 is a genuine and effective antitelomerase agent.


Predicting Growth and Carcass Traits in Swine Using Microbiome Data and Machine Learning Algorithms.
In this paper, we evaluated the power of microbiome measures taken at three time points over the growth test period (weaning, 15 and 22 weeks) to foretell growth and carcass traits in 1039 individuals of a line of crossbred pigs. We measured prediction accuracy as the correlation between actual and predicted phenotypes in a five-fold cross-validation setting. Phenotypic traits measured included live weight measures and carcass composition obtained during the trial as well as at slaughter. We employed a null model excluding microbiome information as a baseline to assess the increase in prediction accuracy stemming from the inclusion of operational taxonomic units (OTU) as predictors. We further contrasted performance of models from the Bayesian alphabet (Bayesian Lasso) as well machine learning approaches (Random Forest and Gradient Boosting) and semi-parametric kernel models (Reproducing Kernel Hilbert space). In most cases, prediction accuracy increased significantly with the inclusion of microbiome data. Accuracy was more substantial with the inclusion of microbiome information taken at weeks 15 and 22, with values ranging from approximately 0.30 for loin traits to more than 0.50 for back fat. Conversely, microbiome composition at weaning resulted in most cases in marginal gains of prediction accuracy, suggesting that later measures might be more useful to include in predictive models. Model choice affected predictions marginally with no clear winner for any model/trait/time point. We, therefore, suggest average prediction across models as a robust strategy in fitting microbiome information. In conclusion, microbiome composition can effectively be used as a predictor of growth and composition traits, particularly for fatness traits. The inclusion of OTU predictors could potentially be used to promote fast growth of individuals while limiting fat accumulation. Early microbiome measures might not be good predictors of growth and OTU information might be best collected at later life stages. Future research should focus on the inclusion of both microbiome as well as host genome information in predictions, as well as the interaction between the two. Furthermore, the influence of the microbiome on feed efficiency as well as carcass and meat quality should be investigated.


Liquid-biopsy proteomics combined with AI identifies cellular drivers of eye aging and disease in vivo.
Single-cell analysis in living humans is essential for understanding disease mechanisms, but it is impractical in non-regenerative organs, such as the eye and brain, because tissue biopsies would cause serious damage. We resolve this problem by integrating proteomics of liquid biopsies with single-cell transcriptomics from all known ocular cell types to trace the cellular origin of 5,953 proteins detected in the aqueous humor. We identified hundreds of cell-specific protein markers, including for individual retinal cell types. Surprisingly, our results reveal that retinal degeneration occurs in Parkinson's disease, and the cells driving diabetic retinopathy switch with disease stage. Finally, we developed artificial intelligence (AI) models to assess individual cellular aging and found that many eye diseases not associated with chronological age undergo accelerated molecular aging of disease-specific cell types. Our approach, which can be applied to other organ systems, has the potential to transform molecular diagnostics and prognostics while uncovering new cellular disease and aging mechanisms.


[Temperature dependence of the kinetics of dark reduction of bacteriochlorophyll P870, oxidized by impulse laser and continuous light in photosynthetic reaction center preparations from Rhodosuedomonas spheroides strain 1760-1].
A comparative study was carried out of temperature dependence of kinetics of dark reduction of bacteriochlorophyll P870 oxidized both by pulsed laser and continuous actinic light in preparations of photosynthetic reaction centres-bacteriochlorophyll-protein complexes from Rhodopseudomonas spheroides, strain 1760-1. Half-time of the recombination of primary products--P870+ and reduced primary electron acceptor A1, which decreases with temperature lowering from 180-240 ms at 120K, is determined. Values of the rate constant of electron transfer from A1 to secondary acceptors at 29,K (2.7.10-1s-1) and the activation energy of this reaction in the range of 298-255K which is 11.8 kcal/mole are calculated.


Molecular model of a type III secretion system needle: Implications for host-cell sensing.
Type III secretion systems are essential virulence determinants for many Gram-negative bacterial pathogens. The type III secretion system consists of cytoplasmic, transmembrane, and extracellular domains. The extracellular domain is a hollow needle protruding above the bacterial surface and is held within a basal body that traverses both bacterial membranes. Effector proteins are translocated, via this external needle, directly into host cells, where they subvert normal cell functions to aid infection. Physical contact with host cells initiates secretion and leads to formation of a pore, thought to be contiguous with the needle channel, in the host-cell membrane. Here, we report the crystal structure of the Shigella flexneri needle subunit MxiH and a complete model for the needle assembly built into our three-dimensional EM reconstruction. The model, combined with mutagenesis data, reveals that signaling of host-cell contact is relayed through the needle via intersubunit contacts and suggests a mode of binding for a tip complex.


Distinct Roles for the N- and C-terminal Regions of M-Sec in Plasma Membrane Deformation during Tunneling Nanotube Formation.
The tunneling nanotube (TNT) is a structure used for intercellular communication, and is a thin membrane protrusion mediating transport of various signaling molecules and cellular components. M-Sec has potent membrane deformation ability and induces TNT formation in cooperation with the Ral/exocyst complex. Here, we show that the N-terminal polybasic region of M-Sec directly binds phosphatidylinositol (4,5)-bisphosphate for its localization to the plasma membrane during the initial stage of TNT formation. We further report a crystal structure of M-Sec, which consists of helix bundles arranged in a straight rod-like shape, similar to the membrane tethering complex subunits. A positively charged surface in the C-terminal domains is required for M-Sec interaction with active RalA to extend the plasma membrane protrusions. Our results suggest that the membrane-associated M-Sec recruits active RalA, which directs the exocyst complex to form TNTs.


Effect of sciatic nerve transection or TTX application on enzyme activity in rat spinal cord.
To clarify the differential effects on spinal circuitry caused by physical vs functional disconnection from the periphery, we compared changes produced by 3-, 7- or 14-day unilateral sciatic axotomy or tetrodotoxin (TTX) nerve blockade on the abundance or activity of NADPH diaphorase (NDP), cytochrome oxidase (CO) and acid phosphatase (AP) in the spinal cord. Following axotomy, AP and NDP were decreased in the dorsal horn and increased in large cells in the dorsolateral motor nuclei while CO was decreased in ventral horn neuropil. TTX induced a decrease of CO in the ventral horn and NDP in the dorsal horn. This suggests that physical vs functional disconnection causes modulation of distinct intracellular pathways in sensory afferents, dorsal horn neurons and motoneurons.


A draft physical map of a D-genome cotton species (Gossypium raimondii).
Genetically anchored physical maps of large eukaryotic genomes have proven useful both for their intrinsic merit and as an adjunct to genome sequencing. Cultivated tetraploid cottons, Gossypium hirsutum and G. barbadense, share a common ancestor formed by a merger of the A and D genomes about 1-2 million years ago. Toward the long-term goal of characterizing the spectrum of diversity among cotton genomes, the worldwide cotton community has prioritized the D genome progenitor Gossypium raimondii for complete sequencing. A whole genome physical map of G. raimondii, the putative D genome ancestral species of tetraploid cottons was assembled, integrating genetically-anchored overgo hybridization probes, agarose based fingerprints and 'high information content fingerprinting' (HICF). A total of 13,662 BAC-end sequences and 2,828 DNA probes were used in genetically anchoring 1585 contigs to a cotton consensus genetic map, and 370 and 438 contigs, respectively to Arabidopsis thaliana (AT) and Vitis vinifera (VV) whole genome sequences. Several lines of evidence suggest that the G. raimondii genome is comprised of two qualitatively different components. Much of the gene rich component is aligned to the Arabidopsis and Vitis vinifera genomes and shows promise for utilizing translational genomic approaches in understanding this important genome and its resident genes. The integrated genetic-physical map is of value both in assembling and validating a planned reference sequence.


Dynamic linear model for the identification of miRNAs in next-generation sequencing data.
Next-generation sequencing technologies are poised to revolutionize the field of biomedical research. The increased resolution of these data promise to provide a greater understanding of the molecular processes that control the morphology and behavior of a cell. However, the increased amounts of data require innovative statistical procedures that are powerful while still being computationally feasible. In this article, we present a method for identifying small RNA molecules, called miRNAs, which regulate genes by targeting their mRNAs for degradation or translational repression. In the first step of our modeling procedure, we apply an innovative dynamic linear model that identifies candidate miRNA genes in high-throughput sequencing data. The model is flexible and can accurately identify interesting biological features while accounting for both the read count, read spacing, and sequencing depth. Additionally, miRNA candidates are also processed using a modified Smith-Waterman sequence alignment that scores the regions for potential RNA hairpins, one of the defining features of miRNAs. We illustrate our method on simulated datasets as well as on a small RNA Caenorhabditis elegans dataset from the Illumina sequencing platform. These examples show that our method is highly sensitive for identifying known and novel miRNA genes.


[Changing modalities of action to address social inequalities in health in international and French policy recommendations].
This article describes the changing modalities of action designed to address social inequalities in health recommended in France, in the light of WHO and other international guidelines. Content analysis of policy recommendations identified eleven categories of actions and five types of changes as a function of target populations and the resources deployed. Recommendations have evolved from interventions designed to improve access to primary care to interventions on the social determinants of health, from reinforcement of individual capacities to global empowerment, from interventions on target populations to social inclusion of everyone, from promotion of health investments to increased financial regulation, from a favourable public health policies approach to a health approach in all policies.Multiple modalities of action have been proposed in France, but have remained poorly implemented. They have evolved over time, usually in response to international reference texts with a certain time gap. Internationally recommended interventions differ considerably from interventions focussing on individual capacities, while the new public health law in France reintroduced targeted behavioural interventions. These findings raise a number of other questions, especially concerning the way in which research into social inequalities in health influence public decisions and the institutional treatment of health in all policies.


Community pharmacists and people with dementia: a cross-sectional survey exploring experiences, attitudes, and knowledge of pain and its management.
To explore community pharmacists' experiences with and attitudes towards people with dementia, and to determine the knowledge they have about pain and its management in this patient population. A questionnaire comprising five sections, including the Approaches to Dementia Questionnaire, was mailed, on two occasions, during February and March 2011, to all community pharmacies in Northern Ireland (n = 530). The response rate was 34.3%. A greater proportion of pharmacists provided pharmaceutical care to people with dementia living at home (91.2%) than those living in care homes (40.1%). Respondents most frequently encountered queries relating to starting and stopping medications, compliance with medication, and availability of formulation types. The mean total score for the Approaches to Dementia Questionnaire measure was 72.8, indicating a positive attitude towards people with dementia, and respondents demonstrated a strong person-centred approach towards this patient population. The majority of respondents recognised the difficulty of assessing pain in people with dementia; however, younger pharmacists (p = 0.041) and pharmacists who provided pharmaceutical care to people with dementia (p = 0.012) were more likely to be aware of the pain assessment tools for use in people with dementia. Pharmacists appeared uncertain about how to appropriately manage pain in people with dementia. The study has revealed that community pharmacists often encounter people with dementia, especially those living in their own homes, and they have positive attitudes towards the patient population. However, training in the assessment and management of pain in people with dementia must be developed to further improve their knowledge in this area.


Dual antiplatelet therapy in patients requiring urgent coronary artery bypass grafting surgery: a position statement of the Canadian Cardiovascular Society.
Acute coronary syndrome (ACS) guidelines recommend that most patients receive dual antiplatelet therapy with clopidogrel and acetylsalicylic acid (ASA) at the time of presentation to prevent recurrent ischemic events. Approximately 10% of ACS patients require coronary artery bypass grafting surgery (CABG) during the index admission. Most studies show that patients who receive ASA and clopidogrel within five days of CABG have an increase in operative bleeding. Current consensus guidelines recommend discontinuation of clopidogrel therapy at least five days before planned CABG to reduce bleeding-related events. However, high-risk individuals may require urgent surgery without delay, to reduce the risk of potentially fatal ischemic events. The present multidisciplinary position statement provides evidence- based recommendations for the optimal use of dual antiplatelet therapy to balance ischemic and bleeding risks in patients with recent ACS who may require urgent CABG. 1. All ACS patients should be considered for dual antiplatelet therapy with ASA and clopidogrel at the earliest opportunity, despite the possibility of a need for urgent CABG. 2. For patients who have received clopidogrel and ASA, and require CABG: * Those at high risk of an early fatal event (eg, with refractory ischemia despite optimal medical treatment, and with high-risk coronary anatomy (eg, severe left main stenosis with severe right coronary artery disease), should be considered for early surgery without discontinuation of clopidogrel. * In patients with a high bleeding risk (eg, previous surgery, complex surgery) who are also at high risk for an ischemic event, consideration should be given to discontinuing clopidogrel for three to five days before surgery. * Patients at a lower risk for ischemic events (most patients) should have clopidogrel discontinued five days before surgery. 3. For patients who have CABG within five days of receiving clopidogrel and ASA, the risk of major bleeding and transfusion can be minimized by applying multiple strategies before and during surgery. 4. Patients who receive clopidogrel pre-CABG for a recent ACS indication should have clopidogrel restarted after surgery to decrease the risk of recurrent ACS. 5. For patients with a recent coronary stent, the decision to continue clopidogrel until the time of surgery or to discontinue will depend on the risk and potential impact of stent thrombosis. Restarting clopidogrel after CABG will depend on whether the stented vessel was revascularized, the type of stent and the time from stent implantation. Clopidogrel should be restarted when hemostasis is assured to prevent recurrent acute ischemic events.


Gluten-Free Diet: Gaps and Needs for a Healthier Diet.
The gluten-free diet (GFD) is currently the only effective treatment in remitting the symptoms of coeliac disease (CD), a chronic systemic autoimmune disorder caused by a permanent intolerance to gluten proteins in genetically susceptible individuals. The diet entails the substitution of gluten-containing products with gluten-free-rendered products. However, over recent decades the nutritional profile of gluten-free (GF) food products has been increasingly questioned within the scientific community. The aim of this paper is to review the nutritional profile of gluten-free-rendered products currently available on the market, and discuss the possible relationship thereof with the nutritional status of coeliac patients on a GFD. Key inadequacies of currently available GF products are low protein content and a high fat and salt content. More adequate levels of dietary fiber and sugar than in the past have been reported. Population studies confirmed the above mentioned inadequacies. Further efforts are required to conceive adoptable interventions for product development and reformulation in order to achieve compliance with nutritional recommendations.


The Strength of the Nutrient Solution Modulates the Functional Profile of Hydroponically Grown Lettuce in a Genotype-Dependent Manner.
Considering that functional components of plant foods are mainly secondary-metabolism products, we investigated the shaping of health-promoting compounds in hydroponically grown butterhead lettuce (Lactuca sativa L. var. capitata) as a function of the strength of the nutrient solution utilized. To this aim, untargeted metabolomics profiling, in vitro antioxidant capacity (total phenolics, 2,2-diphenyl-1-picrylhydrazyl (DPPH), 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) (ABTS), cupric reducing antioxidant capacity (CUPRAC), and ferric reducing antioxidant power (FRAP) assays), and the inhibition of selected enzyme activities were investigated in two butterhead lettuce cultivars with different pigmentation, i.e., green and red Salanova. Full-strength nutrition, together with half- and quarter-strength solutions of macronutrients, was tested. Our results indicate that by reducing the nutrients strength, we could elicit a distinctive shaping of the phenolic profile of lettuce. It is noteworthy that only specific classes of phenolics (namely, lignans and phenolic acids, followed by flavones and anthocyanins) were modulated by the induction of nutritional eustress (fold-change values in the range between -5 and +11). This indicates that specific responses, rather than a generalized induction of phenolic compounds, could be observed. Nonetheless, a genotype-dependent response could be observed, with the red cultivar being much more responsive to nutritional deprivation than the green Salanova lettuce. Indeed, analysis of variance (ANOVA) confirmed a genotype x nutrition interaction in red Salanova (p < 0.001). As a consequence of the changes in phenolic composition, also the antioxidant capacity (p < 0.001) and amylase inhibition (p < 0.001) properties were affected by the growing conditions. However, the effect on cholinesterase and tyrosinase inhibition was poorly affected by the nutritional strength. Provided that yields are not compromised, the application of a controlled nutritional eustress in hydroponically cultivated lettuce may represent a valuable strategy to produce food with tailored functional features in a sustainable manner.


How low does iron go? Chasing the active species in fe-catalyzed cross-coupling reactions.
The catalytic cross-coupling reactions of organic halides or related substrates with organometallic nucleophiles form the cornerstone of many carbon-carbon bond-forming processes. While palladium-based catalysts typically mediate such reactions, there are increasing concerns about the long-term sustainability of palladium in synthesis. This is due to the high cost of palladium, coupled with its low natural abundance, environmentally deleterious extraction (∼6 g of metal are produced per ton of ore), toxicity, and competition for its use from the automotive and consumer electronics sectors. Therefore, there is a growing interest in replacing palladium-based catalysts with those incorporating more earth-abundant elements. With its low cost, high natural abundance, and low toxicity, iron makes a particularly appealing alternative, and accordingly, the development of iron-catalyzed cross-coupling is undergoing explosive growth. However, our understanding of the mechanisms that underpin the iron-based catalytic cycles is still very much in its infancy. Mechanistic insight into catalytic reactions is not only academically important but also allows us to maximize the efficiency of processes or even to develop entirely new transformations. Key to the development of robust mechanistic models for cross-coupling is knowing the lowest oxidation state in the cycle. Once this is established, we can explore subsequent redox processes and build the catalytic manifold. Until we know with confidence what the lowest oxidation state is, any cycles proposed are largely just guesswork. To date, Fe(-II), Fe(-I), Fe(0), Fe(I), and Fe(II) have been proposed as contenders for the lowest-oxidation-state species in the cycle in iron-catalyzed cross-coupling; the aim of this Account is to pull together the various pieces of evidence in support, or otherwise, of each of these suggestions in turn. There currently exists no direct evidence that oxidation states below Fe(0) are active in the catalytic cycle. Meanwhile, the reactivity required of the lowest-oxidation-state species has been observed with model compounds in higher oxidation states, implying that there is no need to invoke such low oxidation states. While subzero-valent complexes do indeed act as effective precatalysts, it is important to recognize that this tells us that they are efficiently converted to an active catalyst but says nothing about the oxidation states of the species in the catalytic cycle. Zero-valent heterogeneous iron nanoparticles can be formed under typical catalytic conditions, but there is no evidence to suggest that homogeneous Fe(0) complexes can be produced under comparable conditions. It seems likely that the zero-valent nanoparticles act as a reservoir for soluble higher-oxidation-state species. Fe(II) complexes can certainly be formed under catalytically relevant conditions, and when bulky nucleophilic coupling partners are exploited, potential intermediates can be isolated. However, the bulky reagents act as poor proxies for most nucleophiles used in cross-coupling, as they give Fe(II) organometallic intermediates that are kinetically stabilized with respect to reductive elimination. When more realistic substrates are exploited, reduction or disproportionation to Fe(I) is widely observed, and while it still has not been conclusively proved, this oxidation state currently represents a likely candidate for the lowest one active in many iron-catalyzed cross-coupling processes.


Updated sesame genome assembly and fine mapping of plant height and seed coat color QTLs using a new high-density genetic map.
Sesame is an important high-quality oil seed crop. The sesame genome was de novo sequenced and assembled in 2014 (version 1.0); however, the number of anchored pseudomolecules was higher than the chromosome number (2n = 2x = 26) due to the lack of a high-density genetic map with 13 linkage groups. We resequenced a permanent population consisting of 430 recombinant inbred lines and constructed a genetic map to improve the sesame genome assembly. We successfully anchored 327 scaffolds onto 13 pseudomolecules. The new genome assembly (version 2.0) included 97.5 % of the scaffolds greater than 150 kb in size present in assembly version 1.0 and increased the total pseudomolecule length from 233.7 to 258.4 Mb with 94.3 % of the genome assembled and 97.2 % of the predicted gene models anchored. Based on the new genome assembly, a bin map including 1,522 bins spanning 1090.99 cM was generated and used to identified 41 quantitative trait loci (QTLs) for sesame plant height and 9 for seed coat color. The plant height-related QTLs explained 3-24 % the phenotypic variation (mean value, 8 %), and 29 of them were detected in at least two field trials. Two major loci (qPH-8.2 and qPH-3.3) that contributed 23 and 18 % of the plant height were located in 350 and 928-kb spaces on Chr8 and Chr3, respectively. qPH-3.3, is predicted to be responsible for the semi-dwarf sesame plant phenotype and contains 102 candidate genes. This is the first report of a sesame semi-dwarf locus and provides an interesting opportunity for a plant architecture study of the sesame. For the sesame seed coat color, the QTLs of the color spaces L*, a*, and b* were detected with contribution rates of 3-46 %. qSCb-4.1 contributed approximately 39 % of the b* value and was located on Chr4 in a 199.9-kb space. A list of 32 candidate genes for the locus, including a predicted black seed coat-related gene, was determined by screening the newly anchored genome. This study offers a high-density genetic map and an improved assembly of the sesame genome. The number of linkage groups and pseudomolecules in this assembly equals the number of sesame chromosomes for the first time. The map and updated genome assembly are expected to serve as a platform for future comparative genomics and genetic studies.


Resilience of alternative states in spatially extended ecosystems.
Alternative stable states in ecology have been well studied in isolated, well-mixed systems. However, in reality, most ecosystems exist on spatially extended landscapes. Applying existing theory from dynamic systems, we explore how such a spatial setting should be expected to affect ecological resilience. We focus on the effect of local disturbances, defining resilience as the size of the area of a strong local disturbance needed to trigger a shift. We show that in contrast to well-mixed systems, resilience in a homogeneous spatial setting does not decrease gradually as a bifurcation point is approached. Instead, as an environmental driver changes, the present dominant state remains virtually 'indestructible', until at a critical point (the Maxwell point) its resilience drops sharply in the sense that even a very local disturbance can cause a domino effect leading eventually to a landscape-wide shift to the alternative state. Close to this Maxwell point the travelling wave moves very slow. Under these conditions both states have a comparable resilience, allowing long transient co-occurrence of alternative states side-by-side, and also permanent co-existence if there are mild spatial barriers. Overall however, hysteresis may mostly disappear in a spatial context as one of both alternative states will always tend to be dominant. Our results imply that local restoration efforts on a homogeneous landscape will typically either fail or trigger a landscape-wide transition. For extensive biomes with alternative stable states, such as tundra, steppe and forest, our results imply that, as climatic change reduces the stability, the effect might be difficult to detect until a point where local disturbances inevitably induce a spatial cascade to the alternative state.


Aluminum-thin-film packaged fiber Bragg grating probes for monitoring the maximum tensile strain of composite materials.
In this paper, new fiber Bragg grating (FBG) sensor probes are designed to intermittently detect the maximum tensile strain of composite materials, so as to evaluate the structural health status. This probe is fabricated by two thin Al films bonded to an FBG optical fiber and two supporting brackets, which are fixed on the surface of composite materials. The residual strain of the Al packaged FBG sensor probe is induced by the strain of composite materials. This residual strain can indicate the maximum strain of composite materials. Two types of sensor probes are prepared-one is an FBG with 18 μm thick Al films, and the other is an FBG with 36 μm thick Al films-to compare the thickness effect on the detection sensitivity. These sensor probes are bonded on the surfaces of carbon fiber reinforced plastics composite specimens. In order to determine the strain sensitivity between the residual strain of the FBG sensor probe and the maximum strain of the composite specimen, tensile tests are performed by universal testing machine, under the loading-unloading test condition. The strain sensitivities of the probes, which have the Al thicknesses of 18 and 36 μm, are determined as 0.13 and 0.23, respectively.


A survey of Italian physicians' opinion about stem cells research: what doctors prefer and what the law requires.
To evaluate the Italian physicians' knowledge/information level about the therapeutic potential of stem cells, the research choice between embryonic and cordonal stem cells, and the preference between autologous and heterologous storage of cordonal stem cells, we performed a national survey. The questionnaire--distributed to 3361 physicians--involved physicians of different religious orientations and of different medical specialities. Most of the physicians involved (67%) were Catholics, and the majority were gynaecologists and paediatricians (43%) who are mainly in charge to inform future mothers about the possibility of cordonal stem cells conservation. The majority of the physicians interviewed do not have specific knowledge about stem cells (59%), most of them having only generic information (92%). The largest part of physicians prefer to use umbilical cord blood cells rather than embryonic stem cells. Nevertheless, a large percentage of physicians were in favour of embryo research, especially when embryos are supernumerary (44% versus 34%). Eighty-seven % of the physicians interviewed proved to have a general knowledge about stem cells and believe in their therapeutic potential. They prefer research on cordonal stem cells rather than on embryo stem cells. Although they are in favour of heterologous stem cells donation, they still prefer cryopreservation for personal use.


Solution structure of human GAIP (Galpha interacting protein): a regulator of G protein signaling.
The solution structure of the human protein GAIP (Galpha interacting protein), a regulator of G protein signaling, has been determined by NMR techniques. Dipolar couplings of the oriented protein in two different liquid crystal media have been used in the structure calculation. The solution structure of GAIP is compared to the crystal structure of an homologous protein from rat (RGS4) complexed to the alpha-subunit of a G protein. Some of RGS4 residues involved in the Galpha-RGS binding interface have similar orientations in GAIP (free form), indicating that upon binding these residues do not suffer conformational rearrangements, and therefore, their role does not seem to be restricted to Galpha interaction but also to RGS folding and stability. We suggest that other structural differences between the two proteins may be related to the process of binding as well as to a distinct efficiency in their respective GTPase activating function.


The risk of ipsilateral versus contralateral recurrent deep vein thrombosis in the leg. The DURAC Trial Study Group.
To investigate the risk of ipsilateral versus contralateral recurrent deep vein thrombosis in the leg. An open prospective long term follow-up multicentre trial. Patients were followed by frequent outpatient visits at each centre during the first 12 months after inclusion and thereafter annually. Sixteen hospitals in central Sweden. A total of 790 consecutive patients with objectively verified first episode of acute deep vein thrombosis and without diagnosed malignant disease were recruited from a randomized study comparing 6 weeks with 6 months of oral antivitamin K therapy as secondary thromboprophylaxis. Deep vein thrombosis in the contralateral leg was confirmed by venography or ultrasound. With regard to the ipsilateral leg, venography was required. A recurrent episode of venous thromboembolism was documented in 192 patients after a mean (+/-SD) period of 31(+/-29) months. In 26 additional patients with ipsilateral symptoms the diagnostic critera were not fulfilled. One hundred and eleven patients have deceased and 69 patients withdrew from the study. The 392 patients without recurrent episodes were followed for a median of 96 months with 90% for at least 48 months. An objectively verified recurrent contralateral and ipsilateral deep vein thrombosis occurred in 95 and 54 cases, respectively, and in 41 patients pulmonary embolism was documented. In two patients thromboses with unusual locations were registered. The risk of contralateral versus ipsilateral recurrence was significantly increased with a risk ratio of 1.6 (95% confidence interval 1.4-1.9) in a time to event model. In a multivariate analysis none of the investigated variables were significantly associated with the side of recurrent thrombosis. The risk of a recurrent deep vein thrombosis is increased in the contralateral leg. This brings into question the importance of an impaired venous flow for recurrent episodes of thrombosis.


Conformational ensemble of an intrinsically flexible loop in mitochondrial import protein Tim21 studied by modeling and molecular dynamics simulations.
Tim21, a subunit of a highly dynamic translocase of the inner mitochondrial membrane (TIM23) complex, translocates proteins by interacting with subunits in the translocase of the outer membrane (TOM) complex and Tim23 channel in the TIM23 complex. A loop segment in Tim21, which is in close proximity of the binding site of Tim23, has different conformations in X-ray, NMR and new crystal contact-free space (CCFS) structures. MD simulations can provide information on the structure and dynamics of the loop in solution. The conformational ensemble of the loop was characterized using loop modeling and molecular dynamics (MD) simulations. MD simulations confirmed mobility of the loop. Multidimensional scaling and clustering were used to characterize the dynamic conformational ensemble of the loop. Free energy landscape showed that the CCFS crystal structure occupied a low energy region as compared to the conventional X-ray crystal structure. Analysis of crystal packing indicates that the CCFS provides larger conformational space for the motions of the loop. Our work reported the conformational ensemble of the loop in solution, which is in agreement with the structure obtained from CCFS approach. The combination of the experimental techniques and computational methods is beneficial for studying highly flexible regions of proteins. Computational methods, such as loop modeling and MD simulations, have proved to be useful for studying conformational flexibility of proteins. These methods in integration with experimental techniques such as CCFS has the potential to transform the studies on flexible regions of proteins.