Potassium ferrate [Fe(VI)] does not mediate self-sterilization of a surrogate Mars soil.
Martian soil is thought to be enriched with strong oxidants such as peroxides and/or iron in high oxidation states that might destroy biological materials. There is also a high flux of ultraviolet radiation at the surface of Mars. Thus, Mars may be inhospitable to life as we know it on Earth. We examined the hypothesis that if the soil of Mars contains ferrates [Fe(VI)], the strongest of the proposed oxidizing species, and also is exposed to high fluxes of UV radiation, it will be self-sterilizing. Under ambient conditions (25 degrees C, oxygen and water present) K2FeO4 mixed into sand mineralized some reactive organic molecules to CO2, while less reactive compounds were not degraded. Dried endospores of Bacillus subtilis incubated in a Mars surrogate soil comprised of dry silica sand containing 20% by weight K2FeO4 and under conditions similar to those now on Mars (extreme desiccation, cold, and a CO2-dominated atmosphere) were resistant to killing by the ferrate-enriched sand. Similar results were observed with permanganate. Spores in oxidant-enriched sand exposed to high fluxes of UV light were protected from the sporocidal activity of the radiation below about 5 mm depths. Based on our data and previously published descriptions of ancient but dormant life forms on Earth, we suggest that if entities resembling bacterial endospores were produced at some point by life forms on Mars, they might still be present and viable, given appropriate germination conditions. Endospores delivered to Mars on spacecraft would possibly survive and potentially compromise life detection experiments.


Hospital admissions for self harm after discharge from psychiatric inpatient care: cohort study.
To determine the risk of non-fatal self harm in the 12 months after discharge from psychiatric inpatient care. Cohort study based on national hospital episode statistics. England. Population Patients aged 16-64 years discharged from psychiatric inpatient care between 1 April 2004 and 31 March 2005 and followed up for one year. 75 401 people were discharged from psychiatric inpatient care over the study period, 4935 (6.5%) of whom were admitted at least once for self harm in the following 12 months. Risk of self harm was greatest in the four weeks after discharge; one third (32%, n=1578) of admissions for self harm occurred in this period. The strongest risk factor for self harm after discharge was admission for self harm in the previous 12 months (hazard ratio 4.9, 95% confidence interval 4.6 to 5.2). The risk of self harm was also higher in females, younger people, those with diagnoses of depression, personality disorders, and substance misuse, and those with short lengths of stay. More than 6% of patients discharged from psychiatric inpatient care are readmitted for an episode of self harm within 12 months, with one third of these episodes occurring in the month after discharge. Self harm after discharge from hospital shares many of the features of suicide after discharge. Interventions should be developed to reduce risk in this period.


Reliable activation to novel stimuli predicts higher fluid intelligence.
The ability to reliably respond to stimuli could be an important biological determinant of differences in fluid intelligence (Gf). However, most electrophysiological studies of Gf employ event-related potential (ERP) measures that average brain activity over trials, and hence have limited power to quantify neural variability. Time-frequency analyses can capture cross-trial variation in the phase of neural activity, and thus can help address the importance of neural reliability to differences in Gf. This study recruited a community sample of healthy adults and measured inter-trial phase clustering (ITPC), total spectral power, and ERP amplitudes elicited by Repeated and Novel non-target stimuli during two visual oddball tasks. Condition effects, relations among the EEG measures, and relations with Gf were assessed. Early visual responses to Repeated stimuli elicited higher ITPC, yet only ITPC elicited by Novel stimuli was associated with Gf. Analyses of spectral power further highlighted the contribution of phase consistency to the findings. The link between Gf and reliable responding to changing inputs suggests an important role for flexible resource allocation in fluid intellectual skills.


Avian extinction and mammalian introductions on oceanic islands.
The arrival of humans on oceanic islands has precipitated a wave of extinctions among the islands' native birds. Nevertheless, the magnitude of this extinction event varies markedly between avifaunas. We show that the probability that a bird species has been extirpated from each of 220 oceanic islands is positively correlated with the number of exotic predatory mammal species established on those islands after European colonization and that the effect of these predators is greater on island endemic species. In contrast, the proportions of currently threatened species are independent of the numbers of exotic mammalian predator species, suggesting that the principal threat to island birds has changed through time as species susceptible to exotic predators have been driven extinct.


Visualizing Changes in Cytosolic-Free Ca2+ during the Response of Stomatal Guard Cells to Abscisic Acid.
In this paper, we report the results of a detailed investigation into abscisic acid (ABA)[mdash]stimulated elevations of guard cell cytosolic-free Ca2+ ([Ca2+]cyt). Fluorescence ratio photometry and ratio imaging techniques were used to investigate this phenomenon. Guard cells of open and closed (opened to 10 to 12 [mu]m before treatment with ABA) stomata were microinjected with the fluorescent Ca2+ indicator Indo-1. Resting [Ca2+]cyt ranged from 50 to 350 nM. ABA (100 nM) stimulated an increase in [Ca2+]cyt in 68 and 81% of guard cells microinjected in the open and closed configuration, respectively. All stomata were observed to close in response to ABA. Increases ranged from 100 to 750 nM above the resting concentration and were arbitrarily grouped into five "classes." ABA-stimulated increases in [Ca2+]cyt were not uniformly distributed across the cytosol of guard cells. Rapid transient increases in [Ca2+]cyt were also observed in the guard cells of stomata microinjected in the closed configuration. We concluded that the ABA-induced turgor loss in guard cells is a Ca2+-dependent process.


Effects of topical application of fipronil spot-on on dogs against the Chagas disease vector Triatoma infestans.
We assessed the insecticidal effects of fipronil spot-on applied to experimental dogs on the blood-feeding success and other vital parameters of the Trypanosoma cruzi vector Triatoma infestans. In the first trial, the cumulative mortality of 30 third or fourth instar nymphs exposed to eight fipronil-treated dogs differed significantly from those exposed to untreated dogs at 1 week post-treatment, but not at baseline or at 2-6 weeks post-treatment. In the second trial, the effects of multiple exposures to fipronil-treated dogs on bug population dynamics were assessed. A population of 80-84 bugs of various life stages were allowed to colonize eight closed experimental huts, and then exposed twice weekly to control or treated dogs over a period of 110 days and censused at monthly intervals. Throughout the trial, multiple exposure to fipronil did not significantly affect bug population size, fecundity, hatching, molting, survival, blood-feeding success and degree of engorgement. Only when engorgement was taken to include only fully fed bugs, did fipronil significantly reduce their degree of engorgement relative to bugs exposed to control dogs. We conclude that at tested dosages fipronil spot-on would have little effect in controlling (peri)domestic Tri. infestans or protecting dogs from contact with the bugs.


Sequential orthotopic heart transplantation in man.
Between January 1968 and March 1980, 202 hearts had been transplanted into 185 patients at Stanford University Medical Center. Occasionally, patients after transplantation develop myocardial failure which is amenable only to retransplantation. Sixteen patients underwent initial orthotopic allograft using standard techniques. Eight patients developed accelerated arteriosclerotic coronary disease, six had unrelenting rejection, and two had donor heart dysrrhythmia or right ventricular failure requiring retransplantation. One patient required a third transplant because of donor left ventricular ischemia. All sequential transplants were managed similarly to the primary transplant. Of the initial transplant hearts at risk, 60% survived for more than 1 year, and 57% survived for more than 2 years. These results are similar to those of patients not requiring retransplantation. Of the secondary transplant hearts at risk, 31% survived for more than 1 year and 29% survived for more than 2 years. The severity of infection and/or rejection contributed most significantly to secondary heart transplant mortality. Sequential orthotopic cardiac transplantation offers an acceptable alternative to patients with allograft failure. Survival is not as favorable as with initial transplantation because of the prolonged immunosuppression during sequential transplantation.


Issues and Challenges Associated with Data-Sharing in LMICs: Perspectives of Researchers in Thailand.
Data-sharing helps advance scientific research and assures the benefits of research data are maximized. Previous work has highlighted ethical challenges, especially in low- and middle-income countrie (LMIC) countries. This study examined the views of researchers in a middle-income country, Thailand, regarding the most important data-sharing challenges. The target researchers worked in biomedical and related research. The survey was distributed to 38 academic and health-science institutes, 18 university hospitals, 84 nonuniversity hospitals, and 22 research institutes across Thailand; 229 researchers in clinical/basic and social/behavioral sciences, and pubxxlic health/policy participated. Thai researchers were less concerned with informed consent and the feasibility of conducting research and sharing data, focusing on the importance of safeguards when handling data, including transfer to others, and possible lack of control over subsequent data use. The respondents felt that researchers should decide what types of project data are shareable and which data are likely useful to the scientific community. They were more concerned with appropriate acknowledgment and protecting the legal rights of the primary data collectors and providers. Although they had concerns about data access conditions, they rated sharing sufficient data and metadata to reproduce the analysis of the primary outcomes as highly important. These results are important for future efforts of the LMIC countries to develop efficient data-sharing frameworks and establish institutional data access committees. They highlight the importance, for the sustainability and fairness of these efforts, to ensure that parties in LMIC countries receive appropriate credit and are involved in determining where/when/how their data may be used.


Coding of Spatial Information in the Somatosensory System: Evidence from Patients with Neglect following Parietal Lobe Damage.
Abstract Unilateral parietal lobe damage, particularly in the right cerebral hemisphere, leads to neglect of stimuli on the contra lateral side. To determine the reference frame within which neglect operates in the somatosensory system, 11 patients with unilateral neglect were touched simultaneously on the left and right side of the wrist of one hand. The hand was tested in both the palm up and the palm down position. Patients neglected the stimuli on the side of space contra lateral to the lesion regardless of hand position. These results indicate that point-localization in the somatosensory system is accomplished with respect to a spatially defined frame-of-reference and not strictly with respect to somatotopically defined coordinates.


DNA delivery from hyaluronic acid-collagen hydrogels via a substrate-mediated approach.
Efficient and controlled gene delivery from biodegradable materials can be employed to stimulate cellular processes that lead to tissue regeneration. In this report, a substrate-mediated approach was developed to deliver DNA from hyaluronic acid-collagen hydrogels. The hydrogels were formed by crosslinking HA with poly(ethylene glycol) diglycidyl ether. Poly(ethylene imine)(PEI)/DNA complexes were immobilized to the substrate using either biotin/neutravidin or non-specific adsorption. Complexes were formed in the presence or absence of salt to regulate complex size, and resulted in complexes with z-average diameters of 1221.7 +/- 152.3 and 139.4 +/- 1.3 nm, respectively. During 48-h incubation in PBS or hyaluronidase, DNA was released slowly from the hydrogel substrate (<30% of immobilized DNA), which was enhanced by incubation with conditioned media (approximately 50% of immobilized DNA). Transgene expression mediated by immobilized, large diameter complexes was 3 to 7-fold greater than for small diameter complexes. However, the percentage of cells expressing the transgene was greater for small diameter complexes (48.7%) than for large diameter complexes (22.3%). Spatially controlled gene transfer was achieved by topographically patterning the hydrogel to pattern cell adhesion. Biomaterial-based gene delivery can be applicable to numerous tissue engineering applications, or as a tool to examine tissue formation.


Self-coherent complex field reconstruction with in-phase and quadrature delay detection without a direct-detection branch.
Self-coherent detection with interferometric field reconstruction aims at retrieving the complex-valued optical field (amplitude and phase) by digitally processing delay interferometer (DI) measurements, in order to realize a differential direct detection receiver with capabilities akin to that of a fully coherent receiver with polarization multiplexing, albeit without requiring a local oscillator laser in the receiver. Here we introduce a novel digital recursive algorithm capable of accurately reconstructing the optical complex field (both amplitude and phase) solely from the quadrature DI outputs, eliminating the AM photo-detector branch. We analyze a key impairment namely the accumulation of errors and fluctuations in the reconstructed amplitude and phase due to ADC quantization noise, recirculating in the recursion. We introduce signal processing measures to effectively mitigate this noise impairment leading to a potentially practical self-coherent receiver, demonstrated in this paper for a single polarization. We also investigate the range of applicability of self-coherent detection concluding that it is most suitable to relatively low baud-rate systems such as passive optical networks, for which application the self-coherent receiver outperforms the coherent homodyne receiver due to its improved laser noise tolerance, obtained due to the removal of the optical local oscillator.


Evaluation of a clinical screening tool for HIV-associated sensory neuropathies.
To evaluate the performance characteristics of a brief clinical neuropathy screening tool for use in sensory neuropathies complicating HIV infection. The authors assessed 80 patients using the Brief Peripheral Neuropathy Screen (BPNS). Patients were defined as having neuropathy if they had both symptoms and signs consistent with this diagnosis. All subjects underwent sensory threshold testing and lower limb epidermal nerve fiber quantification using punch skin biopsy as objective measures. Individuals defined as having neuropathy using the BPNS (n = 37) performed less well on sensory threshold testing than other HIV-infected individuals (p < 0.0001 for warming, cooling, and vibration) and also had lower distal calf epidermal nerve fiber densities (p < 0.0001). Individuals who had symptoms but no neuropathic signs (n = 13) did not perform differently on any objective testing compared with neuropathy-free individuals, supporting the decision to require signs as well as symptoms as an operational criterion for the diagnosis of neuropathy. Of the symptoms listed in the screening tool, the presence of numbness had the greatest diagnostic efficiency for identifying those with neuropathy. The Brief Neuropathy Screening Tool (and the chosen definition of neuropathy) accurately detects those HIV-infected individuals with the greatest degree of peripheral nerve dysfunction and pathology. This is a valid neuropathy screening tool for use in the context of HIV infection, and is simple enough to be applicable in resource-limited settings.


Use of key performance indicators in histological dissection.
Reports into standards in the National Health Service and quality in pathology have focused on the way we work in pathology and how to provide assurance that this is of a high standard. There are a number of external quality assurance schemes covering pathology and histopathology specifically; however, there is no scheme covering the process of histological surgical dissection. This is an area undergoing development, emerging from the sole preserve of medically qualified pathologists to a field populated by a number of highly trained biomedical scientists, but remains without any formal quality assurance. This work builds on Barnes, taking the guidance of the Royal College of Pathologists (RCPath)and Institute of Biomedical Science (IBMS)to form a series of key performance indicators relating to dissection. These were developed for use as an indicator of individual practice, highlighting areas of variation, weakness or strength. Once identified, a feedback event provided opportunities to address these errors and omissions, or to enable areas of strength to be shared. The data obtained from the checklists demonstrate a large variation in practice at the outset of this study. The use of the checklists alone served to reduce this variation in practice, the addition of the training event showed further reduction in variation. The combination of these two tools was an effective method for enhancing standardisation of practice. The results of this work show that training events serve to reduce variation in practice by, and between, dissectors, driving up standards in dissection-directly addressing the needs of the modern pathology service.


Bacterial acetone and butanol production by industrial fermentation in the Soviet Union: use of hydrolyzed agricultural waste for biorefinery.
Clostridial acetone-butanol fermentation from renewable carbohydrates used to be the largest biotechnological process second only to yeast ethanol fermentation and the largest process ever run under sterile conditions. With the rising prices for mineral oil, it has now the economical and technological potential to replace petrochemistry for the production of fuels from renewable resources. Various methods for using non-food biomass such as cellulose and hemicellulose in agricultural products and wastes have been developed at laboratory scale. To our knowledge, the AB plants in Russia were the only full-scale industrial plants which used hydrolyzates of lignocellosic waste for butanol fermentation. These plants were further developed into the 1980s, and the process was finally run in a continual mode different from plants in Western countries. A biorefinery concept for the use of all by-products has been elaborated and was partially put into practice. The experience gained in the Soviet Union forms a promising basis for the development of modern large-scale processes to replace a considerable fraction of the current chemical production of fuel for our future needs on a sustainable basis.


Spinal appearance questionnaire: factor analysis, scoring, reliability, and validity testing.
Cross sectional. This study presents the factor analysis of the Spinal Appearance Questionnaire (SAQ) and its psychometric properties. Although the SAQ has been administered to a large sample of patients with adolescent idiopathic scoliosis (AIS) treated surgically, its psychometric properties have not been fully evaluated. This study presents the factor analysis and scoring of the SAQ and evaluates its psychometric properties. The SAQ and the Scoliosis Research Society-22 (SRS-22) were administered to AIS patients who were being observed, braced or scheduled for surgery. Standard demographic data and radiographic measures including Lenke type and curve magnitude were also collected. Of the 1802 patients, 83% were female; with a mean age of 14.8 years and mean initial Cobb angle of 55.8° (range, 0°-123°). From the 32 items of the SAQ, 15 loaded on two factors with consistent and significant correlations across all Lenke types. There is an Appearance (items 1-10) and an Expectations factor (items 12-15). Responses are summed giving a range of 5 to 50 for the Appearance domain and 5 to 20 for the Expectations domain. The Cronbach's α was 0.88 for both domains and Total score with a test-retest reliability of 0.81 for Appearance and 0.91 for Expectations. Correlations with major curve magnitude were higher for the SAQ Appearance and SAQ Total scores compared to correlations between the SRS Appearance and SRS Total scores. The SAQ and SRS-22 Scores were statistically significantly different in patients who were scheduled for surgery compared to those who were observed or braced. The SAQ is a valid measure of self-image in patients with AIS with greater correlation to curve magnitude than SRS Appearance and Total score. It also discriminates between patients who require surgery from those who do not.


Human pEg3 kinase associates with and phosphorylates CDC25B phosphatase: a potential role for pEg3 in cell cycle regulation.
The pEg3 protein is a member of the evolutionarily conserved KIN1/PAR-1/MARK kinase family which is involved in cell polarity and microtubule dynamics. In Xenopus, pEg3 has been shown to be a cell cycle dependent kinase whose activity increases to a maximum level during mitosis of the first embryonic cell division. CDC25B is one of the three CDC25 phosphatase genes identified in human. It is thought to regulate the G2/M progression by dephosphorylating and activating the CDK/cyclin complexes. In the present study we show that the human pEg3 kinase is able to specifically phosphorylate CDC25B in vitro. One phosphorylation site was identified and corresponded to serine 323. This residue is equivalent to serine 216 in human CDC25C which plays an important role in the regulation of phosphatase during the cell cycle and at the G2 checkpoint. pEg3 is also able to specifically associate with CDC25B in vitro and in vivo. We show that the ectopic expression of active pEg3 in human U2OS cells induces an accumulation of cells in G2. This effect is counteracted by overexpression of CDC25B. Taken together these results suggest that pEg3 is a potential regulator of the G2/M progression and may act antagonistically to the CDC25B phosphatase.


Harnessing Viscous Flow to Simplify the Actuation of Fluidic Soft Robots.
Soft robots powered by pressurized fluid have recently enabled a variety of innovative applications in areas as diverse as space exploration, search and rescue systems, biomimetics, medical surgery, and rehabilitation. Although soft robots have been demonstrated to be capable of performing a number of different tasks, they typically require independent inflation of their constituent actuators, resulting in multiple input lines connected to separate pressure supplies and a complex actuation process. To circumvent this limitation, we embed the actuation sequencing in the system by connecting fluidic actuators with narrow tubes to exploit the effects of viscous flow. We developed modeling and optimization tools to identify optimal tube characteristics and we demonstrate the inverse design of fluidic soft robots capable of achieving a variety of complex target responses when inflated with a single pressure input. Our study opens avenues toward the design of a new generation of fluidic soft robots with embedded actuation control, in which a single input line is sufficient to achieve a wide range of functionalities.


Infective endocarditis in bicuspid aortic valve: atrioventricular block as sign of perivalvular abscess.
A 46-year-old man presenting with fever, peripheral edema, and chest pain was admitted to the emergency department. Electrocardiogram showed sinus tachycardia and first-degree atrioventricular block. Transesophageal echocardiogram showed infective endocarditis in bicuspid aortic valve, complicated with severe aortic regurgitation, ring abscess, and sinus-of-Valsalva aneurysm extending to mitroaortic fibrous continuity. The patient, who was unaware of his bicuspid aortic valve condition, reported having undergone an orthodontic procedure complicated with dental abscess 1 month prior, which was treated with combined clavulanate-amoxicillin antibiotic therapy. Blood cultures were positive for Bacteroides fragilis resistant to metronidazole. Intravenous antibiotic therapy was undertaken, with rapid resolution of fever. He eventually underwent successful aortic homograft implantation and mitral valve repair with residual first-degree atrioventricular block.


X-linked immunodeficient mice exhibit enhanced susceptibility to Cryptococcus neoformans Infection.
ABSTRACT Bruton's tyrosine kinase (Btk) is a signaling molecule that plays important roles in B-1 B cell development and innate myeloid cell functions and has recently been identified as a target for therapy of B cell lymphomas. We examined the contribution of B-1 B cells to resistance to Cryptococcus neoformans infection by utilizing X-linked immunodeficient (XID) mice (CBA-CaHN-XID), which possess a mutation in Btk. XID mice had significantly higher brain fungal burdens than the controls 6 weeks after infection with C. neoformans strain 52D (CN52D); however, consistent with the propensity for greater virulence of C. neoformans strain H99 (CNH99), CNH99-infected XID mice had higher lung and brain fungal burdens than the controls 3 weeks after infection. Further studies in a chronic CN52D model revealed markedly lower levels of total and C. neoformans-specific serum IgM in XID mice than in the control mice 1 and 6 weeks after infection. Alveolar macrophage phagocytosis was markedly impaired in CN52D-infected XID mice compared to the controls, with XID mice exhibiting a disorganized lung inflammatory pattern in which Gomori silver staining revealed significantly more enlarged, extracellular C. neoformans cells than the controls. Adoptive transfer of B-1 B cells to XID mice restored peritoneal B-1 B cells but did not restore IgM levels to those of the controls and had no effect on the brain fungal burden at 6 weeks. Taken together, our data support the hypothesis that IgM promotes fungal containment in the lungs by enhancing C. neoformans phagocytosis and restricting C. neoformans enlargement. However, peritoneal B-1 B cells are insufficient to reconstitute a protective effect in the lungs. IMPORTANCE Cryptococcus neoformans is a fungal pathogen that causes an estimated 600,000 deaths per year. Most infections occur in individuals who are immunocompromised, with the majority of cases occurring in those with HIV/AIDS, but healthy individuals also develop disease. Immunoglobulin M (IgM) has been linked to resistance to disease in humans and mice. In this article, we found that X-linked immunodeficient (XID) mice, which have markedly reduced levels of IgM, were unable to contain Cryptococcus in the lungs. This was associated with reduced yeast uptake by macrophages, an aberrant tissue inflammatory response, an enlargement of the yeast cells in the lungs, and fungal dissemination to the brain. Since XID mice have a mutation in the Bruton's tyrosine kinase (Btk) gene, our data suggest that treatments aimed at blocking the function of Btk could pose a higher risk for cryptococcosis.


Shifting paradigms: from Flexner to competencies.
Realizing medical education is on the brink of a major paradigm shift from structure- and process-based to competency-based education and measurement of outcomes, the authors reviewed the existing medical literature to provide practical insight into how to accomplish full implementation and evaluation of this new paradigm. They searched Medline and the Educational Resource Information Clearinghouse from the 1960s until the present, reviewed the titles and abstracts of the 469 articles the search produced, and chose 68 relevant articles for full review. The authors found that in the 1970s and 1980s much attention was given to the need for and the development of professional competencies for many medical disciplines. Little attention, however, was devoted to defining the benchmarks of specific competencies, how to attain them, or the evaluation of competence. Lack of evaluation strategies was likely one of the forces responsible for the three-decade lag between initiation of the movement and wide-spread adoption. Lessons learned from past experiences include the importance of strategic planning and faculty and learner buy-in for defining competencies. In addition, the benchmarks for defining competency and the thresholds for attaining competence must be clearly delineated. The development of appropriate assessment tools to measure competence remains the challenge of this decade, and educators must be responsible for studying the impact of this paradigm shift to determine whether its ultimate effect is the production of more competent physicians.


Long-term rates of knee arthroplasty in a cohort of 834 393 patients with a history of arthroscopic partial meniscectomy.
The aim of this study was to determine the long-term risk of undergoing knee arthroplasty in a cohort of patients with meniscal tears who had undergone arthroscopic partial meniscectomy (APM). A retrospective national cohort of patients with a history of isolated APM was identified over a 20-year period. Patients with prior surgery to the same knee were excluded. The primary outcome was knee arthroplasty. Hazard ratios (HRs) were adjusted by patient age, sex, year of APM, Charlson comorbidity index, regional deprivation, rurality, and ethnicity. Risk of arthroplasty in the index knee was compared with the patient's contralateral knee (with vs without a history of APM). A total of 834 393 patients were included (mean age 50 years; 37% female). Of those with at least 15 years of follow-up, 13.49% (16 256/120 493; 95% confidence interval (CI) 13.30 to 13.69) underwent subsequent arthroplasty within this time. In women, 22.07% (95% CI 21.64 to 22.51) underwent arthroplasty within 15 years compared with 9.91% of men (95% CI 9.71 to 10.12), corresponding to a risk ratio (RR) of 2.23 (95% CI 2.16 to 2.29). Relative to the general population, patients with a history of APM were over ten times more likely (RR 10.27; 95% CI 10.07 to 10.47) to undergo arthroplasty rising to almost 40 times more likely (RR 39.62; 95% CI 27.68 to 56.70) at a younger age (30 to 39 years). In patients with a history of APM in only one knee, the risk of arthroplasty in that knee was greatly elevated in comparison with the contralateral knee (no APM; HR 2.99; 95% CI 2.95 to 3.02). Patients developing a meniscal tear undergoing APM are at greater risk of knee arthroplasty than the general population. This risk is three-times greater in the patient's affected knee than in the contralateral knee. Women in the cohort were at double the risk of progressing to knee arthroplasty compared with men. These important new reference data will inform shared decision making and enhance approaches to treatment, prevention, and clinical surveillance. Cite this article: Bone Joint J 2019;101-B:1071-1080.


Postdisaster PTSD over four waves of a panel study of Mexico's 1999 flood.
Samples of adults representative of Tezuitlán, Puebla and Villahermosa, Tobasco (combined N = 561), were interviewed 6, 12, 18, and 24 months after the devastating 1999 floods and mudslides in Mexico. Current DSM-IV PTSD and major depressive disorder (MDD) were assessed with the Composite International Diagnostic Interview. At Wave 1, PTSD was highly prevalent (24% combined), especially in Tezuitlán (46%), which had experienced mass casualties and displacement. Both linear and quadratic effects of time emerged, as PTSD symptoms initially declined but subsequently stabilized. Differences between cities lessened as time passed. Comorbidity between PTSD and MDD was substantial. The findings demonstrate that the international health community needs to be prepared for epidemics of PTSD when disasters strike developing areas of the world.


Neurodevelopmental outcomes in children surviving d-transposition of the great arteries.
We investigated the prevalence of neurological abnormalities and learning problems in a population cohort of children with dextro-transposition of the great arteries (d-TGA) born between January 1, 1981 and July 1, 1990. Fifty-seven of the 60 survivors and 35 siblings in the control group underwent neurodevelopmental assessments. As compared with population norms, children with d-TGA were more likely to have abnormal neurological examination findings, learning disabilities, and behavioral disorders. There was no significant difference in IQ or frequency of abnormal neurological examination results between children undergoing atrial as compared with arterial switch procedures. Compared with their siblings, the children with d-TGA had more neurological findings and learning disabilities. The siblings of children with d-TGA had more learning problems than expected. The findings suggest that ongoing surveillance is indicated for children surviving d-TGA. Furthermore, a familial tendency for learning differences should to be taken into consideration when neurodevelopmental outcomes of various perioperative parameters are examined.


Murine regulatory T cells contain hyperproliferative and death-prone subsets with differential ICOS expression.
Regulatory T cells (Treg) are crucial for self-tolerance. It has been an enigma that Treg exhibit an anergic phenotype reflected by hypoproliferation in vitro after TCR stimulation but undergo vigorous proliferation in vivo. We report in this study that murine Treg are prone to death but hyperproliferative in vitro and in vivo, which is different from conventional CD4(+)Foxp3(-) T cells (Tcon). During in vitro culture, most Treg die with or without TCR stimulation, correlated with constitutive activation of the intrinsic death pathway. However, a small portion of the Treg population is more sensitive to TCR stimulation, particularly weak stimulation, proliferates more vigorously than CD4(+) Tcon, and is resistant to activation-induced cell death. Treg proliferation is enhanced by IL-2 but is less dependent on CD28-mediated costimulation than that of Tcon. We demonstrate further that the surviving and proliferative Treg are ICOS(+) whereas the death-prone Treg are ICOS(-). Moreover, ICOS(+) Treg contain much stronger suppressive activity than that of ICOS(-) Treg. Our data indicate that massive death contributes to the anergic phenotype of Treg in vitro and suggest modulation of Treg survival as a therapeutic strategy for treatment of autoimmune diseases and cancer.


Lysine 313 of T-box is crucial for modulation of protein stability, DNA binding, and threonine phosphorylation of T-bet.
A T-box-containing protein expressed in T cells (T-bet) is a key transcription factor involved in the regulation of Th cell differentiation. Although T-bet-deficient CD4(+) T cells fail to produce IFN-γ and typically differentiate into Th2 cells in vitro, ectopic overexpression of T-bet elevates IFN-γ and suppresses production of IL-2 and Th2 cytokines through different mechanisms. Despite the importance of the T-bet protein level, the regulatory mechanisms that control T-bet protein stability are largely unknown. In this study, we found that T-bet underwent proteasomal degradation via ubiquitination at Lys-313. Despite its robust accumulation following lysine mutation, T-bet(K313R) failed to increase IFN-γ production because of diminished DNA binding activity, as demonstrated in the crystal structure of T-bet-DNA complex. Strikingly, T-bet(K313R) entirely lost the ability to suppress IL-2 production and Th2 cell development; this was due to loss of its interaction with NFAT1. We further identified that the T-bet(K313R) reduced the phosphorylation of T-bet at Thr-302, and that threonine phosphorylation was essential for T-bet interaction with NFAT1 and suppression of NFAT1 activity. Retroviral transduction of T-bet(T302A) into T-bet-deficient cells restored IFN-γ levels compared with those induced by wild-type T-bet, but this mutant failed to inhibit IL-2 and Th2 cytokine production. Collectively, these data show that Lys-313 in the T-box domain is essential for controlling T-bet protein stability via ubiquitin-dependent degradation, T-bet binding to the IFN-γ promoter, and for the interaction with and suppression of NFAT1. Thus, multiple posttranslational modifications of T-bet are involved in fine-tuning cytokine production during Th cell development.


The in vitro regulation of ovarian follicle development using alginate-extracellular matrix gels.
The extracellular matrix (ECM) provides a three-dimensional structure that promotes and regulates cell adhesion and provides signals that direct the cellular processes leading to tissue development. In this report, synthetic matrices that present defined ECM components were employed to investigate these signaling effects on tissue formation using ovarian follicle maturation as a model system. In vitro systems for follicle culture are being developed to preserve fertility for women, and cultures were performed to test the hypothesis that the ECM regulates follicle maturation in a manner that is dependent on both the ECM identity and the stage of follicle development. Immature mouse follicles were cultured within alginate-based matrices that were modified with specific ECM components (e.g., laminin) or RGD peptides. The matrix maintains the in vivo like morphology of the follicle and provides an environment that supports follicle development. The ECM components signal the somatic cells of the follicle, affecting their growth and differentiation, and unexpectedly also affect the meiotic competence of the oocyte. These effects depend upon both the identity of the ECM components and the initial stage of the follicle, indicating that the ECM is a dynamic regulator of follicle development. The development of synthetic matrices that promote follicle maturation to produce meiotically competent oocytes may provide a mechanism to preserve fertility, or more generally, provide design principles for scaffold-based approaches to tissue engineering.


Pre-programmed self-assembly of polynuclear clusters.
This perspective reviews our recent efforts towards the self-assembly of polynuclear clusters with ditopic and tritopic multidentate ligands HL1 (2-phenyl-4,5-bis{6-(3,5-dimethylpyrazol-1-yl)pyrid-2-yl}-1H-imidazole) and H2L2 (2,6-bis-[5-(2-pyridinyl)-1H-pyrazole-3-yl]pyridine), both of which are planar and rigid molecules. HL1 was found to be an excellent support for tetranuclear [Fe4] complexes, [FeII4(L1)4](BF4)4 ([FeII4]) and [FeIII2FeII2(L1)4](BF4)6 ([FeIII2FeII2]). The homovalent system was found to exhibit multistep spin crossover (SCO), while the mixed-valence [FeIII2FeII2] complex shows wavelength-dependent tuneable light-induced excited spin state trapping (LIESST). For H2L2, a variety of polynuclear complexes were obtained through complexation with different transition metal ions, allowing the isolation of rings, grids, and helix structures. The rigidity of the ligand, difference in its coordination sites, and affinity for different metal ions dictates its coordination behaviour. In this paper, we summarise these ligand pre-programmed self-assembled clusters and their diverse physical properties.


Importance of social support in preventing alcohol-exposed pregnancies with American Indian communities.
Recent research concludes that prevention of alcohol-exposed pregnancies (AEP) must occur with preconceptional women, either by reducing alcohol consumption in women at-risk or planning pregnancy or preventing pregnancy in women drinking at risky levels. One AEP prevention program currently underway with non-pregnant American Indian women is the Oglala Sioux Tribe (OST) Changing High-risk alcohOl use and Increasing Contraception Effectiveness Study (CHOICES) Program. The OST CHOICES Program shows promise in lowering the AEP risk in American Indian women, and it is a natural next step to evaluate the potential impact that social support can have on further encouraging behavioral changes. Focus groups with community members and key informant interviews with health and social service professionals were completed. To uncover and interpret interrelated themes, a conventional content analysis methodology was used. Eight focus groups were held with 58 American Indian participants, including adult women of child-bearing age, elder women, and adult men. Key informant interviews were completed with 25 health and social service professionals. Based on input from the focus groups and key informant interviews, several subthemes regarding social support in the prevention of AEP stood out, including the role of family (especially elders), the impact community can have, and the important function of culture. In this study, we highlighted the important influence that social support can have on AEP prevention, especially among the American Indian population, where social support has cultural and historical significance.


Inter-assay variation and reproducibility of progesterone measurements during ovarian stimulation for IVF.
In recent years there is increasing evidence that elevated progesterone levels during ovarian stimulation for IVF / ICSI have a negative impact on the ART-outcome. However, different progesterone assays were used in the previous studies and different assays might produce varying results. This retrospective study evaluated the reproducibility and reliability of different progesterone assays with a special focus on progesterone levels below 1.5 ng/ml, as this range is crucial for early detection of progesterone rise during ovarian stimulation for IVF. A total of 413 blood samples were categorized in different progesterone ranges and whether they were retrieved on the day of final oocyte maturation and the results were compared regarding their reproducibility and reliability. To compare the reproducibility between the different progesterone assays, the Intraclass Correlation Coefficient (ICC) was calculated and interpretation of the ICC results was done according to Cicchetti, ranging from poor to excellent. The correlation of the assays was excellent when all samples were compared including samples retrieved on day of final oocyte maturation, however in the ranges of progesterone levels 1.0 ng/ml to < 1.5 ng/ml, 0.8 ng/ml to < 1.0 ng/ml and < 0.8 ng/ml, the ICC varied between poor and excellent. The assays "gen III" and "Architect" showed an excellent reproducibility of progesterone results throughout all ranges of progesterone levels. This analysis demonstrates, that different progesterone assays have a limited reproducibility and that the results depend on the assay used and the range of progesterone level. This fact leads to two important conclusions. Firstly the limited reproducibility might lead to substantially different treatment decisions in ovarian stimulation treatment for IVF and secondly critical interpretation of thresholds, provided by meta-analysis, is crucial despite the risk that the so far gained clinical experience might become irrelevant and has to be adjusted to the results, obtained by each assay.


Input and frequency-specific entrainment of postsynaptic firing by IPSPs of perisomatic or dendritic origin.
Correlated activity of cortical neurons underlies cognitive processes. Networks of several distinct classes of gamma-aminobutyric acid (GABA)ergic interneurons are capable of synchronizing cortical neurons at behaviourally relevant frequencies. Here we show that perisomatic and dendritic GABAergic inputs provided by two classes of GABAergic cells, fast spiking and bitufted interneurons, respectively, entrain the timing of postsynaptic spikes differentially in both pyramidal cells and interneurons at beta and gamma frequencies. Entrainment of pyramidal as well as regular spiking non-pyramidal cells was input site and inhibitory postsynaptic potential frequency dependent. Gamma frequency input from fast spiking cells entrained pyramidal cells on the positive phase of an intrinsic cellular theta oscillation, whereas input from bitufted cells was most effective in gamma frequency entrainment on the negative phase of the theta oscillation. The discharge of regular spiking interneurons was phased at gamma frequency by dendritic input from bitufted cells, but not by perisomatic input from fast spiking cells. Action potentials in fast spiking GABAergic neurons were phased at gamma frequency by both other fast spiking and bitufted cells, regardless of whether the presynaptic GABAergic input was at gamma or beta frequency. The interaction of cell type-specific intrinsic properties and location-selective GABAergic inputs could result in a spatio-temporally regulated synchronization and gating of cortical spike propagation in the network.


Heterozygous orthodenticle homeobox 2 mutations are associated with variable pituitary phenotype.
Although recent studies have suggested a positive role of OTX2 in pituitary as well as ocular development and function, detailed pituitary phenotypes in OTX2 mutations and OTX2 target genes for pituitary function other than HESX1 and POU1F1 remain to be determined. We aimed to examine such unresolved issues. We studied 94 Japanese patients with various ocular or pituitary abnormalities. We identified heterozygous p.K74fsX103 in case 1, p.A72fsX86 in case 2, p.G188X in two unrelated cases (3 and 4), and a 2,860,561-bp microdeletion involving OTX2 in case 5. Clinical studies revealed isolated GH deficiency in cases 1 and 5; combined pituitary hormone deficiency in case 3; abnormal pituitary structures in cases 1, 3, and 5; and apparently normal pituitary function in cases 2 and 4, together with ocular anomalies in cases 1-5. The wild-type Orthodenticle homeobox 2 (OTX2) protein transactivated the GNRH1 promoter as well as the HESX1, POU1F1, and IRBP (interstitial retinoid-binding protein) promoters, whereas the p.K74fsX103-OTX2 and p.A72fsX86-OTX2 proteins had no transactivation functions and the p.G188X-OTX2 protein had reduced ( approximately 50%) transactivation functions for the four promoters, with no dominant-negative effect. cDNA screening identified positive OTX2 expression in the hypothalamus. The results imply that OTX2 mutations are associated with variable pituitary phenotype, with no genotype-phenotype correlations, and that OTX2 can transactivate GNRH1 as well as HESX1 and POU1F1.


The hemodynamic effects of S-nitrosocaptopril in anesthetized dogs.
We studied the effects of a unique vasoactive agent, S-nitrosocaptopril (SnoCap), in an anesthetized canine preparation. We have previously demonstrated that this agent manifests the properties of both a direct nitrovasodilator and an angiotensin-converting enzyme inhibitor in vitro. The present investigation was performed to evaluate the effects of SnoCap in vivo. Intravenous administration of SnoCap produced immediate reductions in blood pressure and significantly attenuated the pressor response to angiotensin I. Equieffective doses of SnoCap had a greater duration of action after intravenous bolus administration compared with nitroglycerin (15.3 +/- 2.6 min vs. 3.2 +/- 0.5 min, respectively; P less than .01); importantly, this effect was apparent despite the relatively short plasma half-life of the compound (T1/2 alpha = 0.48 min, T1/2 beta = 5.54 min) and did not appear to be the result of inhibition of angiotensin-converting enzyme. Another unexpected property of SnoCap was that its nitrovasodilator effect was 10- to 30-fold less potent than nitroglycerin when administered as a bolus, but more efficacious when given by continuous infusion. These data support the view that SnoCap is a vasoactive substance with the properties of a nitrovasodilator and an angiotensin-converting enzyme inhibitor, as well as the unique properties of an extended duration of action and greater potency when administered by continuous intravenous infusion than by bolus injection. The clinical utility of this compound in humans and in individuals with specific disease states remains to be demonstrated.


Optical detection of target molecule induced aggregation of nanoparticles by means of high-Q resonators.
We theoretically investigate a novel scheme to detect target molecule induced, or suppressed, aggregation of nanoparticles. High-Q optical resonators are used to both optically trap gold nanoparticle clusters and to detect their presence via a shift in the resonance wavelength. The well depth of the optical trap is chosen to be relatively low compared to the thermal energy of the nanoparticles, so that trapping of single nanoparticles is marginal and results in a comparatively small wavelength shift. Aggregation of functionalized gold nanoparticles is mediated or suppressed via binding to a target molecule. The well depth for the resulting nanoparticle clusters scales much more favorably relative to Brownian motion, resulting in large nanoparticle concentration enhancements in the evanescent field region of the resonator. We predict a target molecule sensitivity in the tens of fM range. In order to predict the resonator response, a complete theory of time resolved nanoparticle cluster trapping dynamics is derived. In particular, the formalism of Kramers' escape time is adapted to 2D (silicon wire) and 3D (ring resonator) optical traps.


Tumor-stromal interactions with direct cell contacts enhance proliferation of human pancreatic carcinoma cells.
Pancreatic ductal adenocarcinoma is often characterized by an abundant desmoplastic stroma that is partially induced by activated pancreatic stellate cells (PSCs). Indirect co-culture has often been used to investigate the effects of cancer-stromal interactions on the proliferation of cancer cells, but the effects of cell-cell adhesion and juxtacrine signaling between cancer and stromal cells cannot be evaluated using this method. This study aimed to establish a simplified direct co-culture system that could be used to quantify populations of cancer cells in co-culture with PSCs, and to evaluate the effects of direct cell contact on the proliferation of cancer cells. We established three green fluorescent protein (GFP)-expressing pancreatic cancer cell lines and were able to quantify them with high reliability and reproducibility, even when co-cultured directly with PSCs, using a color plate reader. We assessed the differential effects of direct and indirect co-culture with PSCs on the proliferation of cancer cells, and found that the proliferation of GFP-expressing pancreatic cancer cell lines was dramatically enhanced by direct co-culture with PSCs, compared with the indirect co-culture system. We also found that direct co-culture of cancer cells and PSCs activated the Notch signaling pathway in both cell types. Direct cell contact between cancer cells and PSCs plays an important role in the control of cancer cell proliferation, and is essential to the understanding of tumor-stromal interactions.


Green infrastructure and its catchment-scale effects: an emerging science.
Urbanizing environments alter the hydrological cycle by redirecting stream networks for stormwater and wastewater transmission and increasing impermeable surfaces. These changes thereby accelerate the runoff of water and its constituents following precipitation events, alter evapotranspiration processes, and indirectly modify surface precipitation patterns. Green infrastructure, or low-impact development (LID), can be used as a standalone practice or in concert with gray infrastructure (traditional stormwater management approaches) for cost-efficient, decentralized stormwater management. The growth in LID over the past several decades has resulted in a concomitant increase in research evaluating LID efficiency and effectiveness, but mostly at localized scales. There is a clear research need to quantify how LID practices affect water quantity (i.e., runoff and discharge) and quality at the scale of catchments. In this overview, we present the state of the science of LID research at the local scale, considerations for scaling this research to catchments, recent advances and findings in scaling the effects of LID practices on water quality and quantity at catchment scales, and the use of models as novel tools for these scaling efforts.


Bayesian design and conduct of phase II single-arm clinical trials with binary outcomes: a tutorial.
The aim of phase II single-arm clinical trials of a new drug is to determine whether it has sufficient promising activity to warrant its further development. For the last several years Bayesian statistical methods have been proposed and used. Bayesian approaches are ideal for earlier phase trials as they take into account information that accrues during a trial. Predictive probabilities are then updated and so become more accurate as the trial progresses. Suitable priors can act as pseudo samples, which make small sample clinical trials more informative. Thus patients have better chances to receive better treatments. The goal of this paper is to provide a tutorial for statisticians who use Bayesian methods for the first time or investigators who have some statistical background. In addition, real data from three clinical trials are presented as examples to illustrate how to conduct a Bayesian approach for phase II single-arm clinical trials with binary outcomes.


Dimensional weighting in cross-dimensional singleton conjunction search.
In order to efficiently deploy our limited visual processing resources, we must decide what information is relevant and to be prioritized and what information should rather be ignored. To detect visual information that we know is relevant but that is not very salient, we need to set our system to prioritize and combine information from different visual dimensions (e.g., size, color, motion). Four experiments examined the allocation of processing resources across different visual dimensions when observers searched for a singleton target defined by a conjunction of size (primary dimension: the target was always large) with either color or motion (secondary dimension: variable across trials) within heterogeneously sized, colored, and moving distractors. The results revealed search reaction times to be substantially increased in a given trial in which the secondary target dimension was changed from the preceding trial--indicative of a suboptimal distribution of dimensional weights carried over from the previous trial and of attentional weight being bound by the (need to filter within the) primary dimension, thereby reducing the weight available for processing the secondary dimensions. Semantic precueing of the secondary dimension and visual marking of the search-irrelevant items in the primary dimension reduced these costs significantly. However, observers were limited in their ability to implement both top-down sets simultaneously. These findings argue in favor of a parallel distribution of dimensional processing resources across multiple visual dimensions and, furthermore, that visual marking releases attentional weight bound to the primary dimension, thus permitting more efficient (parallel) processing in the secondary dimensions.


Hypoxia modulates the development of a corneal stromal matrix model.
Deposition of matrix proteins during development and repair is critical to the transparency of the cornea. While many cells respond to a hypoxic state that can occur in a tumor, the cornea is exposed to hypoxia during development prior to eyelid opening and during the diurnal sleep cycle where oxygen levels can drop from 21% to 8%. In this study, we used 2 three-dimensional (3-D) models to examine how stromal cells respond to periods of acute hypoxic states. The first model, a stromal construct model, is a 3-D stroma-like construct that consists of human corneal fibroblasts (HCFs) stimulated by a stable form of ascorbate for 1, 2, and 4 weeks to self-assemble their own extracellular matrix. The second model, a corneal organ culture model, is a corneal wound-healing model, which consists of wounded adult rat corneas that were removed and placed in culture to heal. Both models were exposed to either normoxic or hypoxic conditions for varying time periods, and the expression and/or localization of matrix proteins was assessed. No significant changes were detected in Type V collagen, which is associated with Type I collagen fibrils; however, significant changes were detected in the expression of both the small leucine-rich repeating proteoglycans and the larger heparan sulfate proteoglycan, perlecan. Also, hypoxia decreased both the number of Cuprolinic blue-positive glycosaminoglycan chains along collagen fibrils and Sulfatase 1, which modulates the effect of heparan sulfate by removing the 6-O-sulfate groups. In the stromal construct model, alterations were seen in fibronectin, similar to those that occur in development and after injury. These changes in fibronectin after injury were accompanied by changes in proteoglycans. Together these findings indicate that acute hypoxic changes alter the physiology of the cornea, and these models will allow us to manipulate the conditions in the extracellular environment in order to study corneal development and trauma.


Data sharing - a case of shared databases and community use of on-line GIS support systems.
Data management is becoming increasingly simple and complex at the same time. The challenge is to effectively use the increasing number of tools available to manage increasing amounts of environmental information for purposes of data capture, analysis, display, sharing and storage. Government is no longer the main collector and provider of data. Community groups possess vast amounts of data collected through daily work of monitoring the environment in their local community. The chief concerns are data access, sharing, integrity and comparability. The capacity of groups to sustain data management is the key to making the sharing possible. The Southeast Environmental Association has been working with Environment Canada to develop a community, on-line database that will be linked to other geo-spatial data sets to allow instant access to geo-referenced data.


Does hearing the patient perspective improve consultation skills in examinations? An exploratory randomized controlled trial in medical undergraduate education.
Medical education increasingly includes patient perspectives, but few studies look at the impact on students' proficiency in standard examinations. We explored students' exam performance after viewing video of patients' experiences. Eighty-eight medical students were randomized to one of two e-learning modules. The experimental group saw video clips of patients describing their colposcopy, while the control group viewed a clinician describing the procedure. Students then completed a Multiple Choice Questionnaire (MCQ) and were assessed by a blinded clinical examiner in an Objective Structured Clinical Examination (OSCE) with a blinded simulated patient (SP). The SP scored students using the Doctors' Interpersonal Skills Questionnaire (DISQ). Students rated the module's effect on their skills and confidence. Regression analyses were used to compare the effect of the two modules on these outcomes, adjusting for gender and graduate entry. The experimental group performed better in the OSCE than the control group (odds ratio 2.7 [95%CI 1.2-6.1]; p = 0.016). They also reported significantly more confidence in key areas, including comfort with patients' emotions (odds ratio 6.4 [95%CI 2.7-14.9]; p < 0.0005). There were no other significant differences. Teaching that included recorded elements of real patient experience significantly improved students' examination performance and confidence.


Anticancer activities of Nigella sativa (black cumin).
Nigella sativa has been used as traditional medicine for centuries. The crude oil and thymoquinone (TQ) extracted from its seeds and oil are effective against many diseases like cancer, cardiovascular complications, diabetes, asthma, kidney disease etc. It is effective against cancer in blood system, lung, kidney, liver, prostate, breast, cervix, skin with much safety. The molecular mechanisms behind its anticancer role is still not clearly understood, however, some studies showed that TQ has antioxidant role and improves body's defense system, induces apoptosis and controls Akt pathway. Although the anti-cancer activity of N. sativa components was recognized thousands of years ago but proper scientific research with this important traditional medicine is a history of last 2∼3 decades. There are not so many research works done with this important traditional medicine and very few reports exist in the scientific database. In this article, we have summarized the actions of TQ and crude oil of N. sativa against different cancers with their molecular mechanisms.


Unveiling relationships between crime and property in England and Wales via density scale-adjusted metrics and network tools.
Scale-adjusted metrics (SAMs) are a significant achievement of the urban scaling hypothesis. SAMs remove the inherent biases of per capita measures computed in the absence of isometric allometries. However, this approach is limited to urban areas, while a large portion of the world's population still lives outside cities and rural areas dominate land use worldwide. Here, we extend the concept of SAMs to population density scale-adjusted metrics (DSAMs) to reveal relationships among different types of crime and property metrics. Our approach allows all human environments to be considered, avoids problems in the definition of urban areas, and accounts for the heterogeneity of population distributions within urban regions. By combining DSAMs, cross-correlation, and complex network analysis, we find that crime and property types have intricate and hierarchically organized relationships leading to some striking conclusions. Drugs and burglary had uncorrelated DSAMs and, to the extent property transaction values are indicators of affluence, twelve out of fourteen crime metrics showed no evidence of specifically targeting affluence. Burglary and robbery were the most connected in our network analysis and the modular structures suggest an alternative to "zero-tolerance" policies by unveiling the crime and/or property types most likely to affect each other.


Plasmodium falciparum-infected erythrocytes: agglutination by diverse Kenyan plasma is associated with severe disease and young host age.
The variant surface antigens (VSAs) of Plasmodium falciparum-infected red blood cells are potentially important targets of naturally acquired immunity to malaria. Natural infections induce agglutinating antibodies specific to the VSA variants expressed by the infecting parasites. Previously, when different parasite isolates were tested against a panel of heterologous plasma from Kenyan children, the proportion of plasma that agglutinated the parasites (the agglutination frequency [AF]) was highly variable among isolates, suggesting the existence of rare and prevalent variants. Here, the AF of 115 isolates from Kenyan children were compared. The results show that the AF of isolates causing severe malaria were significantly higher than those of isolates causing mild malaria; and AF decreased significantly with the increasing age of the infected child. We propose that parasites causing severe disease tend to express a subset of VSA variants that are preferentially associated with infections of children with low immunity.


BMP2 inhibits TGF-β-induced pancreatic stellate cell activation and extracellular matrix formation.
Activation of pancreatic stellate cells (PSCs) by transforming growth factor (TGF)-β is the key step in the development of pancreatic fibrosis, a common pathological feature of chronic pancreatitis (CP). Bone morphogenetic proteins (BMPs), members of the TGF-β superfamily, have anti-fibrogenic functions, in contrast to TGF-β, in the kidney, lung, and liver. However, it is not known whether BMPs have an anti-fibrogenic role in the pancreas. The current study was designed to investigate the potential anti-fibrogenic role of BMPs in the pancreas using an in vivo CP model and an in vitro PSC model. CP was induced by repetitive intraperitoneal injections of cerulein in adult Swiss Webster mice. The control mice received saline injections. Compared with the control, cerulein injections induced a time-dependent increase in acinar injury and progression of fibrosis and a steady increase in inflammation. Cerulein injections also induced increases of the extracellular matrix (ECM) protein fibronectin and of α-smooth muscle actin (α-SMA)-positive stellate cells (PSCs). The mice receiving cerulein injections showed increased BMP2 protein levels and phosphorylated Smad1 levels up to 4 wk and then declined at 8 wk to similar levels as the control. In vitro, the isolated mouse and human PSCs were cultured and pretreated with BMP2 followed by TGF-β treatment. BMP2 pretreatment inhibited TGF-β-induced α-SMA, fibronectin, and collagen type Ia expression. Knocking down Smad1 with small-interfering RNA reversed the inhibitory effect of BMP2 on TGF-β-induced α-SMA and fibronectin expression. Thus, BMP2 opposes the fibrogenic function of TGF-β in PSCs through the Smad1 signaling pathway.


Carriage of antibiotic-resistant enteric bacteria varies among sites in Galapagos reptiles.
Increased overlap between humans and wildlife populations has increased the risk for novel disease emergence. Detecting contacts with a high risk for transmission of pathogens requires the identification of dependable measures of microbial exchange. We evaluated antibiotic resistance as a molecular marker for the intensity of human-wildlife microbial connectivity in the Galápagos Islands. We isolated Escherichia coli and Salmonella enterica from the feces of land iguanas (Conolophus sp.), marine iguanas (Amblyrhynchus cristatus), giant tortoises (Geochelone nigra), and seawater, and tested these bacteria with the use of the disk diffusion method for resistance to 10 antibiotics. Antibiotic-resistant bacteria were found in reptile feces from two tourism sites (Isla Plaza Sur and La Galapaguera on Isla San Cristóbal) and from seawater close to a public use beach near Puerto Baquerizo Moreno on Isla San Cristóbal. No resistance was detected at two protected beaches on more isolated islands (El Miedo on Isla Santa Fe and Cape Douglas on Isla Fernandina) and at a coastal tourism site (La Lobería on Isla San Cristóbal). Eighteen E. coli isolates from three locations, all sites relatively proximate to a port town, were resistant to ampicillin, doxycycline, tetracycline, and trimethoprin/sulfamethoxazole. In contrast, only five S. enterica isolates showed a mild decrease in susceptibility to doxycycline and tetracycline from these same sites (i.e., an intermediate resistance phenotype), but no clinical resistance was detected in this bacterial species. These findings suggest that reptiles living in closer proximity to humans potentially have higher exposure to bacteria of human origin; however, it is not clear from this study to what extent this potential exposure translates to ongoing exchange of bacterial strains or genetic traits. Resistance patterns and bacterial exchange in this system warrant further investigation to understand better how human associations influence disease risk in endemic Galápagos wildlife.


Consequences of General Anesthesia in Infancy on Behavior and Brain Structure.
One in 7 children will need general anesthesia (GA) before the age of 3. Brain toxicity of anesthetics is controversial. Our objective was to clarify whether exposure of GA to the developing brain could lead to lasting behavioral and structural brain changes. A first study was performed in mice. The behaviors (fear conditioning, Y-maze, and actimetry) and brain anatomy (high-resolution magnetic resonance imaging) of 6- to 8-week-old Swiss mice exposed or not exposed to GA from 4 to 10 days old were evaluated. A second study was a complementary analysis from the preexisting APprentissages EXécutifs et cerveau chez les enfants d'âge scolaire (APEX) cohort to assess the replicability of our data in humans. The behaviors (behavior rating inventory of executive function, emotional control, and working memory score, Backward Digit Span, and Raven 36) and brain anatomy (high-resolution magnetic resonance imaging) were compared in 102 children 9 to 10 years of age exposed or not exposed to a single GA (surgery) during infancy. The animal study revealed chronic exacerbated fear behavior in the adult mice (95% confidence interval [CI], 4-80; P = .03) exposed to postnatal GA; this was associated with an 11% (95% CI, 7.5-14.5) reduction of the periaqueductal gray matter (P = .046). The study in humans suggested lower emotional control (95% CI, 0.33-9.10; P = .06) and a 6.1% (95% CI, 4.3-7.8) reduction in the posterior part of the right inferior frontal gyrus (P = .019) in the children who had been exposed to a single GA procedure. The preclinical and clinical findings of these independent studies suggest lasting effects of early life exposure to anesthetics on later emotional control behaviors and brain structures.


Metastatic Squamous Cell Carcinoma of the Pleura: A Rare Complication of Hidradenitis Suppurativa.
BACKGROUND Squamous cell carcinoma (SCC), also known as Marjolin ulcer, is a rare complication of hidradenitis suppurativa (HS). Metastatic SCC from HS typically involves the axial skeleton or abdominopelvic viscera. Metastatic disease to the lungs is a rare phenomenon with only three reported cases of lung parenchyma. We present a biopsy proven case of metastatic SCC to the pleura from gluteal HS. CASE REPORT A 46-year-old male with a history of recently diagnosed Marjolin ulcer secondary to gluteal HS was transferred to our intensive care unit for acute hypoxemic respiratory failure secondary to recurrent pleural effusion. On examination, patient was febrile (38.3 °C), normotensive (blood pressure 98/65 mm Hg), tachycardic (116 beats/minute) and tachypneic (40 breaths/minute) with oxygen saturation of 93% on room air. He was in moderate distress requiring endotracheal intubation and mechanical ventilation. Chest examination revealed decreased breath sounds bilaterally and skin examination was significant for 18 cm wide sacral lesion. CT thorax showed bilateral pleural effusions, pleural thickening, and scattered nodular densities within both lungs concerning for metastatic disease. Thoracentesis showed lymphocyte predominant exudate with negative cytology for malignant cells. A video-assisted thoracoscopic surgery (VATS) illustrated thickened pleural rind with histopathology and positive p40 stain consistent with invasive well-to-moderately differentiated keratinizing SCC. CONCLUSIONS SCC arising from HS is rare and metastatic disease to the pleura has not been reported previously. Strong clinical suspicion for malignancy is warranted in patients with advanced HS and evolving pulmonary symptoms despite negative cytology.


The distribution of Y chromosome haplogroups in the nationalities from Yunnan Province of China.
The genetic structure of 26 identified nationalities from Yunnan Province of China was studied using Y chromosome haplogroups. A total of 12 haplogroups were obtained in 1214 male samples from all the nationalities. The genetic relationships among 26 nationalities were studied. The ethnic groups were compared according to their different ancient lineages. The ancient lineages had their own characteristics in the distribution of Y chromosome haplogroups. Our results showed that Yunnan Province has great genetic diversity in its people. The ethnic groups differ from each other in the number of haplogroups and haplogroup frequencies. The genetic evidence was in agreement with the study of linguistic and historical records.


Outcome measures for clinical trials in paediatric IBD: an evidence-based, expert-driven practical statement paper of the paediatric ECCO committee.
Although paediatric-onset IBD is becoming more common, few medications have a registered paediatric indication. There are multiple hurdles to performing clinical trials in children, emphasising the importance of choosing an appropriate outcome measure, which can facilitate enrolment, and thereby also drug approval. The aim of this consensus statement is to highlight paediatric specific issues and key factors critical for the optimal conduct of paediatric IBD trials. The Paediatric European Crohn's and Colitis Organisation (ECCO) committee has established an international expert panel to determine the best outcome measures in paediatric IBD, following a literature search and a modified Delphi process. All recommendations were endorsed by at least 80% agreement. Recognising the importance of mucosal healing (MH), the panel defined steroid-free MH as primary outcome measure for all drugs of new category with one or two postintervention endoscopies per trial (at 8-12 weeks and/or 54 weeks). Since endoscopic evaluation is a barrier for recruitment in children, trials with medications already shown to induce MH in children or adults, could use paediatric-specific disease activity scores as primary outcome, including a modified Paediatric Crohn's Disease Activity Index in Crohn's disease and the Paediatric Ulcerative Colitis Activity Index in UC. Secondary outcomes should include safety issues, MR enterography-based damage and inflammatory scores (in Crohn's disease), faecal calprotectin, quality of life scales, and a patient-reported outcome. It is crucial to perform paediatric trials early in the development of new drugs in order to reduce off-label use of IBD medication in children. The thoughtful choice of feasible and standardised outcome measures can help move us towards this goal.


Critical evaluation and comparison of fluid distribution systems for industrial scale expanded bed adsorption chromatography columns.
The hydrodynamic properties of an expanded bed contactor with 30 cm or 150 cm internal diameter, which employs a rotating or oscillating fluid distributor, were compared to prototype columns of 60 cm or 150 cm diameter employing local stirring (fixed wall nozzles plus central bottom mounted stirrer) for fluid distribution. Fluid introduction through a rotating fluid distributor was found to give superior hydrodynamic characteristics in the 30 cm and 150 cm diameter column compared to using the local stirrer in both the 60 cm and 150 cm diameter columns. The shortcomings of the local stirring distributor at large scale were apparent: dead zones were present which could not be removed by increasing rotation rates or flow rates, and such changes led to a deterioration in hydrodynamic properties. In contrast, during fluid introduction through a rotating distributor no dead zones were observed, and residence time distribution tests showed that plate numbers remained constant or increased slightly as flow rate was raised from 200 cm h(-1) to 470 cm h(-1). Under the conditions studied, oscillation of the rotating fluid distributor led to increased mixing and poorer performance than rotary movement. The results imply that further improvement in distributor design is needed and careful attention should be given to the trade off between turbulence and adequate fluid distribution.


Enhanced HTS hit selection via a local hit rate analysis.
The postprocessing of high-throughput screening (HTS) results is complicated by the occurrence of false positives (inactive compounds misidentified as active by the primary screen) and false negatives (active compounds misidentified as inactive by the primary screen). An activity cutoff is frequently used to select "active" compounds from HTS data; however, this approach is insensitive to both false positives and false negatives. An alternative method that can minimize the occurrence of these artifacts will increase the efficiency of hit selection and therefore lead discovery. In this work, rather than merely using the activity of a given compound, we look at the presence and absence of activity among all compounds in its "chemical space neighborhood" to give a degree of confidence in its activity. We demonstrate that this local hit rate (LHR) analysis method outperforms hit selection based on ranking by primary screen activity values across ten diverse high throughput screens, spanning both cell-based and biochemical assay formats of varying biology and robustness. On average, the local hit rate analysis method was approximately 2.3-fold and approximately 1.3-fold more effective in identifying active compounds and active chemical series, respectively, than selection based on primary activity alone. Moreover, when applied to finding false negatives, this method was 2.3-fold better than ranking by primary activity alone. In most cases, novel hit series were identified that would have otherwise been missed. Additional uses of and observations regarding this HTS analysis approach are also discussed.


A comparative effectiveness trial of two family-based childhood obesity treatment programs in a medically underserved region: Rationale, design & methods.
While there is a large body of literature documenting the efficacy of family-based childhood obesity (FBCO) treatment interventions, there is little evidence that these interventions have been systematically translated into regular practice - particularly in health disparate regions. To address this research-practice gap, this project was guided by a community advisory board (CAB) and the RE-AIM planning and evaluation framework within a systems-based and community-based participatory research approach. Families with overweight or obese children between 5 and 12 years old, in the medically-underserved Dan River Region, were randomly assigned to one of two FBCO treatment programs (iChoose vs. Family Connections) delivered by local Parks & Recreation staff. Both programs have previously demonstrated clinically meaningful child BMI z-score reductions, but vary in intensity, structure, and implementation demands. Two clinical CAB partners embedded recruitment methods into their regional healthcare organization, using procedures representative to what could be used if either program was taken to scale. The primary effectiveness outcome is child BMI z-scores at 6-months, with additional assessments at 3-months and at 12-months. Secondary goals are to determine: (1) reach into the intended audience; (2) effectiveness on secondary child and parent outcomes; (3) intervention adoption by organizations and staff; (4) fidelity, cost, and capacity for intervention implementation; and (5) maintenance of individual-level changes and organizational-level sustainability. This research addresses literature gaps related to the features within clinical and community settings that could improve both child weight status and the translation of FBCO interventions into typical practice in medically-underserved communities. IDENTIFIERS: Clincialtrials.gov: NCT03245775.


Down-regulation of myeloid cell leukemia 1 by epigallocatechin-3-gallate sensitizes rheumatoid arthritis synovial fibroblasts to tumor necrosis factor alpha-induced apoptosis.
Overexpression of the antiapoptotic protein myeloid cell leukemia 1 (Mcl-1) in rheumatoid arthritis (RA) synovial fibroblasts is a major cause of their resistance to tumor necrosis factor alpha (TNFalpha)-induced apoptosis. This study was undertaken to evaluate the efficacy of epigallocatechin-3-gallate (EGCG) in down-regulating Mcl-1 expression and its mechanism of RA synovial fibroblast sensitization to TNFalpha-induced apoptosis. EGCG effects on cultured RA synovial fibroblast cell morphology, proliferation, and viability over 72 hours were determined by microscopy and a fluorescent cell enumeration assay. Caspase 3 activity was determined by a colorimetric assay. Western blotting was used to evaluate the apoptosis mediators poly(ADP-ribose) polymerase (PARP), Mcl-1, Bcl-2, Akt, and nuclear translocation of NF-kappaB. In RA synovial fibroblasts, EGCG (5-50 microM) inhibited constitutive and TNFalpha-induced Mcl-1 protein expression in a concentration- and time-dependent manner (P<0.05). Importantly, EGCG specifically abrogated Mcl-1 expression in RA synovial fibroblasts and affected Mcl-1 expression to a lesser extent in osteoarthritis and normal synovial fibroblasts or endothelial cells. Inhibition of Mcl-1 by EGCG triggered caspase 3 activity in RA synovial fibroblasts, which was mediated via down-regulation of the TNFalpha-induced Akt and NF-kappaB pathways. Caspase 3 activation by EGCG also suppressed RA synovial fibroblast growth, and this effect was mimicked by Akt and NF-kappaB inhibitors. Interestingly, Mcl-1 degradation by EGCG sensitized RA synovial fibroblasts to TNFalpha-induced PARP cleavage and apoptotic cell death. Our findings indicate that EGCG itself induces apoptosis and further sensitizes RA synovial fibroblasts to TNFalpha-induced apoptosis by specifically blocking Mcl-1 expression and, hence, may be of promising adjunct therapeutic value in regulating the invasive growth of synovial fibroblasts in RA.


A serologic correlate of protective immunity against community-onset Staphylococcus aureus infection.
Staphylococcus aureus is among the leading causes of human infection. Widespread drug resistance, emergence of highly virulent strains, and the ability of S. aureus to colonize >30% of the human population contribute to this organism's pathogenic success. Human serologic responses to S. aureus and their relationship to protective immunity remain incompletely defined, challenging the strategic development of efficacious vaccines. We measured humoral responses to 2 staphylococcal exotoxins, α-hemolysin (Hla) and Panton-Valentine leukocidin (PVL; LukF-PV/LukS-PV subunits), both premier targets of current vaccine and immunotherapy development. We correlated acute and convalescent serum antibody levels with incidence of recurrent infection over 12 months follow-up in 235 children with S. aureus colonization, primary or recurrent skin and soft tissue infection, or invasive disease. Cutaneous infection elicited transient increases in anti-Hla and anti-PVL antibodies; however, subsequent infection risk was similar between primary and recurrent cutaneous infection cohorts. Patients with invasive infections had the lowest preexisting titers against Hla and LukF but displayed the highest convalescent titers. Across cohorts, convalescent anti-Hla titers correlated with protection against subsequent S. aureus infection. Cutaneous S. aureus infection does not reliably provoke durable, protective immune responses. This study provides the first link between protection from disease recurrence and the humoral response to Hla, a virulence factor already implicated in disease pathogenesis. These observations can be utilized to refine ongoing vaccine and immunotherapy efforts and inform the design of clinical trials.


Better diet quality relates to larger brain tissue volumes: The Rotterdam Study.
To investigate the relation of diet quality with structural brain tissue volumes and focal vascular lesions in a dementia-free population. From the population-based Rotterdam Study, 4,447 participants underwent dietary assessment and brain MRI scanning between 2005 and 2015. We excluded participants with an implausible energy intake, prevalent dementia, or cortical infarcts, leaving 4,213 participants for the current analysis. A diet quality score (0-14) was calculated reflecting adherence to Dutch dietary guidelines. Brain MRI was performed to obtain information on brain tissue volumes, white matter lesion volume, lacunes, and cerebral microbleeds. The associations of diet quality score and separate food groups with brain structures were assessed using multivariable linear and logistic regression. We found that better diet quality related to larger brain volume, gray matter volume, white matter volume, and hippocampal volume. Diet quality was not associated with white matter lesion volume, lacunes, or microbleeds. High intake of vegetables, fruit, whole grains, nuts, dairy, and fish and low intake of sugar-containing beverages were associated with larger brain volumes. A better diet quality is associated with larger brain tissue volumes. These results suggest that the effect of nutrition on neurodegeneration may act via brain structure. More research, in particular longitudinal research, is needed to unravel direct vs indirect effects between diet quality and brain health.


Psychometric validation of the Columbia-Suicide Severity rating scale in Spanish-speaking adolescents.
Adolescent suicide is a major public health issue, and early and accurate detection is of great concern. There are many reliable instruments for this purpose, such as the Columbia-Suicide severity rating scale (C-SSRS), but no validation exists for Spanish speaking Latin American adolescents. To assess psychometric properties and cut-off scores of the C-SSRS in Spanish speaking adolescents. Exploratory assessment with principal component analysis (PCA) and Varimax rotation, and confirmatory analysis (CFA) were performed on two groups with 782 and 834 participants respectively (N=1616). Mean age was 24.8 years. A Receiver operator analysis was applied to distinguish between control and suicide-risk subgroups adolescents. Promax rotation yielded two 10-items factors, for suicide ideation and behavior respectively. C-SSRS was positively correlated with other suicide risk scales, such as Beck Depression Inventory-II, Suicidal Behaviors Questionnaire-Revised, or PHQ-9. Confirmatory factor analysis yielded a two-factor solution as the best goodness of fit model. C-SSRS showed adequate ability to detect suicide risk group with positive predictive value of 68.3%. ROC analyses showed cutoff scores of ≥ 6 and ≥ 4 for suicide ideation and behavior scales respectively. This research offers data supporting psychometric validity and reliability of C-SSRS in nonclinical Spanish-speaking students. Added benefits are flexible scoring and management easiness. This questionnaire yields data on distinct aspects of suicidality, being more parsimonious than separate administration of a bunch of questionnaires.


Quantification of Carotenoids, α-Tocopherol, and Ascorbic Acid in Amber, Mulligan, and Laird's Large Cultivars of New Zealand Tamarillos (Solanum betaceum Cav.).
Amber (yellow), Laird's Large (red) and Mulligan (purple-red) cultivars of New Zealand tamarillo fruit were separated into pulp (endo- and mesocarp) and peel (exocarp), and analyzed by liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) for carotenoids, α-tocopherol and ascorbic acid contents. Fresh Mulligan pulp had the highest content of β-carotene (0.9 mg/100 g), α-tocopherol (1.9 mg/100 g), and ascorbic acid (28 mg/100 g). Higher concentrations of β-carotene and ascorbic acid, and lower concentrations of α-tocopherol were detected in pulps compared with peels. Compared with standard serves of other fruit, tamarillo had the highest β-carotene (9-20% RDI (recommended dietary intake)/serve), high ascorbic acid (67-75% RDI/serve), and α-tocopherol (16-23% adequate intake/serve). All cultivars had diverse carotenoid profiles dominated by provitamin A carotenoids (β-carotene and β-cryptoxanthin) and xanthophyll carotenoids (lutein; zeaxanthin and antheraxanthin). Favorable growth conditions (high light intensity and low temperature) may explain the higher antioxidant vitamin content in New Zealand tamarillos compared to those from other countries. Tamarillo peels may be used as natural food coloring agent to reduce waste and deliver sustainable production.


Decreased risk of pneumonia in stroke patients receiving acupuncture: A nationwide matched-pair retrospective cohort study.
Acupuncture treatment is common among stroke patients, but there is limited information available on whether acupuncture effectively prevents post-stroke pneumonia. The aim of this study was to analyze the differential risk of pneumonia after stroke between patients who did and did not receive acupuncture after discharge. We used the Taiwan National Health Insurance Research Database to conduct a retrospective cohort study using propensity score matched-pairs of new stroke patients in 2000-2004 who did and did not receive acupuncture post-stroke. Both cohorts were followed up until the end of 2009 for new-onset pneumonia. After correcting for immortal time bias, the incidence and adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) of pneumonia associated with acupuncture use were calculated using multivariate Cox proportional hazard models. Overall, 12557 stroke patients with 12557 paired controls were included in the analysis; pneumonia was diagnosed in 6796 (27.1%). Stroke patients receiving acupuncture had a lower incidence of pneumonia than those without acupuncture (53.4 vs. 58.9 per 1000 person-years), with an adjusted HR of 0.86 (95% CI 0.82-0.90). The association between pneumonia risk and acupuncture use was significant in men (HR 0.92, 95% CI 0.86-0.98) and women (HR 0.79, 95% 0.70-0.82) and was also observed in every age group from 20-79 years. Stroke patients receiving acupuncture had a lower risk of pneumonia than those who did not. Further randomized control studies are needed to validate the protective effect of acupuncture on the risk of pneumonia among stroke patients.


Rational optimization of culture conditions for the most efficient ethanol production in Scheffersomyces stipitis using design of experiments.
Optimization of culture parameters for achieving the most efficient ethanol fermentation is challenging due to multiple variables involved. Here we presented a rationalized methodology for multi-variables optimization through the design of experiments DoE approach. Three critical parameters, pH, temperature, and agitation speed, affecting ethanol fermentation in S. stipitis was investigated. A predictive model showed that agitation speed significantly affected ethanol synthesis. Reducing pH and temperature also improved ethanol production. The model identified the optimum culture conditions for the most efficient ethanol production with the yield and productivity of 0.46 g/g and 0.28 g/l h, respectively, which is consistent with experimental observation. The results also indicated the scalability of the model from shake flask to bioreactor. Thus, DoE is a promising tool permitting the rapid establishment of culture conditions for the most efficient ethanol fermentation in S. stipitis. The approach could be useful to reduce process development time in lignocellulosic ethanol industry.


Diurnal regulation of plant growth.
Life occurs in an ever-changing environment. Some of the most striking and predictable changes are the daily rhythms of light and temperature. To cope with these rhythmic changes, plants use an endogenous circadian clock to adjust their growth and physiology to anticipate daily environmental changes. Most studies of circadian functions in plants have been performed under continuous conditions. However, in the natural environment, diurnal outputs result from complex interactions of endogenous circadian rhythms and external cues. Accumulated studies using the hypocotyl as a model for plant growth have shown that both light signalling and circadian clock mutants have growth defects, suggesting strong interactions between hypocotyl elongation, light signalling and the circadian clock. Here, we review evidence suggesting that light, plant hormones and the circadian clock all interact to control diurnal patterns of plant growth.