Different nuclease requirements for exosome-mediated degradation of normal and nonstop mRNAs.
Two general pathways of mRNA decay have been characterized in yeast. In one pathway, the mRNA is degraded by the cytoplasmic form of the exosome. The exosome has both 3' to 5' exoribonuclease and endoribonuclease activity, and the available evidence suggests that the exonuclease activity is required for the degradation of mRNAs. We confirm here that this is true for normal mRNAs, but that aberrant mRNAs that lack a stop codon can be efficiently degraded in the absence of the exonuclease activity of the exosome. Specifically, we show that the endo- and exonuclease activities of the exosome are both capable of rapidly degrading nonstop mRNAs and ribozyme-cleaved mRNAs. Additionally, the endonuclease activity of the exosome is not required for endonucleolytic cleavage in no-go decay. In vitro, the endonuclease domain of the exosome is active only under nonphysiological conditions, but our findings show that the in vivo activity is sufficient for the rapid degradation of nonstop mRNAs. Thus, whereas normal mRNAs are degraded by two exonucleases (Xrn1p and Rrp44p), several endonucleases contribute to the decay of many aberrant mRNAs, including transcripts subject to nonstop and no-go decay. Our findings suggest that the nuclease requirements for general and nonstop mRNA decay are different, and describe a molecular function of the core exosome that is not disrupted by inactivating its exonuclease activity.


Dietary assessment toolkits: an overview.
A wide variety of methods are available to assess dietary intake, each one with different strengths and weaknesses. Researchers face multiple challenges when diet and nutrition need to be accurately assessed, particularly in the selection of the most appropriate dietary assessment method for their study. The goal of the current collaborative work is to present a collection of available resources for dietary assessment implementation.Design/Setting/ParticipantsAs a follow-up to the 9th International Conference on Diet and Physical Activity Methods held in 2015, developers of dietary assessment toolkits agreed to collaborate in the preparation of the present paper, which provides an overview of each toolkit. The toolkits presented include: the Diet, Anthropometry and Physical Activity Measurement Toolkit (DAPA; UK); the National Cancer Institute's (NCI) Dietary Assessment Primer (USA); the Nutritools website (UK); the Australasian Child and Adolescent Obesity Research Network (ACAORN) method selector (Australia); and the Danone Dietary Assessment Toolkit (DanoneDAT; France). An at-a-glance summary of features and comparison of the toolkits is provided. The present review contains general background on dietary assessment, along with a summary of each of the included toolkits, a feature comparison table and direct links to each toolkit, all of which are freely available online. This overview of dietary assessment toolkits provides comprehensive information to aid users in the selection and implementation of the most appropriate dietary assessment method, or combination of methods, with the goal of collecting the highest-quality dietary data possible.


The devil is in the details: trends in avoidable hospitalization rates by geography in British Columbia, 1990-2000.
Researchers and policy makers have focussed on the development of indicators to help monitor the success of regionalization, primary care reform and other health sector restructuring initiatives. Certain indicators are useful in examining issues of equity in service provision, especially among older populations, regardless of where they live. AHRs are used as an indicator of primary care system efficiency and thus reveal information about access to general practitioners. The purpose of this paper is to examine trends in avoidable hospitalization rates (AHRs) during a period of time characterized by several waves of health sector restructuring and regionalization in British Columbia. AHRs are examined in relation to non-avoidable and total hospitalization rates as well as by urban and rural geography across the province. Analyses draw on linked administrative health data from the province of British Columbia for 1990 through 2000 for the population aged 50 and over. Joinpoint regression analyses and t-tests are used to detect and describe trends in the data. Generally speaking, non-avoidable hospitalizations constitute the vast majority of hospitalizations in a given year (i.e. around 95%) with AHRs constituting the remaining 5% of hospitalizations. Comparing rural areas and urban areas reveals that standardized rates of avoidable, non-avoidable and total hospitalizations are consistently higher in rural areas. Joinpoint regression results show significantly decreasing trends overall; lines are parallel in the case of avoidable hospitalizations, and lines are diverging for non-avoidable and total hospitalizations, with the gap between rural and urban areas being wider at the end of the time interval than at the beginning. These data suggest that access to effective primary care in rural communities remains problematic in BC given that rural areas did not make any gains in AHRs relative to urban areas under recent health sector restructuring initiatives. It remains important to continue to monitor the discrepancy between them as a reflection of inequity in service provision. In addition, it is important to consider alternative explanations for the observed trends paying particular attention to the needs of rural and urban populations and the factors influencing local service provision.


Enhanced ex vivo stimulation of Mycobacterium tuberculosis-specific T cells in human immunodeficiency virus-infected persons via antigen delivery by the Bordetella pertussis adenylate cyclase vector.
The genetically detoxified Bordetella pertussis adenylate cyclase is a promising delivery system for immunodominant tuberculosis antigens in gamma interferon release assays. This system has not been evaluated in human immunodeficiency virus (HIV)-infected persons in high tuberculosis prevalence areas. A whole-blood gamma interferon release assay with Mycobacterium tuberculosis antigens (early-secreted antigenic target 6, culture filtrate protein 10, alpha-crystallin 2, and TB10.3) delivered by adenylate cyclase in addition to native tuberculosis antigens (without adenylate cyclase delivery) was evaluated in 119 adults in Khayelitsha Township, Cape Town, South Africa. Results were compared to tuberculin skin test results of 41 HIV-positive and 42 HIV-negative asymptomatic persons, in addition to 36 HIV-positive persons with recently diagnosed smear- or culture-positive pulmonary tuberculosis. Delivery of tuberculosis antigens by adenylate cyclase decreased by 10-fold the amount of antigen required to restimulate T cells. Furthermore, the responses of HIV-positive persons with a low response to native tuberculosis antigens were enhanced when these antigens were delivered by adenylate cyclase. When gamma interferon responses to the tuberculosis antigens (with or without delivery by adenylate cyclase) were combined, a significantly higher number of patients were scored positive than by tuberculin skin testing. Ex vivo responses to tuberculosis antigens delivered by adenylate cyclase are maintained in the context of HIV infection. Our findings suggest that the majority of those in this population are infected with tuberculosis, which is of significant public health importance.


Detection of exosomes by ZnO nanowires coated three-dimensional scaffold chip device.
Exosomes as cell-derived vesicles have the potential to be novel biomarkers for noninvasive diagnosis of cancers. However, cost-effective detection of exosomes in routine clinical settings is still challenging. Herein, we present a ZnO nanowires coated three-dimensional (3D) scaffold chip device for effective immunocapture and classically visible and colorimetric detection of exosomes. The chip device is composed of 3D polydimethylsiloxane (PDMS) scaffold skeleton covered by free-standing ZnO nanowire array. The interconnected micropores of 3D scaffold induces the fluid flow with chaotic or vortex feature, and ZnO nanowire array provides large surface area for immobilization of exosome specific antibody as well as size exclusion-like effect for retaining exosomes. These synergistically and significantly enhance the capture of exosomes at a high flow rate. The captured exosomes are detected by horseradish peroxidase (HRP) labeled antibody which can initiate 3,3',5,5'-tetramethylbenzidine (TMB)-based colorimetric sensing. The quantitative readout of exosomes is easily accomplished by UV-vis spectrometry or microplate reader with a linear range of 2.2 × 105 to 2.4 × 107 particles/μL and a minimal detectable concentration of 2.2 × 104 particles/μL. This chip device was applicable to clinical samples where cancer patients demonstrate statistically significant increase in exosomes compared with healthy individuals. Thus, our chip device is cost-effective and easy-to-use, facilitating visible and colorimetric assay with high sensitivity toward clinical applications.


Stem cell origin of myelodysplastic syndromes.
Myelodysplastic syndromes (MDS) are common hematologic disorders that are characterized by decreased blood counts due to ineffective hematopoiesis. MDS is considered a 'preleukemic' disorder linked to a significantly elevated risk of developing an overt acute leukemia. Cytopenias can be observed in all three myeloid lineages suggesting the involvement of multipotent, immature hematopoietic cells in the pathophysiology of this disease. Recent studies using murine models of MDS as well as primary patient-derived bone marrow samples have provided direct evidence that the most immature, self-renewing hematopoietic stem cells (HSC), as well as lineage-committed progenitor cells, are critically altered in patients with MDS. Besides significant changes in the number and distribution of stem as well as immature progenitor cells, genetic and epigenetic aberrations have been identified, which confer functional changes to these aberrant stem cells, impairing their ability to proliferate and differentiate. Most importantly, aberrant stem cells can persist and further expand after treatment, even upon transient achievement of clinical complete remission, pointing to a critical role of these cells in disease relapse. Ongoing preclinical and clinical studies are particularly focusing on the precise molecular and functional characterization of aberrant MDS stem cells in response to therapy, with the goal to develop stem cell-targeted strategies for therapy and disease monitoring that will allow for achievement of longer-lasting remissions in MDS.


Seven-coordinated iron(ii) spin-crossover molecules: some learning from iron substitution in [FexMn1-x(L222N3O2)(CN)2]·H2O solid solutions.
The purpose of this work is to study the influence of the substitution of Fe(ii) by Mn(ii) on the spin crossover behaviour of [FexMn1-x(L222N3O2)(CN)2]·H2O solid solutions where L222N3O2 is a macrocyclic ligand = 2,13-dimethyl-6,9-dioxa-3,12,18-triazabicyclo[12.3.1]-octadeca-1(18),2,12,14,16-pentaene. The pure Fe(ii) complex is known to present a change of the coordination number from 7 at high temperature to 6 at low temperature. The target of the solid solution study was to investigate the effect of metal dilution on this coordination change. We have then measured the thermal spin crossover features as well as the metastable HS state lifetime generated by rapid thermal quenching, which was probed through the determination of the T(TIESST) value. A discussion of the spin-state as a function of temperature is given based on the phase diagram of this series and based on the investigation of the crystal structure of the [Mn(L222N3O2)(CN)2]·H2O complex and its comparison with the published [Fe(L222N3O2)(CN)2]·H2O master compound.


Medical Image Retrieval: A Multimodal Approach.
Medical imaging is becoming a vital component of war on cancer. Tremendous amounts of medical image data are captured and recorded in a digital format during cancer care and cancer research. Facing such an unprecedented volume of image data with heterogeneous image modalities, it is necessary to develop effective and efficient content-based medical image retrieval systems for cancer clinical practice and research. While substantial progress has been made in different areas of content-based image retrieval (CBIR) research, direct applications of existing CBIR techniques to the medical images produced unsatisfactory results, because of the unique characteristics of medical images. In this paper, we develop a new multimodal medical image retrieval approach based on the recent advances in the statistical graphic model and deep learning. Specifically, we first investigate a new extended probabilistic Latent Semantic Analysis model to integrate the visual and textual information from medical images to bridge the semantic gap. We then develop a new deep Boltzmann machine-based multimodal learning model to learn the joint density model from multimodal information in order to derive the missing modality. Experimental results with large volume of real-world medical images have shown that our new approach is a promising solution for the next-generation medical imaging indexing and retrieval system.


Adenosine release and uptake in cerebellar granule neurons both occur via an equilibrative nucleoside carrier that is modulated by G proteins.
These is debate about the mechanisms mediating adenosine release from neurons. In this study, the release of adenosine evoked by depolarizing cultured cerebellar granule neurons with 50 mM K+ was inhibited by 49 +/- 7% in Ca2+-free medium. The remaining release was blocked by dipyridamole (IC50 = 6.4 x 10(-8) M) and nitrobenzylthioinosine (IC50 = 3.6 x 10(-8) M), inhibitors of adenosine uptake. Ca2+-dependent release was reduced by 78 +/- 9% following a 21-h pretreatment of the cells with pertussis toxin, which ADP-ribosylates Gi/Go G proteins, thereby preventing their dissociation. The nucleoside transporter-mediated component of K+-induced adenosine release also was inhibited by 62 +/- 8% by pertussis toxin and was potentiated by 78 +/- 11% following cholera toxin treatment, which permanently activates Gs. Uptake of [3H]adenosine into cultured cerebellar granule neurons over a 10-min period was not dependent on extracellular Na+ but was reduced by dipyridamole (IC50 = 3.2 x 10(-8) M) and nitrobenzylthioinosine (IC50 = 2.6 x 10(-8) M). Thus, adenosine uptake likely occurs via the same transporter mediating Ca2+-independent adenosine release. Adenosine uptake was potentiated by cholera toxin pretreatment (152 +/- 15% of control), but pertussis toxin had no statistically significant effect. It is possible that Gs, Gi/Go, or free Gbetagamma dimer modulate the equilibrative, inhibitor-sensitive nucleoside carrier to enhance adenosine transport.


The safety of peri-articular local anaesthetic injection for patients undergoing total knee replacement with autologous blood transfusion: a randomised trial.
Intra-operative, peri-articular injection of local anaesthesia is an increasingly popular way of controlling pain following total knee replacement. At the same time, the problems associated with allogenic blood transfusion have led to interest in alternative methods for managing blood loss after total knee replacement, including the use of auto-transfusion of fluid from the patient's surgical drain. It is safe to combine peri-articular infiltration with auto-transfusion from the drain. We performed a randomised clinical trial to compare the concentration of local anaesthetic in the blood and in the fluid collected in the knee drain in patients having either a peri-articular injection or a femoral nerve block. Clinically relevant concentrations of local anaesthetic were found in the fluid from the drains of patients having peri-articular injections (4.92 μg/ml (sd 3.151)). However, none of the patients having femoral nerve blockade had detectable levels. None of the patients in either group had clinically relevant concentrations of local anaesthetic in their blood after re-transfusion. The evidence from this study suggests that it is safe to use peri-articular injection in combination with auto-transfusion of blood from peri-articular drains during knee replacement surgery.


A pragmatic randomized controlled trial of a group self-management support program versus treatment-as-usual for anxiety disorders: study protocol.
The integration of a personal recovery-oriented practice in mental health services is an emerging principle in policy planning. Self-management support (SMS) is an intervention promoting recovery that aims at educating patients on the nature of their mental disorder, improving their strategies to manage their day-to-day symptoms, fostering self-efficacy and empowerment, preventing relapse, and promoting well-being. While SMS is well established for chronic physical conditions, there is a lack of evidence to support the implementation of structured SMS programs for common mental disorders, and particularly for anxiety disorders. This study aims to examine the effectiveness of a group-based self-management support program for anxiety disorders as an add-on to treatment-as-usual in community-based care settings. We will conduct a multicentre pragmatic randomized controlled trial with a pre-treatment, post-treatment (4-month post-randomization), and follow-ups at 8, 12 and 24-months. TREATMENT AND CONTROL GROUPS: a) group self-management support (10 weekly 2.5-h group web-based sessions with 10-15 patients with two trained facilitators); b) treatment-as-usual. Participants will include adults meeting DSM-5 criteria for Panic Disorder, Agoraphobia, Social Anxiety Disorder, and/or Generalized Anxiety Disorder. The primary outcome measure will be the Beck Anxiety Inventory; secondary outcome measures will comprise self-reported instruments for anxiety and depressive symptoms, recovery, self-management, quality of life, and service utilisation. Data will be analysed based on intention-to-treat with a mixed effects regression model accounting for between and within-subject variations in the effects of the intervention. This study will contribute to the limited knowledge base regarding the effectiveness of structured group self-management support for anxiety disorders. It is expected that changes in patients' self-management behaviour will lead to better anxiety management and, consequently, to improved patient outcomes. ClinicalTrials.gov: NCT05124639 . Prospectively registered 18 November 2021.


Transcriptome, carbohydrate, and phytohormone analysis of Petunia hybrida reveals a complex disturbance of plant functional integrity under mild chilling stress.
Cultivation of chilling-tolerant ornamental crops at lower temperature could reduce the energy demands of heated greenhouses. To provide a better understanding of how sub-optimal temperatures (12°C vs. 16°C) affect growth of the sensitive Petunia hybrida cultivar 'SweetSunshine Williams', the transcriptome, carbohydrate metabolism, and phytohormone homeostasis were monitored in aerial plant parts over 4 weeks by use of a microarray, enzymatic assays and GC-MS/MS. The data revealed three consecutive phases of chilling response. The first days were marked by a strong accumulation of sugars, particularly in source leaves, preferential up-regulation of genes in the same tissue and down-regulation of several genes in the shoot apex, especially those involved in the abiotic stress response. The midterm phase featured a partial normalization of carbohydrate levels and gene expression. After 3 weeks of chilling exposure, a new stabilized balance was established. Reduced hexose levels in the shoot apex, reduced ratios of sugar levels between the apex and source leaves and a higher apical sucrose/hexose ratio, associated with decreased activity and expression of cell wall invertase, indicate that prolonged chilling induced sugar accumulation in source leaves at the expense of reduced sugar transport to and reduced sucrose utilization in the shoot. This was associated with reduced levels of indole-3-acetic acid and abscisic acid in the apex and high numbers of differentially, particularly up-regulated genes, especially in the source leaves, including those regulating histones, ethylene action, transcription factors, and a jasmonate-ZIM-domain protein. Transcripts of one Jumonji C domain containing protein and one expansin accumulated in source leaves throughout the chilling period. The results reveal a dynamic and complex disturbance of plant function in response to mild chilling, opening new perspectives for the comparative analysis of differently tolerant cultivars.


Leisure time physical activity and depressive symptoms among adolescents in Sweden.
Mental health problems have increased noticeably among adolescents. Physical activity has been identified as an important factor in the promotion of mental health. The purpose of this study was to explore how leisure time physical activity was associated with depressive symptoms among adolescents in Sweden. Using binary logistic regression we analyzed Swedish data collected as part of the Children of Immigrants: Longitudinal Survey in Four European Countries. The complete sample used for analysis consisted of 3787 adolescents (including 1855 boys and 1932 girls). Adolescents who participated in physical activity during their leisure time on a daily, weekly, or monthly basis had substantially lower odds of often feeling depressed than those who were physically inactive. This pattern applied to both boys and girls. Relative to boys, girls had significantly higher odds of often feeling depressed. The findings of this study suggested that participation in physical activity regularly during leisure time was associated with a lower level of depressive symptoms among adolescents in Sweden. Because of the cross-sectional study design conclusions about causality cannot be drawn. Future research based on longitudinal data is needed to further explore the mechanisms behind the association. This study calls for recognition of the value of physical activity in promoting mental health among adolescents.


Association between hormonal genetic polymorphisms and early-onset prostate cancer.
We investigated the association between seven polymorphisms in four candidate genes involved in vitamin D and androgen metabolism with early-onset prostate cancer (CaP) risk. The polymorphisms were genotyped in 288 UK males who were diagnosed with CaP at the age of 55 y or younger and up to 700 population-based controls. An additional 50 cases (not selected for age) and 76 controls were also genotyped. Short (< or =22 repeats) AR (CAG)(n) repeats were associated with a significantly reduced risk of early onset CaP (OR 0.68, 95% CI 0.50-0.91) compared with men with long (> 22) repeats. Men homozygous for the leucine variant of SRD5A2 p.89V > L were also found to be at a significantly increased risk of CaP compared with men who were homozygous for the valine allele (OR 1.84, 95% CI 1.15-2.98). No associations were found with the AR (GGC)(n), CYP17 Msp A1 I, VDR Taq I, SRD5A2 (TA)(n) and p.49A >T polymorphisms and CaP risk. These findings suggest that common polymorphisms in the AR and SRD5A2 genes may be associated with early-onset CaP in British men.


Hemodynamic management of septic shock.
We present a review of the hemodynamic management of septic shock. Although substantial amount of evidence is present in this area, most key decisions on the management of these patients remain dependent on physiological reasoning and on pathophysiological principles rather than randomized controlled trials. During primary (early) resuscitation, restoration of adequate arterial pressure and cardiac output using fluids and vasopressor and/or inotropic drugs is guided by basic hemodynamic monitoring and physical examination in the emergency department. When more advanced level of monitoring is present in these patients, i.e. during secondary resuscitation (later phase in the emergency department and in the ICU), hemodynamic management can be guided by more advanced measurements of the macrocirculation. Our understanding of the microcirculation in septic shock is limited and reliable therapeutic modalities to optimize it do not yet exist. No specific hemodynamic treatment strategy, be it medications including fluids, monitoring devices or treatment algorithms has yet been proved to improve outcome. Moreover, there is virtually no data on the optimal management of the resolution phase of septic shock. Despite these gaps in knowledge, the data from observational studies and trials suggests that mortality in septic shock has been generally decreasing during the last decade.


The Coonrad-Morrey total elbow arthroplasty in patients who have rheumatoid arthritis. A ten to fifteen-year follow-up study.
Sixty-nine patients (seventy-eight elbows) who had rheumatoid arthritis were managed with a Coonrad-Morrey total elbow arthroplasty between 1981 and 1986. At the time of the present review, forty-one patients (forty-six elbows) were alive and had been followed for at least ten years after the procedure (Group 1). The remaining twenty-eight patients (thirty-two elbows) had died or had had a revision less than ten years after the procedure or had been followed for less than ten years (Group 2). The patients in Group 1 had a younger mean age at the time of the procedure, but all other preoperative parameters were similar for both groups. At the latest follow-up evaluation, 97 per cent of the elbows (forty-five of the forty-six in Group 1 and thirty-one of the thirty-two in Group 2) were not painful or were only mildly painful. The mean arc of flexion-extension was 28 to 131 degrees; this represents an increase of 13 degrees (15 degrees in Group 1 and 7 degrees in Group 2) compared with the preoperative value. The mean arc of pronation was 68 degrees, and the mean arc of supination was 62 degrees; this represents an increase of 21 degrees. The results for seventy-four of the seventy-eight elbows (all forty-six in Group 1 and twenty-eight of the thirty-two in Group 2) were considered satisfactory by the patients. One patient thought that the status of the elbow was unchanged compared with preoperatively, and three thought that it was worse. Seventy-six of the seventy-eight elbows had long-term radiographic evaluation; the two remaining elbows were excluded because a resection arthroplasty had been performed. There were two loose ulnar components; one was associated with an infection, and the other had been causing no symptoms at the time of the patient's death. In addition, both components were radiographically loose in an elbow that had had a revision without cement after a previous total elbow arthroplasty. Five bushings (7 per cent) were completely worn, and six (8 per cent) were partially worn. Complications occurred in eleven elbows (14 per cent) and were serious, necessitating reoperation, in ten (13 per cent). Delayed complications included three avulsions of the triceps, two deep infections, two ulnar fractures, and one fracture of an ulnar component. In addition, two elbows were revised because of aseptic loosening. No patient had persistent ulnar neuritis or serious skin complications. At the latest clinical follow-up evaluation, according to the Mayo elbow performance score, forty-three of the seventy-eight elbows had an excellent result; twenty-six, a good result; seven, a fair result; and two (both in Group 2), a poor result. The rate of survival of the prosthesis was 92.4 per cent, with 86 per cent good or excellent and 14 per cent fair or poor results.


Importance of accurate dynamic polarizabilities for the ionic dispersion interactions of alkali halides.
Ab initio quantum mechanical calculations of the dynamic polarizability of alkali metal and halide ions are performed as a function of imaginary frequency. Electron correlation is shown to provide a significant correction to ionic polarizabilities. Ab initio ion-surface dispersion coefficients are compared with single- and multimode London approximations. The commonly employed single-mode model with the characteristic frequency taken from the ionization potential of the ion is shown to be inadequate, underestimating dispersion forces with an average error around 40% or as high as 80% for halide ions. Decomposition of the polarizability data into five modes covers the major modes of each ion adequately (four modes for Li(+)). Illustrative calculations of surface potentials at the mica surface in aqueous alkali halide electrolytes are made. Charge reversal is obtained with the more polarizable cations, K(+) and Rb(+). The error in the single-mode ionization potential models is seen as a strong shift in the surface potential from negative toward positive values.


Evaluation of a scheme to enhance palliative cancer care in rural Wales.
Since the early 1990s, the United Kingdom has seen several initiatives designed to improve the quality of cancer palliative care in the community. We report on the evaluation of a project that took place in the rural county of Powys in Wales in which a group of general practitioner clinical facilitators (GPCFs) sought to raise the overall standard of palliative care among primary health care teams (PHCTs). The evaluation was conducted over 3 years and made use of several methods: interviews with facilitators and other key stakeholders at regular intervals throughout the project; a survey of PHCT members at two time points; an analysis of patterns of opioid prescribing in the county before and during the project; monitoring of referrals to specialist palliative care services out of county; and an analysis of place of death of those dying from cancer. The evaluation found that local general practitioners (GPs) were willing to work as facilitators and that they made contact with over two thirds of those in the PHCTs. Facilitators undertook a variety of clinical, educational and service development initiatives but did report on problems of role definition and time management. There were no marked changes in patterns of referral to specialist palliative care or in place of death, but there was some evidence to suggest that the facilitators had an influence on their colleagues' opioid prescribing patterns.


Legal themes concerning obesity regulation in the United States: Theory and practice.
Despite national health objectives to reduce the incidence of obesity to 15% of the population by 2010, public health data suggest that the incidence of obesity in the United States is actually increasing. The U.S. recognizes that it (like other industrialized countries) faces an epidemic of obesity and related health conditions. How can U.S. jurisdictions (federal, state, and local) and the private sector respond to this epidemic through laws and policies that are directly or indirectly designed to address obesity? This article analyzes the theoretical and practical roles of law as a tool to curb obesity in the U.S. It proffers ten major legal themes to address obesity among the U.S. population, including: (1) use of incentives to encourage healthier behaviors; (2) use of financial disincentives to discourage unhealthy behaviors; (3) requirements to improve food quality, diversity, or availability; (4) compensation for injured persons seeking recourse; (5) restriction of access to unhealthy foods; (6) regulations aimed at influencing consumer choices; (7) control of marketing and advertising; (8) creation of communities that support healthy lifestyles; (9) physical education/fitness requirements; and (10) insurance coverage mandates.


Embedded Philanthropic CSR in Digital China: Unified View of Prosocial and Pro-environmental Practices.
In recent decades, China has transformed from a conventional society into a digitally competitive nation. From an economic perspective, embedded corporate social responsibility (CSR) is gaining a new height where gamified charity is a trendy approach. By adopting the norm activation model from the point of view of the stimulus-organism-response framework, this research theoretically conceptualized the role of the mobile application environment (including telepresence, functional transparency, and accessibility) to map the cognition and philanthropic behavioral intentions of consumers in the gamified setting. The quantified survey comprised 669 respondents. The findings highlighted the critical role of functional transparency and telepresence of a mobile application in driving consumers' warm glow and ascribed responsibility. The research underlined the presence of the unique DNA of Internet Plus Charity (Public Benefits) for prosocial and pro-environmental purposes in China under the umbrella of philanthropic CSR.


Pulmonary tuberculosis incidence and risk factors in rural areas of China: a cohort study.
The incidence of tuberculosis (TB) and its risk factors in China remains unclear. This study examined TB incidence and relative risk factors in rural areas of China. Participants (n = 177,529) were recruited in Xiangtan County (in the central area of China) and in Danyang County (in the eastern area of China) in 2009 and a followed-up study was conducted for one year. The incidence density of pulmonary TB and smear-positive TB were 91.6 (95% CI: 78.7, 106.0) per 100,000 person-year and 36.7 (95% CI: 33.1, 52.4) per 100,000 person-year respectively in Xiangtan, and 47.3 (95% CI: 38.2, 57.5) per 100,000 person-year and 22.7 (95% CI: 16.5, 30.8) per 100,000 person-year in Danyang. The medical history of TB was associated with TB, with the relative risk (RR) of 7.00 (95% CI: 2.76, 17.18) in Xiangtan and that of 31.08 (95% CI: 13.22, 73.10) in Danyang. The association between TB and per capita living space over median was found in Xiangtan, with the RR of 1.86 (95% CI: 1.15, 3.01). No association was found between TB and the insurance status, the contact history with TB, the history of diabetes, smoking, or per capita annual income. The host genetic susceptibility, and social factors such as education and income could be considered in future studies.


Single-Crystal Epitaxial Thin Films of the Isotropic Metallic Oxides Sr1-xCaxRuO3 (0 le x le 1).
Single-crystal epitaxial thin films of the isotropic metallic oxides Sr1-xCaxRuO(3) (0 </= x </= 1) were grown on miscut SrTiO(3)(100) substrates in situ by 90 degrees off-axis sputtering. These thin films exhibit low isotropic resistivities, excellent chemical and thermal stability, good surface smoothness, and high crystalline quality. Furthermore, the lattice parameters and magnetic properties can be varied by simply changing the strontium/calcium ratio. These epitaxial thin films, and their multilayer structures with other oxide materials, can be used for the fabrication of superconducting, ferroelectric, magneto-optic, and electro-optic devices.


MtDNA haplogroup analysis of black Brazilian and sub-Saharan populations: implications for the Atlantic slave trade.
Seventy individuals from two African and four black Brazilian populations were studied for the first hypervariable segment of mtDNA. To delineate a more complete phylogeographic scenario of the African mtDNA haplogroups in Brazil and to provide additional information on the nature of the Atlantic slave trade, we analyzed our data together with previously published data. The results indicate different sources of African slaves for the four major Brazilian regions. In addition, the data revealed patterns that differ from those expected on the basis of historical registers, thus suggesting the role of ethnic sex differences in the slave trade.


A case control study of bacterial species and colony count in milk of breastfeeding women with chronic pain.
An infectious etiology for chronic breast pain in breastfeeding women continues to be debated. Although recent data suggest that Staphylococcus aureus and coagulase-negative Staphylococcus (CNS) may cause chronic breast pain, no studies have used quantitative cultures to address this question. In this study we compared bacterial species and colony counts between breastfeeding women with (cases) and without (controls) chronic pain. We enrolled 114 breastfeeding women in a prospective cohort study. Cases (n=61), breastfeeding women with breast pain for >1 week and no signs of acute infection, were matched with controls (n=53) by weeks postpartum and parity. More cases had a history of mastitis (14% vs. 2%, p=0.036), cracked nipples (64% vs. 17%, p=0.001), and other breastfeeding difficulties. Enterobacter species growth was less likely in cases (0% vs. 7.5%, p=0.029). Cases had a significantly higher growth of S. aureus (19.7% vs. 1.9%, p=0.003). CNS frequency was similar between groups (75% vs. 79%, p=0.626), but median colony count growth was significantly lower in cases (900 colony-forming units/mL vs. 5,000 colony-forming units/ml, p=0.003). Growth of CNS and S. aureus was negatively correlated (r=-0.265, p=0.004). Higher S. aureus growth in cases supports a pathogenic role for S. aureus and reinforces the need for future antibiotic treatment studies in breastfeeding women with chronic pain. In contrast, similar CNS frequency between groups, lower CNS colony counts in cases, and a negative correlation between S. aureus and CNS growth suggest that neither CNS, nor its overgrowth, causes chronic breast pain.


Targeting GIPC/synectin in pancreatic cancer inhibits tumor growth.
Various studies have shown the importance of the GAIP interacting protein, COOH-terminus (GIPC, also known as Synectin) as a central adaptor molecule in different signaling pathways and as an important mediator of receptor stability. GIPC/Synectin is associated with different growth-promoting receptors such as insulin-like growth factor receptor I (IGF-IR) and integrins. These interactions were mediated through its PDZ domain. GIPC/Synectin has been shown to be overexpressed in pancreatic and breast cancer. The goal of this study was to show the importance of GIPC/Synectin in pancreatic cancer growth and to evaluate a possible therapeutic strategy by using a GIPC-PDZ domain inhibitor. Furthermore, the effect of targeting GIPC on the IGF-I receptor as one of its associated receptors was tested. The in vivo effects of GIPC/Synectin knockdown were studied after lentiviral transduction of luciferase-expressing pancreatic cancer cells with short hairpin RNA against GIPC/Synectin. Additionally, a GIPC-PDZ--targeting peptide was designed. This peptide was tested for its influence on pancreatic cancer growth in vitro and in vivo. Knockdown of GIPC/Synectin led to a significant inhibition of pancreatic adenocarcinoma growth in an orthotopic mouse model. Additionally, a cell-permeable GIPC-PDZ inhibitor was able to block tumor growth significantly without showing toxicity in a mouse model. Targeting GIPC was accompanied by a significant reduction in IGF-IR expression in pancreatic cancer cells. Our findings show that targeting GIPC/Synectin and its PDZ domain inhibits pancreatic carcinoma growth and is a potential strategy for therapeutic intervention of pancreatic cancer.


A randomized phase I clinical and biologic study of two schedules of sorafenib in patients with myelodysplastic syndrome or acute myeloid leukemia: a NCIC (National Cancer Institute of Canada) Clinical Trials Group Study.
Sorafenib is a small molecule inhibitor of RAF kinase, VEGFR-2, c-KIT, and FLT3. In this randomized phase I study, eligible patients had relapsed/refractory acute myeloid leukemia (AML), and one prior induction regimen, or were age >65 with untreated myelodysplastic syndrome (MDS) or secondary AML. Sorafenib was given orally for 28 days (cont) or 14 days (int) every 4 weeks at three dose levels (100, 200, and 400 mg BID); 300 mg cont was also tested. Forty-two patients were enrolled (median age 71 [37-82]; prior chemotherapy: 22). Dose-limiting toxicity (DLT) was: 100 mg BID: 0/7 patients; 200 mg BID: 2/12 patients; 400 mg BID: 1/17 patients. Sorafenib 400 mg cont was not tolerated in this population: 6/8 received <14 days of treatment due to toxicity; no DLT was seen with 300 mg cont. One CR was seen in a patient with AML with FLT3-ITD. Flow cytometry studies suggest that sorafenib inhibits ERK phosphorylation via c-KIT. The recommended phase II dose in AML is 300 mg BID continuously, and testing in combination and in FLT3-ITD AML is warranted.


Postoperative subcutaneous instillation of low-dose ketorolac but not hydromorphone reduces wound exudate concentrations of interleukin-6 and interleukin-10 and improves analgesia following cesarean delivery.
The objectives of this study were to test the effects of low-dose ketorolac and hydromorphone added to continuous local anesthetic wound instillation on surgical-site inflammatory mediators, postoperative pain, and opioid consumption. Sixty healthy women undergoing cesarean delivery were enrolled in this randomized, double-blinded study. Patients were randomized to receive a subcutaneous wound instillation of bupivacaine .5% at 10 mg/hour (active control), bupivacaine .5% with ketorolac .6 mg/hour, or bupivacaine .5% with hydromorphone .04 mg/hour for 48 hours postcesarean. Wound exudate was sampled at 4, 24, and 48 hours postcesarean and assayed for interleukins IL-1β, IL-2, IL-6, IL-8, IL-10, and IL-12, tumor necrosis factor (TNF-α), interferon (INF-γ), and granulocyte-macrophage colony stimulating factor (GM-CSF). The addition of ketorolac to bupivacaine significantly decreased IL-6 (P = .012) and IL-10 (P = .005) compared to plain bupivacaine. Ketorolac, but not hydromorphone, was associated with a decrease in pain (P = .018) and analgesic use (P = .020) following cesarean delivery. Our results are compatible with the view that significant analgesics effects are mediated through local modulation of inflammatory events. Low-dose ketorolac administered into surgical wounds exert significant anti-inflammatory and analgesic effects and may be a valuable analgesic alternative to systemic nonsteroidal anti-inflammatories (NSAIDs) but with potentially fewer side effects. This article demonstrates that low-dose ketorolac administered into wounds modulates local inflammatory events, decreases postoperative pain, and reduces opioid consumption. These results suggest that administration of NSAIDs into surgical wounds may be an analgesic alternative to higher systemic dosing of NSAIDs.


Machine Learning on DNA-Encoded Libraries: A New Paradigm for Hit Finding.
DNA-encoded small molecule libraries (DELs) have enabled discovery of novel inhibitors for many distinct protein targets of therapeutic value. We demonstrate a new approach applying machine learning to DEL selection data by identifying active molecules from large libraries of commercial and easily synthesizable compounds. We train models using only DEL selection data and apply automated or automatable filters to the predictions. We perform a large prospective study (∼2000 compounds) across three diverse protein targets: sEH (a hydrolase), ERα (a nuclear receptor), and c-KIT (a kinase). The approach is effective, with an overall hit rate of ∼30% at 30 μM and discovery of potent compounds (IC50 < 10 nM) for every target. The system makes useful predictions even for molecules dissimilar to the original DEL, and the compounds identified are diverse, predominantly drug-like, and different from known ligands. This work demonstrates a powerful new approach to hit-finding.


Parallel confocal detection of single biomolecules using diffractive optics and integrated detector units.
The past few years we have witnessed a tremendous surge of interest in so-called array-based miniaturised analytical systems due to their value as extremely powerful tools for high-throughput sequence analysis, drug discovery and development, and diagnostic tests in medicine (see articles in Issue 1). Terminologies that have been used to describe these array-based bioscience systems include (but are not limited to): DNA-chip, microarrays, microchip, biochip, DNA-microarrays and genome chip. Potential technological benefits of introducing these miniaturised analytical systems include improved accuracy, multiplexing, lower sample and reagent consumption, disposability, and decreased analysis times, just to mention a few examples. Among the many alternative principles of detection-analysis (e.g.chemiluminescence, electroluminescence and conductivity), fluorescence-based techniques are widely used, examples being fluorescence resonance energy transfer, fluorescence quenching, fluorescence polarisation, time-resolved fluorescence, and fluorescence fluctuation spectroscopy (see articles in Issue 11). Time-dependent fluctuations of fluorescent biomolecules with different molecular properties, like molecular weight, translational and rotational diffusion time, colour and lifetime, potentially provide all the kinetic and thermodynamic information required in analysing complex interactions. In this mini-review article, we present recent extensions aimed to implement parallel laser excitation and parallel fluorescence detection that can lead to even further increase in throughput in miniaturised array-based analytical systems. We also report on developments and characterisations of multiplexing extension that allow multifocal laser excitation together with matched parallel fluorescence detection for parallel confocal dynamical fluorescence fluctuation studies at the single biomolecule level.


1001 lights: luciferins, luciferases, their mechanisms of action and applications in chemical analysis, biology and medicine.
Bioluminescence (BL) is a spectacular phenomenon involving light emission by live organisms. It is caused by the oxidation of a small organic molecule, luciferin, with molecular oxygen, which is catalysed by the enzyme luciferase. In nature, there are approximately 30 different BL systems, of which only 9 have been studied to various degrees in terms of their reaction mechanisms. A vast range of in vitro and in vivo analytical techniques have been developed based on BL, including tests for different analytes, immunoassays, gene expression assays, drug screening, bioimaging of live organisms, cancer studies, the investigation of infectious diseases and environmental monitoring. This review aims to cover the major existing applications for bioluminescence in the context of the diversity of luciferases and their substrates, luciferins. Particularly, the properties and applications of d-luciferin, coelenterazine, bacterial, Cypridina and dinoflagellate luciferins and their analogues along with their corresponding luciferases are described. Finally, four other rarely studied bioluminescent systems (those of limpet Latia, earthworms Diplocardia and Fridericia and higher fungi), which are promising for future use, are also discussed.


Total anti-oxidant capacity, flavonoid, phenolic acid and polyphenol content in ten selected species of Zingiberaceae rhizomes.
Natural products such as herbs, fruits, spices, beverages, vegetables are becoming more popular among scientific community and consumers because of their potential to arrest the effect of free radicals in human system. This study determined the total antioxidant capacity of ten selected species of Zingiberaceae (Ginger) used as spices and for medicinal purposes in Southeast Asia. Methanol was used as the extraction solvent, 2,2 - diphenyl-1-picrylhydrazil (DPPH) for free radical scavenging activity and ferric reducing antioxidant power (FRAP) assays. Phenolic compounds were measured using Total flavonoid, Phenolic acid and Polyphenols content assay to evaluate the quality of the antioxidant capacity of the rhizomes and vitamin C as positive control. The results obtained revealed that Curcuma longa and Zingiber officinale had the highest free radical scavenging capacity of 270.07mg/TE/g DW and 266.95mg/TE/g DW and FRAP assay, Curcuma longa and Zingiber officinale also gave the highest ferric reducing power of 231.73mg/TE/g DW and 176.26mg/TE/g DW respectively. For Phenolic compounds, Curcuma longa and Curcuma xanthorrhiza gave the highest values of flavonoid (741.36mg/NGN/g DW and 220.53mg/NGN/g DW), phenolic acid (42.71mg/GAE/g DW and 22.03mg/GAE/g DW) and polyphenols (39.38mg/GAE/g DW and 38.01mg/GAE/g DW) respectively. Significant and positive linear correlations were found between Total antioxidant capacity and Phenolic compounds (R = 0.65 - 0.96). This study provides evidence that extracts of Zingiberaceae (Ginger) rhizomes are a potential source of natural antioxidants and could serve as basis for future drugs and food supplements.


Achieving Remission in Gulf War Illness: A Simulation-Based Approach to Treatment Design.
Gulf War Illness (GWI) is a chronic multi-symptom disorder affecting up to one-third of the 700,000 returning veterans of the 1991 Persian Gulf War and for which there is no known cure. GWI symptoms span several of the body's principal regulatory systems and include debilitating fatigue, severe musculoskeletal pain, cognitive and neurological problems. Using computational models, our group reported previously that GWI might be perpetuated at least in part by natural homeostatic regulation of the neuroendocrine-immune network. In this work, we attempt to harness these regulatory dynamics to identify treatment courses that might produce lasting remission. Towards this we apply a combinatorial optimization scheme to the Monte Carlo simulation of a discrete ternary logic model that represents combined hypothalamic-pituitary-adrenal (HPA), gonadal (HPG), and immune system regulation in males. In this work we found that no single intervention target allowed a robust return to normal homeostatic control. All combined interventions leading to a predicted remission involved an initial inhibition of Th1 inflammatory cytokines (Th1Cyt) followed by a subsequent inhibition of glucocorticoid receptor function (GR). These first two intervention events alone ended in stable and lasting return to the normal regulatory control in 40% of the simulated cases. Applying a second cycle of this combined treatment improved this predicted remission rate to 2 out of 3 simulated subjects (63%). These results suggest that in a complex illness such as GWI, a multi-tiered intervention strategy that formally accounts for regulatory dynamics may be required to reset neuroendocrine-immune homeostasis and support extended remission.


Major alterations in the mononuclear phagocyte landscape associated with COVID-19 severity.
Dendritic cells (DCs) and monocytes are crucial mediators of innate and adaptive immune responses during viral infection, but misdirected responses by these cells may contribute to immunopathology. Here, we performed high-dimensional flow cytometry-analysis focusing on mononuclear phagocyte (MNP) lineages in SARS-CoV-2-infected patients with moderate and severe COVID-19. We provide a deep and comprehensive map of the MNP landscape in COVID-19. A redistribution of monocyte subsets toward intermediate monocytes and a general decrease in circulating DCs was observed in response to infection. Severe disease coincided with the appearance of monocytic myeloid-derived suppressor cell-like cells and a higher frequency of pre-DC2. Furthermore, phenotypic alterations in MNPs, and their late precursors, were cell-lineage-specific and associated either with the general response against SARS-CoV-2 or COVID-19 severity. This included an interferon-imprint in DC1s observed in all patients and a decreased expression of the coinhibitory molecule CD200R in pre-DCs, DC2s, and DC3 subsets of severely sick patients. Finally, unsupervised analysis revealed that the MNP profile, alone, pointed to a cluster of COVID-19 nonsurvivors. This study provides a reference for the MNP response to SARS-CoV-2 infection and unravels mononuclear phagocyte dysregulations associated with severe COVID-19.


Genomic rearrangements in mouse C3H/10T1/2 cells transformed by X-rays, UV-C, and 3-methylcholanthrene, detected by a DNA fingerprint assay.
Genomic rearrangements occurring in C3H/10T1/2 cells transformed by X-rays were examined with a DNA fingerprint assay. Four multilocus and multiallele probes were employed (M, X, H10, and H16) that detect different families of minisatellite sequences dispersed throughout the genome. Genomic rearrangements were detectable only with probe M. This specificity may be explained by a genomic instability owing to a specific sequence or structure of DNA recognized by probe M. Genomic rearrangements were detected in 5 of 12 type III foci transformed by 600 cGy of X-rays and in all clones isolated from a previously transformed clone exposed to a second dose of 600 cGy and recloned. The latter data suggest that the stage of transformation and the occurrence of genomic rearrangement induced by X-rays may be related. An intensity shift or a complete deletion of band 2 was common to these X-ray-induced clones, as well as to clones transformed by UV-C (1 of 5) or 3-methylcholanthrene (4 of 6). This band did not hybridize to probes for the retinoblastoma gene RB or for p53. We hypothesize that the loss of band 2 may reflect a significant genetic change in the transformation of 10T1/2 cells, perhaps representing the inactivation of a tumor suppressor gene other than RB or p53. Additional rearrangements occurred in X-ray-transformed clones; these rearrangements were not observed with the other carcinogens. Aside from the changes in band 2, however, no specific pattern of genomic rearrangement was associated with X-ray transformation, and the presence or absence of rearrangements did not correlate with tumorigenicity in syngeneic nonimmunosuppressed C3H mice.


Prices For Common Cardiovascular Drugs In The US Are Not Consistently Aligned With Value.
Health care reimbursement agencies in countries other than the US often rely on cost-effectiveness evidence for drug coverage decisions, signaling to drug manufacturers their expectations for value-based pricing. To see whether drug prices in the US are influenced by value, we estimated the range of cost-effectiveness for thirty frequently prescribed cardiovascular drugs. We extrapolated evidence from randomized controlled trials to determine average lifetime quality-adjusted life-years (QALYs) and payer-related costs and to calculate incremental cost-effectiveness ratios (ICERs), the principal metric of cost-effectiveness studies. Across the thirty drugs, the ICERs ranged from cost-saving with increased QALYs to more costly with decreased QALYs. This range suggests that drug pricing is not consistently influenced by value, or that such influence is masked by inaccessible factors, such as price discounts. Our findings highlight the need to debate how to define and use value-based evidence to inform US coverage and reimbursement decision making.


Altered cortical synaptic morphology and impaired memory consolidation in forebrain- specific dominant-negative PAK transgenic mice.
Molecular and cellular mechanisms for memory consolidation in the cortex are poorly known. To study the relationships between synaptic structure and function in the cortex and consolidation of long-term memory, we have generated transgenic mice in which catalytic activity of PAK, a critical regulator of actin remodeling, is inhibited in the postnatal forebrain. Cortical neurons in these mice displayed fewer dendritic spines and an increased proportion of larger synapses compared to wild-type controls. These alterations in basal synaptic morphology correlated with enhanced mean synaptic strength and impaired bidirectional synaptic modifiability (enhanced LTP and reduced LTD) in the cortex. By contrast, spine morphology and synaptic plasticity were normal in the hippocampus of these mice. Importantly, these mice exhibited specific deficits in the consolidation phase of hippocampus-dependent memory. Thus, our results provide evidence for critical relationships between synaptic morphology and bidirectional modifiability of synaptic strength in the cortex and consolidation of long-term memory.


Spatial-temporal clustering of malaria using routinely collected health facility data on the Kenyan Coast.
The over-distributed pattern of malaria transmission has led to attempts to define malaria "hotspots" that could be targeted for purposes of malaria control in Africa. However, few studies have investigated the use of routine health facility data in the more stable, endemic areas of Africa as a low-cost strategy to identify hotspots. Here the objective was to explore the spatial and temporal dynamics of fever positive rapid diagnostic test (RDT) malaria cases routinely collected along the Kenyan Coast. Data on fever positive RDT cases between March 2018 and February 2019 were obtained from patients presenting to six out-patients health-facilities in a rural area of Kilifi County on the Kenyan Coast. To quantify spatial clustering, homestead level geocoded addresses were used as well as aggregated homesteads level data at enumeration zone. Data were sub-divided into quarterly intervals. Kulldorff's spatial scan statistics using Bernoulli probability model was used to detect hotspots of fever positive RDTs across all ages, where cases were febrile individuals with a positive test and controls were individuals with a negative test. Across 12 months of surveillance, there were nine significant clusters that were identified using the spatial scan statistics among RDT positive fevers. These clusters included 52% of all fever positive RDT cases detected in 29% of the geocoded homesteads in the study area. When the resolution of the data was aggregated at enumeration zone (village) level the hotspots identified were located in the same areas. Only two of the nine hotspots were temporally stable accounting for 2.7% of the homesteads and included 10.8% of all fever positive RDT cases detected. Taking together the temporal instability of spatial hotspots and the relatively modest fraction of the malaria cases that they account for; it would seem inadvisable to re-design the sub-county control strategies around targeting hotspots.


Electronic structure of SmO and SmO- via slow photoelectron velocity-map imaging spectroscopy and spin-orbit CASPT2 calculations.
The chemi-ionization reaction of atomic samarium, Sm + O → SmO+ + e-, has been investigated by the Air Force Research Laboratory as a means to modify local electron density in the ionosphere for reduction of scintillation of high-frequency radio waves. Neutral SmO is a likely unwanted byproduct. The spectroscopy of SmO is of great interest to aid in interpretation of optical emission spectra recorded following atmospheric releases of Sm as part of the Metal Oxide Space Cloud (MOSC) observations. Here, we report a joint experimental and theoretical study of SmO using slow photoelectron velocity-map imaging spectroscopy of cryogenically cooled SmO- anions (cryo-SEVI) and high-level spin-orbit complete active space calculations with corrections from second order perturbation theory (CASPT2). With cryo-SEVI, we measure the electron affinity of SmO to be 1.0581(11) eV and report electronic and vibrational structure of low-lying electronic states of SmO in good agreement with theory and prior experimental work. We also obtain spectra of higher-lying excited states of SmO for direct comparison to the MOSC results.


Geochemical Evidence of the Seasonality, Affinity and Pigmenation of Solenopora jurassica.
Solenopora jurassica is a fossil calcareous alga that functioned as an important reef-building organism during the Palaeozoic. It is of significant palaeobiological interest due to its distinctive but poorly understood pink and white banding. Though widely accepted as an alga there is still debate over its taxonomic affinity, with recent work arguing that it should be reclassified as a chaetetid sponge. The banding is thought to be seasonal, but there is no conclusive evidence for this. Other recent work has, however demonstrated the presence of a unique organic boron-containing pink/red pigment in the pink bands of S. jurassica. We present new geochemical evidence concerning the seasonality and pigmentation of S. jurassica. Seasonal growth cycles are demonstrated by X-ray radiography, which shows differences in calcite density, and by varying δ13C composition of the bands. Temperature variation in the bands is difficult to constrain accurately due to conflicting patterns arising from Mg/Ca molar ratios and δ18O data. Fluctuating chlorine levels indicate increased salinity in the white bands, when combined with the isotope data this suggests more suggestive of marine conditions during formation of the white band and a greater freshwater component (lower chlorinity) during pink band precipitation (δ18O). Increased photosynthesis is inferred within the pink bands in comparison to the white, based on δ13C. Pyrolysis Gas Chromatography Mass Spectrometry (Py-GCMS) and Fourier Transform Infrared Spectroscopy (FTIR) show the presence of tetramethyl pyrrole, protein moieties and carboxylic acid groups, suggestive of the presence of the red algal pigment phycoerythrin. This is consistent with the pink colour of S. jurassica. As phycoerythrin is only known to occur in algae and cyanobacteria, and no biomarker evidence of bacteria or sponges was detected we conclude S. jurassica is most likely an alga. Pigment analysis may be a reliable classification method for fossil algae.


Aspergillus texensis: A Novel Aflatoxin Producer with S Morphology from the United States.
Aflatoxins are carcinogenic metabolites produced primarily by fungi within Aspergillus section Flavi. These fungi infect a wide range of crops in warm regions. Molecular phylogenetic analyses of fungi with S morphology (average sclerotium size < 400 µm) within section Flavi collected from across the United States (US) resulted in the discovery of a novel aflatoxin-producing species, Aspergillus texensis. Aspergillus texensis was isolated from maize grown in Arkansas, Louisiana, and Texas, and from soils cropped to maize in Texas. Aspergillus texensis produces sparse conidia and abundant sclerotia on various culture media, and on maize. Physiological studies have revealed optimal growth on culture media at 35 °C. All isolates of A. texensis produced B and G aflatoxins, cyclopiazonic acid and aspergillic acid. Aspergillus texensis and A. flavus S strain morphotypes produced similar concentrations of total aflatoxins on maize (p > 0.05). Phylogenetic analyses of aflatoxin-producers based on partial gene sequences of the β-tubulin (0.9 kb), calmodulin (1.2 kb), and nitrate reductase (2.1 kb) genes placed A. texensis in a highly supported monophyletic clade closely related to A. minisclerotigenes and a previously reported unnamed lineage designated Lethal Aflatoxicosis Fungus.


The Impact of cDNA Normalization on Long-Read Sequencing of a Complex Transcriptome.
Normalization of cDNA is widely used to improve the coverage of rare transcripts in analysis of transcriptomes employing next-generation sequencing. Recently, long-read technology has been emerging as a powerful tool for sequencing and construction of transcriptomes, especially for complex genomes containing highly similar transcripts and transcript-spliced isoforms. Here, we analyzed the transcriptome of sugarcane, a highly polyploidy plant genome, by PacBio isoform sequencing (Iso-Seq) of two different cDNA library preparations, with and without a normalization step. The results demonstrated that, while the two libraries included many of the same transcripts, many longer transcripts were removed, and many new generally shorter transcripts were detected by normalization. For the same input cDNA and data yield, the normalized library recovered more total transcript isoforms and number of predicted gene families and orthologous groups, resulting in a higher representation for the sugarcane transcriptome, compared to the non-normalized library. The non-normalized library, on the other hand, included a wider transcript length range with more longer transcripts above ∼1.25 kb and more transcript isoforms per gene family and gene ontology terms per transcript. A large proportion of the unique transcripts comprising ∼52% of the normalized library were expressed at a lower level than the unique transcripts from the non-normalized library, across three tissue types tested including leaf, stalk, and root. About 83% of the total 5,348 predicted long noncoding transcripts was derived from the normalized library, of which ∼80% was derived from the lowly expressed fraction. Functional annotation of the unique transcripts suggested that each library enriched different functional transcript fractions. This demonstrated the complementation of the two approaches in obtaining a complete transcriptome of a complex genome at the sequencing depth used in this study.


Donor-recipient sex mismatch in kidney transplantation.
The lack of reliable human proxies for minor (ie, non-HLA) histocompatibility loci hampers the ability to leverage these factors toward improving transplant outcomes. Despite conflicting reports of the effect of donor-recipient sex mismatch on renal allografts, the association between acute rejection of renal allografts and the development of human alloantibodies to the male H-Y antigen suggested to us that donor-recipient sex mismatch deserved re-evaluation. To evaluate whether the relationships between donor sex and allograft failure differed by recipient sex. We studied recipients of deceased-donor (n = 125,369) and living-donor (n = 63,139) transplants in the United States Renal Data System. Using Cox proportional hazards models stratified by donor type, we estimated the association between donor-recipient sex mismatch and death-censored allograft failure with adjustment for known risk factors, with and without the use of multiple imputation methods to account for potential bias and/or loss of efficiency due to missing data. The advantage afforded by male donor kidneys was more pronounced among male than among female recipients (8% vs 2% relative risk reduction; interaction P < 0.01). This difference is of the order of magnitude of several other risk factors affecting donor selection decisions. Donor-recipient sex mismatch affects renal allograft survival in a direction consistent with immune responses to sexually determined minor histocompatibility antigens. Our study provides a paradigm for clinical detection of markers for minor histocompatibility loci.


The Uncontrolled Manifold Theory Could Explain Part of the Inter-Trial Variability of Knee Contact Force During Level Walking.
Accurate predictions of joint contact forces through computer simulation of musculoskeletal dynamics can provide insight, in a non-invasive manner, into the joint loads of patients with osteoarthritis and healthy controls. The current approach to assume optimal control, in terms of metabolic energy expenditure, remains a major limitation of the prediction of muscle activation patterns that determine joint contact forces. Stochastically optimal muscle control, in the form of a stochastic component superimposed to the optimal control, could potentially explain the inter-trial variability as observed in measured knee contact forces during level walking. A probabilistic approach was used to predict sets of possible muscle activation patterns within a 5 and 10% limit from the optimal muscle activation pattern. The knee contact forces determined by both the optimal and stochastically optimal muscle activation patterns were compared to the corresponding knee contact force patterns measured by an instrumented implant. The range of muscle control patterns captured the inter-trial variability of knee contact forces for most of the gait cycle, suggesting that the probabilistic approach used here is representative of a stochastically optimal control that accounts for co-contraction, whereas during some time intervals a more explicit representation of the motor control strategy is required. These findings underline the importance of stochastically optimal muscle control in the prediction of knee forces within a multi-body dynamics approach.


MAF amplification licenses ERα through epigenetic remodelling to drive breast cancer metastasis.
MAF amplification increases the risk of breast cancer (BCa) metastasis through mechanisms that are still poorly understood yet have important clinical implications. Oestrogen-receptor-positive (ER+) BCa requires oestrogen for both growth and metastasis, albeit by ill-known mechanisms. Here we integrate proteomics, transcriptomics, epigenomics, chromatin accessibility and functional assays from human and syngeneic mouse BCa models to show that MAF directly interacts with oestrogen receptor alpha (ERα), thereby promoting a unique chromatin landscape that favours metastatic spread. We identify metastasis-promoting genes that are de novo licensed following oestrogen exposure in a MAF-dependent manner. The histone demethylase KDM1A is key to the epigenomic remodelling that facilitates the expression of the pro-metastatic MAF/oestrogen-driven gene expression program, and loss of KDM1A activity prevents this metastasis. We have thus determined that the molecular basis underlying MAF/oestrogen-mediated metastasis requires genetic, epigenetic and hormone signals from the systemic environment, which influence the ability of BCa cells to metastasize.


Pulmonary hilar stereotactic body radiation therapy in the rat.
Stereotactic Body Radiation therapy (SBRT) is an emerging modality of treatment for early stage non-small cell lung carcinoma. Concerns have arisen related to increased toxicities for medial tumors. We have developed a model of high dose, hypofractionated radiotherapy to the pulmonary hilum using the Leksell Gamma-Knife. Sprague-Dawley rats received hypofractionated SBRT to the unilateral lung hilum using a custom immobilization device on the Gamma Knife. Each animal was individually scanned, treatment planned, and treated with either two 4 mm or one 8 mm collimated shots at escalating doses of 20, 40, and 80 Gy to the 50% isodose volume, encompassing the right mainstem bronchus. All animals were carefully followed post-treatment and imaged by plain film and CT. In addition, histopathological analysis of all rats was performed at selected time points. Animals treated with 4 mm collimated shots demonstrated no appreciable changes on plain films or sequential, follow-up CT scans, or histopathologically. Animals irradiated with the 8 mm collimator were less active, gained weight at a reduced rate, and demonstrated histopathological changes in 7/34 animals six months post-irradiation. Cellular atypia and interstitial pneumonitis were found, three of the seven of the animals showed clear bronchial damage and two showed vascular damage. Significant volume and time effects were found. Utilizing a novel Gamma Knife based animal model to study SBRT toxicity, it was found that the bronchus will tolerate small volumes of very high dose radiotherapy. It was postulated that radiation of the surrounding support stroma and normal tissue are important in the etiology of bronchial or hilar damage.


Different DMRT3 Genotypes Are Best Adapted for Harness Racing and Riding in Finnhorses.
Previous studies showed a positive effect of the DMRT3 "gait keeper" mutation on harness racing performance in Standardbreds, French-, and Nordic trotters. The mutation has also been shown to influence riding traits in multiple breeds. This study investigated the effect of the DMRT3 mutation on harness racing performance and riding traits in Finnhorses. Finnhorses used for harness racing (n = 180) and for riding (n = 59) were genotyped for the DMRT3 mutation. For the trotters the genotypes were evaluated for association with racing performance (number of starts, victories, placings, earnings, and race times). At 3-6 years of age the AA genotype was superior compared with the CA and CC genotypes. The AA horses had a significantly higher proportion of victories (P = 1.4×10(-6)) and placings (P = 4.1×10(-7)), better race times (P = 0.01), and earned more money (P = 0.009) compared with C-horses. For the Finnhorses used for riding the owners answered a questionnaire to score how well the horse performed the gaits walk, trot, and canter on a scale from 1 to 6. These scores were tested for association with the DMRT3 genotypes. Although AA horses were more successful as racehorses, the CC and CA horses appear more adapted for classical riding disciplines. The AA horses received significantly lower gait scores compared with C-horses for the majority of gaits. Except for rhythm in extended canter (P = 0.05), there were no significant differences between CA and CC horses. This study shows that there are different optimal genotypes for different disciplines and the DMRT3 mutation clearly influences gaits and performance in Finnhorses.


Lymphadenitis caused by Loa loa.
The World Health Organization's Collaborating Centre for the Histopathology of Filarial Diseases of Man contains specimens of lymph node from 13 patients infected by the filarial nematode Loa loa. Ten of these nodes have distinctive microscopic features characterized by distended sinuses that contain histiocytes and eosinophils and by atrophy of lymphoid follicles. Less striking features include fibrosis of capsule and trabeculae, dilated lymphatic vessels of capsule and medulla, and inflammatory cell infiltrates. We believe that these changes, although in themselves nonspecific, are characteristic of lymphadenitis caused by Loa loa. These 10 lymph nodes were removed from the inguinal region--one from each of 10 native Zairians . At the time of herniorrhaphy the nodes in eight patients were found to be enlarged and were removed for diagnosis. Seven of the 10 patients were infected with Dipetalonema perstans as well as Loa loa, and one of these seven had three filarial infections--L. loa, D. perstans and D. streptocerca . Lymph nodes from other patients infected by other filariae that were available for study at the AFIP did not have these histopathologic features.


Vaginal Pessary Use and Management for Pelvic Organ Prolapse: Developed by the joint writing group of the American Urogynecologic Society and the Society of Urologic Nurses and Associates. Individual writing group members are noted in the Acknowledgments section.
Over the past 50 years, pessary use has increased in popularity and has become an essential pelvic organ prolapse (POP) management tool. However, evidence is lacking to define care standardization, including pessary fitting, routine maintenance, and management of pessary-related complications. This clinical consensus statement (CCS) on vaginal pessary use and management for POP reflects statements drafted by content experts from the American Urogynecologic Society and Society of Urologic Nurses and Associates. The purpose of this CCS is to identify areas of expert consensus and nonconsensus regarding pessary fitting, follow-up, and management of pessary complications to improve the safety and quality of care where evidence is currently limited. The American Urogynecologic Society and Society of Urologic Nurses and Associates' vaginal pessary for POP writing group used a modified Delphi process to assess statements that were evaluated for consensus after a structured literature search. A total of 31 statements were assessed and divided into 3 categories: (1) fitting and follow-up, (2) complications, and 3) quality of life. Of the 31 statements that were assessed, all statements reached consensus after 2 rounds of the Delphi survey. This CCS document hopefully serves as a first step toward standardization of pessary care, but the writing group acknowledges that improved research will grow the base of knowledge and evidence providing clinicians a foundation to manage pessary care effectively and confidently.


Assessment of Mean Platelet Volume in Patients with Systemic Lupus Erythematosus.
The Mean Platelet Volume (MPV) is a platelet activation biomarker that has been recently correlated with disease activity in SLE. We aimed to evaluate the MPV in patients with SLE comparing it with healthy individuals, to study the correlation between MPV and SLE Disease Activity Index (SLEDAI) in SLE patients and to analyze possible correlation between MPV and Erythrocyte Sedimentation Rate (ESR), C-Reactive Protein (CRP), and complement components C3 and C4. This is a cross-sectional study in which 81 patients with SLE according to the American College of Rheumatology (ACR) diagnostic classification criteria and 58 healthy controls were included. Active disease was defined as SLEDAI>0. Patients with active SLE had decreased MPV when compared to inactive disease group (10.0±0.7fL vs. 10.7±1.0fL, p=0.005, respectively) and when compared to control group (10.9±1.0fL, p<0.001). Our study found a weak negative correlation between the SLEDAI and the MPV (r=-0.29, p=0.009). There was no correlation between MPV and CRP, ESR, C3 and C4. Also, no correlation between SLEDAI and CRP, ESR, C3 and C4 was found. MPV decreases in patients with active SLE and is inversely correlated with SLEDAI.


A simple colorimetric sensor for the detection of moisture in organic solvents and building materials: applications in rewritable paper and fingerprint imaging.
A simple off-the-shelf dye molecule, 1,4-dihydroxy-9,10-anthraquinone or quinizarin (1), has been investigated for the effective detection of moisture in organic solvents and building materials. Anion-induced deprotonation of 1 to 1.F followed by re-protonation with water is the working principle of the sensor system. Changes in colour, UV-Vis spectra and emission intensity indicate the moisture detection of 1.F in various organic solvents. The probe 1.F is more effective at the detection of water in acetonitrile and THF with a LOD of 0.0011 and 0.0026 wt%. Probe 1.F is reversible, reusable, highly selective, and sensitive and has a fast response time both in solution phase and in test papers. Probe 1.F is also applied for the detection of unknown moisture content in raw building materials such as cement, fly ash, foundry sand, and limestone. 1.F incorporated cellulose-based papers are applicable for inkless writing and stamping in the read-erase manner. Furthermore, these papers are also suitable for fingerprint imaging and sweat pore mapping by the simple colour change method.


Effects of diltiazem on cation transport across erythrocyte membranes of hypertensive humans.
The effects of the calcium antagonist diltiazem on diastolic blood pressure and various parameters of erythrocyte membrane cation transport were evaluated in hypertensive patients with diastolic blood pressure between 95 and 110 mm Hg in a placebo-controlled, double-blind parallel study. Twenty-one patients completed the study; 13 received placebo, while 8 received diltiazem. Diastolic blood pressure, intracellular sodium and calcium concentrations, ouabain-sensitive Na+,K+-adenosine triphosphatase (ATPase) activity, and net sodium efflux and potassium influx across red blood cell membranes were examined in both groups at the end of placebo run-in, at the end of the titration phase, and at the completion of study. In the placebo group, none of the parameters changed significantly. In the drug-treated group, diastolic blood pressure declined by approximately 10% (placebo, 95.1 +/- 8.9; drug-treated, 86.9 +/- 4.9 mm Hg; p less than 0.03) at the end of the study. There were also reductions in intracellular sodium (placebo, 7.9 +/- 1.8; drug-treated, 5.2 +/- 0.4 mmol/L cells; p less than 0.002) and calcium (placebo, 13.5 +/- 1.6; drug-treated 10.8 +/- 3.3 mumol/L cells; p less than 0.03) concentrations, accompanied by a simultaneous rise in the activity of the ouabain-sensitive Na+,K+-ATPase of erythrocyte membranes (placebo, 7.1 +/- 1.1 X 10(-2); drug-treated, 9.0 +/- 0.6 X 10(-2) microM inorganic phosphate/hr/mg; p less than 0.001) at the end of the study. However, no significant change in the ouabain-insensitive moiety of the ATPase pump was found. Diltiazem treatment increased net sodium efflux and potassium influx.(ABSTRACT TRUNCATED AT 250 WORDS)


Reaction Kinetic Models of Antibiotic Heteroresistance.
Bacterial heteroresistance (i.e., the co-existence of several subpopulations with different antibiotic susceptibilities) can delay the clearance of bacteria even with long antibiotic exposure. Some proposed mechanisms have been successfully described with mathematical models of drug-target binding where the mechanism's downstream of drug-target binding are not explicitly modeled and subsumed in an empirical function, connecting target occupancy to antibiotic action. However, with current approaches it is difficult to model mechanisms that involve multi-step reactions that lead to bacterial killing. Here, we have a dual aim: first, to establish pharmacodynamic models that include multi-step reaction pathways, and second, to model heteroresistance and investigate which molecular heterogeneities can lead to delayed bacterial killing. We show that simulations based on Gillespie algorithms, which have been employed to model reaction kinetics for decades, can be useful tools to model antibiotic action via multi-step reactions. We highlight the strengths and weaknesses of current models and Gillespie simulations. Finally, we show that in our models, slight normally distributed variances in the rates of any event leading to bacterial death can (depending on parameter choices) lead to delayed bacterial killing (i.e., heteroresistance). This means that a slowly declining residual bacterial population due to heteroresistance is most likely the default scenario and should be taken into account when planning treatment length.


Strain-specific probiotic (Lactobacillus helveticus) inhibition of Campylobacter jejuni invasion of human intestinal epithelial cells.
Campylobacter jejuni is the most common bacterial cause of enterocolitis in humans, leading to diarrhoea and chronic extraintestinal diseases. Although probiotics are effective in preventing other enteric infections, beneficial microorganisms have not been extensively studied with C. jejuni. The aim of this study was to delineate the ability of selected probiotic Lactobacillus strains to reduce epithelial cell invasion by C. jejuni. Human colon T84 and embryonic intestine 407 epithelial cells were pretreated with Lactobacillus strains and then infected with two prototypic C. jejuni pathogens. Lactobacillus helveticus, strain R0052 reduced C. jejuni invasion into T84 cells by 35-41%, whereas Lactobacillus rhamnosus R0011 did not reduce pathogen invasion. Lactobacillus helveticus R0052 also decreased invasion of one C. jejuni isolate (strain 11168) into intestine 407 cells by 55%. Lactobacillus helveticus R0052 adhered to both epithelial cell types, which suggest that competitive exclusion could contribute to protection by probiotics. Taken together, these findings indicate that the ability of selected probiotics to prevent C. jejuni-mediated disease pathogenesis depends on the pathogen strain, probiotic strain and the epithelial cell type selected. The data support the concept of probiotic strain selectivity, which is dependent on the setting in which it is being evaluated and tested.


Regulation of Hepcidin by Erythropoiesis: The Story So Far.
Hepcidin is the master regulator of systemic iron homeostasis, facilitating iron balance by controlling intestinal iron absorption and recycling. Hepcidin levels are suppressed when erythropoiesis is stimulated, for example following acute blood loss, appropriately enhancing cellular iron export to the plasma to support production of new red blood cells. However, persistent increased and ineffective erythropoiesis, for example in thalassemia, results in sustained elevations in iron absorption, which cause iron overload with associated organ toxicities. The ligands, receptors, and canonical pathways by which iron loading and inflammation upregulate hepcidin expression have been largely established. However, although several mechanisms have been proposed, the means by which erythropoiesis causes hepcidin suppression have been unclear. The erythroid-derived hormone erythroferrone appears to be a convincing candidate for the link between increased erythropoiesis and hepcidin suppression. If confirmed to be clinically and physiologically relevant in humans, potentiation or inhibition of erythroferrone activity could be a crucial pharmaceutical strategy.


Towards better implementation of cancer screening in Europe through improved monitoring and evaluation and greater engagement of cancer registries.
Proposals to improve implementation, monitoring and evaluation of breast, cervical and colorectal cancer screening programmes have been developed in a European project involving scientists and professionals experienced in cancer registration (EUROCOURSE). They call for a clear and more active role for cancer registries through better interfaces with cancer screening programmes and adapting data contents of cancer registries for evaluation purposes. Cancer registries are recognised as essential for adequate evaluation of cancer screening programmes, but they are not involved in screening evaluation in several European countries. This is a key barrier to improving the effectiveness of programmes across Europe. The variation in Europe in the implementation of cancer screening offers a unique opportunity to learn from best practices in collaboration between cancer registries and screening programmes. Population-based cancer registries have experience and tools in collecting and analysing relevant data, e.g. for diagnostic and therapeutic determinants of mortality. In order to accelerate improvements in cancer control we argue that cancer registries should take co-responsibility in promoting effective screening evaluation in Europe. Additional investments are vital to further development of infrastructures and activities for screening evaluation and monitoring in the national settings and also at the pan-European level. The EUROCOURSE project also aimed to harmonise implementation of the European quality assurance guidelines for cancer screening programmes across Europe through standardising routine data collection and analysis, and definitions for key performance indicators for screening registers. Data linkage between cancer and screening registers and other repositories of demographic data and cause of death and where available clinical registers is key to implementing the European screening standards and thereby reducing the burden of disease through early detection. Greater engagement of cancer registries in this collaborative effort is also essential to develop adequate evaluation of innovations in cancer prevention and care.


Association of PIP5K2A with schizophrenia: a study in an indonesian family sample.
PIP5K2A variants have been shown to be associated with schizophrenia in Caucasian populations. This study tested 12 PIP5K2A SNPs for association with schizophrenia in a sample of 152 sib-pair families of Indonesian descent. All SNPs had previously been tested for association with schizophrenia in a German family sample by Schwab et al. [2006; Mol Psychiatry] and seven SNPs were nominally associated with schizophrenia in this previous study. The purpose of the study was to examine whether previously implicated PIP5K2A variants influence susceptibility to schizophrenia in populations of non-European descent. No single markers showed nominal association with schizophrenia in this Indonesian family sample, however multi-marker haplotypes including a previously associated exonic SNP marker revealed nominally significant association (P = 0.03). Power to detect association was greater than 80% for all previously implicated variants except for rs11013052, where power was greatly reduced due to the low minor allele frequency of this marker in the Indonesian sample. An explorative study combining the results of this study with those of our previous study indicated that rs11013052 was significantly associated with schizophrenia in the combined sample (P = 0.002). The results of this study suggest that any contribution of previously implicated DNA variants within the PIP5K2A gene to schizophrenia susceptibility in the Indonesian population is only minor.


Melittin suppresses PMA-induced tumor cell invasion by inhibiting NF-kappaB and AP-1-dependent MMP-9 expression.
Matrix metalloproteinase-9 (MMP-9) plays an important role in the invasion and metastasis of cancer cells. In this study, we examined the inhibitory effect of bee venom (BV) and its major peptides, melittin and apamin, on PMA-induced invasion induced by MMP-9 expression in Caki-1 renal cancer cells. BV and melittin, but not apamin, significantly suppressed PMA-induced invasion by inhibiting MMP-9 expression in Caki-1 cells. Furthermore, as evidenced by MMP-9 promoter assays, melittin inhibited MMP-9 gene expression by blocking the PMA-stimulated activations of activator protein-1 (AP-1) and nuclear factor-kappa B (NF-kappaB). In addition, melittin suppressed the PMA-induced phosphorylations of ERK and JNK mitogen-activated protein kinases, upstream factors involved in Ap-1 and NF-kappaB. These results suggest that the suppression of MMP-9 expression contributes to the anti-tumor properties of melittin.


Brachypodium distachyon. A new model system for functional genomics in grasses.
A new model for grass functional genomics is described based on Brachypodium distachyon, which in the evolution of the Pooideae diverged just prior to the clade of "core pooid" genera that contain the majority of important temperate cereals and forage grasses. Diploid ecotypes of B. distachyon (2n = 10) have five easily distinguishable chromosomes that display high levels of chiasma formation at meiosis. The B. distachyon nuclear genome was indistinguishable in size from that of Arabidopsis, making it the simplest genome described in grasses to date. B. distachyon is a self-fertile, inbreeding annual with a life cycle of less than 4 months. These features, coupled with its small size (approximately 20 cm at maturity), lack of seed-head shatter, and undemanding growth requirements should make it amenable to high-throughput genetics and mutant screens. Immature embryos exhibited a high capacity for plant regeneration via somatic embryogenesis. Regenerated plants display very low levels of albinism and have normal fertility. A simple transformation system has been developed based on microprojectile bombardment of embryogenic callus and hygromycin selection. Selected B. distachyon ecotypes were resistant to all tested cereal-adapted Blumeria graminis species and cereal brown rusts (Puccinia reconditia). In contrast, different ecotypes displayed resistance or disease symptoms following challenge with the rice blast pathogen (Magnaporthe grisea) and wheat/barley yellow stripe rusts (Puccinia striformis). Despite its small stature, B. distachyon has large seeds that should prove useful for studies on grain filling. Such biological characteristics represent important traits for study in temperate cereals.


Assessment of the prevalence of vCJD through testing tonsils and appendices for abnormal prion protein.
The objective of this study was to determine the age group or groups which will provide the most information on the potential size of the vCJD epidemic in Great Britain via the sampling of tonsil and appendix material to detect the presence of abnormal prion protein (PrP(Sc)). A subsidiary aim was to determine the degree to which such an anonymous age-stratified testing programme will reduce current uncertainties in the size of the epidemic in future years. A cohort- and time-stratified model was used to generate epidemic scenarios consistent with the observed vCJD case incidence. These scenarios, together with data on the age distribution of tonsillectomies and appendectomies, were used to evaluate the optimal age group and calendar time for undertaking testing and to calculate the range of epidemic sizes consistent with different outcomes. The analyses suggested that the optimal five-year age group to test is 25-29 years, although a random sample of appendix tissue from all age groups is nearly as informative. A random sample of tonsil tissue from all age groups is less informative, but the information content is improved if sampling is restricted to tissues removed from those over ten years of age. Based on the assumption that the test is able to detect infection in the last 75% of the incubation period, zero detected infections in an initial random sample of 1000 tissues would suggest that the epidemic will be less than 870,000 cases. If infections are detected, then the model prediction suggests that both relatively small epidemics (800+ cases if one is detected or 8300+ if two are detected) and larger epidemics (21,000+ cases if three or more are detected) are possible. It was concluded that testing will be most informative if undertaken using appendix tissues or tonsil tissues removed from those over ten years of age. Large epidemics can only be excluded if a small number of infections are detected and the test is able to detect infection early in the incubation period.


Bionomics of anopheline vectors in Zabid District, Al-Hodeidah Governorate, Republic of Yemen.
The bionomics of anopheline vectors were analysed in randomly selected centres, representing fixed and spot-check stations. Three anopheline species were found. Anopheles arabiensis was the most prevalent species (84.2%) with a sporozoite rate of 0.7%, followed by A. culicifacies adenensis (14.9%) and A. rhodesiensis rupicolus (0.9%). Maximum indoor resting density was recorded during March, July and August. Positive sprayed sites for females were higher in bedrooms (40.4%) than animal sheds (26.9%). A total of 2560 anopheline larvae were collected of which 79.5% were A. arabiensis, 19.4% were A. culicifacies adenensis and 1.1% A. rhodesiensis rupicolus. A. arabiensis was assumed to be the most efficient malaria vector based on epidemiological evidence and the finding of natural sporozoite infected females.


Asthma and oral health: a review.
Asthma is a chronic inflammatory condition that causes the airways to constrict and produce excess mucus, making breathing difficult. It is characterized by the obstruction of airflow which is variable over a short period of time. This condition is reversible, either spontaneously or can be controlled with the help of drugs. Asthma medication comprises bronchodilators, corticosteroids and anticholinergic drugs. Most of these drugs are inhaled using various forms of inhalers or nebulizers. The effect of these drugs on oral health is the subject of debate among dental practitioners. Patients taking asthma medication may be at risk of dental caries, dental erosion, periodontal diseases and oral candidiasis. Hence, patients with bronchial asthma on medication should receive special prophylactic attention. This article reviews the correlation between asthma and oral health, and suggests various measures to counter possible oral health problems related to asthma.


Carbon accumulation of tropical peatlands over millennia: a modeling approach.
Tropical peatlands cover an estimated 440,000 km2 (~10% of global peatland area) and are significant in the global carbon cycle by storing about 40-90 Gt C in peat. Over the past several decades, tropical peatlands have experienced high rates of deforestation and conversion, which is often associated with lowering the water table and peat burning, releasing large amounts of carbon stored in peat to the atmosphere. We present the first model of long-term carbon accumulation in tropical peatlands by modifying the Holocene Peat Model (HPM), which has been successfully applied to northern temperate peatlands. Tropical HPM (HPMTrop) is a one-dimensional, nonlinear, dynamic model with a monthly time step that simulates peat mass remaining in annual peat cohorts over millennia as a balance between monthly vegetation inputs (litter) and monthly decomposition. Key model parameters were based on published data on vegetation characteristics, including net primary production partitioned into leaves, wood, and roots; and initial litter decomposition rates. HPMTrop outputs are generally consistent with field observations from Indonesia. Simulated long-term carbon accumulation rates for 11,000-year-old inland, and 5000-year-old coastal peatlands were about 0.3 and 0.59 Mg C ha(-1) yr(-1), and the resulting peat carbon stocks at the end of the 11,000-year and 5000-year simulations were 3300 and 2900 Mg C ha(-1), respectively. The simulated carbon loss caused by coastal peat swamp forest conversion into oil palm plantation with periodic burning was 1400 Mg C ha(-1) over 100 years, which is equivalent to ~2900 years of C accumulation in a hectare of coastal peatlands.


Interaction Patterns in Adolescent Romantic Relationships: A Typological Analysis.
While several studies in adolescents have addressed issues related to romantic relationships and dating violence, there is a limited understanding of their interaction patterns. This study aims to document interactions in conflict situations by identifying profiles of adolescent romantic relationships. Qualitative analysis based on the dimensions of the Circumplex Model of Marital and Family Systems was used to investigate the interaction task of 40 dyads. A typological analysis revealed four profiles: (1) rigid, (2) entangled, (3) hampered, and (4) balanced. Results highlight the diversity of romantic experiences and offer a better understanding of the intricacies of different interaction profiles. Dating violence prevention efforts and programs promoting harmonious and egalitarian romantic relationships could benefit from the insights of the identified profiles.