Persistent, biologically meaningful prostate cancer after 1 year of androgen ablation and docetaxel treatment.
Clinicians are increasingly willing to treat prostate cancer within the primary site in the presence of regional lymph node or even limited distant metastases. However, no formal study on the merits of this approach has been reported. We used a preoperative clinical discovery platform to prioritize pathways for assessment as therapeutic targets and to test the hypothesis that the primary site harbors potentially lethal tumors after aggressive treatment. Patients with locally advanced or lymph node-metastatic prostate cancer underwent 1 year of androgen ablation and three cycles of docetaxel therapy, followed by prostatectomy. All specimens were characterized for stage by accepted criteria. Expression of select molecular markers implicated in disease progression and therapy resistance was determined immunohistochemically and compared with that in 30 archived specimens from untreated patients with high-grade prostate cancer. Marker expression was divided into three groups: intracellular signaling pathways, stromal-epithelial interaction pathways, and angiogenesis. Forty patients were enrolled, 30 (75%) of whom underwent prostatectomy and two (5%) who underwent cystoprostatectomy. Twenty-nine specimens contained sufficient residual tumor for inclusion in a tissue microarray. Immunohistochemical analysis showed increased epithelial and stromal expression of CYP17, SRD5A1, and Hedgehog pathway components, and modulations of the insulin-like growth factor I pathway. A network of molecular pathways reportedly linked to prostate cancer progression is activated after 1 year of therapy; biomarker expression suggests that potentially lethal cancers persist in the primary tumor and may contribute to progression.


Genome Mining of the Marine Actinomycete Streptomyces sp. DUT11 and Discovery of Tunicamycins as Anti-complement Agents.
Marine actinobacteria are potential producers of various secondary metabolites with diverse bioactivities. Among various bioactive compounds, anti-complement agents have received great interest for drug discovery to treat numerous diseases caused by inappropriate activation of the human complement system. However, marine streptomycetes producing anti-complement agents are still poorly explored. In this study, a marine-derived strain Streptomyces sp. DUT11 showing superior anti-complement activity was focused, and its genome sequence was analyzed. Gene clusters showing high similarities to that of tunicamycin and nonactin were identified, and their corresponding metabolites were also detected. Subsequently, tunicamycin I, V, and VII were isolated from Streptomyces sp. DUT11. Anti-complement assay showed that tunicamycin I, V, VII inhibited complement activation through the classic pathway, whereas no anti-complement activity of nonactin was detected. This is the first time that tunicamycins are reported to have such activity. In addition, genome analysis indicates that Streptomyces sp. DUT11 has the potential to produce novel lassopeptides and lantibiotics. These results suggest that marine Streptomyces are rich sources of anti-complement agents for drug discovery.


Reasons for the observed tropospheric ozone weakening over south-western Europe during COVID-19: Strict lockdown versus the new normal.
In this work we investigate the variation in tropospheric ozone concentrations in south-western Europe in March and April 2020 in the context of COVID-19 disease, and to what extent the former situation was recovered one year after the pandemic outbreak. To carry this study, data from 15 regional background sites in Spain, from 2010 onwards, are used. Historic (2010-2019) and most recent tropospheric ozone concentrations are compared. March and April 2020 ozone concentrations declined over 15% in most cases, rising to 23-28% at sites facing the Mediterranean. Most of the decay was related to the reduction of hemispheric background concentrations, but those sites downwind continental emissions from the Iberian Peninsula and neighbouring countries experienced an additional lessening. By exploring O3 concentrations one year after, March and April 2021, the general decline with respect to 2010-2019 persist but its magnitude was substantially lessened with respect to the strict lockdown period. The pandemic situation unveiled that air pollution is not an endemic matter but it should be tackle with adequate actions. Ozone abatement plans for Mediterranean countries should need a pan-regional covenant in order to drop precursor emissions.


ALT telomeres get together with nuclear receptors.
Nuclear receptors bind chromosome ends in "alternative lengthening of telomeres" (ALT) cancer cells that maintain their ends by homologous recombination instead of telomerase. Marzec et al. now demonstrate that, in ALT cells, nuclear receptors not only trigger distal chromatin associations to mediate telomere-telomere recombination events, but also drive chromosome-internal targeted telomere insertions (TTI).


Neoadjuvant durvalumab plus radiation versus durvalumab alone in stages I-III non-small cell lung cancer: survival outcomes and molecular correlates of a randomized phase II trial.
We previously reported the results of a randomized phase II trial (NCT02904954) in patients with early-stage non-small cell lung cancer (NSCLC) who were treated with either two preoperative cycles of the anti-PD-L1 antibody durvalumab alone or combined with immunomodulatory doses of stereotactic radiation (DRT). The trial met its primary endpoint of major pathological response, which was significantly higher following DRT with no new safety signals. Here, we report on the prespecified secondary endpoint of disease-free survival (DFS) regardless of treatment assignment and the prespecified exploratory analysis of DFS in each arm of the trial. DFS at 2 and 3 years across patients in both arms of the trial were 73% (95% CI: 62.1-84.5) and 65% (95% CI: 52.5-76.9) respectively. For the exploratory endpoint of DFS in each arm of the trial, three-year DFS was 63% (95% CI: 46.0-80.4) in the durvalumab monotherapy arm compared to 67% (95% CI: 49.6-83.4) in the dual therapy arm. In addition, we report post hoc exploratory analysis of progression-free survival as well as molecular correlates of response and recurrence through high-plex immunophenotyping of sequentially collected peripheral blood and gene expression profiles from resected tumors in both treatment arms. Together, our results contribute to the evolving landscape of neoadjuvant treatment regimens for NSCLC and identify easily measurable potential biomarkers of response and recurrence.


Cloning and characterization of mouse intestinal MUC3 mucin: 3' sequence contains epidermal-growth-factor-like domains.
Mucin glycoproteins are a heterogeneous family of high-molecular-mass, heavily glycosylated proteins differentially expressed in epithelial tissue of the gastrointestinal, reproductive and respiratory tracts. We report here the cloning of a mouse caecal mucin (MCM). Amino acid analysis of purified MCM revealed a high content of serine (10.8%) and threonine (25.1%). Antibodies against deglycosylated MCM were prepared for immunohistochemical analysis and for screening a mouse caecal cDNA library. Immunohistochemical analysis showed strong staining of goblet cells and patchy staining of surface columnar cells in the duodenum, small intestine, caecum, colon and rectum. Screening of a mouse caecal cDNA library yielded clones containing tandem repeats of 18 bp with two predominant peptide sequences of TTTADV and TTTVVV. The tandem repeat domain is followed by 1137 bp of non-repetitive sequence and 521 bp of 3' untranslated sequence prior to the poly(A) tail. Two cysteine-rich regions lie within the 3' non-repetitive domain. The arrangement of the cysteines within these regions corresponds to epidermal growth factor-like domains. Following the second cysteine-rich region is a stretch of 19 hydrophobic amino acids which may act as a transmembrane domain or allow for interaction with hydrophobic molecules. Northern blot analysis indicates the mRNA is approximately 13.5 kb with greatest expression in the caecum and lesser amounts in the colon and small intestine. No MCM message is found in mouse stomach, trachea, lung, kidney, oesophagus or pancreas. In situ hybridization studies show that MCM message is expressed at the tips of villi in the intestine and in the upper crypts and surface cells of the caecum and colon. Chromosomal analysis assigns this gene to mouse chromosome 5 in a region of conserved linkage with human chromosome 7, the location of the human MUC3 gene. We conclude that we have identified a mouse caecal mucin which represents the mouse homologue of human MUC3. The mouse MUC3 cDNA sequence suggests that it is a novel non-polymerizing mucin which may participate in membrane or intermolecular interactions through its 3' non-repetitive region.


Predictors of lung cancer: noteworthy cell type differences.
To study risk factors for cell types of lung cancer. Cohort study of 126,293 persons with 1852 subjects with incident cancer. We performed Cox proportional hazards models (8 covariates) to estimate risk of the 4 most numerous specific cell types: adenocarcinoma, squamous cell carcinoma, small cell carcinoma, and bronchioloalveolar carcinoma. Smoking 1 or more cigarette packs per day was a powerful predictor (p < 0.0001) of all cell types, with hazard ratios ranging from 5.8 for bronchioloalveolar to 62.7 for squamous cell carcinoma. Other hazard ratio ranges included male/female from 0.6 (bronchioloalveolar, p < 0.05) to 2.0 (squamous, p < 0.001); black/white from 0.8 (small cell, p < 0.05) to 1.7 (squamous, p < 0.001); Asian/white from 0.8 (small cell) to 1.9 (bronchioloalveolar); and alcohol intake of 3 or more drinks per day from 1.0 (squamous) to 1.5 (adenocarcinoma, p < 0.01). College graduation and increasing body mass index were inversely related to risk of several cell types. Noteworthy sex-specific associations included increased risk of Asian vs white women for adenocarcinoma, squamous cell carcinoma and bronchioloalveolar carcinoma and substantially increased risk of adenocarcinoma in women with alcohol intake of 3 or more drinks per day. These risk factor disparities for lung cancer cell types presumably reflect biologic differences. Future investigation may contribute to increased understanding of tumorigenesis and optimal treatment.


Optically tunable/switchable omnidirectionally spherical microlaser based on a dye-doped cholesteric liquid crystal microdroplet with an azo-chiral dopant.
This paper presents an optically wavelength-tunable and intensity-switchable dye-doped cholesteric liquid crystal (DDCLC) spherical microlaser with an azo-chiral dopant. Experimental results present that two functions of optical control - tunability of lasing wavelength and switchability of lasing intensity - can be obtained for this spherical microlaser at low and high intensity regimes of non-polarized UV irradiation, respectively. If the DDCLC microdroplet is subjected to weak UV irradiation, azo-chiral molecules may transform to the bent cis state at a low concentration rate. The effect can slightly decrease the local order of LCs and thus the helical twisting power of the CLC in the microdroplet. As a result, the CLC pitch may become slightly elongated, which will cause the gradual red-shift of both omnidirectional PBG and lasing emission of the DDCLC spherical microdroplet. In contrast, when the microdroplet is subjected to strong UV irradiation, numerous azo-chiral molecules may simultaneously change to bent cis-isomers to seriously disarrange the helical texture of the CLC, which will quickly deform the PBG and deactivate the lasing emission of the microdroplet. Prolonged irradiation of a blue beam after strong UV irradiation may cause the cis azo-chiral molecules quickly convert back rod-like trans-isomers, which may then regenerate the CLC Bragg onion and PBG structures and reactivate the lasing emission of the microdroplet. Optical control of the DDCLC spherical microlaser is realized on a scale of seconds and minutes when UV irradiation is strong and weak, respectively. The 3D DDCLC spherical microlaser is a highly promising controllable 3D micro-light source or microlaser (e.g., all-optical 3D single photon microlaser) for applications of 3D all-optical integrated photonics, laser displays, and biomedical imaging and therapy, and as a 3D UV microdosagemeter or microsensor.


Diabetes empowerment related to Pender's Health Promotion Model: a meta-synthesis.
Diabetes self-management is a challenge for both clients and health-care professionals. Empowerment plays a vital role in helping clients to achieve successful self-management. This study adopted a meta-ethnographic approach. Nine qualitative studies were synthesized in order to contribute to a deeper understanding of what clients perceive as being important in an effective empowerment strategy for diabetes self-management. Four central metaphors that influenced empowerment were identified: trust in nurses' competence and awareness, striving for control, a desire to share experiences, and nurses' attitudes and ability to personalize. The lines-of-argument synthesis suggested the need for an evaluation system to appraise clients' diabetes knowledge, health beliefs, and negative emotions, as well as the outcome of interventions. Based on Pender's Health Promotion Model, this study emphasizes the fact that health-care professionals need to understand and address modifiable behavior-specific variables. The study suggests that an effective empowerment strategy would be to use activity-related affect, as well as interpersonal and situational influences, as a means of facilitating and enhancing clients' health-promoting behaviors.


Characterization of Long-Term Cultured Murine Submandibular Gland Epithelial Cells.
Human and rat salivary gland cell lines derived from tumors or genetic modification are currently available for research. Here, we attempted to culture and characterize long-term cultured cells spontaneously derived from wild type murine submandibular glands (SGs). SGs were removed from 3-week-old C57B/6J female mice and dissociated by collagenase type 1 and hyaluronidase digestion. Isolated SG epithelial cells were cultured in low calcium, serum-free growth media in the presence of cholera toxin (CT) during early passages. Single-cell colonies were isolated by limiting dilution culture after 25 passages. Early- and late-stage cell cultures were characterized for keratin 14, keratin 18, α-smooth muscle actin, and p63 by immunostaining and quantitative real-time PCR analysis. SG epithelial cells cultured in optimized media maintained their proliferative ability and morphology for over 80 passages. Long-term cultured cells expressed keratin 14, keratin 18, and p63, indicative of an epithelial phenotype. Epithelial cells originating from wild type murine SGs could be cultured for longer periods of time and remain phenotypically similar to ductal basal epithelium.


Pharmacies as providers of expanded health services for people who inject drugs: a review of laws, policies, and barriers in six countries.
People who inject drugs (PWID) are underserved by health providers but pharmacies may be their most accessible care settings. Studies in the U.S., Russia, Vietnam, China, Canada and Mexico employed a three-level (macro-, meso-, and micro-) model to assess feasibility of expanded pharmacy services for PWID. Studies employed qualitative and quantitative interviews, review of legal and policy documents, and information on the knowledge, attitudes, and practices of key stakeholders. Studies produced a mixed assessment of feasibility. Provision of information and referrals by pharmacies is permissible in all study sites and sale and safe disposal of needles/syringes by pharmacies is legal in almost all sites, although needle/syringe sales face challenges related to attitudes and practices of pharmacists, police, and other actors. Pharmacy provision of HIV testing, hepatitis vaccination, opioid substitution treatment, provision of naloxone for drug overdose, and abscess treatment, face more serious legal and policy barriers. Challenges to expanded services for drug users in pharmacies exist at all three levels, especially the macro-level characterized by legal barriers and persistent stigmatization of PWID. Where deficiencies in laws, policies, and community attitudes block implementation, stakeholders should advocate for needed legal and policy changes and work to address community stigma and resistance. Laws and policies are only as good as their implementation, so attention is also needed to meso- and micro- levels. Policies, attitudes, and practices of police departments and pharmacy chains as well as knowledge, attitudes, and practices of individual PWID, individual pharmacies, and police officers should support rather than undermine positive laws and expanded services. Despite the challenges, pharmacies remain potentially important venues for delivering health services to PWID.


Folate Augmentation of Treatment--Evaluation for Depression (FolATED): randomised trial and economic evaluation.
Folate deficiency is associated with depression. Despite the biological plausibility of a causal link, the evidence that adding folate enhances antidepressant treatment is weak. (1) Estimate the clinical effectiveness and cost-effectiveness of folic acid as adjunct to antidepressant medication (ADM). (2) Explore whether baseline folate and homocysteine predict response to treatment. (3) Investigate whether response to treatment depends on genetic polymorphisms related to folate metabolism. FolATED (Folate Augmentation of Treatment - Evaluation for Depression) was a double-blind and placebo-controlled, but otherwise pragmatic, randomised trial including cost-utility analysis. To yield 80% power of detecting standardised difference on the Beck Depression Inventory version 2 (BDI-II) of 0.3 between groups (a 'small' effect), FolATED trialists sought to analyse 358 participants. To allow for an estimated loss of 21% of participants over three time points, we planned to randomise 453. Clinical - Three centres in Wales - North East Wales, North West Wales and Swansea. Trial management - North Wales Organisation for Randomised Trials in Health in Bangor University. Biochemical analysis - University Hospital of Wales, Cardiff. Genetic analysis - University of Liverpool. Four hundred and seventy-five adult patients presenting to primary or secondary care with confirmed moderate to severe depression for which they were taking or about to start ADM, and able to consent and complete assessments, but not (1) folate deficient, vitamin B12 deficient, or taking folic acid or anticonvulsants; (2) misusing drugs or alcohol, or suffering from psychosis, bipolar disorder, malignancy or other unstable or terminal illness; (3) (planning to become) pregnant; or (4) participating in other clinical research. Once a day for 12 weeks experimental participants added 5 mg of folic acid to their ADM, and control participants added an indistinguishable placebo. All participants followed pragmatic management plans initiated by a trial psychiatrist and maintained by their general medical practitioners. Assessed at baseline, and 4, 12 and 25 weeks thereafter, and analysed by 'area under curve' (main); by analysis of covariance at each time point (secondary); and by multi-level repeated measures (sensitivity analysis): Mental health - BDI-II (primary), Clinical Global Impression (CGI), Montgomery-Åsberg Depression Rating Scale (MADRS), UKU side effects scale, and Mini International Neuropsychiatric Interview (MINI) suicidality subscale; General health - UK 12-item Short Form Health Survey (SF-12), European Quality of Life scale - 5 Dimensions (EQ-5D); Biochemistry - serum folate, B12, homocysteine; Adherence - Morisky Questionnaire; Economics - resource use. Folic acid did not significantly improve any of these measures. For example it gained a mean of just 2.9 quality-adjusted life-days [95% confidence interval (CI) from -12.7 to 7.0 days] and saved a mean of just £48 (95% CI from -£292 to £389). In contrast it significantly reduced mental health scores on the SF-12 by 3.0% (95% CI from -5.2% to -0.8%). The FolATED trial generated no evidence that folic acid was clinically effective or cost-effective in augmenting ADM. This negative finding is consistent with improving understanding of the one-carbon folate pathway suggesting that methylfolate is a better candidate for augmenting ADM. Hence the findings of FolATED undermine treatment guidelines that advocate folic acid for treating depression, and suggest future trials of methylfolate to augment ADM. Current Controlled Trials ISRCTN37558856. This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 18, No. 48. See the HTA programme website for further project information.


Bone targeted therapies in advanced breast cancer
Bone targeted therapies are of increasing importance, not only for bone health in the clinical course of breast cancer, but recently also in the adjuvant setting as preventative, anticancer and prognosis-improving agents. It is well established that women with advanced breast cancer receive bisphosphonates or denosumab to prevent therapy-related osteoporosis. As many as 70% of these patients suffer from bone metastases and receive bone targeted agents in order to prevent skeletal related events (SREs), which are debilitating or diminish the quality of life. A number of trials provided guidance, identifying zoledronic acid as the most efficient bisphosphonate, showing that intravenous bisphosphonate administration is superior to oral intake and illustrating the different safety profile of denosumab, which has been reported to be more beneficial than zoledronic acid in delaying the time to first and subsequent (multiple) SREs. New studies have suggested that bone targeted therapies improve rates of overall survival and contribute to preventing recurrence of breast cancer at all sites. Increased bone turnover is both a consequence and a driving factor for tumour growth, expansion, formation of bone lesions and potentially also activation of disseminated tumour cells, leading to bone relapses. We review the current knowledge of bone targeted therapies in advanced breast cancer, with a focus on new insights into their bone-preserving and antitumor activity. Current guidelines, pathology of bone metastasis, mode of action and common side effects have been summarised. We also elaborate on the use of bisphosphonates and denosumab in early breast cancer, during adjuvant therapy with aromatase inhibitors.


N-acetyl-L-cysteine inhibits primary human T cell responses at the dendritic cell level: association with NF-kappaB inhibition.
N-acetyl-L-cysteine (NAC) is an antioxidant molecule endowed with immunomodulatory properties. To investigate the effect of NAC on the induction phase of T cell responses, we analyzed its action on human dendritic cells (DC) derived from adherent PBMC cultured with IL-4 and granulocyte-macrophage CSF. We first found that NAC inhibited the constitutive as well as the LPS-induced activity of the transcription factor NF-kappaB. In parallel, NAC was shown to down-regulate the production of cytokines by DC as well as their surface expression of HLA-DR, CD86 (B7-2), and CD40 molecules both at the basal state and upon LPS activation. NAC also inhibited DC responses induced by CD40 engagement. The inhibitory effects of NAC were not due to nonspecific toxicity as neither the viability of DC nor their mannose receptor-mediated endocytosis were modified by NAC. Finally, we found that the addition of NAC to MLR between naive T cells and allogeneic DC resulted in a profound inhibition of alloreactive responses, which could be attributed to a defect of DC as APC-independent T cell responses were not inhibited by NAC. Altogether, our results suggest that NAC might impair the generation of primary immune responses in humans through its inhibitory action on DC.


Continuous sweep versus discrete step protocols for studying effects of wearable robot assistance magnitude.
Different groups developed wearable robots for walking assistance, but there is still a need for methods to quickly tune actuation parameters for each robot and population or sometimes even for individual users. Protocols where parameters are held constant for multiple minutes have traditionally been used for evaluating responses to parameter changes such as metabolic rate or walking symmetry. However, these discrete protocols are time-consuming. Recently, protocols have been proposed where a parameter is changed in a continuous way. The aim of the present study was to compare effects of continuously varying assistance magnitude with a soft exosuit against discrete step conditions. Seven participants walked on a treadmill wearing a soft exosuit that assists plantarflexion and hip flexion. In Continuous-up, peak exosuit ankle moment linearly increased from approximately 0 to 38% of biological moment over 10 min. Continuous-down was the opposite. In Discrete, participants underwent five periods of 5 min with steady peak moment levels distributed over the same range as Continuous-up and Continuous-down. We calculated metabolic rate for the entire Continuous-up and Continuous-down conditions and the last 2 min of each Discrete force level. We compared kinematics, kinetics and metabolic rate between conditions by curve fitting versus peak moment. Reduction in metabolic rate compared to Powered-off was smaller in Continuous-up than in Continuous-down at most peak moment levels, due to physiological dynamics causing metabolic measurements in Continuous-up and Continuous-down to lag behind the values expected during steady-state testing. When evaluating the average slope of metabolic reduction over the entire peak moment range there was no significant difference between Continuous-down and Discrete. Attempting to correct the lag in metabolics by taking the average of Continuous-up and Continuous-down removed all significant differences versus Discrete. For kinematic and kinetic parameters, there were no differences between all conditions. The finding that there were no differences in biomechanical parameters between all conditions suggests that biomechanical parameters can be recorded with the shortest protocol condition (i.e. single Continuous directions). The shorter time and higher resolution data of continuous sweep protocols hold promise for the future study of human interaction with wearable robots.


Gender and ethnic differences in the control of hyperlipidaemia and other vascular risk factors: insights from the CEntralised Pan-South African survey on tHE Under-treatment of hypercholeSterolaemia (CEPHEUS SA) study.
The aim of the CEntralised Pan-South African survey on tHE Under-treatment of hypercholeSterolaemia (CEPHEUS SA) was to evaluate the current use and efficacy of lipid-lowering drugs (LLDs) in urban patients of different ethnicity with hyperlipidaemia, and to identify possible patient characteristics associated with failure to achieve low-density lipoprotein cholesterol (LDL-C) targets. There is little published data on LDL-C attainment from developing countries. The survey was conducted in 69 study centres in South Africa and recruited consecutive patients who had been prescribed LLDs for at least three months with no dose adjustment for six weeks. All patients provided written consent. One visit was scheduled for data collection, including fasting lipid and glucose, and HbA1c levels. Of the 3 001 patients recruited, 2 996 were included in the final analyses; 1 385 subjects were of Caucasian origin (818 male), 510 of African ancestry (168 male), 481 of mixed ancestry (222 male) and 620 of Asian origin (364 male). Only 60.5% of patients on LLDs for at least three months achieved the LDL-C targets recommended by the NCEP ATP III/2004 updated NCEP ATP III guidelines and 52.3% the fourth JETF/South African guidelines. African females were on average younger than females of other ethnic origins, and had the lowest smoking rates but the highest prevalence of obesity, hypertension, the metabolic syndrome and diabetes mellitus (DM), with the worst glycaemic control. Although women were less likely than men to reach goal [OR 0.65 (CI 0.54-0.77), p < 0.001 for NCEP ATP III guidelines and OR 0.76 (CI 0.64-0.91), p < 0.003 for fourth JETF guidelines], women of African ancestry were just as likely not to reach goal as their Caucasian counterparts. The results of this survey highlight the sub-optimal lipid control achieved in many South African patients, and profile important gender and ethnic differences. Control of cardiovascular disease risk factors across gender and ethnic groups remains poor.


Coagulation and placenta-mediated complications.
Pregnancy is a physiological hypercoagulable state, preparing the mother for the hemostatic challenge of delivery. However, this is associated with an increased risk of venous thrombosis and placenta-mediated complications, which present major challenges for mother and fetus. Although these conditions are heterogeneous in their pathophysiology, hereditary and acquired thrombophilia has been associated with recurrent pregnancy loss and gestational vascular complications, such as early-onset pre-eclampsia and placental abruption. Prevention of such placenta-mediated complications, which collectively complicate up to 15% of pregnancies, is a major issue for women's health. Prospective interventional studies stratified by current knowledge of pathophysiological mechanisms related to placental and systemic hemostatic alterations will impact on the management of pregnancies at risk of these complications.


The risk of bleeding in thrombocytopenic patients with acute myeloid leukemia.
Patients with acute myeloid leukemia are at risk of bleeding. The risk factors for different severities of bleeding are poorly studied. Data from Rebulla et al. were analyzed in an exploratory analysis using multivariate Cox regression analyses for time-to-first bleed with time-depend- ent covariates reflecting measures of clinical and laboratory variables on the previous day. The relationships of the variables with three bleeding categories were studied: mild bleeding (WHO grades 1 and 2) clinically significant (bleeding grades 2, 3 and 4) and severe (bleeding grades 3 and 4). Bleeding of any severity occurred in 149 (58.4%) of 255 patients. There were 743 days of bleeding over 7335 patient-days of observation. Risk factors for mild bleeding included increased body temperature and decreased platelet count; the risk was decreased with administration of antifungal medication or platelet transfusion on the previous day. Risk factors for clinically significant bleeding included grade 1 bleeding on the previous day, decreased platelet count and elevated body temperature. Decreased platelet count and mild bleeding on the previous day were risk factors for severe bleeding. Higher hemoglobin values were associated with a delay in the time-to-first clinically significant bleed. These results support clinical guidelines for increasing the platelet transfusion threshold in the presence of fever and support the use of milder bleeding symptoms as an outcome in clinical trials. The suggestion that hemo- globin concentration maybe predictive of bleeding risk supports the hypothesis that this maybe a valuable intervention in anemic thrombocytopenic patients at high risk of bleeding.


Temporal variability is a personalized feature of the human microbiome.
It is now apparent that the complex microbial communities found on and in the human body vary across individuals. What has largely been missing from previous studies is an understanding of how these communities vary over time within individuals. To the extent to which it has been considered, it is often assumed that temporal variability is negligible for healthy adults. Here we address this gap in understanding by profiling the forehead, gut (fecal), palm, and tongue microbial communities in 85 adults, weekly over 3 months. We found that skin (forehead and palm) varied most in the number of taxa present, whereas gut and tongue communities varied more in the relative abundances of taxa. Within each body habitat, there was a wide range of temporal variability across the study population, with some individuals harboring more variable communities than others. The best predictor of these differences in variability across individuals was microbial diversity; individuals with more diverse gut or tongue communities were more stable in composition than individuals with less diverse communities. Longitudinal sampling of a relatively large number of individuals allowed us to observe high levels of temporal variability in both diversity and community structure in all body habitats studied. These findings suggest that temporal dynamics may need to be considered when attempting to link changes in microbiome structure to changes in health status. Furthermore, our findings show that, not only is the composition of an individual's microbiome highly personalized, but their degree of temporal variability is also a personalized feature.


Vascular effects of bisphosphonates-a systematic review.
Osteoporosis and cardiovascular disease are interconnected entities with pathophysiological similarities. Bisphosphonates are therapeutic options available for resorptive bone diseases; however, experimental evidence has demonstrated a role for bisphosphonates in the inhibition of atherogenesis. A systematic review of the vascular effects of bisphosphonates on atherosclerosis was performed. Vascular effects were evaluated by the thickening of the intima-media of carotid arteries and calcification of the coronary and aorta arteries. Electronic databases PubMed, The Cochrane Library, and Embase from January 1980 to May 2011 were searched. Of 169 potentially relevant articles, 9 clinical trials were selected. Two articles showed the benefit of the use of etidronate (-0.038 mm, P < 0.005) and alendronate (-0.025 mm, P < 0.05) on carotid artery intima-media thickening (CIMT) after one year. One article found no changes associated with the use of alendronate. The use of risedronate was associated with a reduction of plaque score on the carotid arteries (decrease of 1% at 1 year, P = 0.015). Of those studies that evaluated the effect on coronary artery calcification (CAC), the results are conflicting: one study showed no changes with use of etidronate and in another, etidronate resulted in inhibition of the process of CAC after 1 year of follow-up (-372 mm(3) in CAC score, P < 0.01). Three studies showed positive effects of etidronate on the aortic calcificaton (AC) score, showing no effect with use of ibandronate, and another showed a inhibition in the progression of the abdominal AC score with use of risendronate (P = 0.043). Bisphosphonates seem to have an inhibitory effect on the atherosclerotic process; however, larger placebo-controlled studies are needed to better clarify this issue.


Prediction of human population responses to toxic compounds by a collaborative competition.
The ability to computationally predict the effects of toxic compounds on humans could help address the deficiencies of current chemical safety testing. Here, we report the results from a community-based DREAM challenge to predict toxicities of environmental compounds with potential adverse health effects for human populations. We measured the cytotoxicity of 156 compounds in 884 lymphoblastoid cell lines for which genotype and transcriptional data are available as part of the Tox21 1000 Genomes Project. The challenge participants developed algorithms to predict interindividual variability of toxic response from genomic profiles and population-level cytotoxicity data from structural attributes of the compounds. 179 submitted predictions were evaluated against an experimental data set to which participants were blinded. Individual cytotoxicity predictions were better than random, with modest correlations (Pearson's r < 0.28), consistent with complex trait genomic prediction. In contrast, predictions of population-level response to different compounds were higher (r < 0.66). The results highlight the possibility of predicting health risks associated with unknown compounds, although risk estimation accuracy remains suboptimal.


A tailored approach to reduce dose of anti-TNF drugs may be equally effective, but substantially less costly than standard dosing in patients with ankylosing spondylitis over 1 year: a propensity score-matched cohort study.
To compare the effectiveness, safety and costs of standard versus individually tailored reduced doses of anti-tumour necrosis factor (TNF) drugs in patients with ankylosing spondylitis (AS) after achieving low-disease activity. This was a single-centre prospective observational study performed within the ATTRA registry. The anti-TNF dose tapering strategy was chosen by treating physicians, without prespecified protocol. We used propensity score (PS) methodology to identify two cohorts of patients matched for relevant baseline characteristics who were treated with either reduced (n=53) or standard (n=83) doses of TNF inhibitors. One-year outcomes and costs of anti-TNF drugs were compared between both PS-matched cohorts. In the reduced dosing group, the median dose of TNF inhibitor corresponded to 0.67 and 0.5 of the standard dose initially and at 12 months respectively, and 21% of patients required return to standard dosing regimen. The mean change per year in Bath Ankylosing Spondylitis Activity Index, C-reactive protein , Health Assessment Questionnaire Disability Index and Bath AS functional index, as well as quality-adjusted life-year area under the curve were no different between both groups. The HR (95% CI) of reduced versus standard dosing group for relapse and any adverse event was 1.46 (0.66 to 3.19) and 0.56 (0.22 to 1.44), respectively. Mean difference (95% CI) in cost of anti-TNF drugs was €-4214 (-4707 to -3701) per year of treatment in favour of reduced dosing strategy. In patients with AS after reaching low-disease activity, a tailored approach to reduce doses of anti-TNF drugs produced similar clinical outcomes at 1 year, but was substantially less costly.


A single serine residue at position 375 of VP16 is critical for complex assembly with Oct-1 and HCF and is a target of phosphorylation by casein kinase II.
We show that VP16 is phosphorylated by cellular kinases in vivo and in vitro and map the major sites of phosphorylation to be on serines towards the C-terminus, downstream of position 370 in both cases. Deletion of the acidic activation domain had no effect on phosphorylation, refining the sites to between position 370 and 411. Within VP16, the C-terminal boundary for complex formation with Oct-1 and HCF lies at position 388, and between 370 and 388 lies one serine, at position 375. This is a consensus casein kinase II (CKII) site and, using purified wild-type and mutant proteins, we show that it is the main CKII site in the body of the N-terminal complex-forming region. This site is also phosphorylated in nuclear extracts. Although other sites, mainly Ser411, are also phosphorylated by nuclear kinase(s), the single substitution of Ser375 to alanine abolishes CKII phosphorylation in vitro and virtually eliminates complex formation. This serine lies in a surface-exposed region of VP16 and, although complex formation is disrupted, other activities of the mutant are unaffected. Ser375 is also required in vivo where substitution to alanine abolishes transactivation, while replacement with threonine restores normal levels of activity.


Treatment of depression in adults with cancer: a systematic review of randomized controlled trials.
Depression is a leading cause of disease burden worldwide and is especially problematic in people with chronic diseases, including cancer. Although depression can be effectively treated in the general population using antidepressant medication and psychological treatments, these treatments may have different benefits and harms in cancer patients. Previous reviews have not adequately addressed this topic. We therefore aimed to determine which, if any, treatments are effective for patients with diagnoses of both cancer and depression. We conducted a systematic review of relevant randomized controlled trials identified through searches of Medline, EMBASE, PsycINFO and The Cochrane Central Register of Controlled Trials (CENTRAL). Seven relatively small trials met the selection criteria. These provided some evidence that antidepressant medication, given alone or in combination with a psychological treatment, may be effective. We found no good evidence for psychological treatments given alone or for any other forms of treatment. There is very limited evidence from clinical trials to guide the treatment of cancer patients with a diagnosis of depression, especially for psychological treatments. High quality trials of treatments for depression in patients with cancer are urgently needed.


Developing a good practice model to evaluate the effectiveness of comprehensive primary health care in local communities.
This paper describes the development of a model of Comprehensive Primary Health Care (CPHC) applicable to the Australian context. CPHC holds promise as an effective model of health system organization able to improve population health and increase health equity. However, there is little literature that describes and evaluates CPHC as a whole, with most evaluation focusing on specific programs. The lack of a consensus on what constitutes CPHC, and the complex and context-sensitive nature of CPHC are all barriers to evaluation. The research was undertaken in partnership with six Australian primary health care services: four state government funded and managed services, one sexual health non-government organization, and one Aboriginal community controlled health service. A draft model was crafted combining program logic and theory-based approaches, drawing on relevant literature, 68 interviews with primary health care service staff, and researcher experience. The model was then refined through an iterative process involving two to three workshops at each of the six participating primary health care services, engaging health service staff, regional health executives and central health department staff. The resultant Southgate Model of CPHC in Australia model articulates the theory of change of how and why CPHC service components and activities, based on the theory, evidence and values which underpin a CPHC approach, are likely to lead to individual and population health outcomes and increased health equity. The model captures the importance of context, the mechanisms of CPHC, and the space for action services have to work within. The process of development engendered and supported collaborative relationships between researchers and stakeholders and the product provided a description of CPHC as a whole and a framework for evaluation. The model was endorsed at a research symposium involving investigators, service staff, and key stakeholders. The development of a theory-based program logic model provided a framework for evaluation that allows the tracking of progress towards desired outcomes and exploration of the particular aspects of context and mechanisms that produce outcomes. This is important because there are no existing models which enable the evaluation of CPHC services in their entirety.


Mobilization of Ca2+ by thapsigargin and 2,5-di-(t-butyl)-1,4-benzohydroquinone in permeabilized insulin-secreting RINm5F cells: evidence for separate uptake and release compartments in inositol 1,4,5-trisphosphate-sensitive Ca2+ pool.
We characterized and directly compared the Ca(2+)-releasing actions of two inhibitors of endoplasmic-reticulum (ER) Ca(2+)-ATPase, thapsigargin and 2,5-di-(t-butyl)-1,4-benzohydroquinone (tBuBHQ), in electropermeabilized insulin-secreting RINm5F cells. Ambient free calcium concentration ([Ca2+]) was monitored by Ca(2+)-selective mini-electrodes. After ATP-dependent Ca2+ uptake, thapsigargin and tBuBHQ released Ca2+ with and EC50 of approximately 37 nM and approximately 2 microM respectively. Both agents mobilized Ca2+ predominantly from the Ins(1,4,5)P3-sensitive Ca2+ pool, and in this respect thapsigargin was more specific than tBuBHQ. The total increase in [Ca2+] obtained with thapsigargin and Ins(1,4,5)P3 was, on the average, only 7% greater than that with Ins(1,4,5)P3 alone. In contrast, the total increase in [Ca2+] obtained with tBuBHQ and Ins(1,4,5)P3 was 33% greater than that obtained with only InsP3 (P < 0.05). Although Ca2+ was rapidly mobilized by thapsigargin and tBuBHQ, complete depletion of the Ins(1,4,5)P3-sensitive Ca2+ pool was difficult to achieve. After the release by thapsigargin or tBuBHQ, Ins(1,4,5)P3 induced additional Ca2+ release. The additional Ins(1,4,5)P3-induced Ca2+ release was not altered by supramaximal concentrations of thapsigargin and tBuBHQ, or by Bafilomycin A1, an inhibitor of V-type ATPases, but was decreased by prolonged treatment with the ER Ca(2+)-ATPase inhibitors. These results suggest the existence of distinct uptake and release compartments within the Ins(1,4,5)P3-sensitive Ca2+ pool. When treated with the inhibitors, the two compartments became distinguishable on the basis of their Ca2+ permeability. Apparently, thapsigargin and tBuBHQ readily mobilized Ca2+ from the uptake compartment, whereas Ca2+ from the release compartment could be mobilized only very slowly, in the absence of Ins(1,4,5)P3.


Comparative treatment of mares susceptible to chronic uterine infection.
Four intrauterine treatment strategies were evaluated for effectiveness in mares that were confirmed to be susceptible to chronic uterine infection. Pretreatment samples were obtained at detection of estrus, and a genital strain of Streptococcus zooepidemicus was infused into the uterus when a preovulatory (> 35 mm) follicle was detected. At 12 hours after inoculation, mares were assigned to 1 of 4 selected treatment groups: autologous plasma, 100 ml (n = 5); potassium penicillin, 5 million U in 100 ml of phosphate-buffered saline solution (PBSS; n = 5); 10 mg of prostaglandin F2 alpha in 100 ml of PBSS (n = 5)' and large-volume lavage with normal saline solution (1,000 ml increments). A fifth group, treated with vehicle alone (100 ml of PBSS), served as a negative control (n = 7). All treatments were administered into the uterus. To assess the effectiveness of the treatment, samples for culture and cytologic examination were collected at 96 hours after bacterial inoculation. An effect of treatment was observed on the number of uterine neutrophils (P = 0.02) and growth of S zooepidemicus (P < 0.01). Intrauterine treatment with potassium penicillin, prostaglandin F2 alpha, and large-volume uterine lavage significantly reduced the growth of S zooepidemicus (P < 0.01) as well as the number of neutrophils (P < 0.02). Autologous plasma reduced the number of neutrophils (P < 0.05), but not growth of S zooepidemicus. There was significant correlation between the number of uterine neutrophils and growth of S zooepidemicus for each treatment group (r = 0.57; P < 0.05).


Species response to environmental change: impacts of food web interactions and evolution.
How environmental change affects species abundances depends on both the food web within which species interact and their potential to evolve. Using field experiments, we investigated both ecological and evolutionary responses of pea aphids (Acyrthosiphon pisum), a common agricultural pest, to increased frequency of episodic heat shocks. One predator species ameliorated the decrease in aphid population growth with increasing heat shocks, whereas a second predator did not, with this contrast caused by behavioral differences between predators. We also compared aphid strains with stably inherited differences in heat tolerance caused by bacterial endosymbionts and showed the potential for rapid evolution for heat-shock tolerance. Our results illustrate how ecological and evolutionary complexities should be incorporated into predictions of the consequences of environmental change for species' populations.


Chemoprevention of bladder cancer.
The data presented herein, although highly supportive for a protective role of various nutrients against bladder cancer, are far from definitive. Many authorities question the validity of current recommendations for nutritional chemoprevention against bladder cancer. The reason for the wide variations reported in epidemiologic studies lies in the nature of observational studies. Dietary studies are limited in their conclusions because the protection afforded by the consumption of a particular nutrient may be multifactorial, with different components of the food exerting potential chemopreventive effects. Furthermore, measuring levels of nutrients in the food intake of populations is confounded by factors that might affect these levels and also the incidence of cancer. For example, vitamin A can come from animal or vegetarian sources. Because animal fat has been identified as a potential carcinogen in man, depending on the source of the vitamin, varying levels of protection might be deduced. In addition, chemoprevention studies using dietary supplements are expected to have mild effects, and large studies would be required to confirm statistical significance. Even with agents such as intravesical chemotherapy, only half the studies achieve statistical significance [29]. Prospective randomized trials with a large sample size, longer follow-up, and an extended duration of treatment are needed to clarify the association between micronutrients and cancer protection. With these caveats in mind, several recommendations can be made. Simple measures, such as drinking more fluids (especially water), can have a profound impact on the incidence of bladder cancer. Vitamins are being extensively studied in chemopreventive trials for different cancers. There is strong evidence for a chemoprotective effect of vitamin A in bladder cancer. The authors recommend 32,000 IU/day of vitamin A initially, with lower doses (24,000 IU) for persons less than 50 kg. Because liver toxicity is a possibility with long-term administration, the dose should be decreased to 16,000 IU after 3 years. High doses of beta-carotene should be avoided based on a large clinical trial reporting a 25% increase in the number of cases of prostate cancer and a statistically significant increase in the incidence of lung cancer. Vitamin B6 has been studied in several clinical trials in bladder cancer. The US-based Veterans Administration cooperative study found benefit for vitamin B6 when given as a single agent. Data for vitamins C and E are insufficient to recommend either agent as stand-alone treatment. Nonetheless, each of these vitamins is known to have beneficial effects, including improved function of the immune system. It is possible that only a small percentage of patients with bladder cancer respond to vitamins B6, C, or E, yet each is safe, nontoxic, and inexpensive. In an effort to pool the efficacy of individual agents and to increase the power of study, the authors evaluated the combination of vitamins A, B6, C, and E in a double-blind trial. The observed 50% 5-year reduction in tumor recurrence was highly significant and greater than would be expected for any of the individual ingredients and suggests that combinations of nutritional agents may be most appropriate. A large-volume study along similar lines is being conducted. Among the numerous other compounds and dietary substances purported to have chemopreventive effect, soybeans, garlic, and green tea stand out as having the greatest promise and can freely be recommended to patients. For synthetically synthesized agents such as celecoxib, piroxicam, or DFMO, recommendations must be deferred until the results of clinical trials are conclusively in favor of their use. Many of the dietary factors found to be protective against bladder cancer are being investigated in other cancers and are beneficial to general health. Although naturally occurring nutrients are ideal, especially because the delicate balance of various micronutrients might be impossible to synthesize in the laboratory, the general population finds it easier to take vitamin supplements. Unfortunately, dietary changes such as decreasing fat and increasing fruit and vegetable intake are more difficult to initiate. There is a mistaken notion that simply because an agent is naturally occurring, it cannot be as beneficial as taking a substance synthesized in the laboratory. Even in a high-risk group such as nuclear-bomb survivors in Japan, high consumption of vegetables and fruit is protective against bladder cancer [44]. Encouraging patients to follow an essentially healthy food habit lifestyle will be a significant contribution in the fight against cancer.


Airborne pollen trends in the Iberian Peninsula.
Airborne pollen monitoring is an effective tool for studying the reproductive phenology of anemophilous plants, an important bioindicator of plant behavior. Recent decades have revealed a trend towards rising airborne pollen concentrations in Europe, attributing these trends to an increase in anthropogenic CO2 emissions and temperature. However, the lack of water availability in southern Europe may prompt a trend towards lower flowering intensity, especially in herbaceous plants. Here we show variations in flowering intensity by analyzing the Annual Pollen Index (API) of 12 anemophilous taxa across 12 locations in the Iberian Peninsula, over the last two decades, and detecting the influence of the North Atlantic Oscillation (NAO). Results revealed differences in the distribution and flowering intensity of anemophilous species. A negative correlation was observed between airborne pollen concentrations and winter averages of the NAO index. This study confirms that changes in rainfall in the Mediterranean region, attributed to climate change, have an important impact on the phenology of plants.


The role of collagen crosslinks in ageing and diabetes - the good, the bad, and the ugly.
The non-enzymatic reaction of proteins with glucose (glycation) is a topic of rapidly growing importance in human health and medicine. There is increasing evidence that this reaction plays a central role in ageing and disease of connective tissues. Of particular interest are changes in type-I collagens, long-lived proteins that form the mechanical backbone of connective tissues in nearly every human organ. Despite considerable correlative evidence relating extracellular matrix (ECM) glycation to disease, little is known of how ECM modification by glucose impacts matrix mechanics and damage, cell-matrix interactions, and matrix turnover during aging. More daunting is to understand how these factors interact to cumulatively affect local repair of matrix damage, progression of tissue disease, or systemic health and longevity. This focused review will summarize what is currently known regarding collagen glycation as a potential driver of connective tissue disease. We concentrate attention on tendon as an affected connective tissue with large clinical relevance, and as a tissue that can serve as a useful model tissue for investigation into glycation as a potentially critical player in tissue fibrosis related to ageing and diabetes.


Extending the search for neutrino point sources with IceCube above the horizon.
Point source searches with the IceCube neutrino telescope have been restricted to one hemisphere, due to the exclusive selection of upward going events as a way of rejecting the atmospheric muon background. We show that the region above the horizon can be included by suppressing the background through energy-sensitive cuts. This improves the sensitivity above PeV energies, previously not accessible for declinations of more than a few degrees below the horizon due to the absorption of neutrinos in Earth. We present results based on data collected with 22 strings of IceCube, extending its field of view and energy reach for point source searches. No significant excess above the atmospheric background is observed in a sky scan and in tests of source candidates. Upper limits are reported, which for the first time cover point sources in the southern sky up to EeV energies.


Obesity and incidence of lung cancer: a meta-analysis.
To date, the relationship between obesity and the incidence of lung cancer remains unclear and inconclusive. Thus, we conducted a meta-analysis of published studies to provide a quantitative evaluation of this association. Relevant studies were identified through PubMed and EMBASE databases from 1966 to December 2011, as well as through the reference lists of retrieved articles. A total of 31 articles were included in this meta-analysis. Overall, excess body weight (body mass index, BMI ≥ 25 kg/m(2)) was inversely associated with lung cancer incidence (relative risk, RR = 0.79; 95% confidence interval, CI: 0.73-0.85) compared with normal weight (BMI = 18.5-24.9 kg/m(2)). The association did not change with stratification by sex, study population, study design, and BMI measurement method. However, when stratified by smoking status, the inverse association between excess body weight and lung cancer incidence in current (RR = 0.63, 95% CI: 0.57-0.70) and former (RR = 0.73, 95% CI: 0.58-0.91) smokers was strengthened. In non-smokers, the association was also statistically significant (RR = 0.83, 95% CI: 0.70-0.98), although the link was weakened to some extent. The stratified analyses also showed that excess body weight was inversely associated with squamous cell carcinoma (RR = 0.68, 95% CI: 0.58-0.80) and adenocarcinoma (RR = 0.79, 95% CI: 0.65-0.96). No statistically significant link was found between excess body weight and small cell carcinoma (RR = 0.99, 95% CI: 0.66-1.48). The results of this meta-analysis indicate that overweight and obesity are protective factors against lung cancer, especially in current and former smokers.


A lanthanide-titanium (LnTi11) oxo-cluster, a potential molecule based fluorescent labelling agent and photocatalyst.
Although a lot of titanium oxo-clusters (TOCs) have been synthesized and characterized, research studies on their application properties are still limited. The work described here is not only aimed at the synthesis and crystal structures of the TOCs, but also aimed at exploration of their potential applications in molecule based fluorescence labelling and photocatalysis. Three heterometallic TOC compounds with lanthanide (Ln) elements Sm(iii) (1), Eu(iii) (2) and Gd(iii) (3) are prepared and their cluster structures are characterized as LnTi11 cages. Compound 2 exhibits the characteristic fluorescence of Eu(iii) and the emission intensity can be decreased upon irradiation and recovered by air oxidation, which is attributed to the energy transfer between Eu(iii) and photo-induced Ti(iii) of the oxo-TiO cluster. The fluorescence intensity of 2 can be significantly increased when treated with 1,10-phenanthroline. The catalytic properties of 2 were determined by the degradation of dyes on a paper substrate. Compound 2 has potential applications as a molecule based fluorescent labelling agent and photodegeneration catalyst.


Nanogram amounts of salicylic acid produced by the rhizobacterium Pseudomonas aeruginosa 7NSK2 activate the systemic acquired resistance pathway in bean.
Root colonization by specific nonpathogenic bacteria can induce a systemic resistance in plants to pathogen infections. In bean, this kind of systemic resistance can be induced by the rhizobacterium Pseudomonas aeruginosa 7NSK2 and depends on the production of salicylic acid by this strain. In a model with plants grown in perlite we demonstrated that Pseudomonas aeruginosa 7NSK2-induced resistance is equivalent to the inclusion of 1 nM salicylic acid in the nutrient solution and used the latter treatment to analyze the molecular basis of this phenomenon. Hydroponic feeding of 1 nM salicylic acid solutions induced phenylalanine ammonia-lyase activity in roots and increased free salicylic acid levels in leaves. Because pathogen-induced systemic acquired resistance involves similar changes it was concluded that 7NSK2-induced resistance is mediated by the systemic acquired resistance pathway. This conclusion was validated by analysis of phenylalanine ammonia-lyase activity in roots and of salicylic acid levels in leaves of soil-grown plants treated with Pseudomonas aeruginosa. The induction of systemic acquired resistance by nanogram amounts of salicylic acid is discussed with respect to long-distance signaling in systemic acquired resistance.


Policies to sustain the nursing workforce: an international perspective.
Examine metrics and policies regarding nurse workforce across four countries. International comparisons inform health policy makers. Data from the OECD were used to compare expenditure, workforce and health in: Australia, Portugal, the United Kingdom (UK) and the United States (US). Workforce policy context was explored. Public spending varied from less than 50% of gross domestic product in the US to over 80% in the UK. Australia had the highest life expectancy. Portugal has fewer nurses and more physicians. The Australian national health workforce planning agency has increased the scope for co-ordinated policy intervention. Portugal risks losing nurses through migration. In the UK, the economic crisis resulted in frozen pay, reduced employment, and reduced student nurses. In the US, there has been limited scope to develop a significant national nursing workforce policy approach, with a continuation of State based regulation adding to the complexity of the policy landscape. The US is the most developed in the use of nurses in advanced practice roles. Ageing of the workforce is likely to drive projected shortages in all countries. There are differences as well as variation in the overall impact of the global financial crisis in these countries. Future supply of nurses in all four countries is vulnerable. Work force planning is absent or restricted in three of the countries. Scope for improved productivity through use of advanced nurse roles exists in all countries.


Seroprevalence of Rift Valley fever and lumpy skin disease in African buffalo (Syncerus caffer) in the Kruger National Park and Hluhluwe-iMfolozi Park, South Africa.
Rift Valley fever and lumpy skin disease are transboundary viral diseases endemic in Africa and some parts of the Middle East, but with increasing potential for global emergence. Wild ruminants, such as the African buffalo (Syncerus caffer), are thought to play a role in the epidemiology of these diseases. This study sought to expand the understanding of the role of buffalo in the maintenance of Rift Valley fever virus (RVFV) and lumpy skin disease virus (LSDV) by determining seroprevalence to these viruses during an inter-epidemic period. Buffaloes from the Kruger National Park (n = 138) and Hluhluwe-iMfolozi Park (n = 110) in South Africa were sampled and tested for immunoglobulin G (IgG) and neutralising antibodies against LSDV and RVFV using an indirect enzyme-linked immunosorbent assay (I-ELISA) and the serum neutralisation test (SNT). The I-ELISA for LSDV and RVFV detected IgG antibodies in 70 of 248 (28.2%) and 15 of 248 (6.1%) buffaloes, respectively. Using the SNT, LSDV and RVFV neutralising antibodies were found in 5 of 66 (7.6%) and 12 of 57 (21.1%), respectively, of samples tested. The RVFV I-ELISA and SNT results correlated well with previously reported results. Of the 12 SNT RVFV-positive sera, three (25.0%) had very high SNT titres of 1:640. Neutralising antibody titres of more than 1:80 were found in 80.0% of the positive sera tested. The LSDV SNT results did not correlate with results obtained by the I-ELISA and neutralising antibody titres detected were low, with the highest (1:20) recorded in only two buffaloes, whilst 11 buffaloes (4.4%) had evidence of co-infection with both viruses. Results obtained in this study complement other reports suggesting a role for buffaloes in the epidemiology of these diseases during inter-epidemic periods.


Worry, Risk Perception, and Controllability Predict Intentions Toward COVID-19 Preventive Behaviors.
The ongoing pandemic of COVID-19 has already had serious worldwide health, socio-economic, political, and educational consequences. In the present study, we investigated what factors can motivate young adults to comply with the recommended preventive measures against coronavirus infection. Even though young people are less likely to suffer severe medical consequences from the virus, they can still transmit it to more vulnerable individuals. Surprisingly, we found no significant effects of previously successful experimental manipulations (e.g., enhancing self-efficacy, and visual aids) that aimed to improve risk understanding and impact COVID-19 related behavioral intentions. Instead, intentions toward preventive behaviors were predicted by self-reported worry, perceived controllability of the pandemic, and risk perception. Interestingly, worry about health, and worry about restricting personal freedom predicted behavioral intentions in diverging directions. In particular, participants who were worried about health, were more willing to obey strict hygiene and social distancing restrictions. In contrast, participants who were worried about personal restrictions, were less ready to adopt these preventive actions.


Defective mismatch repair, microsatellite mutation bias, and variability in clinical cancer phenotypes.
Microsatellite instability is associated with 10% to 15% of colorectal, endometrial, ovarian, and gastric cancers, and has long been used as a diagnostic tool for hereditary nonpolyposis colorectal carcinoma-related cancers. Tumor-specific length alterations within microsatellites are generally accepted to be a consequence of strand slippage events during DNA replication, which are uncorrected due to a defective postreplication mismatch repair (MMR) system. Mutations arising within microsatellites associated with critical target genes are believed to play a causative role in the evolution of MMR-defective tumors. In this review, we summarize current evidence of mutational biases within microsatellites arising as a consequence of intrinsic DNA sequence effects as well as variation in MMR efficiency. Microsatellite mutational biases are generally not considered during clinical testing; however, we suggest that such biases may be clinically significant as a factor contributing to phenotypic variation among microsatellite instability-positive tumors.


Factors affecting adherence with treatment advice in a clinical trial of patients with severe asthma.
Understanding why patients with severe asthma do not follow healthcare provider (HCP) advice to adjust treatment is critical to achieving personalised disease management. We reviewed patient choice to follow HCP advice to adjust asthma treatment in a UK-based randomised, controlled, single-blind (study participant), multicentre, parallel group 48-week clinical study comparing biomarker-directed treatment adjustment with standard care in severe asthma. Of 1572 treatment advisories (291 participants), instructions were followed in 1377 cases (87.6%). Patients were more likely to follow advice to remain on treatment (96.7%) than to either reduce (70.3%) or increase (67.1%) their treatment, with 64% of patients following all treatment advice. Multivariate analysis associated belonging to an ethnic minority group (OR 3.10, 95% CI 1.68-5.73) and prior study medication changes (two or more changes: OR 2.77, 95% CI 1.51-5.10) with failure to follow treatment advice. In contrast, emergency room attendance in the prior year (OR 0.54, 95% CI 0.32-0.92) was associated with following treatment advice. The largest effect was seen with transition onto or off oral corticosteroids (OR 29.28, 95% CI 16.07-53.36) when compared with those requested to maintain treatment. Centre was also an important determinant regarding the likelihood of patients to follow treatment advice. Belonging to an ethnic minority group and multiple prior treatment adjustments were associated with not following HCP treatment advice. Patients also responded differently to HCP advice across UK specialist centres. These findings have implications for the generalisability of models of care in severe asthma and require further focused studies.


Intermolecular effect in molecular electronics.
We investigate the effects of lateral interactions on the conductance of two molecules connected in parallel to semi-infinite leads. The method we use combines a Green function approach to quantum transport with density functional theory for the electronic properties. The system, modeled after a self-assembled monolayer, consists of benzylmercaptane molecules sandwiched between gold electrodes. We find that the conductance increases when intermolecular interaction comes into play. The source of this increase is the indirect interaction through the gold substrate rather than direct molecule-molecule interaction. A striking resonance is produced only 0.3 eV above the Fermi energy.


Minimally invasive parathyroidectomy with or without intraoperative parathyroid hormone for primary hyperparathyroidism.
The improvement of intraoperative parathyroid hormone (IOPTH) assay and localization studies has enabled a minimally invasive parathyroidectomy (MIP) in primary hyperparathyroidism (pHPT). The aim of this study is to analyze the demographics, clinical presentations, and surgical outcomes of the pHPT patients who received surgical management with versus without IOPTH. Analysis of a database was performed on 53 patients who underwent parathyroidectomy for pHPT from 2004 to 2013. Preoperative localization was done by both sestamibi scan and ultrasonography. We divided the patients into two groups (without IOPTH versus with IOPTH) and analyzed the surgical outcomes statistically between two groups. The concordance rate of Technetium 99m sestamibi scan and ultrasonography was 73.6% and 90.6%, respectively. The overall cure rate of group 1 (without IOPTH) was 94.9% and that of group 2 (with IOPTH) was 100%. The decline of PTH at postoperative 5 minutes and 10 minutes was 75.2% ± 14.9% and 84.9% ± 8.6% in cured patients. On the other hand, that of noncured patients at 5 minutes and 10 minutes was 17.2% ± 9.7% and 8.2% ± 2.2%. There was a significant difference in the drop rate of IOPTH between cured and persistent patients (P < 0.01). Pathological examination showed adenoma in 41 of 53 patients (77.4%) and hyperplasia in 10 of 53 patients (18.9%). Even though the localization studies were successful, IOPTH monitoring is essential to avoid a surgical failure in MIP.


Prostate cancer induces C/EBPβ expression in surrounding epithelial cells which relates to tumor aggressiveness and patient outcome.
Implantation of rat prostate cancer cells into the normal rat prostate results in tumor-stimulating adaptations in the tumor-bearing organ. Similar changes are seen in prostate cancer patients and they are related to outcome. One gene previously found to be upregulated in the non-malignant part of tumor-bearing prostate lobe in rats was the transcription factor CCAAT/enhancer-binding protein-β (C/EBPβ). To explore this further, we examined C/EBPβ expression by quantitative RT-PCR, immunohistochemistry, and Western blot in normal rat prostate tissue surrounding slow-growing non-metastatic Dunning G, rapidly growing poorly metastatic (AT-1), and rapidly growing highly metastatic (MatLyLu) rat prostate tumors-and also by immunohistochemistry in a tissue microarray (TMA) from prostate cancer patients managed by watchful waiting. In rats, C/EBPβ mRNA expression was upregulated in the surrounding tumor-bearing prostate lobe. In tumors and in the surrounding non-malignant prostate tissue, C/EBPβ was detected by immunohistochemistry in some epithelial cells and in infiltrating macrophages. The magnitude of glandular epithelial C/EBPβ expression in the tumor-bearing prostates was associated with tumor size, distance to the tumor, and metastatic capacity. In prostate cancer patients, high expression of C/EBPβ in glandular epithelial cells in the surrounding tumor-bearing tissue was associated with accumulation of M1 macrophages (iNOS+) and favorable outcome. High expression of C/EBPβ in tumor epithelial cells was associated with high Gleason score, high tumor cell proliferation, metastases, and poor outcome. This study suggest that the expression of C/EBP-beta, a transcription factor mediating multiple biological effects, is differentially expressed both in the benign parts of the tumor-bearing prostate and in prostate tumors, and that alterations in this may be related to patient outcome.


Interleukin-2 is present in human blood vessels and released in biologically active form by heparanase.
Interleukin-2 (IL-2) is a multifaceted cytokine with immunostimulatory and immunosuppressive properties. Our laboratory recently demonstrated that the availability of IL-2 is regulated, in part, by association with perlecan, a heparan sulfate proteoglycan. Given the abundance of perlecan in blood vessels, we asked whether IL-2 is present in vessel walls. Our results indicate that IL-2 is associated with endothelial and smooth muscle cells within the human arterial wall. This IL-2 is released by heparanase, and promotes the proliferation of an IL-2-dependent cell line. Given the presence of IL-2 in human arteries, we asked whether the large vessels of IL-2-deficient mice were normal. The aortas of IL-2-deficient mice exhibited a loss of smooth muscle cells, suggesting that IL-2 may contribute to their survival. In their entirety, these results suggest a here-to-fore unrecognized role of IL-2 in vascular biology, and have significant implications for both the immune and cardiovascular systems.


Thermography--a feasible method for screening breast cancer?
Potential use of thermography for more effective detection of breast carcinoma was evaluated on 26 patients scheduled for breast carcinoma surgery. Ultrasonographic scan, mammography and thermography were performed at the University Hospital for Tumors. Thermographic imaging was performed using a new generation of digital thermal cameras with high sensitivity and resolution (ThermoTracer TH7102WL, NEC). Five images for each patient were recorded: front, right semi-oblique, right oblique, left- semi oblique and left oblique. While mammography detected 31 changes in 26 patients, thermography was more sensitive and detected 6 more changes in the same patients. All 37 changes were subjected to the cytological analysis and it was found that 16 of samples were malignant, 8 were suspected malignant and 11 were benign with atypia or proliferation while only 2 samples had benign findings. The pathohistological method (PHD) recorded 75.75% malignant changes within the total number of samples. Statistical analysis of the data has shown a probability of a correct mammographic finding in 85% of the cases (sensitivity of 85%, specificity of 84%) and a probability of a correct thermographic finding in 92% of the cases (sensitivity of 100%, specificity of 79%). As breast cancer remains the most prevalent cancer in women and thermography exhibited superior sensitivity, we believe that thermography should immediately find its place in the screening programs for early detection of breast carcinoma, in order to reduce the sufferings from this devastating disease.


Glucose-lowering therapies, adequacy of metabolic control, and their relationship with comorbid depression in outpatients with type 2 diabetes in a tertiary hospital in Kenya.
Depression and diabetes mellitus are important comorbid conditions with serious health consequences. When depression and diabetes are comorbid, depression negatively affects self-management activities of diabetes with serious consequences. Relationship between treatment regimens of diabetes, the adequacy of glycemic control, and occurrence of comorbid depression is not known among our patients. This was a cross-sectional descriptive study at the outpatient diabetes clinic of the Kenyatta National Hospital where 220 ambulatory patients with type 2 diabetes on follow-up were systematically sampled. Sociodemographic data and clinical information were documented. The Patient Health Questionnaire-9 (PHQ-9) was used to assess depression. Ethylenediaminetetraacetic acid-anticoagulated blood was used for glycated hemoglobin (HbA1C) assay on automated system, COBAS INTEGRA machine. Two hundred twenty patients with type 2 diabetes were enrolled. The prevalence of comorbid depression by PHQ-9 was 32.3% (95% confidence interval: 26.4%-38.6%). The majority, 69.5%, had poor glycemic control, HbA1C >7.0%, mean HbA1C was 8.9%±2.4%. Half, 50.4%, of the study subjects were on insulin-containing regimens. Over 8% (84.5%) of the participants with comorbid depression had poor glycemic control, which worsened with increasing severity of depression. There was significant correlation between comorbid depression and poor glycemic control, which is more consistent in the insulin-treated patients. However, patients on oral agents only, both with and without comorbid depression, were similar in their glycemic control. Among our type 2 diabetic population with comorbid depression, a large proportion had poor glycemic control, which worsened with increasing severity of depression. The insulin treatment increased the odds of comorbid depression and poor glycemic control in patients. It is justifiable to screen for comorbid depression in patients with type 2 diabetes who are in poor glycemic control, especially the insulin-treated, and then provide specific and appropriate interventions that are necessary to optimize their metabolic outcomes.


High-resolution linkage mapping for susceptibility genes in human polygenic disease: insulin-dependent diabetes mellitus and chromosome 11q.
Insulin-dependent diabetes mellitus (IDDM) has a complex pattern of genetic inheritance. In addition to genes mapping to the major histocompatibility complex (MHC), several lines of evidence point to the existence of other genetic susceptibility factors. Recent studies of the nonobese diabetic mouse (NOD) model of IDDM have suggested the presence, on mouse chromosome 9, of a susceptibility gene linked to the locus encoding the T-cell antigen, Thy-1. A region on human chromosome 11q is syntenic to this region on mouse chromosome 9. We have used a set of polymorphic DNA markers from chromosome 11q to investigate this region for linkage to a susceptibility gene in 81 multiplex diabetic pedigrees. The data were investigated by maximization of lod scores over genetic models and by multiple-locus affected-sib-pair analysis. We were able to exclude the presence of a susceptibility gene (location scores less than -2) throughout greater than 90% of the chromosome 11q homology region, under the assumption that the susceptibility factor would cause greater than 50% of affected sib pairs to share two alleles identical by descent. Theoretical estimates of the power to map susceptibility genes with a high-resolution map of linked markers in a candidate region were made, using HLA as a model locus. This result illustrates the feasibility that IDDM linkage studies using mapped sets of polymorphic DNA markers have, both for other areas of the genome in IDDM and for other polygenic diseases. The analytic approaches introduced here will be useful for affected-sib-pair studies of other complex phenotypes.


The spiritual meaning of pre-loss music therapy to bereaved caregivers of advanced cancer patients.
The aim of this study was to learn how music therapy sessions, held prior to the death of a loved one, impact spirituality in surviving caregivers of advanced cancer patients. The method of naturalistic inquiry was used to investigate the spiritual meaning of pre-loss music therapy sessions. Bereaved caregivers of seven different patients, who had been receiving music therapy through a home-based hospice program, participated in individual open-ended interviews. Interviews were recorded, transcribed, and coded. Themes were organized as they emerged. As caregivers reflected on their experiences in music therapy, they reported autonomous joy (music therapy affected the caregiver directly) and empathic joy (caregivers' joy was based in remembering seeing the patient happy in music therapy). They also noted feelings of empowerment due to the ways they felt they had contributed in the care of the patients through music therapy. The caregivers were found to engage in processes of reflection that inspired these spiritual themes: reflection on the present (connectedness), reflection on the past (remembrance), and reflection on the future (hope). They referred to the ways that the music therapy sessions helped them find connection with self, others (through bringing their loved ones "back to life" and have a "renewal of self"), and the "beyond"; and that times in music therapy brought them happy memories and sentiments of hope. Meaning through transcendence was found to be the overarching trend in this study, as caregivers were lifted from remorse into heightened sense of meaning and gained "airplane views" of their lives. Pre-loss music therapy can potentially assist caregivers during times of bereavement, as they retain memories of joy and empowerment, rather than memories of pain and distress, and find meaning through transcendence.


Inhibition of Na-Ca exchange by general anesthetics.
General anesthetics, typically octanol, were found to inhibit the influx of calcium in isolated sodium-loaded adult rat heart cells, using 45Ca, quin 2, or indo 1. Inhibition by octanol, like inhibition by sodium, was competitive with calcium. Octanol and sodium together inhibited calcium influx synergistically. At physiological levels of extracellular calcium and sodium, the EC50 was 177 +/- 37 microM for octanol and 48 +/- 5 microM for decanol. These values are threefold to fourfold larger than those reported to cause 50% loss of righting reflex in tadpoles, a measure of their anesthetic effectiveness. We conclude that general anesthetics inhibit Na-Ca exchange at the sarcolemma. We suggest that octanol inhibits like sodium, and the synergism stems from the cooperativity of sodium inhibition at the binding and regulatory sites of the exchanger. Insofar as Na-Ca exchange may regulate inotropy, the inhibition of Na-Ca exchange by general anesthetics could contribute to their negative inotropic effect.


My approach to the interpretation of endometrial biopsies and curettings.
A major proportion of the workload in many histopathology laboratories is accounted for by endometrial biopsies, either curettage specimens or outpatient biopsy specimens. The increasing use of pipelle and other methods of biopsy not necessitating general anaesthesia has resulted in greater numbers of specimens with scant tissue, resulting in problems in assessing adequacy and in interpreting artefactual changes, some of which appear more common with outpatient biopsies. In this review, the criteria for adequacy and common artefacts in endometrial biopsies, as well as the interpretation of endometrial biopsies in general, are discussed, concentrating on areas that cause problems for pathologists. An adequate clinical history, including knowledge of the age, menstrual history and menopausal status, and information on the use of exogenous hormones and tamoxifen, is necessary for the pathologist to critically evaluate endometrial biopsies. Topics such as endometritis, endometrial polyps, changes that are induced by hormones and tamoxifen within the endometrium, endometrial metaplasias and hyperplasias, atypical polypoid adenomyoma, adenofibroma, adenosarcoma, histological types of endometrial carcinoma and grading of endometrial carcinomas are discussed with regard to endometrial biopsy specimens rather than hysterectomy specimens. The value of ancillary techniques, especially immunohistochemistry, is discussed where appropriate.


Myxoid mesenchymal neoplasm presenting as massive arm and chest wall oedema with pleural effusion.
Myxoid mesenchymal tumours are a heterogeneous group of neoplasms characterised histologically by their abundant mucoid and myxoid extracellular matrix (ECM). Encompassing a broad spectrum of clinical behaviour ranging from benign to malignant, there are more than 60 reactive and neoplastic entities currently classified under its domain. Its varied clinical and histopathologic features continue to pose a diagnostic challenge to clinicians and pathologists. Here, we describe a rare case of myxoid mesenchymal tumour presenting as oedema of the upper extremity with pleural metastasis and partial response to chemotherapy, which to the best of our knowledge has not yet been described in the literature.


Single cell RNA sequencing identifies TGFβ as a key regenerative cue following LPS-induced lung injury.
Many lung diseases result from a failure of efficient regeneration of damaged alveolar epithelial cells (AECs) after lung injury. During regeneration, AEC2s proliferate to replace lost cells, after which proliferation halts and some AEC2s transdifferentiate into AEC1s to restore normal alveolar structure and function. Although the mechanisms underlying AEC2 proliferation have been studied, the mechanisms responsible for halting proliferation and inducing transdifferentiation are poorly understood. To identify candidate signaling pathways responsible for halting proliferation and inducing transdifferentiation, we performed single cell RNA sequencing on AEC2s during regeneration in a murine model of lung injury induced by intratracheal LPS. Unsupervised clustering revealed distinct subpopulations of regenerating AEC2s: proliferating, cell cycle arrest, and transdifferentiating. Gene expression analysis of these transitional subpopulations revealed that TGFβ signaling was highly upregulated in the cell cycle arrest subpopulation and relatively downregulated in transdifferentiating cells. In cultured AEC2s, TGFβ was necessary for cell cycle arrest but impeded transdifferentiation. We conclude that during regeneration after LPS-induced lung injury, TGFβ is a critical signal halting AEC2 proliferation but must be inactivated to allow transdifferentiation. This study provides insight into the molecular mechanisms regulating alveolar regeneration and the pathogenesis of diseases resulting from a failure of regeneration.


Improving the Management of Psoriatic Arthritis and Axial Spondyloarthritis: Roundtable Discussions with Healthcare Professionals and Patients.
Psoriatic arthritis (PsA) and axial spondyloarthritis (AxSpA) are both chronic, inflammatory conditions that result in a substantial burden of disease and reduced quality of life for patients. Patient involvement in developing optimal disease management strategies, including defining appropriate goals, therapies, and treatment options, as well as in setting policy priorities and agendas, is key. A working group of patient organization representatives and rheumatologists explored what patients consider to be unmet needs, important treatment gaps, and future priorities in PsA and AxSpA management. Reducing pain and fatigue, and improving physical and social functioning and work productivity were identified as important treatment goals for patients. Although the major treatment target for both PsA and AxSpA is remission, with low/minimal disease activity an alternative target for patients with established or long-standing disease, the meaning of remission from the patient's perspective needs to be explored further as it may differ considerably from the physician's perspective. Key recommendations from the working group to tackle unmet needs included reducing time to diagnosis, increasing patient and physician disease awareness, focusing on patients' priorities for treatment goals, and improving patient-physician communication. By addressing these key action points moving forward, the hope is that outcomes will continue to improve for patients with PsA and AxSpA.


Carbamazepine- and oxcarbazepine-induced hyponatremia in people with epilepsy.
To ascertain possible determinants of carbamazepine (CBZ)- and oxcarbazepine (OXC)-induced hyponatremia in a large cohort of people with epilepsy. We collected data on serum sodium levels in people with epilepsy who were attending a tertiary epilepsy center while on treatment with CBZ or OXC. We defined hyponatremia as Na+ ≤134 mEq/L and severe hyponatremia as Na+ ≤128 mEq/L. We identified 1,782 people who had used CBZ (n = 1,424) or OXC (n = 358), of whom 50 were treated with both drugs. Data on sodium level measurements were available in 1,132 on CBZ and in 289 on OXC. Hyponatremia occurred in 26% of those taking CBZ and 46% of those taking OXC. This was severe in 7% in the CBZ group and 22% in the OXC group. Hyponatremia was symptomatic in 48% and led to admissions in 3%. Age over 40 years, high serum levels of CBZ and OXC, and concomitant use of other antiepileptic drugs were the main risk factors for hyponatremia in both treatment groups. Female patients on OXC were at a higher risk than male patients of hyponatremia. The risk of hyponatremia on CBZ was significantly associated with the risk of hyponatremia on OXC within a subgroup that used both drugs consecutively. Hyponatremia is a common problem in people taking CBZ or OXC. Regular ascertainment of sodium levels in those taking either drug is recommended and results should be acted on.


A tale of two antennules: the performance of crab odour-capture organs in air and water.
Odour capture is an important part of olfaction, where dissolved chemical cues (odours) are brought into contact with chemosensory structures. Antennule flicking by marine crabs is an example of discrete odour capture (sniffing) where an array of chemosensory hairs is waved through the water to create a flow-no flow pattern based on a narrow range of speeds, diameters of and spacings between hairs. Changing the speed of movement and spacing of hairs at this scale to manipulate flow represents a complicated fluid dynamics problem. In this study, we use numerical simulation of the advection and diffusion of a chemical gradient to reveal how morphological differences of the hair arrays affect odour capture. Specifically, we simulate odour capture by a marine crab (Callinectes sapidus) and a terrestrial crab (Coenobita rugosus) in both air and water to compare performance. We find that the antennule morphologies of each species are adaptions to capturing odours in their native habitats. Sniffing is an important part of odour capture for marine crabs in water where the diffusivity of odorant molecules is low and flow through the array is necessary. On the other hand, flow within the hair array diminishes odour-capture performance in air where diffusivities are high. This study highlights some of the adaptations necessary to transition from water to air.


Characterization of the yrbA gene of Bacillus subtilis, involved in resistance and germination of spores.
Insertional inactivation of the yrbA gene of Bacillus subtilis reduced the resistance of the mutant spores to lysozyme. The yrbA mutant spores lost their optical density at the same rate as the wild-type spores upon incubation with L-alanine but became only phase gray and did not swell. The response of the mutant spores to a combination of asparagine, glucose, fructose, and KCl was also extremely poor; in this medium yrbA spores exhibited only a small loss in optical density and gave a mixture of phase-bright, -gray, and -dark spores. Northern blot analysis of yrbA transcripts in various sig mutants indicated that yrbA was transcribed by RNA polymerase with sigma(E) beginning at 2 h after the start of sporulation. The yrbA promoter was localized by primer extension analysis, and the sequences of the -35 (TCATAAC) and -10 (CATATGT) regions were similar to the consensus sequences of genes recognized by sigma(E). Sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis of proteins solubilized from intact yrbA mutant spores showed an alteration in the protein profile, as 31- and 36-kDa proteins, identified as YrbA and CotG, respectively, were absent, along with some other minor changes. Electron microscopic examination of yrbA spores revealed changes in the spore coat, including a reduction in the density and thickness of the outer layer and the appearance of an inner coat layer-like structure around the outside of the coat. This abnormal coat structure was also observed on the outside of the developing forespores of the yrbA mutant. These results suggest that YrbA is involved in assembly of some coat proteins which have roles in both spore lysozyme resistance and germination.


Finite Element Implementation of Computational Fluid Dynamics With Reactive Neutral and Charged Solute Transport in FEBio.
The objective of this study was to implement a novel fluid-solutes solver into the open-source finite element software FEBio, that extended available modeling capabilities for biological fluids and fluid-solute mixtures. Using a reactive mixture framework, this solver accommodates diffusion, convection, chemical reactions, electrical charge effects, and external body forces, without requiring stabilization methods that were deemed necessary in previous computational implementations of the convection-diffusion-reaction equation at high Peclet numbers. Verification and validation problems demonstrated the ability of this solver to produce solutions for Peclet numbers as high as 1011, spanning the range of physiological conditions for convection-dominated solute transport. This outcome was facilitated by the use of a formulation that accommodates realistic values for solvent compressibility, and by expressing the solute mass balance such that it properly captured convective transport by the solvent and produced a natural boundary condition of zero diffusive solute flux at outflow boundaries. Since this numerical scheme was not necessarily foolproof, guidelines were included to achieve better outcomes that minimize or eliminate the potential occurrence of numerical artifacts. The fluid-solutes solver presented in this study represents an important and novel advancement in the modeling capabilities for biomechanics and biophysics as it allows modeling of mechanobiological processes via the incorporation of chemical reactions involving neutral or charged solutes within dynamic fluid flow. The incorporation of charged solutes in a reactive framework represents a significant novelty of this solver. This framework also applies to a broader range of nonbiological applications.


Storage and executive processes in the frontal lobes.
The human frontal cortex helps mediate working memory, a system that is used for temporary storage and manipulation of information and that is involved in many higher cognitive functions. Working memory includes two components: short-term storage (on the order of seconds) and executive processes that operate on the contents of storage. Recently, these two components have been investigated in functional neuroimaging studies. Studies of storage indicate that different frontal regions are activated for different kinds of information: storage for verbal materials activates Broca's area and left-hemisphere supplementary and premotor areas; storage of spatial information activates the right-hemisphere premotor cortex; and storage of object information activates other areas of the prefrontal cortex. Two of the fundamental executive processes are selective attention and task management. Both processes activate the anterior cingulate and dorsolateral prefrontal cortex.


Quinone electrophiles selectively adduct "electrophile binding motifs" within cytochrome c.
Electrophiles generated endogenously, or via the metabolic bioactivation of drugs and other environmental chemicals, are capable of binding to a variety of nucleophilic sites within proteins. Factors that determine site selective susceptibility to electrophile-mediated post-translational modifications, and the consequences of such alterations, remain largely unknown. To identify and characterize chemical-mediated protein adducts, electrophiles with known toxicity were utilized. Hydroquinone, and its mercapturic acid pathway metabolites, cause renal proximal tubular cell necrosis and nephrocarcinogenicity in rats. The adverse effects of HQ and its thioether metabolites are in part a consequence of their oxidation to the corresponding electrophilic 1,4-benzoquinones (BQ). We now report that BQ and 2-(N-acetylcystein-S-yl)benzoquinone (NAC-BQ) preferentially bind to solvent-exposed lysine-rich regions within cytochrome c. Furthermore, we have identified specific glutamic acid residues within cytochrome c as novel sites of NAC-BQ adduction. The microenvironment at the site of adduction governs both the initial specificity and the structure of the final adduct. The solvent accessibility and local pKa of the adducted and neighboring amino acids contribute to the selectivity of adduction. Postadduction chemistry subsequently alters the nature of the final adduct. Using molecular modeling, the impact of BQ and NAC-BQ adduction on cytochrome c was visualized, revealing the spatial rearrangement of critical residues necessary for protein-protein interactions. Consequently, BQ-adducted cytochrome c fails to initiate caspase-3 activation in native lysates and also inhibits Apaf-1 oligomerization into an apoptosome complex in a purely reconstituted system. In summary, a combination of mass spectroscopic, molecular modeling, and biochemical approaches confirms that electrophile-protein adducts produce structural alterations that influence biological function.