Combination of computer simulations and experimental measurements as the training dataset for statistical estimation of epicardial activation maps from venous catheter recordings.
One of the epicardial mapping techniques requires the insertion of multiple multi-electrode catheters into the coronary vessels. The recordings from the intracoronary catheters reflect the electrical activity on the nearby epicardial sites; however, most of epicardial surface is still inaccessible. In order to overcome this limited access problem, a method called the linear least squares estimation was proposed for the reconstruction of high-resolution maps using sparse measurements. In this technique, the relationship between catheter measurements and the remaining sites on the epicardium is created from previously obtained high-resolution maps (training dataset). Even though open-chest surgery is still a relatively frequent occurrence, an additional burden on the patient to obtain epicardial maps might impose an important risk on the patient. In this study, we hypothesize that epicardial maps created from computer simulations might be used in combination with the experimental data. In order to test this hypothesis, we used high-resolution epicardial activation maps acquired from 13 experiments performed on canine hearts that were stimulated via unipolar pacing from sites distributed all over the epicardium. We investigated the feasibility of the Aliev-Panfilov model that generated focal epicardial arrhythmias on Auckland heart. We started the simulations from the sites that corresponded to the pacing sites on the experimental geometry after a registration procedure between the experimental and simulation geometries. We then compared the simulation results with the corresponding experimental activation maps. Finally, we included simulated activation maps alone (100%) and in combination (simulated maps constituted 90%, 75%, 50%, 25%, 10%, and 0% of the training dataset) with experimental maps in the training set, performed the statistical estimation, and obtained the error statistics. The mean correlation coefficient (CC) between the simulated epicardial activation maps with the experimental maps was 0.88. The results of the estimation indicated that only 2.6 mm localization error and 0.05 CC value degradation occurred on average for the replacement of 75% of the experimental maps with the simulated counterparts. This indicated that including an important percentage from simulations may lead to decreased need for open-chest procedures and less burden on the patients.


Anti-tau oligomers passive vaccination for the treatment of Alzheimer disease.
The aggregation and accumulation of the microtubule-associated protein (Tau) is a pathological hallmark of Alzheimer's disease (AD) and many neurodegenerative diseases. Despite the poor correlation between neurofirillary tangles (NFTs) and disease progression, and evidence showing, that neuronal loss in AD actually precedes NFTs formation research until recently focused on them and other large meta-stable inclusions composed of aggregated hyperphosphorylated tau protein. Lately, the significance and toxicity of NFTs has been challenged and new aggregated tau entity has emerged as the true pathogenic species in tauopathies and a possible mediator of Aβ toxicity in AD. Tau intermediate aggregate (tau oligomers; aggregates of an intermediate that is between monomers and NFTs in size) can cause neurodegeneration and memory impairment in the absence of Aβ. This exciting body of evidence includes results from human brain samples, transgenic mouse and cell-based studies. Despite extensive efforts to develop a safe and efficacious vaccine for AD using Aβ peptide as an immunogen in active vaccination approaches or anti Aβ antibodies for passive vaccination, success has been modest. Nonetheless, these studies have produced a wealth of fundamental knowledge that has potential to application to the development of a tau-based immunotherapy. Herein, I discuss the evidence supporting the critical role of tau oligomers in AD, the potential and challenges for targeting them by immunotherapy as a novel approach for AD treatment.


Requirement of CD9 on the egg plasma membrane for fertilization.
CD9 is an integral membrane protein associated with integrins and other membrane proteins. Mice lacking CD9 were produced by homologous recombination. Both male and female CD9-/- mice were born healthy and grew normally. However, the litter size from CD9-/- females was less than 2% of that of the wild type. In vitro fertilization experiments indicated that the cause of this infertility was due to the failure of sperm-egg fusion. When sperm were injected into oocytes with assisted microfertilization techniques, however, the fertilized eggs developed to term. These results indicate that CD9 has a crucial role in sperm-egg fusion.


Multimodal image data fusion for Alzheimer's Disease diagnosis by sparse representation.
Alzheimer's Diasese (AD) diagnosis can be carried out by analysing functional or structural changes in the brain. Functional changes associated to neurological disorders can be figured out by positron emission tomography (PET) as it allows to study the activation of certain areas of the brain during specific task development. On the other hand, neurological disorders can also be discovered by analysing structural changes in the brain which are usually assessed by Magnetic Resonance Imaging (MRI). In fact, computer-aided diagnosis tools (CAD) that have been recently devised for the diagnosis of neurological disorders use functional or structural data. However, functional and structural data can be fused out in order to improve the accuracy and to diminish the false positive rate in CAD tools. In this paper we present a method for the diagnosis of AD which fuses multimodal image (PET and MRI) data by combining Sparse Representation Classifiers (SRC). The method presented in this work shows accuracy values up to 95% and clearly outperforms the classification outcomes obtained using single-modality images.


HspB1, HspB5 and HspB4 in Human Cancers: Potent Oncogenic Role of Some of Their Client Proteins.
Human small heat shock proteins are molecular chaperones that regulate fundamental cellular processes in normal unstressed cells as well as in many cancer cells where they are over-expressed. These proteins are characterized by cell physiology dependent changes in their oligomerization and phosphorylation status. These structural changes allow them to interact with many different client proteins that subsequently display modified activity and/or half-life. Nowdays, the protein interactomes of small Hsps are under intense investigations and will represent, when completed, key parameters to elaborate therapeutic strategies aimed at modulating the functions of these chaperones. Here, we have analyzed the potential pro-cancerous roles of several client proteins that have been described so far to interact with HspB1 (Hsp27) and its close members HspB5 (αB-crystallin) and HspB4 (αA-crystallin).


Stroke mimics which complicate the clinical management of 'stroke patients'.
Not all patients presenting as 'stroke patients' have cerebrovascular disease, as some conditions mimic stroke clinically. A significant degree of misdiagnosis of stroke has been documented. Clinical presentation of patients with stroke mimics can confound emergency care physicians and lead to significant morbidity and mortality for the patient, if unrecognised. We highlight some conditions that can mimic stroke emphasising ways in which these stroke mimics can be differentiated from stroke. Correct identification and management of these conditions can reduce morbidity and mortality in 'stroke patients.


Theoretical study of birefringent filters as intracavity wavelength selectors.
A detailed theoretical study of the transmission function of birefringent filters using exact 4 x 4 matrix formalisms is presented. The Brewster-angle effect for the filters acting as intracavity wavelength selectors is also analyzed. Finally, the change in phase of the transmitted wave is calculated and the resonance condition of a cavity with a birefringent-type selector is obtained. The results are compared with those obtained from the usual Jones method.


The impact of humic acid on chromium phytoextraction by aquatic macrophyte Lemna minor.
Studies assessing chromium phytoextration from natural waters rarely consider potential implications of chromium speciation in the presence of ubiquitous humic substances. Therefore, the present study investigated the influence of environmentally relevant concentration of humic acid (TOC = 10 mg L(-1)) on chromium speciation (Cr = 0.15 mg L(-1)) and consequently on phytoextraction by aquatic macrophyte duckweed Lemna minor. In absence of humic acid, only hexavalent chromium was present in water samples and easily taken up by L. minor. Chromium uptake resulted in a significant reduction of growth rate by 22% and decrease of chlorophyll a and chlorophyll b contents by 48% and 43%, respectively. On the other hand, presence of humic acid significantly reduced chromium bioavailability (57% Cr uptake decrease) and consequently it did not cause any measurable effect to duckweed. Such effect was related to abiotic reduction of hexavalent chromium species to trivalent. Hence, findings of our study suggest that presence of humic acid and chromium speciation cannot be neglected during phytoextraction studies.


Health Care Administrative Costs in the United States and Canada, 2017.
Before Canada's single-payer reform, its payment system, health costs, and number of health administrative personnel per capita resembled those of the United States. By 1999, administration accounted for 31% of U.S. health expenditures versus 16.7% in Canada. No recent comprehensive analyses of those costs are available. To quantify 2017 spending for administration by insurers and providers. Analyses of government reports, accounting data that providers file with regulators, surveys of physicians, and census-collected data on employment in health care. United States and Canada. Insurance overhead; administrative expenditures of hospitals, physicians, nursing homes, home care agencies, and hospices. U.S. insurers and providers spent $812 billion on administration, amounting to $2497 per capita (34.2% of national health expenditures) versus $551 per capita (17.0%) in Canada: $844 versus $146 on insurers' overhead; $933 versus $196 for hospital administration; $255 versus $123 for nursing home, home care, and hospice administration; and $465 versus $87 for physicians' insurance-related costs. Of the 3.2-percentage point increase in administration's share of U.S. health expenditures since 1999, 2.4 percentage points was due to growth in private insurers' overhead, mostly because of high overhead in their Medicare and Medicaid managed-care plans. Estimates exclude dentists, pharmacies, and some other providers; accounting categories for the 2 countries differ somewhat; and methodological changes probably resulted in an underestimate of administrative cost growth since 1999. The gap in health administrative spending between the United States and Canada is large and widening, and it apparently reflects the inefficiencies of the U.S. private insurance-based, multipayer system. The prices that U.S. medical providers charge incorporate a hidden surcharge to cover their costly administrative burden. None.


Between two fern genomes.
Ferns are the only major lineage of vascular plants not represented by a sequenced nuclear genome. This lack of genome sequence information significantly impedes our ability to understand and reconstruct genome evolution not only in ferns, but across all land plants. Azolla and Ceratopteris are ideal and complementary candidates to be the first ferns to have their nuclear genomes sequenced. They differ dramatically in genome size, life history, and habit, and thus represent the immense diversity of extant ferns. Together, this pair of genomes will facilitate myriad large-scale comparative analyses across ferns and all land plants. Here we review the unique biological characteristics of ferns and describe a number of outstanding questions in plant biology that will benefit from the addition of ferns to the set of taxa with sequenced nuclear genomes. We explain why the fern clade is pivotal for understanding genome evolution across land plants, and we provide a rationale for how knowledge of fern genomes will enable progress in research beyond the ferns themselves.


Cancer incidence in Nigeria: a report from population-based cancer registries.
Cancer has become a major source of morbidity and mortality globally. Despite the threat that cancer poses to public health in sub-Saharan Africa (SSA), few countries in this region have data on cancer incidence. In this paper, we present estimates of cancer incidence in Nigeria based on data from 2 population-based cancer registries (PBCR) that are part of the Nigerian national cancer registry program. We analyzed data from 2 population based cancer registries in Nigeria, the Ibadan Population Based Cancer Registry (IBCR) and the Abuja Population Based Cancer Registry (ABCR) covering a 2 year period 2009-2010. Data are reported by registry, gender and in age groups. We present data on the age specific incidence rates of all invasive cancers and report age standardized rates of the most common cancers stratified by gender in both registries. The age standardized incidence rate for all invasive cancers from the IBCR was 66.4 per 100000 men and 130.6 per 100000 women. In ABCR it was 58.3 per 100000 for men and 138.6 per 100000 for women. A total of 3393 cancer cases were reported by the IBCR. Of these cases, 34% (1155) were seen among males and 66% (2238) in females. In Abuja over the same period, 1128 invasive cancers were reported. 33.6% (389) of these cases were in males and 66.4% (768) in females. Mean age of diagnosis of all cancers in men for Ibadan and Abuja were 51.1 and 49.9 years respectively. For women, mean age of diagnosis of all cancers in Ibadan and Abuja were 49.1 and 45.4 respectively. Breast and cervical cancer were the commonest cancers among women and prostate cancer the most common among men. Breast cancer age standardized incidence rate (ASR) at the IBCR was 52.0 per 100000 in IBCR and 64.6 per 100000 in ABCR. Cervical cancer ASR at the IBCR was 36.0 per 100000 and 30.3 per 100000 at the ABCR. The observed differences in incidence rates of breast, cervical and prostate cancer between Ibadan and Abuja, were not statistically significant. Cancer incidence data from two population based cancer registries in Nigeria suggests substantial increase in incidence of breast cancer in recent times. This paper highlights the need for high quality regional cancer registries in Nigeria and other SSA countries.


Hybridization and Covalency in the Group 2 and Group 12 Metal Cation/Rare Gas Complexes.
We provide a consistent set of interaction energy curves for the group 2 (IIA) and group 12 (IIB) metal cation/rare gas complexes, M+-RG, where M+ = Be+-Ra+ and Zn+-Hg+ and RG = He-Rn. We report spectroscopic constants derived from these, compare them with available data, and discuss trends in the values. We gain insight into the interactions that occur using a range of approaches: reduced potential energy curves; charge and population analyses; molecular orbital diagrams and contour plots; and Birge-Sponer plots. Although sp hybridization occurs in the Be+-RG, Mg+-RG and group 12 M+-RG complexes, this appears to be minimal and covalency is the main aspect of the interaction. However, major sd hybridization occurs in the heavier group 2 M+-RG systems, which increases their interaction energies but there is minimal covalency. Examination of Birge-Sponer plots reveals significant curvature in many cases, which we ascribe to the changing amounts of hybridization or covalency as a function of internuclear separation. This suggests why the use of a simple electrostatics-based model potential to describe the interactions is inadequate.


Uncovering the arrhythmogenic potential of TRPM4 activation in atrial-derived HL-1 cells using novel recording and numerical approaches.
Transient receptor potential cation channel subfamily melastatin member 4 (TRPM4), a Ca2+-activated nonselective cation channel abundantly expressed in the heart, has been implicated in conduction block and other arrhythmic propensities associated with cardiac remodelling and injury. The present study aimed to quantitatively evaluate the arrhythmogenic potential of TRPM4. Patch clamp and biochemical analyses were performed using expression system and an immortalized atrial cardiomyocyte cell line (HL-1), and numerical model simulation was employed. After rapid desensitization, robust reactivation of TRPM4 channels required high micromolar concentrations of Ca2+. However, upon evaluation with a newly devised, ionomycin-permeabilized cell-attached (Iono-C/A) recording technique, submicromolar concentrations of Ca2+ (apparent Kd = ∼500 nM) were enough to activate this channel. Similar submicromolar Ca2+ dependency was also observed with sharp electrode whole-cell recording and in experiments coexpressing TRPM4 and L-type voltage-dependent Ca2+ channels. Numerical simulations using a number of action potential (AP) models (HL-1, Nygren, Luo-Rudy) incorporating the Ca2+- and voltage-dependent gating parameters of TRPM4, as assessed by Iono-C/A recording, indicated that a few-fold increase in TRPM4 activity is sufficient to delay late AP repolarization and further increases (≥ six-fold) evoke early afterdepolarization. These model predictions are consistent with electrophysiological data from angiotensin II-treated HL-1 cells in which TRPM4 expression and activity were enhanced. These results collectively indicate that the TRPM4 channel is activated by a physiological range of Ca2+ concentrations and its excessive activity can cause arrhythmic changes. Moreover, these results demonstrate potential utility of the first AP models incorporating TRPM4 gating for in silico assessment of arrhythmogenicity in remodelling cardiac tissue.


Living In A Country With A Strong Primary Care System Is Beneficial To People With Chronic Conditions.
In light of the growing pressure that multiple chronic diseases place on health care systems, we investigated whether strong primary care was associated with improved health outcomes for the chronically ill. We did this by combining country- and individual-level data for the twenty-seven countries of the European Union, focusing on people's self-rated health status and whether or not they had severe limitations or untreated conditions. We found that people with chronic conditions were more likely to be in good or very good health in countries that had a stronger primary care structure and better coordination of care. People with more than two chronic conditions benefited most: Their self-rated health was higher if they lived in countries with a stronger primary care structure, better continuity of care, and a more comprehensive package of primary care services. In general, while having access to a strong primary care system mattered for people with chronic conditions, the degree to which it mattered differed across specific subgroups (for example, people with primary care-sensitive conditions) and primary care dimensions. Primary care reforms, therefore, should be person centered, addressing the needs of subgroups of patients while also finding a balance between structure and service delivery.


Acidified seawater increases accumulation of cobalt but not cesium in manila clam Ruditapes philippinarum.
The pH of seawater around the world is expected to continue its decline in the near future in response to ocean acidification that is driven by heightened atmospheric CO2 emissions. Concomitantly, economically-important molluscs that live in coastal waters including estuaries and embayments, may be exposed to a wide assortment of contaminants, including trace metals and radionuclides. Seawater acidification may alter both the chemical speciation of select elements as well as the physiology of organisms, and may thus pose at risk to many shellfish species, including the manila clam Ruditapes philippinarum. The bioconcentration efficiency of two common radionuclides associated with the nuclear fuel cycle, 134Cs and 57Co, were investigated by exposing live clams to dissolved 134Cs and 57Co at control (pH = 8.1) and two lowered pH (pH = 7.8 and 7.5) levels using controlled aquaria. The uptake and depuration kinetics of the two radionuclides in the whole-body clam were followed for 21 and 35 days, respectively. At steady-state equilibrium, the concentration factor (CFss) for 57Co increased as the pH decreased (i.e. 130 ± 5, 194 ± 6, and 258 ± 10 at pH levels 8.1, 7.8 and 7.5, respectively), whereas the 134Cs uptake was not influenced by a change in pH conditions. During depuration, the lowest depuration rate constant of 57Co by the manila clam was observed at the intermediate pH of 7.8. An increase in the accumulation of 57Co at the intermediate pH value was thought to be caused mainly by the aragonitic shell of the clam, as well as the low salinity and alkalinity of seawater used in the experiment. Considering that accumulation consists of uptake and depuration, among the three pH conditions moderately acidified seawater enhanced most the accumulation of 57Co. Accumulation of 134Cs was not strongly influenced by a reduced pH condition, as represented by an analogous uptake constant rate and CFss in each treatment. Such results suggest that future seawater pH values that are projected to be lower in the next decades, may pose a risk for calcium-bearing organisms such as shellfish.


A computational approach to interface engineering of lead-free CH3NH3SnI3 highly-efficient perovskite solar cells.
Perovskite solar cells (PSCs) based on organic-inorganic metal halide perovskites are a recent ground-breaking advancement in attaining power conversion efficiencies exceeding 21%. However, the toxicity of lead in these PSCs could be a deterrent for large-scale development due to the environmental concerns. The methylammonium tin triiodide (CH3NH3SnI3) perovskite has been successfully employed in lead-free PSCs as an alternative to CH3NH3PbI3 perovskite. The PSCs have mostly been realized with a highly expensive spiro-OMeTAD hole-transporting material (HTM). Herein, copper thiocyanate (CuSCN) was implemented as a HTM instead of the highly expensive spiro-OMeTAD counterpart. The results show that CuSCN is a promising HTM for the lead-free CH3NH3SnI3-based PSCs. We investigated and optimized the parameters of the lead-free CH3NH3SnI3-based PSCs with the CuSCN HTM. The simulated device shows a power conversion efficiency exceeding 26% under AM 1.5G illumination and an absorption onset up to 1080 nm. The reported CH3NH3SnI3-based PSCs provide a viable path to the realization of environmentally benign, low-cost, and high-efficiency PSCs.


Fluoroquinolone efflux in Streptococcus suis is mediated by SatAB and not by SmrA.
Streptococcus suis is an emerging zoonotic pathogen. With the lack of an effective vaccine, antibiotics remain the main tool to fight infections caused by this pathogen. We have previously observed a reserpine-sensitive fluoroquinolone (FQ) efflux phenotype in this species. Here, SatAB and SmrA, two pumps belonging to the ATP binding cassette (ABC) and the major facilitator superfamily (MFS), respectively, have been analyzed in the fluoroquinolone-resistant clinical isolate BB1013. Genes encoding these pumps were overexpressed either constitutively or in the presence of ciprofloxacin in this strain. These genes could not be cloned in plasmids in Escherichia coli despite strong expression repression. Finally, site-directed insertion of smrA and satAB in the amy locus of the Bacillus subtilis chromosome using ligated PCR amplicons allowed for the functional expression and study of both pumps. Results showed that SatAB is a narrow-spectrum fluoroquinolone exporter (norfloxacin and ciprofloxacin), susceptible to reserpine, whereas SmrA was not involved in fluoroquinolone resistance. Chromosomal integration in Bacillus is a novel method for studying efflux pumps from Gram-positive bacteria, which enabled us to demonstrate the possible role of SatAB, and not SmrA, in fluoroquinolone efflux in S. suis.


Aberrant expression of DNA damage response proteins is associated with breast cancer subtype and clinical features.
Landmark studies of the status of DNA damage checkpoints and associated repair functions in preneoplastic and neoplastic cells has focused attention on importance of these pathways in cancer development, and inhibitors of repair pathways are in clinical trials for treatment of triple negative breast cancer. Cancer heterogeneity suggests that specific cancer subtypes will have distinct mechanisms of DNA damage survival, dependent on biological context. In this study, status of DNA damage response (DDR)-associated proteins was examined in breast cancer subtypes in association with clinical features; 479 breast cancers were examined for expression of DDR proteins γH2AX, BRCA1, pChk2, and p53, DNA damage-sensitive tumor suppressors Fhit and Wwox, and Wwox-interacting proteins Ap2α, Ap2γ, ErbB4, and correlations among proteins, tumor subtypes, and clinical features were assessed. In a multivariable model, triple negative cancers showed significantly reduced Fhit and Wwox, increased p53 and Ap2γ protein expression, and were significantly more likely than other subtype tumors to exhibit aberrant expression of two or more DDR-associated proteins. Disease-free survival was associated with subtype, Fhit and membrane ErbB4 expression level and aberrant expression of multiple DDR-associated proteins. These results suggest that definition of specific DNA repair and checkpoint defects in subgroups of triple negative cancer might identify new treatment targets. Expression of Wwox and its interactor, ErbB4, was highly significantly reduced in metastatic tissues vs. matched primary tissues, suggesting that Wwox signal pathway loss contributes to lymph node metastasis, perhaps by allowing survival of tumor cells that have detached from basement membranes, as proposed for the role of Wwox in ovarian cancer spread.


Menopausal transitions, symptoms and country of birth: the Australian Longitudinal Study on Women's Health.
To assess differences among the menopausal transitions and symptoms experienced by women participating in the Australian Longitudinal Study on Women's Health, according to their countries of birth. Data from 8,466 women aged 45-50 in 1996, who responded to surveys in 1996 and 1998 and had not had a hysterectomy, were analysed. Women were categorised by country of birth and cross-sectionally by menopausal status at Survey 1 and 2, as well as longitudinally by transition through menopause between Surveys 1 and 2. Four endocrine-related and 10 general symptoms were assessed. Women bom in Asia were twice as likely as Australian-bom women to be post-menopausal at Survey 1, twice as likely to become post-menopausal between surveys, less likely to remain peri-menopausal, and less likely to report hot flushes and night sweats. Odds ratios for each symptom at Survey 2 were near unity for all country of birth groups compared with Australian bom women, with or without adjustment for symptoms at Survey 1, menopausal transition category, behaviour, lifestyle and demographics. Asian-born women entered menopause earlier and passed through it more quickly, but once this was taken into account all women showed the same prevalences of symptoms. There may be differences between ethnic groups that influence the timing of menopause, but the subjective experience appears similar. The timing of menopause may be affected by biological or dietary differences. Asian-bom women's lower reported prevalence of symptoms may be explained by a more rapid peri-menopausal transition. With increasing numbers of Asian-Australian women reaching menopause, an understanding of country-of-birth differences has implications for public health.


Oxidative stress induces ADAM9 protein expression in human prostate cancer cells.
The ADAM (a disintegrin and metalloprotease) family is a group of transmembrane proteins containing cell adhesive and proteolytic functional domains. Microarray analysis detected elevated ADAM9 during the transition of human LNCaP prostate cancer cells from an androgen-dependent to an androgen-independent and metastatic state. Using a prostate tissue array (N = 200), the levels of ADAM9 protein expression were also elevated in malignant as compared with benign prostate tissues. ADAM9 protein expression was found in 43% of benign glands with light staining and 87% of malignant glands with increasing intensity of staining. We found that ADAM9 mRNA and protein expressions were elevated on exposure of human prostate cancer cells to stress conditions such as cell crowding, hypoxia, and hydrogen peroxide. We uncovered an ADAM9-like protein, which is predominantly induced together with the ADAM9 protein by a brief exposure of prostate cancer cells to hydrogen peroxide. Induction of ADAM9 protein in LNCaP or C4-2 cells can be completely abrogated by the administration of an antioxidant, ebselen, or genetic transfer of a hydrogen peroxide degradative enzyme, catalase, suggesting that reactive oxygen species (ROS) are a common mediator. The induction of ADAM9 by stress can be inhibited by both actinomycin D and cycloheximide through increased gene transcription and protein synthesis. In conclusion, intracellular ROS and/or hydrogen peroxide, generated by cell stress, regulate ADAM9 expression. ADAM9 could be responsible for supporting prostate cancer cell survival and progression. By decreasing ADAM9 expression, we observed apoptotic cell death in prostate cancer cells.


Changing trends in infectious disease in heart transplantation.
During the past 25 years, advances in immunosuppression and the use of selective anti-microbial prophylaxis have progressively reduced the risk of infection after heart transplantation. This study presents a historical perspective of the changing trends of infectious disease after heart transplantation. Infectious complications in 4 representative eras of immunosuppression and anti-microbial prophylaxis were analyzed: (1) 38 in the pre-cyclosporine era (1978-1980), (2) 72 in the early cyclosporine era (1982-1984), where maintenance immunosuppression included high-dose cyclosporine and corticosteroid therapy; (3) 395 in the cyclosporine era (1988-1997), where maintenance immunosuppression included cyclosporine, azathioprine, and lower corticosteroid doses; and (4) 167 in the more recent era (2002-2005), where maintenance immunosuppression included cyclosporine and mycophenolate mofetil. The overall incidence of infections decreased in the 4 cohorts from 3.35 episodes/patient to 2.03, 1.35, and 0.60 in the more recent cohorts (p < 0.001). Gram-positive bacteria are emerging as the predominant cause of bacterial infections (28.6%, 31.4%, 51.0%, 67.6%, p = 0.001). Cytomegalovirus infections have significantly decreased in incidence and occur later after transplantation (88 +/- 77 days, pre-cyclosporine era; 304 +/- 238 days, recent cohort; p < 0.001). Fungal infections also decreased, from an incidence of 0.29/patient in the pre-cyclosporine era to 0.08 in the most recent era. A major decrease in Pneumocystis jiroveci and Nocardia infections has also occurred. The overall incidence and mortality associated with infections continues to decrease in heart transplantation and coincides with advances in immunosuppression, the use of selective anti-microbial prophylaxis, and more effective treatment regimens.


Protocol for a randomised trial of early kangaroo mother care compared to standard care on survival of pre-stabilised preterm neonates in The Gambia (eKMC).
Complications of preterm birth cause more than 1 million deaths each year, mostly within the first day after birth (47%) and before full post-natal stabilisation. Kangaroo mother care (KMC), provided as continuous skin-to-skin contact for 18 h per day to fully stabilised neonates ≤ 2000 g, reduces mortality by 36-51% at discharge or term-corrected age compared with incubator care. The mortality effect of starting continuous KMC before stabilisation is a priority evidence gap, which we aim to investigate in the eKMC trial, with a secondary aim of understanding mechanisms, particularly for infection prevention. We will conduct a single-site, non-blinded, individually randomised, controlled trial comparing two parallel groups to either early (within 24 h of admission) continuous KMC or standard care on incubator or radiant heater with KMC when clinically stable at > 24 h of admission. Eligible neonates (n = 392) are hospitalised singletons or twins < 2000 g and 1-24 h old at screening who are mild to moderately unstable as per a trial definition using cardio-respiratory parameters. Randomisation is stratified by weight category (< 1200 g; ≥ 1200 g) and in random permuted blocks of varying sizes with allocation of twins to the same arm. Participants are followed up to 28 ± 5 days of age with regular inpatient assessments plus criteria-led review in the event of clinical deterioration. The primary outcome is all-cause neonatal mortality by age 28 days. Secondary outcomes include the time to death, cardio-respiratory stability, hypothermia, exclusive breastfeeding at discharge, weight gain at age 28 days, clinically suspected infection (age 3 to 28 days), intestinal carriage of extended-spectrum beta-lactamase producing (ESBL) Klebsiella pneumoniae (age 28 days), and duration of the hospital stay. Intention-to-treat analysis will be applied for all outcomes, adjusting for twin gestation. This is one of the first clinical trials to examine the KMC mortality effect in a pre-stabilised preterm population. Our findings will contribute to the global evidence base in addition to providing insights into the infection prevention mechanisms and safety of using this established intervention for the most vulnerable neonatal population. ClinicalTrials.gov NCT03555981. Submitted 8 May 2018 and registered 14 June 2018. Prospectively registered.


Direct and converse piezoelectric responses at the nanoscale from epitaxial BiFeO3 thin films grown by polymer assisted deposition.
We use an original water-based chemical method to grow pure epitaxial BiFeO3 (BFO) ultra-thin films with excellent piezoelectric properties. Particularly, we show that this novel chemical route produces higher natural ferroelectric domain size distribution and coercive field compared to similar BFO films grown by physical methods. Moreover, we measured the d33 piezoelectric coefficient of 60 nm thick BFO films by a direct approach, using Direct Piezoelectric Force Microscopy (DPFM). As a result, first piezo-generated charge maps of a very thin BFO layer were obtained applying this novel technology. We also performed a comparative study of the d33 coefficients between standard PFM analysis and DPFM microscopy showing similar values i.e. 17 pm V-1 and 22 pC N-1, respectively. Finally, we proved that the directionality of the piezoelectric effect in BFO ferroelectric thin films is preserved at low thickness dimensions demonstrating the potential of chemical processes for the development of low cost functional ferroelectric and piezoelectric devices.


Comparative in situ analysis reveals the dynamic nature of sclerenchyma cell walls of the fern Asplenium rutifolium.
A key structural adaptation of vascular plants was the evolution of specialized vascular and mechanical tissues, innovations likely to have generated novel cell wall architectures. While collenchyma is a strengthening tissue typically found in growing organs of angiosperms, a similar tissue occurs in the petiole of the fern Asplenium rutifolium. The in situ cell wall (ultra)structure and composition of this tissue was investigated and characterized mechanically as well as structurally through nano-indentation and wide-angle X-ray diffraction, respectively. Structurally the mechanical tissue resembles sclerenchyma, while its biomechanical properties and molecular composition both share more characteristics with angiosperm collenchyma. Cell wall thickening only occurs late during cell expansion or after cell expansion has ceased. If the term collenchyma is reserved for walls that thicken during expansive growth, the mechanical tissue in A. rutifolium represents sclerenchyma that mimics the properties of collenchyma and has the ability to modify its mechanical properties through sclerification. These results support the view that collenchyma does not occur in ferns and most probably evolved in angiosperms.


Therapeutic manipulation of angiogenesis with miR-27b.
Multiple studies demonstrated pro-angiogenic effects of microRNA (miR)-27b. Its targets include Notch ligand Dll4, Sprouty (Spry)-2, PPARγ and Semaphorin (SEMA) 6A. miR-27 effects in the heart are context-dependent: although it is necessary for ventricular maturation, targeted overexpression in cardiomyocytes causes hypertrophy and dysfunction during development. Despite significant recent advances, therapeutic potential of miR-27b in cardiovascular disease and its effects in adult heart remain unexplored. Here, we assessed the therapeutic potential of miR-27b mimics and inhibitors in rodent models of ischemic disease and cancer. We have used a number of models to demonstrate the effects of miR-27b mimicry and inhibition in vivo, including subcutaneous Matrigel plug assay, mouse models of hind limb ischemia and myocardial infarction and subcutaneous Lewis Lung carcinoma. Using mouse model of myocardial infarction due to the coronary artery ligation, we showed that miR-27b mimic had overall beneficial effects, including increased vascularization, decreased fibrosis and increased ejection fraction. In mouse model of critical limb ischemia, miR-27b mimic also improved tissue re-vascularization and perfusion. In both models, miR-27b mimic clearly decreased macrophage recruitment to the site of hypoxic injury. In contrast, miR-27b increased the recruitment of bone marrow derived cells to the neovasculature, as was shown using mice reconstituted with fluorescence-tagged bone marrow. These effects were due, at least in part, to the decreased expression of Dll4, PPARγ and IL10. In contrast, blocking miR-27b significantly decreased vascularization and reduced growth of subcutaneous tumors and decreased BMDCs recruitment to the tumor vasculature. Our study demonstrates the utility of manipulating miR-27b levels in the treatment of cardiovascular disease and cancer.


Genome-wide discovery of somatic regulatory variants in diffuse large B-cell lymphoma.
Diffuse large B-cell lymphoma (DLBCL) is an aggressive cancer originating from mature B-cells. Prognosis is strongly associated with molecular subgroup, although the driver mutations that distinguish the two main subgroups remain poorly defined. Through an integrative analysis of whole genomes, exomes, and transcriptomes, we have uncovered genes and non-coding loci that are commonly mutated in DLBCL. Our analysis has identified novel cis-regulatory sites, and implicates recurrent mutations in the 3' UTR of NFKBIZ as a novel mechanism of oncogene deregulation and NF-κB pathway activation in the activated B-cell (ABC) subgroup. Small amplifications associated with over-expression of FCGR2B (the Fcγ receptor protein IIB), primarily in the germinal centre B-cell (GCB) subgroup, correlate with poor patient outcomes suggestive of a novel oncogene. These results expand the list of subgroup driver mutations that may facilitate implementation of improved diagnostic assays and could offer new avenues for the development of targeted therapeutics.


Feasibility and preliminary efficacy of progressive resistance exercise training in lung cancer survivors.
Lung cancer survivors exhibit poor functional capacity, physical functioning, and quality of life (QoL). Here, we report the feasibility and preliminary efficacy of a progressive resistance exercise training (PRET) intervention in post-treatment lung cancer survivors. Seventeen post-treatment lung cancer survivors (10 female), with a mean age of 67 (range 50-85), mean BMI of 25, and diagnosed with non-small cell lung cancer (94%) were recruited in Edmonton, Canada between August 2009 and August 2010 to undergo PRET. The primary outcomes focused on feasibility including eligibility and recruitment rate, loss to follow-up, measurement completion, exercise adherence, and program evaluation. Secondary outcomes addressed preliminary efficacy and included changes in muscular strength (1 repetition maximum), muscular endurance (repetitions at 70% of 1 repetition maximum), body composition (DXA scan), physical functioning (6-minute-walk-test, up-and-go, sit-to-stand, arm curls), and patient-reported outcomes including QoL (SF-36, FACT-L), fatigue (FACT-F), dyspnea (MRCD), and patient-rated function (LLFI). Forty of 389 lung cancer survivors were eligible (10%) and 17 of the 40 (43%) were recruited. Over 80% of participants were able to complete all testing; two participants were lost to follow-up, and the median adherence rate was 96% (range: 25-100%). Ratings of testing burden were low (i.e., less than two out of seven for all items), and trial evaluation was high (i.e., greater than six out of seven for all measures). Paired t-tests showed significant increases in muscular strength (p<.001), muscular endurance (p<.001), six-minute walk distance (p<.001), up-and-go time (p<.05), number of arm curls (p<.001), and number of chair stands (p<.001). There were no significant changes in body composition or patient-reported outcomes. PRET is a feasible intervention with potential health benefits for a small proportion of lung cancer survivors in the post-treatment setting.


The Hunter syndrome-functional outcomes for clinical understanding scale (HS-FOCUS) questionnaire: evaluation of measurement properties.
This study was to conduct the psychometric validation of the patient and parent versions of the Hunter syndrome-functional outcomes for clinical understanding scale (HS-FOCUS). Data collected in a 53-week placebo-controlled multinational trial were used to evaluate item performance and reliability, validity, and ability to detect change of the six HS-FOCUS function domains. HS-FOCUS was completed by 49 patients above 12 years old and 84 parents. Floor effects and high average inter-item correlations suggested that some items were less informative or redundant. For both patients and parents, the internal consistency and test-retest reliability met the >0.70 criteria for all domains except for the breathing, sleeping, and schooling/work in patients. Construct validity showed moderate to high correlations with CHAQ, CHQ, and HUI3 in activity-related concepts. Significant differences in domain scores were found in most domains among severity in disability measured by CHAQ DIS. Significant differences in HS-FOCUS change scores were found in patients whose CHAQ DIS score also changed. Psychometric validation of the HS-FOCUS demonstrates it is a reliable, valid, and responsive instrument that can be applied in clinical trials or disease registries. Findings on the individual item performance suggest some items could be removed without compromising its validity.


High-throughput enzyme screening platform for the IPP-bypass mevalonate pathway for isopentenol production.
Isopentenol (or isoprenol, 3-methyl-3-buten-1-ol) is a drop-in biofuel and a precursor for commodity chemicals such as isoprene. Biological production of isopentenol via the mevalonate pathway has been optimized extensively in Escherichia coli, yielding 70% of its theoretical maximum. However, high ATP requirements and isopentenyl diphosphate (IPP) toxicity pose immediate challenges for engineering bacterial strains to overproduce commodities utilizing IPP as an intermediate. To overcome these limitations, we developed an "IPP-bypass" isopentenol pathway using the promiscuous activity of a mevalonate diphosphate decarboxylase (PMD) and demonstrated improved performance under aeration-limited conditions. However, relatively low activity of PMD toward the non-native substrate (mevalonate monophosphate, MVAP) was shown to limit flux through this new pathway. By inhibiting all IPP production from the endogenous non-mevalonate pathway, we developed a high-throughput screening platform that correlated promiscuous PMD activity toward MVAP with cellular growth. Successful identification of mutants that altered PMD activity demonstrated the sensitivity and specificity of the screening platform. Strains with evolved PMD mutants and the novel IPP-bypass pathway increased titers up to 2.4-fold. Further enzymatic characterization of the evolved PMD variants suggested that higher isopentenol titers could be achieved either by altering residues directly interacting with substrate and cofactor or by altering residues on nearby α-helices. These altered residues could facilitate the production of isopentenol by tuning either kcat or Ki of PMD for the non-native substrate. The synergistic modification made on PMD for the IPP-bypass mevalonate pathway is expected to significantly facilitate the industrial scale production of isopentenol.


Mortality in treated heterozygous familial hypercholesterolaemia: implications for clinical management. Scientific Steering Committee on behalf of the Simon Broome Register Group.
Clinical management of heterozygous familial hypercholesterolaemia is largely based on evidence from a small number of observational studies and extrapolation from the results of clinical trials of lipid-lowering in patients with polygenic hypercholesterolaemia The objectives of this study were (i) to determine the absolute and relative mortality of patients with treated heterozygous familial hypercholesterolaemia, (ii) to estimate the effect of changes in treatment efficacy on mortality trends over time, and (iii) to examine the implications of these findings for patient management. A cohort of 605 men and 580 women aged 20-79 years with heterozyous familial hypercholesterolaemia were recruited from 21 out-patient lipid clinics in the UK. Patients were followed prospectively from 1980 to 1995 for 8770 person-years. Absolute mortality was calculated, and relative risk was expressed as the ratio of the number of observed deaths to the number expected in the general population of England and Wales. Forty six of the 73 deaths were due to coronary heart disease. In women aged 20-39, despite treatment, the relative risk of a fatal coronary event was increased 125-fold (95% confidence intervals 15-451) and the annual coronary mortality was 0.17%. In men aged 20-39 the relative risk was increased 48-fold (17-105) and the annual coronary mortality was 0.46%. The relative risk decreased with age but the absolute risk increased. For men and women aged 60-79, the annual coronary mortality was 1.1% representing a significant excess mortality for women (relative risk 2.6, 1.3-4.5) but not for men (RR 1.1, 0.5-2.3). Non-coronary mortality was not increased at any age (RR for all ages 0.68, 0.45-0.99). There was a decline in the relative risk for coronary mortality in patients aged 20-59 from an eight-fold (4.8-7.2) increased risk before 1992 to 3.7 (1.6-7.2.) thereafter (P=0.08). The results suggest that the prognosis for patients with heterozygous familial hypercholesterolaemia has improved with the introduction of more effective treatment, and that lipid-lowering therapy is not associated with increased non-coronary mortality. These findings and the excess coronary mortality observed suggest that all affected adult men and post-menopausal women should be treated with HMG-CoA reductase inhibitors.


Albumin replacement by fatty acids in clonal growth of mammalian cells.
Clonal growth of Chinese hamster strain CHD-3 cells in a synthetic nutrient mixture supplemented with 10 micrograms of purified fetuin per milliliter exhibits an apparent requirement for serum albumin. The albumin can be replaced by linoleic acid, which occurs as a tightly bound component of most albumin preparations. Linolenic acid and corn oil can also replace albumin, while oleic acid and esters of linoleic and linolenic acids cannot.


The role of furry pets in eczema: a systematic review.
To systematically search, summarize, and critically appraise the literature to examine whether pet exposure in early life is associated with an increased risk of eczema. We searched MEDLINE (1950 to June 2006) supplemented by citation lists in retrieved articles and contact with researchers. No language restrictions were imposed. Cohort studies were sufficiently similar to allow pooled analysis. Meta-analysis was not possible for cross-sectional studies owing to differences in methods and populations. Incidence or prevalence of eczema. Evidence from longitudinal studies showed that previous exposure to cats (pooled odds ratio [OR], 0.76; 95% confidence interval [CI], 0.62-0.92), dogs (pooled OR, 0.68; 95% CI, 0.53-0.87), or "any furry pet" (pooled OR, 0.79; 95% CI, 0.74-0.84) is associated with a lower risk of eczema. However, in the only cohort study adjusted for avoidance behavior, this "protective effect" disappeared (for cats: OR, 0.80; 95% CI, 0.33-1.97). Stratified analysis by family history in 2 birth cohort studies showed that dog exposure was protective in patients with atopic families. For cats, 1 study showed reduced risk in atopic families only; the other study showed no effect. Eight cross-sectional studies evaluated past pet exposure; a protective effect was seen in 3 studies for cat, dog, or any pet; no study demonstrated an increased risk. There was no clear evidence that early pet exposure is associated with increased risks of subsequent eczema. We found some evidence of a possible protective effect of early pet exposure, but this might be explained by avoidance behavior in high-risk families.


Clusters of imipenem-resistant Acinetobacter baumannii clones producing different carbapenemases in an intensive care unit.
During a 2-year period (April 2005-March 2007), 31 intensive care unit (ICU) patients in a Greek hospital were infected or colonised with imipenem-resistant isolates of Acinetobacter baumannii. Twelve patients died, with imipenem-resistant A. baumannii infection contributing to the death of seven patients. The 31 representative A. baumannii isolates were multidrug-resistant and clustered in four distinct clones, each of which contained different carbapenemase genes: clone I was predominant and contained bla(VIM-1), bla(OXA-58) and the intrinsic bla(OXA-66) gene; clone II contained bla(VIM-4), bla(OXA-58) and the intrinsic bla(OXA-69) gene; clone III contained bla(OXA-58) and the intrinsic bla(OXA-69) gene; and clone IV contained only the intrinsic bla(OXA-66) gene. ISAba1 was not associated with the intrinsic bla(OXA-51-like) alleles, whereas ISAba3 was found upstream and downstream of bla(OXA-58) in isolates of clone I, and upstream of bla(OXA-58) in isolates of clone III, but was not detected in isolates of clone II. PCR, curing and hybridisation experiments indicated that the bla(VIM) alleles were chromosomally located, whereas the bla(OXA-58) alleles were plasmid-located. This study provides the first description of the clonal spread of multidrug-resistant A. baumannii isolates carrying bla(VIM-1) and bla(VIM-4) metallo-beta-lactamase genes, and revealed that distinct carbapenem-resistant A. baumannii clusters bearing different carbapenemase genes may emerge and cause severe infections, even in a well-defined regional hospital setting.


Sumoylation at chromatin governs coordinated repression of a transcriptional program essential for cell growth and proliferation.
Despite numerous studies on specific sumoylated transcriptional regulators, the global role of SUMO on chromatin in relation to transcription regulation remains largely unknown. Here, we determined the genome-wide localization of SUMO1 and SUMO2/3, as well as of UBC9 (encoded by UBE2I) and PIASY (encoded by PIAS4), two markers for active sumoylation, along with Pol II and histone marks in proliferating versus senescent human fibroblasts together with gene expression profiling. We found that, whereas SUMO alone is widely distributed over the genome with strong association at active promoters, active sumoylation occurs most prominently at promoters of histone and protein biogenesis genes, as well as Pol I rRNAs and Pol III tRNAs. Remarkably, these four classes of genes are up-regulated by inhibition of sumoylation, indicating that SUMO normally acts to restrain their expression. In line with this finding, sumoylation-deficient cells show an increase in both cell size and global protein levels. Strikingly, we found that in senescent cells, the SUMO machinery is selectively retained at histone and tRNA gene clusters, whereas it is massively released from all other unique chromatin regions. These data, which reveal the highly dynamic nature of the SUMO landscape, suggest that maintenance of a repressive environment at histone and tRNA loci is a hallmark of the senescent state. The approach taken in our study thus permitted the identification of a common biological output and uncovered hitherto unknown functions for active sumoylation at chromatin as a key mechanism that, in dynamically marking chromatin by a simple modifier, orchestrates concerted transcriptional regulation of a network of genes essential for cell growth and proliferation.


Clinical practice guidelines for the management of hypothyroidism.
Hypothyroidism has long been known for its effects on different organ systems, leading to hypometabolism. However, subclinical hypothyroidism, its most prevalent form, has been recently related to cardiovascular risk and also to maternal-fetal complications in pregnant women. In these clinical practice guidelines, several aspects of this field have been discussed with the clear objectives of helping physicians treat patients with hypothyroidism, and of sharing some of our Latin American-based clinical experience. The Latin American Thyroid Society commissioned a Task Force on Hypothyroidism to develop evidence-based clinical guidelines on hypothyroidism. A systematic review of the available literature, focused on the primary databases of MedLine/PubMed and Lilacs/SciELO was performed. Filters to assess methodological quality were applied to select the best quality studies. The strength of recommendation on a scale from A-D was based on the Oxford Centre for Evidence--based Medicine, Levels of Evidence 2009, allowing an unbiased opinion devoid of subjective viewpoints. The areas of interest for the studies comprised diagnosis, screening, treatment and a special section for hypothyroidism in pregnancy. Several questions based on diagnosis, screening, treatment of hypothyroidism in adult population and specifically in pregnant women were posed. Twenty six recommendations were created based on the answers to these questions. Despite the fact that evidence in some areas of hypothyroidism, such as therapy, is lacking, out of 279 references, 73% were Grade A and B, 8% Grade C and 19% Grade D. These evidence-based clinical guidelines on hypothyroidism will provide unified criteria for management of hypothyroidism throughout Latin America. Although most of the studies referred to are from all over the world, the point of view of thyroidologists from Latin America is also given.


Intimate partner violence functions as both a risk marker and risk factor for women's HIV infection: findings from Indian husband-wife dyads.
Female victims of intimate partner violence (IPV) consistently demonstrate elevated sexually transmitted infection/HIV prevalence. IPV is thought to function indirectly as a marker of abusive men's elevated sexually transmitted infection/HIV infection and/or directly via facilitating transmission to wives. The present examination utilizes a nationally representative sample of married Indian couples to test these mechanisms and determine whether (1) abusive husbands demonstrate higher HIV infection prevalence compared with nonabusive husbands and (2) the risk of wives' HIV infection based on husbands' HIV infection varies as a function of their exposure to IPV. The Indian National Family Health Survey-3 was conducted across all Indian states in 2005-2006. Analyses were limited to 20,425 husband-wife dyads, which provided both IPV data and HIV test results. Logistic regression models estimated the odds ratios and 95% confidence intervals (CIs) to evaluate the following associations: (1) husbands' HIV acquisition outside the marital relationship based on their perpetration of IPV and (2) wives' HIV infection based on husbands' HIV infection, as a function of their IPV exposure. One third (37.4%) of wives experienced IPV; 0.4% of husbands and 0.2% of wives were HIV infected. Compared with nonabusive husbands, abusive husbands demonstrated increased odds of HIV acquisition outside the marital relationship in adjusted models (adjusted odds ratio [AOR] = 1.91; 95% CI 1.11 to 3.27). Husbands' HIV infection was associated with increased HIV risk among wives; this risk was elevated 7-fold in abusive relationships in adjusted models (AOR = 7.22; 95% CI 1.05 to 49.88). Findings provide the first empirical evidence that abused wives face increased HIV risk based both on the greater likelihood of HIV infection among abusive husbands and elevated HIV transmission within abusive relationships. Thus, IPV seems to function both as a risk marker and as a risk factor for HIV among women, indicating the need for interwoven efforts to prevent both men's sexual risk and IPV perpetration.


Preservation of ovarian function.
In the last years, advances in diagnosis and new treatments of cancer patient have increased the life expectancy of children, adolescent and women with cancer. Unfortunately, the ovaries are very sensitive to chemio-radiotherapy that may induce the loss of ovarian function and fertility with consequent premature ovarian failure. The different cryopreservation options available for fertility preservation in cancer patients are embryo cryopreservation, oocyte cryopreservation and ovarian tissue cryopreservation. The choice depends on different parameters: the type and timing of cancer treatment, the type of disease, the patient's age. The advances in reproductive technology have made fertility preservation a real possibility for patients whether they are girls or young women whose gonadal function is threatened by natural premature menopause, or by cancer therapy or surgical sterilisation.


Co-overexpression of AVP1 and PP2A-C5 in Arabidopsis makes plants tolerant to multiple abiotic stresses.
Abiotic stresses are major threats to agricultural production. Drought and salinity as two of the major abiotic stresses cause billions of losses in agricultural productivity worldwide each year. Thus, it is imperative to make crops more tolerant. Overexpression of AVP1 or PP2A-C5 was previously shown to increase drought and salt stress tolerance, respectively, in transgenic plants. In this study, the hypothesis that co-overexpression of AVP1 and PP2A-C5 would combine their respective benefits and further improve salt tolerance was tested. The two genes were inserted into the same T-DNA region of the binary vector and then introduced into the Arabidopsis genome through Agrobacterium-mediated transformation. Transgenic Arabidopsis plants expressing both AVP1 and PP2A-C5 at relatively high levels were identified and analyzed. These plants displayed enhanced tolerance to NaCl compared to either AVP1 or PP2A-C5 overexpressing plants. They also showed tolerance to other stresses such as KNO3 and LiCl at harmful concentrations, drought, and phosphorus deficiency at comparable levels with either AVP1 or PP2A-C5 overexpressing plants. This study demonstrates that introducing multiple genes in single T-DNA region is an effective approach to create transgenic plants with enhanced tolerance to multiple stresses.


[Development of high boron content liposomes and their promising antitumor effect for neutron capture therapy].
High accumulation and selective delivery of boron into tumor tissue are the most important requirements to achieve the efficient cell-killing effect of boron neutron capture therapy (BNCT) that relies on the nuclear reaction of two essentially nontoxic species, boron-10 ((10)B) and thermal neutrons in boron-loaded tissues. Recent development of boron cluster lipids and their liposomal boron delivery system (BDS) are summarized in this article. Boron compounds that have no affinity to tumor can potentially be delivered to tumor tissues by liposomes, therefore, liposomal BDS would be one of the most attractive approaches for efficient BNCT of various cancers. There are two approaches for BDS: encapsulation of boron compounds into liposomes and incorporation of boron-conjugated lipids into the liposomal bilayer. The combination of both approaches has a potential for reduction of the total dose of liposomes without reducing the efficacy of BNCT.


Arsenic and benzo[a]pyrene co-exposure acts synergistically in inducing cancer stem cell-like property and tumorigenesis by epigenetically down-regulating SOCS3 expression.
Arsenic and benzo[a]pyrene (BaP) are among the most common environmental carcinogens causing lung cancer. Millions of people are exposed to arsenic through consuming arsenic-contaminated drinking water. High levels of BaP are found in well-done barbecued meat and other food in addition to cigarette smoke. Hence, arsenic and BaP co-exposure in humans is common. However, the combined health effect and the underlying mechanism of arsenic and BaP co-exposure have not been well-understood. In this study we investigate the combined tumorigenic effect of arsenic and BaP co-exposure and the mechanism using both cell culture and mouse models. It was found that arsenic (sodium arsenite, 1.0 µM) and BaP (2.5 µM) co-exposure for 30 weeks synergizes in inducing malignant transformation of immortalized non-tumorigenic human bronchial epithelial cells and cancer stem cell (CSC)-like property to enhance their tumorigenicity. In animal studies, A/J mice were exposed to arsenic in drinking water (sodium arsenite, 20 ppm) starting from gestation day 18. After birth, the dams continuously received arsenic water throughout lactation. At weaning (3 weeks of age), male offspring were exposed to either arsenic alone via drinking the same arsenic water or exposed to arsenic plus BaP. BaP was administered via oral gavage (3 µmol per mouse per week) once a week starting from 3 weeks of age for 8 weeks. All mice were euthanized 34-weeks after the first BaP exposure. It was found that mice in control and arsenic exposure alone group did not develop lung tumors. All mice in BaP exposure alone group developed lung adenomas. However, arsenic and BaP co-exposure synergized in increasing lung tumor multiplicity and tumor burden. Furthermore, 30% of mice in arsenic and BaP co-exposure group also developed lung adenocarcinomas. Mechanistic studies revealed that arsenic and BaP co-exposure does not produce more BPDE-DNA adducts than BaP exposure alone; but acts synergistically in activating aryl hydrocarbon receptor (AhR) to up-regulate the expression of a histone H3 lysine 9 methyltransferase SUV39H1 and increase the level of suppressive H3 lysine 9 dimethylation (H3K9me2), which down-regulates the expression of tumor suppressive SOCS3 leading to enhanced activation of Akt and Erk1/2 to promote cell transformation, CSC-like property and tumorigenesis. Together, these findings suggest that arsenic and BaP co-exposure synergizes in causing epigenetic dysregulation to enhance cell transformation, CSC-like property and tumorigenesis.


Psychosocial stress in pregnancy and its relation to the onset of premature labour.
A modified life events inventory was presented over a four-month period to 132 consecutive women going into spontaneous labour in Hull and Manchester. Three study groups were identified according to the duration of pregnancy. The levels of psychosocial stress in pregnancy were found to be particularly high in the mothers whose babies were born preterm. Stressful events may precipitate preterm labour in some women. The concept of antenatal care may have to be broadened if the incidence of premature labour and resulting perinatal mortality are to be reduced.


Fecundability and spontaneous abortions in women with self-reported oligo-amenorrhea and/or hirsutism: Northern Finland Birth Cohort 1966 Study.
Women with polycystic ovary syndrome (PCOS) suffer from anovulatory infertility and hospital-based studies suggest that they have an increased risk of spontaneous abortion. Our aim was to investigate the proportion of women, with self-reported oligo-amenorrhea and/or hirsutism in a general population, who had suffered from infertility, the percentage of them managing to conceive and their rate of spontaneous abortion. At age 31, a postal questionnaire including questions about hirsutism and oligo-amenorrhea was sent to all women from the population-based Northern Finland Birth Cohort 1966 (total n = 5889). Of these, 4535 (79.5%) answered the questionnaire, 1103 reported hirsutism and/or oligo/amenorrhea (symptomatic women) and 3420 were non-symptomatic. The fecundability ratio (FR) was defined as the probability of conception of a clinically detectable pregnancy within 12 months. The overall pregnancy (77.7% versus 75.6%) and spontaneous abortion (19.3% versus 18.6%) rates did not differ between the two groups and the risk of spontaneous abortion was not associated with body mass index (BMI), waist-to-hip ratio (WHR) or waist circumference. Symptomatic women had suffered more often from infertility than non-symptomatic women (19.4% versus 11.1%, P < 0.01). Oligo-amenorrhea and/or hirsutism (FR = 0.74, P < 0.001) and obesity (FR = 0.68, P = 0.002) were both independently associated with decreased fecundability, but symptomatic women had become pregnant and had one or two successful deliveries as often as non-symptomatic women. Women with self-reported oligo-amenorrhea and/or hirsutism had lower fecundability and suffered more often from infertility, but had at least one delivery as often as non-symptomatic women, and did not exhibit an increased risk of spontaneous abortion.


Observer perceptions of the justifiability of the actions of nations in conflict: The relative importance of conveying national vulnerability versus strength.
Because the underdog in a conflict typically gains the support of observers, nations will often adopt a narrative that persuades both their domestic following and international allies that they are the true victim in the conflict. Three survey studies were conducted to assess the perceptions of citizens of a third-party observer nation (Canada) in relation to two nations in conflict that differ in their historical persecution, namely the U.S. and Israel. Perceptions of the vulnerability of their safety and survival, and their strength to protect themselves against their opponents were hypothesized to mediate differences in the perceived justification for each nation's conflict actions. Study 1 (N = 91) supported this mediational model, with the U.S. seen as less vulnerable and more powerful than Israel, and perceptions of vulnerability accounting for differences in the justifiability of their respective conflict actions. Study 2 (N = 315) further demonstrated a moderating effect of Canadians' shared identity with the nations in conflict; only at lower levels of a shared identity was Israel perceived to be more vulnerable and the mediated relation with the perceived justifiability of its conflict actions retained. Study 3 was conducted 10 years later (2018), administering measures to an independent sample of Canadian participants (N = 300). Canadians were found to be significantly less likely to share a common identity with Americans than previously; once again, the mediating role of the perceived vulnerability of the nations in conflict and the justifiability of their actions was conditional on shared identification. The findings contribute to understanding influences on the credibility of victim claims by nations in conflict, as well as implications for how their actions are construed by citizens of a third-party observer nation.


Spray drift evaluation with point clouds data of 3D LiDAR as a potential alternative to the sampling method.
Spray drift is an inescapable consequence of agricultural plant protection operation, which has always been one of the major concerns in the spray application industry. Spray drift evaluation is essential to provide a basis for the rational selection of spray technique and working surroundings. Nowadays, conventional sampling methods with passive collectors used in drift evaluation are complex, time-consuming, and labor-intensive. The aim of this paper is to present a method to evaluate spray drift based on 3D LiDAR sensor and to test the feasibility of alternatives to passive collectors. Firstly, a drift measurement algorithm was established based on point clouds data of 3D LiDAR. Wind tunnel tests included three types of agricultural nozzles, three pressure settings, and five wind speed settings were conducted. LiDAR sensor and passive collectors (polyethylene lines) were placed downwind from the nozzle to measure drift droplets in a vertical plane. Drift deposition volume on each line and the number of LiDAR droplet points in the corresponding height of the collecting line were calculated, and the influencing factors of this new method were analyzed. The results show that 3D LiDAR measurements provide a rich spatial information, such as the height and width of the drift droplet distribution, etc. High coefficients of determination (R 2 > 0.75) were observed for drift points measured by 3D LiDAR compared to the deposition volume captured by passive collectors, and the anti-drift IDK12002 nozzle at 0.2 MPa spray pressure has the largest R 2 value, which is 0.9583. Drift assessment with 3D LiDAR is sensitive to droplet density or drift mass in space and nozzle initial droplet spectrum; in general, larger droplet density or drift mass and smaller droplet size are not conducive to LiDAR detection, while the appropriate threshold range still needs further study. This study demonstrates that 3D LiDAR has the potential to be used as an alternative tool for rapid assessment of spray drift.


Comparison of metabolic syndrome incidence among schizophrenia patients treated with aripiprazole versus olanzapine or placebo.
Metabolic syndrome is a strong determinant of new-onset diabetes and coronary heart disease in general populations. Given the higher prevalence of metabolic syndrome among mentally ill patients, the syndrome poses a greater health risk to this population. Atypical antipsychotic treatment may exacerbate this condition. We compared both the rate and incidence of metabolic syndrome among schizophrenia patients (DSM-IV criteria) treated with the atypical antipsychotics aripiprazole or olanzapine or placebo from 4 double-blind, randomized, controlled clinical trials. Metabolic syndrome was defined according to the Third Adult Treatment Panel (ATP III) Guidelines as the presence on follow-up of 3 of the following abnormalities: waist circumference > 102 cm if male and > 88 cm if female, high density lipoprotein (HDL) < 40 mg/dL if male and < 50 mg/dL if female, diastolic blood pressure >or= 85 mm Hg or systolic blood pressure >or= 130 mm Hg, fasting triglycerides >or= 150 mg/dL, fasting plasma glucose >or= 110 mg/dL. Both the rate of metabolic syndrome and the person-time incidence were computed from the on-treatment follow-up. In the placebo-controlled trials, the rate of metabolic syndrome was 25.8% among 155 placebo patients and 19.9% for 267 aripiprazole patients (p = .466 by stratified log rank). The incidence of metabolic syndrome was 14.3% for 91 placebo patients versus 5.3% for 151 aripiprazole patients (p < .001). In the active comparator trials, patients treated with olanzapine (N = 373) versus aripiprazole (N = 380) exhibited rates of 41.6% and 27.9%, respectively (p = .0002). Incidence rates were 27.4% for 212 olanzapine patients versus 15.7% for 198 aripiprazole patients (p = .0055). Both the rate and incidence of clinically relevant metabolic syndrome differ according to the choice of antipsychotic agent. The association between metabolic syndrome and treatment warrants careful consideration in the choice of antipsychotic agents.


Association Between Modifiable Risk Factors and Pharmaceutical Expenditures Among Adults With Atherosclerotic Cardiovascular Disease in the United States: 2012-2013 Medical Expenditures Panel Survey.
Atherosclerotic cardiovascular disease (ASCVD) causes most deaths in the United States and accounts for the highest healthcare spending. The association between the modifiable risk factors (MRFs) of ASCVD and pharmaceutical expenditures are largely unknown. We examined the association between MRFs and pharmaceutical expenditures among adults with ASCVD using the 2012 and 2013 Medical Expenditure Panel Survey. A 2-part model was used while accounting for the survey's complex design to obtain nationally representative results. All costs were adjusted to 2013 US dollars using the gross domestic product deflator. The annual total pharmaceutical expenditure among those with ASCVD was $71.6 billion, 33% of which was for medications for cardiovascular disease and 14% medications for diabetes mellitus. The adjusted relationship between MRFs and pharmaceutical expenditures showed significant marginal increase in average annual pharmaceutical expenditure associated with inadequate physical activity ($519 [95% confidence interval (CI), $12-918; P=0.011]), dyslipidemia ($631 [95% CI, $168-1094; P=0.008]), hypertension: ($1078 [95% CI, $697-1460; P<0.001)], and diabetes mellitus ($2006 [95% CI, $1470-2542]). Compared with those with optimal MRFs (0-1), those with average MRFs (2-3) spent an average of $1184 (95% CI, $805-1564; P<0.001) more on medications, and those with poor MRFs (≥4) spent $2823 (95% CI, $2338-3307; P<0.001) more. Worsening MRFs were proportionally associated with higher annual pharmaceutical expenditures among patients with established ASCVD regardless of non-ASCVD comorbidity. In-depth studies of the roles played by other factors in this association can help reduce medication-related expenditures among ASCVD patients.


Mathematical modeling of Erk activity waves in regenerating zebrafish scales.
Erk signaling regulates cellular decisions in many biological contexts. Recently, we have reported a series of Erk activity traveling waves that coordinate regeneration of osteoblast tissue in zebrafish scales. These waves originate from a central source region, propagate as expanding rings, and impart cell growth, thus controlling tissue morphogenesis. Here, we present a minimal reaction-diffusion model for Erk activity waves. The model considers three components: Erk, a diffusible Erk activator, and an Erk inhibitor. Erk stimulates both its activator and inhibitor, forming a positive and negative feedback loop, respectively. Our model shows that this system can be excitable and propagate Erk activity waves. Waves originate from a pulsatile source that is modeled by adding a localized basal production of the activator, which turns the source region from an excitable to an oscillatory state. As Erk activity periodically rises in the source, it can trigger an excitable wave that travels across the entire tissue. Analysis of the model finds that positive feedback controls the properties of the traveling wavefront and that negative feedback controls the duration of Erk activity peak and the period of Erk activity waves. The geometrical properties of the waves facilitate constraints on the effective diffusivity of the activator, indicating that waves are an efficient mechanism to transfer growth factor signaling rapidly across a large tissue.


MITA/STING and Its Alternative Splicing Isoform MRP Restrict Hepatitis B Virus Replication.
An efficient clearance of hepatitis B virus (HBV) requires the coordinated work of both the innate and adaptive immune responses. MITA/STING, an adapter protein of the innate immune signaling pathways, plays a key role in regulating innate and adaptive immune responses to DNA virus infection. Previously, we identified an alternatively spliced isoform of MITA/STING, called MITA-related protein (MRP), and found that MRP could specifically block MITA-mediated interferon (IFN) induction while retaining the ability to activate NF-κB. Here, we asked whether MITA/STING and MRP were able to control the HBV replication. Both MITA/STING and MRP significantly inhibited HBV replication in vitro. MITA overexpression stimulated IRF3-IFN pathway; while MRP overexpression activated NF-κB pathway, suggesting these two isoforms may inhibit HBV replication through different ways. Using a hydrodynamic injection (HI) mouse model, we found that HBV replication was reduced following MITA/STING and MRP expression vectors in mice and was enhanced by the knockout of MITA/STING (MITA/STING-/-). The HBV specific humoral and CD8+ T cell responses were impaired in MITA/STING deficient mice, suggesting the participation of MITA/STING in the initiation of host adaptive immune responses. In summary, our data suggest that MITA/STING and MRP contribute to HBV control via modulation of the innate and adaptive responses.


Who sends the email? Using electronic surveys in violence research.
Students aged 16-24 years are at greatest risk for interpersonal violence and the resulting short and long-term health consequences. Electronic survey methodology is well suited for research related to interpersonal violence. Yet methodological questions remain about best practices in using electronic surveys. While researchers often indicate that potential participants receive multiple emails as reminders to complete the survey, little mention is made of the sender of the recruitment email. The purpose of this analysis is to describe the response rates from three violence-focused research studies when the recruitment emails are sent from a campus office, researcher or survey sampling firm. Three violence-focused studies were conducted about interpersonal violence among college students in the United States. Seven universities and a survey sampling firm were used to recruit potential participants to complete an electronic survey. The sender of the recruitment emails varied within and across the each of the studies depending on institutional review boards and university protocols. An overall response rate of 30% was noted for the 3 studies. Universities in which researcher-initiated recruitment emails were used had higher response rates compared to universities where campus officials sent the recruitment emails. Researchers found lower response rates to electronic surveys at Historically Black Colleges or Universities and that other methods were needed to improve response rates. The sender of recruitment emails for electronic surveys may be an important factor in response rates for violence-focused research. For researchers identification of best practices for survey methodology is needed to promote accurate disclosure and increase response rates.


Multivariate analysis of variations in intrinsic foot musculature among hominoids.
Comparative analysis of the foot muscle architecture among extant great apes is important for understanding the evolution of the human foot and, hence, human habitual bipedal walking. However, to our knowledge, there is no previous report of a quantitative comparison of hominoid intrinsic foot muscle dimensions. In the present study, we quantitatively compared muscle dimensions of the hominoid foot by means of multivariate analysis. The foot muscle mass and physiological cross-sectional area (PCSA) of five chimpanzees, one bonobo, two gorillas, and six orangutans were obtained by our own dissections, and those of humans were taken from published accounts. The muscle mass and PCSA were respectively divided by the total mass and total PCSA of the intrinsic muscles of the entire foot for normalization. Variations in muscle architecture among human and extant great apes were quantified based on principal component analysis. Our results demonstrated that the muscle architecture of the orangutan was the most distinctive, having a larger first dorsal interosseous muscle and smaller abductor hallucis brevis muscle. On the other hand, the gorilla was found to be unique in having a larger abductor digiti minimi muscle. Humans were distinguished from extant great apes by a larger quadratus plantae muscle. The chimpanzee and the bonobo appeared to have very similar muscle architecture, with an intermediate position between the human and the orangutan. These differences (or similarities) in architecture of the intrinsic foot muscles among humans and great apes correspond well to the differences in phylogeny, positional behavior, and locomotion.


Moscatilin induces apoptosis in human colorectal cancer cells: a crucial role of c-Jun NH2-terminal protein kinase activation caused by tubulin depolymerization and DNA damage.
To study the effect of moscatilin (purified from the stem of orchid Dendrobrium loddigesii) on the proliferation of human colorectal cancer HCT-116 cells in vitro and in vivo. The growth inhibition of moscatilin was screened on several human cancer cell lines. The effect of moscatilin on tubulin was detected in vitro. Following moscatilin treatment on HCT-116 cells, c-Jun NH(2)-terminal protein kinase (JNK) and caspase activation was studied by Western blot analysis, and DNA damage was done by Comet assay. Specific JNK inhibitor SP600125 was cotreated to reverse moscatilin-induced apoptosis. Tumor growth inhibition of moscatilin was done on HCT-116 xenograft models. Moscatilin induced a time-dependent arrest of the cell cycle at G(2)-M, with an increase of cells at sub-G(1). Moscatilin inhibited tubulin polymerization, suggesting that it might bind to tubulins. Moscatilin also induced the phosphorylation of JNK1/2. SP600125 significantly inhibited the activation of caspase-9 and caspase-3 and the subsequent moscatilin-induced apoptosis. The data suggest that JNK activation may contribute to moscatilin-mediated apoptosis signaling. A parallel experiment showed that SP600125 significantly inhibits Taxol- and vincristine-induced HCT-116 cell apoptosis. This suggests that the JNK activation may be a common mechanism for tubulin-binding agents. Moreover, moscatilin induces DNA damage, phosphorylation of H2AX and p53, and up-regulation of p21. Our HCT-116 xenograft models show the in vivo efficacy of moscatilin. In summary, our results suggest that moscatilin induces apoptosis of colorectal HCT-116 cells via tubulin depolymerization and DNA damage stress and that this leads to the activation of JNK and mitochondria-involved intrinsic apoptosis pathway.


Enset in Ethiopia: a poorly characterized but resilient starch staple.
Enset (Ensete ventricosum, Musaceae) is an African crop that currently provides the staple food for approx. 20 million Ethiopians. Whilst wild enset grows over much of East and Southern Africa and the genus extends across Asia to China, it has only ever been domesticated in the Ethiopian Highlands. Here, smallholder farmers cultivate hundreds of landraces across diverse climatic and agroecological systems. Enset has several important food security traits. It grows over a relatively wide range of conditions, is somewhat drought-tolerant, and can be harvested at any time of the year, over several years. It provides an important dietary starch source, as well as fibres, medicines, animal fodder, roofing and packaging. It stabilizes soils and microclimates and has significant cultural importance. In contrast to the other cultivated species in the family Musaceae (banana), enset has received relatively little research attention. Here, we review and critically evaluate existing research, outline available genomic and germplasm resources, aspects of pathology, and explore avenues for crop development. Enset is an underexploited starch crop with significant potential in Ethiopia and beyond. Research is lacking in several key areas: empirical studies on the efficacy of current agronomic practices, the genetic diversity of landraces, approaches to systematic breeding, characterization of existing and emerging diseases, adaptability to new ranges and land-use change, the projected impact of climate change, conservation of crop wild relatives, by-products or co-products or non-starch uses, and the enset microbiome. We also highlight the limited availability of enset germplasm in living collections and seedbanks, and the lack of knowledge of reproductive and germination biology needed to underpin future breeding. By reviewing the current state of the art in enset research and identifying gaps and opportunities, we hope to catalyse the development and sustainable exploitation of this neglected starch crop.


Fruit, Mediterranean-style, and high-fat and -sugar diets are associated with the risk of night sweats and hot flushes in midlife: results from a prospective cohort study.
Diet has been suggested to be a potential risk factor for vasomotor menopausal symptoms (VMSs), ie, hot flushes and night sweats. We investigated the associations between dietary patterns and risk of VMSs by using data from middle-aged women born between 1946 and 1951 in the Australian Longitudinal Study on Women's Health. A prospective cohort study of 6040 women with a natural menopause were followed up at 3-y intervals over 9 y. Dietary intake was assessed at baseline in 2001, and the presence of VMSs was assessed at baseline and follow-up. Factor analysis and generalized estimating equation models for binary repeated measures were performed. Six dietary patterns were identified from factor analysis: cooked vegetables, fruit, Mediterranean style, meat and processed meat, dairy, and high fat and sugar. A higher consumption of the fruit or Mediterranean-style diet was inversely associated with VMSs in a comparison of the top with the bottom quintile, with adjusted ORs of 0.81 (95% CI: 0.71, 0.93; P-trend = 0.0009) and 0.80 (95% CI: 0.69, 0.92; P-trend = 0.0004), respectively. The high-fat and -sugar pattern increased the risk of VMSs in a comparison of the top with the bottom quintile, with an adjusted OR of 1.23 (95% CI: 1.05, 1.44; P-trend = 0.02). Consumption of a fruit or Mediterranean-style diet decreased the risk of reporting VMSs, whereas consumption of a high-fat and -sugar diet increased the risk of VMSs. These results may eventually lead to a basis for the development of dietary preventive measures for VMSs.


Do cardiovascular risk factors explain the link between white matter hyperintensities and brain volumes in old age? A population-based study.
White matter hyperintensities (WMHs) and brain atrophy frequently coexist in older people. However, it is unclear whether the association between these two brain lesions is dependent on the aging process, a vascular mechanism or genetic susceptibility. It was therefore investigated whether the association between load of WMHs and brain atrophy measures is related to age, vascular risk factors (VRFs) or the APOE-ε4 allele. This population-based study included 492 participants (age ≥60 years, 59.6% women) free of dementia and stroke. Data on demographics, VRFs and APOE genotypes were collected through interviews, clinical examination and laboratory tests. WMHs on magnetic resonance images were assessed using manual visual rating and automatic volumetric segmentation. Hippocampal and ventricular volumes were manually delineated, whereas total gray matter (GM) volume was measured by automatic segmentation. Data were analyzed with multivariate linear regression models. More global WMHs, assessed using either a visual rating scale or a volumetric approach, were significantly associated with lower GM volume and higher ventricular volume; the associations remained significant after adjusting for age, VRFs and the APOE-ε4 allele. In contrast, the association between global WMHs and hippocampal volume was no longer significant after adjusting for age, whereas adjustment for VRFs and APOE-ε4 had no influential effect. The association of global WMHs with lower GM volume and higher ventricular volume is independent of age, VRFs and APOE-ε4 allele, suggesting that the process of cerebral microvascular disease and neurodegeneration are associated independently of the normal aging process, vascular mechanisms or genetic susceptibility.


A microengineered pathophysiological model of early-stage breast cancer.
A mounting body of evidence in cancer research suggests that the local microenvironment of tumor cells has a profound influence on cancer progression and metastasis. In vitro studies on the tumor microenvironment and its pharmacological modulation, however, are often hampered by the technical challenges associated with creating physiological cell culture environments that integrate cancer cells with the key components of their native niche such as neighboring cells and extracellular matrix (ECM) to mimic complex microarchitecture of cancerous tissue. Using early-stage breast cancer as a model disease, here we describe a biomimetic microengineering strategy to reconstitute three-dimensional (3D) structural organization and microenvironment of breast tumors in human cell-based in vitro models. Specifically, we developed a microsystem that enabled co-culture of breast tumor spheroids with human mammary ductal epithelial cells and mammary fibroblasts in a compartmentalized 3D microfluidic device to replicate microarchitecture of breast ductal carcinoma in situ (DCIS). We also explored the potential of this breast cancer-on-a-chip system as a drug screening platform by evaluating the efficacy and toxicity of an anticancer drug (paclitaxel). Our microengineered disease model represents the first critical step towards recapitulating pathophysiological complexity of breast cancer, and may serve as an enabling tool to systematically examine the contribution of the breast cancer microenvironment to the progression of DCIS to an invasive form of the disease.


Human leukemia inhibitory factor inhibits development of experimental atherosclerosis.
The effect of human leukemia inhibitory factor (hLIF) on the development of atherosclerosis was investigated in an experimental animal model. Two conditions were examined: one in which lesions could arise because of the influence of both "injury" (cuffed vessel) and diet and one in which only the effect of diet could be significant in other areas of the vasculature (aorta). At time zero, the right carotid artery of rabbits (n = 32) was ensheathed in a soft Silastic cuff, and an osmotic minipump (2-mL capacity; 2.5 microL/h; 28 days) containing either hLIF or saline was inserted into the peritoneal cavity. Rabbits were divided into four groups (n = 8): group 1 received normal diet/saline; group 2, normal diet/LIF (30 micrograms.kg-1.d-1); group 3, 1% cholesterol diet/saline; and group 4, 1% cholesterol diet/LIF (30 micrograms.kg-1.d-1). After 28 days, the cholesterol diet (group 3) resulted in a sixfold increase in plasma cholesterol level compared with group 1 rabbits on a normal diet (3.80 +/- 0.50 versus 0.55 +/- 0.01 mmol/L). This was significantly lower (P = .01) with hLIF treatment in group 4 rabbits (2.80 +/- 0.44 mmol/L). Group 2 rabbits had higher aortic tissue cholesterol levels (1.40 +/- 0.35 mg/g) compared with group 1 rabbits on a normal diet (0.10 +/- 0.06 mg/g) (P = .01), whereas hLIF treatment decreased tissue cholesterol levels by 60% in group 4 rabbits (0.60 +/- 0.05 mg/g) (P = .01). Group 3 rabbits developed lipid-filled lesions covering 63.25 +/- 17.66% of the thoracic aorta surface, whereas lesions were significantly reduced (9.88 +/- 8.79%) (P = .01) with LIF treatment (group 4).(ABSTRACT TRUNCATED AT 250 WORDS)


Transportability and feasibility of Social Cognition And Interaction Training (SCIT) in community settings.
Social Cognition and Interaction Training (SCIT) is a manual-based group intervention designed to improve social cognition in schizophrenia. Initial studies conducted by the developers of SCIT suggest that the intervention has promise in ameliorating social cognitive dysfunction in both inpatients and outpatients. The current study is a preliminary evaluation of SCIT in community samples. An uncontrolled, pre-post design was used in this initial feasibility study. A collaborative research-clinical approach was employed to enable research evaluation while also meeting the administrative goals of participating clinics, and working within the constraints of real-world clinical practice. Transportability, acceptability, and feasibility of SCIT were evaluated in terms of pre- and post-treatment evaluations, client attendance data (N = 50), and clinic administrators' decisions about whether to integrate SCIT into regular programming. Social-cognitive outcome measures assessed emotion perception, Theory of Mind, and attributional bias. These support the transportability, acceptability, and feasibility of SCIT in community settings. SCIT has been integrated into routine practice at several test sites. Tentative support was found for improvement in emotion perception and Theory of Mind, but not attributional bias. SCIT may be a promising intervention for community agencies serving individuals with psychotic disorders who seek to improve their social functioning.


Protective effects of farnesoid X receptor (FXR) on hepatic lipid accumulation are mediated by hepatic FXR and independent of intestinal FGF15 signal.
There is a growing evidence that bile acids are involved in the regulation of triglyceride-, cholesterol-homoeostasis and fat absorption. In this study organ-specific Fxr knockout mice were used to further investigate the influence of farnesoid X receptor FXR in lipogenesis. Liver- and intestine-specific Fxr knockout mice were fed a 1% cholesterol diet for 28 days. Histological examination of frozen tissue sections included Sudan III/H&E, BODIPY staining and liver X receptor (LXR) immunohistochemistry. Liver triglycerides, serum cholesterol, serum bile acids and nuclear LXR protein were measured. mRNA expression of several genes involved in bile acid-, cholesterol-homoeostasis and lipogenesis was quantified by real-time PCR. Hepatic FXR deficiency contributes to lipid accumulation under 1% cholesterol administration which is not observed in intestinal Fxr knockout mice. Strong lipid accumulation, characterized by larger vacuoles could be observed in hepatic Fxr knockout sections, while intestinal Fxr knockout mice show no histological difference to controls. In addition, these mice have the ability to maintain normal serum cholesterol and bile acid levels. Hepatic Fxr knockouts were characterized by elevated triglycerides and bile acid levels. Expression level of LXR was significantly elevated under control and 1% cholesterol diet in hepatic Fxr knockout mice and was followed by concomitant lipogenic target gene induction such as Fas and Scd-1. This protective FXR effect against hepatic lipid accumulation was independent of intestinal Fgf15 induction. These results show that the principal site of protective bile acid signalling against lipid accumulation is located in the liver since the absence of hepatic but not intestinal FXR contributes to lipid accumulation under cholesterol diet.


Low investment in sexual reproduction threatens plants adapted to phosphorus limitation.
Plant species diversity in Eurasian wetlands and grasslands depends not only on productivity but also on the relative availability of nutrients, particularly of nitrogen and phosphorus. Here we show that the impacts of nitrogen:phosphorus stoichiometry on plant species richness can be explained by selected plant life-history traits, notably by plant investments in growth versus reproduction. In 599 Eurasian sites with herbaceous vegetation we examined the relationship between the local nutrient conditions and community-mean life-history traits. We found that compared with plants in nitrogen-limited communities, plants in phosphorus-limited communities invest little in sexual reproduction (for example, less investment in seed, shorter flowering period, longer lifespan) and have conservative leaf economy traits (that is, a low specific leaf area and a high leaf dry-matter content). Endangered species were more frequent in phosphorus-limited ecosystems and they too invested little in sexual reproduction. The results provide new insight into how plant adaptations to nutrient conditions can drive the distribution of plant species in natural ecosystems and can account for the vulnerability of endangered species.


[Observation on the therapeutic effect of needling method for harmonizing spleen-stomach on diabetic gastroparesis].
To compare the therapeutic effects of acupuncture and Motilium on diabetic gastroparesis (DGP). Seventy-two cases of DGP were randomly divided into a treatment group and a control group. The treatment group were treated with needling method for harmonizing spleen-stomach as main, with Quchi (LI 11), Hegu (LI 4), Zhongwan (CV 12), Zusanli (ST 36), Fenglong (ST 40), Yinlingquan (SP 9), Sanyinjiao (SP 6), Xuehai (SP 10), Diji (SP 8), and others selected, twice each day, 10 days constituting one course, with an in terval of 2 days; the control group were treated with oral administration of Motilium 10 mg, 3 times each day, 30 min before meals. The total effective rate of 91.7% in the treatment group was better than 77.8% in the control group (P < 0.05). The therapeutic effect of the needling method for harmonizing spleen-stomach on diabetic gastroparesis is better than that of Motilium.