Strengthening the Case for Cluster Set Resistance Training in Aged and Clinical Settings: Emerging Evidence, Proposed Benefits and Suggestions.
Resistance training (RT) is a fundamental component of exercise prescription aimed at improving overall health and function. RT techniques such as cluster set (CS) configurations, characterized by additional short intra-set or inter-repetition rest intervals, have been shown to maintain acute muscular force, velocity, and 'power' outputs across a RT session, and facilitate positive longer-term neuromuscular adaptations. However, to date CS have mainly been explored from a human performance perspective despite potential for application in health and clinical exercise settings. Therefore, this current opinion piece aims to highlight emerging evidence and provide a rationale for why CS may be an advantageous RT technique for older adults, and across several neurological, neuromuscular, cardiovascular and pulmonary settings. Specifically, CS may minimize acute fatigue and adverse physiologic responses, improve patient tolerance of RT and promote functional adaptations (i.e., force, velocity, and power). Moreover, we propose that CS may be a particularly useful exercise rehabilitation technique where injury or illness, persistent fatigue, weakness and dysfunction exist. We further suggest that CS offer an alternative RT strategy that can be easily implemented alongside existing exercise/rehabilitation programs requiring no extra cost, minimal upskilling and/or time commitment for the patient and professional. In light of the emerging evidence and likely efficacy in clinical exercise practice, future research should move toward further direct investigation of CS-based RT in a variety of adverse health conditions and across the lifespan given the already demonstrated benefits in healthy populations.


The decrease of mitochondrial substrate uptake caused by trialkyltin and trialkyl-lead compounds in chloride media and its relevance to inhibition of oxidative phosphorylation.
1. In a 100 mM-KCl medium (pH 6.8) containing ATP, triethyltin (1 muM) causes a decrease in the uptake of pyruvate, malate, citrate or beta-hydroxybutyrate by rat liver mitochondria, but no decrease is observed in a 100 mM-KNO3 medium. This response is not modified by the presence of rotenone in the incubation medium. 2. In the KCl medium at least 1 muM-triethyltin is required to cause maximum inhibition of pyruvate uptake. 3. Trimethyltin, tributyltin and the trialkyl-lead analogues at 1 muM, to varying degrees, also cause a decrease in pyruvate uptake by mitochondria only in the KCl medium. 4. Triethyltin stimulates resting respiration of mitochondria with all the substrates tested in the KCl medium but not in the KNO3 medium, yet this stimulation of O2 uptake occurs under conditions when substrate uptake is decreased. 5. In contrast, both O2 uptake during state 3 respiration and ATP synthesis when linked to the oxidation of pyruvate, malate or citrate are strongly inhibited by 1 muM-triethyltin in a KCl medium, but O2 uptake and ATP synthesis during the oxidation of beta-hydroxybutyrate are only slightly affected. In a KNO3 medium O2 uptake and ATP synthesis linked to the oxidation of all substrates are only slightly affected. 6. The relevance of the decrease in substrate uptake by mitochondria caused by triethyltin in a KCl medium to the greater sensitivity of various mitochondrial functions observed in vitro is discussed. It is concluded that decrease of matrix substrate content is probably not the major cause of the greater sensitivity of oxidative phosphorylation to triethyltin in a KCl medium observed previously.


Pain and function in patients after primary unicompartmental and total knee arthroplasty.
Unicompartmental knee arthroplasty has received renewed interest; however, its short-term advantages over total knee arthroplasty should be weighed against a higher risk of reoperation. Information regarding pain and function after unicompartmental and total knee arthroplasty is therefore needed. Patient-reported data regarding pain and function were collected, at least two years postoperatively and by way of postal questionnaire, from 1344 patients who were listed on the Norwegian Arthroplasty Register as having had an unrevised primary total knee arthroplasty (972 patients) or a unicompartmental knee arthroplasty (372 patients) for the treatment of arthritis. Outcomes were assessed (with a score of zero indicating the worst possible outcome and a score of 100 indicating the best possible outcome) with use of the five subscales from the Knee Injury and Osteoarthritis Outcome Score, the scores from visual analog scales regarding degree of pain and satisfaction with the surgery, and the change in index score (from preoperative to postoperative) on the EuroQol-5D health-related quality-of-life instrument. We also used all forty-two questions from the Knee Injury and Osteoarthritis Outcome Score as outcome measures. To be regarded as clinically significant, the differences needed to be eight units for the Knee Injury and Osteoarthritis Outcome Score outcomes, ten units for the pain and satisfaction scales, and 0.4 unit for the detailed Knee Injury and Osteoarthritis Outcome Score questions. Unicompartmental knee implants performed better than total knee implants on the Knee Injury and Osteoarthritis Outcome subscales for "Symptoms" (adjusted mean difference, 2.7; p = 0.04), "Function in Daily Living" (adjusted mean difference, 4.1; p = 0.01), and "Function in Sport and Recreation" (adjusted mean difference, 5.4; p = 0.006). Of the forty-two analyses of the detailed questions, four differences were significant. These differences were in favor of unicompartmental knee arthroplasty, but only the question "Can you bend your knee fully?" reached the level of clinical significance. We found only small or no differences in pain and function between the scores, at least two years following surgery, of patients who underwent unicompartmental knee arthroplasty and those of patients who underwent total knee arthroplasty; however, patients with unicompartmental knee implants had fewer problems with activities that involved bending the knee.


Mesenchymal cells reactivate Snail1 expression to drive three-dimensional invasion programs.
Epithelial-mesenchymal transition (EMT) is required for mesodermal differentiation during development. The zinc-finger transcription factor, Snail1, can trigger EMT and is sufficient to transcriptionally reprogram epithelial cells toward a mesenchymal phenotype during neoplasia and fibrosis. Whether Snail1 also regulates the behavior of terminally differentiated mesenchymal cells remains unexplored. Using a Snai1 conditional knockout model, we now identify Snail1 as a regulator of normal mesenchymal cell function. Snail1 expression in normal fibroblasts can be induced by agonists known to promote proliferation and invasion in vivo. When challenged within a tissue-like, three-dimensional extracellular matrix, Snail1-deficient fibroblasts exhibit global alterations in gene expression, which include defects in membrane type-1 matrix metalloproteinase (MT1-MMP)-dependent invasive activity. Snail1-deficient fibroblasts explanted atop the live chick chorioallantoic membrane lack tissue-invasive potential and fail to induce angiogenesis. These findings establish key functions for the EMT regulator Snail1 after terminal differentiation of mesenchymal cells.


[O.V. Palladin Institute of Biochemistry of the Ukrainian National Academy of Sciences--75 years].
The article deals with a short record including the information about the history of creation and main developmental stages of the first and presently the single in Ukraine Palladin Institute of Biochemistry of National Academy of Sciences of Ukraine. The record contains the main achievements of the Institute scientific subdivisions for the 75 years period of their creative work in the field of the most urgent problems of fundamental and applied biochemistry. As well it displays the information about comprehensive and extensive publishing and educational activity conducted by the staff,, the work on training the scientific manpower of the highest qualification--Doctors of Science (D.Sc.) and Philosophy Doctors (Ph. D.), active participation of the research scientists in attracting to science the talented young people representing the students and school-children taking interest in the biological chemistry. The article shows the great role of the Institute famous scientists-biochemists in forming some scientific schools on functional biochemistry acknowledged in the world biochemistry. There are also some data about the each of nine scientific departments of the Institute for the period of last 20-25 years of their activity in the field of the most urgent problems of the contemporary biochemistry. These are the following Departments: Neurochemistry, Metabolism Regulation, Muscular Biochemistry, Protein Structure Functions, Coenzymes Biochemistry, Enzymes Chemistry and Biochemistry, Molecular Immunology, Biochemistry of Lipids, Sensor and Regulator Systems Biochemistry. There is also a short review regarding the history of foundation, development and scientific achievements of the Institute division in L'viv including four scientific departments: Biochemistry of Cellular Differentiation, Biochemical Genetics, Regulation of Low Molecular Compounds Synthesis, Regulation of Cells Differentiation.


Relationships between typical histopathological hallmarks and the ferritin in the hippocampus from patients with Alzheimer's disease.
Oxidative stress is one of the possible mechanisms of neurodegeneration. One of the elements of this mechanism are altered iron homeostasis and changes concerning of iron metabolism regulatory proteins. The primary iron storage protein in cells is ferritin, composed of heavy (H) and light (L) chains. In brain tissue neurons contain mainly ferritin H-chains, whereas glial cells are rich in L-chains. To the best of our knowledge, this is the first study that compares structure of ferritin and histopathological hallmarks in hippocampal tissue affected by the pathological process of Alzheimer's disease (AD). Our data indicate a statistically significant correlation between the concentration of L chains of ferritin, the H/L ratio and the amount of senile plaques in the subiculum, CA1 and CA4 sectors of the hippocampus (p<0.001, p=0.025, p=0.029). A significant correlation was also found between the concentration of L-ferritin and neuronal loss (p=0.0026). These findings indicate an important role of ferritin light chains in neurodegeneration, that is linked to chronic inflammation processes and the associated activation of the microglia rich of L chains.


Use of artificial intelligence in structure-affinity correlations of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) receptor ligands.
The Computer-Automated Structure Evaluation (CASE) Program, an expert system that automatically selects relevant descriptors for structure-activity relationships, has been used to analyze the binding of various ligands to the tetrachloro-dibenzo-p-dioxin (TCDD) receptor or Ah receptor. Two databases were analyzed. One database contained 136 polycyclic aromatic hydrocarbons (PAH), substituted dibenzo-p-dioxins, dibenzofurans and biphenyls whose binding affinities were measured by a sucrose density gradient technique. The other 87 compound database contained PAH, nitro-PAH, halo-PAH and N-heterocycles. Their binding affinities were measured by the electrofocusing assay. Within each training set significant correlations between the affinity for the TCDD receptor and relevant molecular fragments identified by the CASE program were observed. Among the halogenated aromatic hydrocarbons, fragments containing lateral halogens and a longitudinal hydrogen appeared important for TCDD receptor binding. The fragments of PAH and heterocyclic compounds that were most activating with respect to TCDD receptor binding were found to contain the classical 'bay' region and were in fact identical to the fragments found previously to be related to carcinogenicity. It was found that the activating fragments from PAH and heterocyclic compounds were different from those found within the halogenated compounds such as dibenzo-p-dioxins, dibenzofurans and biphenyls. One interpretation of the data is that two different recognition sites may be involved in Ah receptor binding.


Cognition in soccer and futsal: evidence of validity of a 4-instrument protocol to assess executive functioning among women athletes.
Evidence suggests that success in sports, especially soccer and futsal are linked to higher levels of executive functioning. Still, the literature does not present a homogeneous set of instruments to measure executive functions, which leads to large variability in results. In this paper, we assembled four already recognised measures to propose a valid 4-instrument protocol to assess executive functions among soccer and futsal athletes. We conducted two studies to validate the proposed protocol. We addressed known-groups validity and latent structure in Study 1 for data collected on 105 female soccer and futsal athletes from elite and lower-division clubs. Findings pointed to partial validity of the protocol - with working memory and inhibition showing the best results. For Study 2, we used performance data from 51 elite female soccer players collected throughout a season of the first division league to assess predictive validity. Our protocol was able to partially replicate previous findings and added new insights on how working memory, processing speed and higher-level executive functions might play different roles for goalscoring and assist-making skills. Specifically, study 1 did not find a significant difference between elite and lower-division athletes in higher-order executive functions as in previous studies, but it did find on visual working memory and inhibitory control which weights towards higher demands of core executive functions. On the other hand, study 2 yielded significant results for processing speed and visual working memory to predict assists among elite soccer players, but not inhibitory control as previous findings suggested. Regardless, the proposed 4-instrument protocol showed adequate criterion and structural validity in both studies.


Double edged effect of gum-resin of ferula assa-foetida on lifespan of neurons.
Based on knowledge from traditional herbal medicine, Ferula assa-foetida (asafoetida) has several therapeutic applications but there is less knowledge about its effect on neurons. In order to evaluate neuronal differentiation, neuronal like cells were stained against neuronal specific markers β-Tubulin III and MAP2. After establishment of neuronal differentiation in cultured cells, aqueous extract of gum-resin of asafoetida were applied on culture medium of neurons with different concentrations then survival rate of neurons were evaluated by cell counting and methyl tetrazolium bromide (MTT) tests. The results showed that asafoetida gum resin particularly with 0.01 and 1 µg/ml concentrations could improve survival rate of neurons, while10 µgr/ml treated group was toxic. RESULTS of this study indicated that gum resin of asafoetida in low doses has neuroprotective effect on neurons and improves survival rate of them, however in higher concentrations it is toxic for neurons.


Automatic for the people: how representations of significant others implicitly affect goal pursuit.
Five studies are presented that explore how representations of significant others may automatically affect goal pursuit. Specifically, evidence is presented that suggests goals may be primed by one's representation of a significant other and that this priming may be moderated by one's closeness to this other individual. It is also shown to be affected by the number of different goals associated with this person. The greater the number of goals associated with a significant other, the less likely this individual will invoke any 1 goal very strongly. Such goal priming is shown to have implications for the extent to which goals are pursued (as seen through task persistence and performance) as well as the extent to which they are inhibited or ignored (especially when an individual is associated with a goal unrelated to a current pursuit).


Sampling 'hard-to-reach' populations in health research: yield from a study targeting Americans living in Canada.
Some populations targeted in survey research can be hard to reach, either because of lack of contact information, or non-existent databases to inform sampling. Here, we present a methodological "case-report" of the yield of a multi-step survey study assessing views on health care among American emigres to Canada, a hard-to-reach population. To sample this hard-to-reach population, we held a live media conference, supplemented by a nation-wide media release announcing the study. We prepared an 'op-ed' piece describing the study and how to participate. We paid for advertisements in 6 newspapers. We sent the survey information to targeted organizations. And lastly, we asked those who completed the web survey to send the information to others. We use descriptive statistics to document the method's yield. The combined media strategies led to 4 television news interviews, 10 newspaper stories, 1 editorial and 2 radio interviews. 458 unique individuals accessed the on-line survey, among whom 310 eligible subjects provided responses to the key study questions. Fifty-six percent reported that they became aware of the survey via media outlets, 26% by word of mouth, and 9% through both the media and word of mouth. Our multi-step communication method yielded a sufficient sample of Americans living in Canada. This combination of paid and unpaid media exposure can be considered by others as a unique methodological approach to identifying and sampling hard-to-reach populations.


Heterologous Expression of Human Metallothionein Gene HsMT1L Can Enhance the Tolerance of Tobacco (Nicotiana nudicaulis Watson) to Zinc and Cadmium.
Metallothionein (MT) is a multifunctional inducible protein in animals, plants, and microorganisms. MT is rich in cysteine residues (10-30%), can combine with metal ions, has a low molecular weight, and plays an essential biological role in various stages of the growth and development of organisms. Due to its strong ability to bind metal ions and scavenge free radicals, metallothionein has been used in medicine, health care, and other areas. Zinc is essential for plant growth, but excessive zinc (Zn) is bound to poison plants, and cadmium (Cd) is a significant environmental pollutant. A high concentration of cadmium can significantly affect the growth and development of plants and even lead to plant death. In this study, the human metallothionein gene HsMT1L under the control of the CaMV 35S constitutive promoter was transformed into tobacco, and the tolerance and accumulation capacity of transgenic tobacco plants to Zn and Cd were explored. The results showed that the high-level expression of HsMT1L in tobacco could significantly enhance the accumulation of Zn2+ and Cd2+ in both the aboveground parts and the roots compared to wild-type tobacco plants and conferred a greater tolerance to Zn and Cd in transgenic tobacco. Subcellular localization showed that HsMT1L was localized to the nucleus and cytoplasm in the tobacco. Our study suggests that HsMT1L can be used for the phytoremediation of soil for heavy metal removal.


An in vitro model of ischemia: metabolic and electrical alterations in the hippocampal slice.
The transverse guinea pig hippocampal slice preparation was used to model the metabolic changes which occur in vivo during ischemia and recovery. Perfusing brain slices with medium devoid of glucose and oxygen elicits rapid decreases in phosphocreatine, ATP, intracellular pH, and in the evoked field potential recorded in the dentate gyrus. AMP and creatine rise during this period, while ADP and lactate levels remain unchanged. Cyclic AMP exhibits a transient increase in concentration. With the exception of ADP and lactate, these responses are very similar to those observed during in vivo ischemia. The return of glucose and oxygen to the incubation medium reverses these metabolic and electrophysiological effects and also leads to pronounced elevations in cyclic nucleotide concentrations. Metabolite concentrations approach, but do not reach, in vitro steady state levels during the first 30 min of recovery. Total adenylate and creatine steady state levels are approximately 50% of in vivo concentrations. The results suggest that, although hippocampal slices differ metabolically from in vivo tissue, they exhibit a similar pattern of metabolic responses to ischemic and reflow conditions.


A three-component reaction by photoinduced electron transfer mechanism with N-protected pyrroles as neutral carbon nucleophiles.
A new photoinduced three-component reaction between a cyanoarene, an alkene and an N-protected pyrrole has been developed. This reaction extended the scope of the photo-NOCAS reaction by introducing pyrrole as a neutral carbon-centered nucleophile. The cyanoarenes used include tetracyanobenzene (TCB), 2,3,5,6-tetrafluoro-1,4-dicyanobenzene (TFDCB) and 1,4-dicyanobenzene (DCB). N-Methyl, N-phenyl and N-Boc pyrroles are suitable nucleophiles in the reaction. Taking advantage of the strong electron acceptor ability of the singlet excited TCB, a wide range of alkenes, including the highly electron deficient 4-fluoro-, 4-chloro-, 2,3,4,5,6-pentafluorostyrenes and N-methylmaleimide take part in this reaction, leading to the simultaneous 1,2-diarylation of the alkene and the regioselective 2-alkylation of the pyrrole ring via sequential formation of two new C-C bonds between the three reactants.


Middle East respiratory syndrome coronavirus quasispecies that include homologues of human isolates revealed through whole-genome analysis and virus cultured from dromedary camels in Saudi Arabia.
ABSTRACT Complete Middle East respiratory syndrome coronavirus (MERS-CoV) genome sequences were obtained from nasal swabs of dromedary camels sampled in the Kingdom of Saudi Arabia through direct analysis of nucleic acid extracts or following virus isolation in cell culture. Consensus dromedary MERS-CoV genome sequences were the same with either template source and identical to published human MERS-CoV sequences. However, in contrast to individual human cases, where only clonal genomic sequences are reported, detailed population analyses revealed the presence of more than one genomic variant in individual dromedaries. If humans are truly infected only with clonal virus populations, we must entertain a model for interspecies transmission of MERS-CoV wherein only specific genotypes are capable of passing bottleneck selection. IMPORTANCE In most cases of Middle East respiratory syndrome (MERS), the route for human infection with the causative agent, MERS coronavirus (MERS-CoV), is unknown. Antibodies to and viral nucleic acids of MERS-CoV have been found in dromedaries, suggesting the possibility that they may serve as a reservoir or vector for human infection. However, neither whole viral genomic sequence nor infectious virus has been isolated from dromedaries or other animals in Saudi Arabia. Here, we report recovery of MERS-CoV from nasal swabs of dromedaries, demonstrate that MERS-CoV whole-genome consensus sequences from dromedaries and humans are indistinguishable, and show that dromedaries can be simultaneously infected with more than one MERS-CoV. Together with data indicating widespread dromedary infection in the Kingdom of Saudi Arabia, these findings support the plausibility of a role for dromedaries in human infection.


Sensitivity and specificity of macroinvertebrate responses to gradients of multiple agricultural stressors.
Environmental degradation of rivers in agricultural landscapes is typically caused by multiple co-occurring stressors, but how interactions among stressors affect freshwater ecosystems is poorly understood. Therefore, we investigated the sensitivity and specificity of several measures of benthic macroinvertebrate community response to the individual and combined effects of the pesticide sulfoxaflor (SFX), increased sand sedimentation and elevated nutrients using outdoor recirculating mesocosms. Among the single stressor treatments, nutrients had no observable impact and sand only affected one community response measure compared to controls. High SFX levels had the largest effects on benthic macroinvertebrate communities, negatively affecting six of seven macroinvertebrate response measures. Sulfoxaflor had similar adverse effects on biota when in combination with sand and nutrients in the multi-stressor treatment, suggesting that generally SFX has overwhelming and pervasive effects irrespective of the presence of the other stressors. In contrast to SFX, elevated nutrients had no detectable effect on macroinvertebrate communities, likely as a consequence of nutrients being rapidly taken up by bacteria rather than by benthic algae. Elevated sand sedimentation increased the negative effects of SFX on sediment sensitive taxa, but generally had limited biological effects. This was despite the levels of sedimentation in our treatments being at concentrations that have caused large impacts in other studies. This research points to direct and rapid toxic effects of SFX on stream macroinvertebrates, contrasting with effects of the other stressors. This study emphasises that pesticide effects could be misattributed to other common freshwater stressors, potentially focussing restoration actions on a stressor of lesser importance.


The borderland between normal aging and dementia.
Alzheimer's disease (AD) has become a global health issue as the population ages. There is no effective treatment to protect against its occurrence or progression. Some argue that the lack of treatment response is due to delays in diagnosis. By the time a diagnosis of AD is made, neurodegenerative changes are at the stage where very few neurons can be salvaged by medication. The AD research community has developed the idea of mild cognitive impairment (MCI) in an attempt to find predementia patients who might benefit from potentially therapeutic drugs that have proven ineffective in the past. However, MCI is heterogeneous in terms of its underlying pathology and practicality for predicting dementia. This article first reviews the conceptual evolution of MCI as the borderland between normal aging and dementia, and then proposes that built environment and sociocultural context are two key elements in formulating a diagnosis of dementia. Dementia is more than a biomedical term. Cognitive impairment is considered a dynamic outcome of how an individual interacts with cognitive challenges. To focus on amyloid deposition as a single etiology for AD does not adequately capture the social implications and geriatric aspects of dementia. Moreover, MCI is nosologically questionable. Unlike a diagnosis of AD, for which a prototype has been well established, MCI is defined by operational criteria and there are no cases seen as typical MCI. Biofluid and imaging markers are under active development for early detection of amyloid deposition and neurofibrillary tangles in the brain, whereas vascular risks, chronic medical diseases, and polypharmacy continue to add to the complexity of dementia in old age. The paradigm of dementia care policy may shift to early diagnosis of AD pathology and comprehensive care for chronic diseases in the elderly population.


Role of TRAF3 in neurological and cardiovascular diseases: an overview of recent studies.
Tumour necrosis factor receptor-associated factor 3 (TRAF3) is a member of the TRAF adaptor protein family, which exerts different effects on the cell depending on the receptor to which it binds and the cell type in which it is expressed. TRAF3 is a major regulator of the innate immune response. To perform its functions properly, TRAF3 is transcriptionally and epigenetically regulated. At the transcriptional level, TRAF3 expression has been associated with neurological and cardiovascular diseases including stroke, among other pathologies. Epigenetic modifications of TRAF3 have been observed at the histone and DNA levels. It has been observed that acetylation of TRAF3, as well as other NF-κβ target genes, is associated with cardiac hypertrophy. Furthermore, TRAF3 methylation has been associated with vascular recurrence after ischemic stroke in patients treated with clopidogrel. In this overview, we summarise the most interesting studies related to transcriptional and epigenetic regulation of TRAF3 focusing on those studies performed in neurological and cardiovascular diseases.


[Application of ESR saturation transfer spectroscopy for the study of molecular mobility of membrane proteins].
The principles and possibilities of saturation transfer spectroscopy--a new approach in the spin label method, enabling one to measure rotational correlation times up to 10(-3) s--are briefly discussed. This approach is applied to the study of the molecular mobility of a membrane protein Ca-dependent ATPase in native sarcoplasmic reticulum membranes and in egg yolk and dipalmitoyllecithin proteoliposomes using spin labels selectively attached to different SH-groups of a protein. The mobility of the labels on two SH-groups was shown to be due to the intramolecular motion of the protein polar head. It is independent of the protein concentration in membrane but is sensitive to substrate binding and to lipid environment. The correlation of this mobility with the ATPase activity was observed when changing lipid environment and temperature.


Occupational UV exposure in French outdoor workers.
Occupational ultraviolet (UV) exposure was evaluated in a population-based sample in France. A random survey was conducted in 2012 in individuals aged 25 to 69 years. The median daily standard erythemal UV dose (SED) was estimated from exposure time and place and matched to satellite UV records. A total of 889 individuals were exposed to solar UV with highest doses observed among gardeners (1.19 SED), construction workers (1.13 SED), agricultural workers (0.95 SED), and culture/art/social science workers (0.92 SED). Information and communication technology, industry, and transport workers were highly exposed (>0.70 SED). Significant factors associated with high occupational UV exposure were sex (P < 0.0001), phototype (P = 0.0003), and taking lunch outdoors (P < 0.0001). This study identified not only expected occupations with high UV exposure but also unexpected occupations with high exposures. This could serve as a basis for future prevention.


Effectiveness of health promotion regarding diet and physical activity among Nepalese mothers and their young children: The Heart-health Associated Research, Dissemination, and Intervention in the Community (HARDIC) trial.
Background: Nepal, like many low- and middle-income countries, exhibits rising burden of cardiovascular diseases. Misconceptions, poor behavior, and a high prevalence of risk factors contribute to this development. Health promotion efforts along with primary prevention strategies, including risk factor reduction in both adults and children, are therefore critical. Objectives: This study assessed the effectiveness of a health promotion intervention on mothers' knowledge, attitude and practice (KAP) and their children's behavior regarding diet and physical activity. Methods: The Heart-health Associated Research, Dissemination and Intervention in the Community (HARDIC), a community-based trial, used peer education to target mothers with 1-9-year-old children in the peri-urban Jhaukhel-Duwakot Health Demographic Surveillance Site, Nepal, during August-November 2016. In the intervention area, 47 peer mothers were trained to conduct four education classes for about 10 fellow mothers (N = 391). After 3 months, all eligible mothers in the intervention and control areas were interviewed and the results were compared with the KAP of all eligible mothers at baseline. Results: Post-intervention, mothers' KAP median scores had improved regarding heart-healthy diet and physical activity. More mothers had 'good' KAP (>75% of maximum possible scores), and mothers with 'good' knowledge increased from 50% to 81%. Corresponding control values increased only from 58% to 63%. Mothers' attitude and practice improved. Additionally, mothers in the intervention area reported improvement in their children's diet and physical activity behavior. Moreover, Difference in Differences analysis showed that the HARDIC intervention significantly increased mothers' KAP scores and children's behavior scores in the intervention area compared to the control area. Conclusions: Our intervention improves KAP scores regarding diet and physical activity and shows potential for expansion via community health workers, volunteers, and/or local women. Moreover, HARDIC can contribute to Nepal's Package of Essential Noncommunicable Diseases Initiative, which currently lacks a specific package for health promotion.


Serum response factor, a novel early diagnostic biomarker of acute kidney injury.
Studies have shown that serum response factor (SRF) is increased in chronic kidney injury, such as diabetic nephropathy, hyperuricemic nephropathy and renal cell carcinoma. The objective is to explore the early diagnostic value of SRF in acute kidney injury (AKI). AKI-related microarray data were analyzed, and the expression and location of SRF were investigated in the early phase of AKI. Bioinformatics results demonstrated that SRF was dramatically elevated 2-4 h after ischemia/reperfusion (I/R) in mouse renal tissue. In I/R rats, SRF was mostly expressed and located in renal tubular epithelial cells (TECs). SRF started to increase at 1 h, peaked at 3-9 h and started to decrease at 12 h after I/R. The areas under the ROC curve of renal SRF mRNA, renal SRF protein, urinary SRF, serum SRF and serum creatinine (Scr) were 87.9%, 83.0%, 81.3%, 78.8%, 68.8%, respectively. SRF is remarkably upregulated in early (before 24 h) AKI and can replace Scr as a potential new early diagnostic biomarker of AKI.


An evaluation of the recovery of mycobacteria from urine specimens using the automated Mycobacteria Growth Indicator Tube system (BACTEC MGIT 960).
The Mycobacteria Growth Indicator Tube (MGIT 960) system was evaluated against Lowenstein-Jensen (LJ) medium and the BACTEC 460 TB system for the recovery of mycobacteria from 1393 consecutive urine specimens. The MGIT had a sensitivity of 91.3% [95% confidence interval (CI), 83.2-99.4] when the combination of BACTEC 460 and LJ medium was used as the reference method. The mean time for positivity for MGIT and BACTEC 460 was 19.3 days and 20 days, respectively, while that for LJ medium was 35 days.The incidence of contamination was highest for LJ medium (n=148), followed by MGIT 960 (n=81), and BACTEC 460 had the lowest incidence of contamination (n=50). In conclusion, the isolation of mycobacteria from urine specimens by the MGIT 960 is comparable to that of the BACTEC 460 TB system and solid media.


Cyclometallated platinum(II) complexes: oxidation to, and C-H activation by, platinum(IV).
A series of cyclometallated phenylpyridine platinum(II) complexes have been synthesised with a systematic variation in both the phenylpyridine and the ancillary ligand. Oxidation of one of the cyclometallated species leads to a number of isomeric platinum(IV) complexes, all of which eventually isomerize to a single compound. The route to these new compounds has been demonstrated to involve an initial slow oxidation followed by a rapid C-H activation to give doubly cyclometallated complexes. The solid state structures of a number of both the platinum(II) and the platinum(IV) species have been solved; many of the structures exhibited extended interactions that result in complex three dimensional packing.


Human distal sciatic nerve fascicular anatomy: implications for ankle control using nerve-cuff electrodes.
The design of neural prostheses to restore standing balance, prevent foot drop, or provide active propulsion during ambulation requires detailed knowledge of the distal sciatic nerve anatomy. Three complete sciatic nerves and branches were dissected from the piriformis to each muscle entry point to characterize the branching patterns and diameters. Fascicle maps were created from serial sections of each distal terminus below the knee through the anastomosis of the tibial and common fibular nerves above the knee. Similar branching patterns and fascicle maps were observed across specimens. Fascicles innervating primary plantar flexors, dorsiflexors, invertors, and evertors were distinctly separate and functionally organized in the proximal tibial, common fibular, and distal sciatic nerves; however, fascicles from individual muscles were not apparent at these levels. The fascicular organization is conducive to selective stimulation for isolated and/or balanced dorsiflexion, plantar flexion, eversion, and inversion through a single multicontact nerve-cuff electrode. These neuroanatomical data are being used to design nerve-cuff electrodes for selective control of ankle movement and improve current lower-limb neural prostheses.


Comparison of the National Emergency Department Overcrowding Scale and the Emergency Department Work Index for quantifying emergency department crowding.
Emergency department (ED) crowding is just beginning to be quantified. The only two scales presently available are the National Emergency Department Overcrowding Scale (NEDOCS) and the Emergency Department Work Index (EDWIN). To assess the value of the NEDOCS and the EDWIN in predicting overcrowding. The hypothesis of this study was that the NEDOCS and the EDWIN would be equally sensitive and specific for overcrowding. The NEDOCS, the EDWIN, and an overcrowding measure (OV) were determined every two hours for a ten-day period in December 2004. The NEDOCS is a statistically derived calculation, and the EDWIN is a formula-based calculation. The overcrowding measure is a composite of physician and charge nurse expert opinion on the degree of overcrowding as measured on a 100-mm visual analogue scale (VAS). The primary outcome, overcrowding, was based on the dichotomized OV VAS score at the midpoint of 50 mm (> or =50, overcrowded; <50, not overcrowded). The area under the receiver operator characteristic curve (AUC) and an index of adequacy (relative prognostic content) of each measure, on the basis of the likelihood ratio chi-square statistic, were computed to evaluate the performance of NEDOCS and EDWIN. There were 130 completed sampling times over ten days. The OV indicated that the ED was overcrowded 62% of the time. The AUC for the NEDOCS was 0.83 (95% CI = 0.75 to 0.90), and the AUC for the EDWIN was 0.80 (95% CI = 0.73 to 0.88). The NEDOCS score accounts for 97% of the prognostic information provided by combining all variables used in each model into one combined model. The EDWIN score accounts for only 86% (chi2 test for difference, p = 0.02). Both scales had high AUCs, correlated well with each other, and showed good discrimination for predicting ED overcrowding. This establishes construct validity for these scales as measures of overcrowding. Which scale is used in an ED is dependent on which set of data is most readily available, with the favored scale being the NEDOCS.


Bacillus Calmette-Guérin and anti-PD-L1 combination therapy boosts immune response against bladder cancer.
Programmed death-ligand 1 (PD-L1) is a critical immune checkpoint molecule which promotes immunosuppression by binding to PD-1 on T-cells in tumor immunity. We have previously identified that activation of toll like receptor 4 (TLR-4), which serves an important role in the induction of antitumor immune response during Bacillus Calmette-Guérin (BCG) immunotherapy, could upregulate PD-L1 expression in bladder cancer (BCa) cells through the classical mitogen-activated protein kinase (MAPK) pathway and subsequently weaken the cytotoxicity of cytotoxic T lymphocyte (CTL). It is, therefore, necessary to investigate the possible potential relationship between PD-L1 expression and BCG immunotherapy. In this study we investigated the effects of BCG treatment on PD-L1 expression in BCa cells and also evaluated the efficacy of BCG and anti-PD-L1 combination therapy in immunocompetent orthotopic rat BCa models. We found that PD-L1 expression was obviously upregulated in BCa cells in response to BCG treatment both in vitro and in vivo. Moreover, BCG and anti-PD-L1 combination treatment activated a potent antitumor immune response with the increase in the number and activity of tumor-infiltrating CD8+ T cells, as well as the reduction in myeloid-derived suppressor cells (MDSCs), and eventually elicits prominent tumor growth inhibition and prolonged survival, and was found to be much more effective than either agent alone. These findings highlight the adaptive dynamic regulation of PD-L1 in response to BCG immunotherapy and suggest that combination of BCG immunotherapy with PD-L1 blockade may be an effective antitumor strategy for improving treatment outcomes of BCa.


Amyloidosis of the Lung.
-Amyloidosis is a heterogeneous group of diseases characterized by the deposition of congophilic amyloid fibrils in the extracellular matrix of tissues and organs. To date, 31 fibril proteins have been identified in humans, and it is now recommended that amyloidoses be named after these fibril proteins. Based on this classification scheme, the most common forms of amyloidosis include systemic AL (formerly primary), systemic AA (formerly secondary), systemic wild-type ATTR (formerly age-related or senile systemic), and systemic hereditary ATTR amyloidosis (formerly familial amyloid polyneuropathy). Three different clinicopathologic forms of amyloidosis can be seen in the lungs: diffuse alveolar-septal amyloidosis, nodular pulmonary amyloidosis, and tracheobronchial amyloidosis. -To clarify the relationship between the fibril protein-based amyloidosis classification system and the clinicopathologic forms of pulmonary amyloidosis and to provide a useful guide for diagnosing these entities for the practicing pathologist. -This is a narrative review based on PubMed searches and the authors' own experiences. -Diffuse alveolar-septal amyloidosis is usually caused by systemic AL amyloidosis, whereas nodular pulmonary amyloidosis and tracheobronchial amyloidosis usually represent localized AL amyloidosis. However, these generalized scenarios cannot always be applied to individual cases. Because the treatment options for amyloidosis are dependent on the fibril protein-based classifications and whether the process is systemic or localized, the workup of new clinically relevant cases should include amyloid subtyping (preferably with mass spectrometry-based proteomic analysis) and further clinical investigation.


Combined Oral Contraceptive Pill-Induced Hypertension and Hypertensive Disorders of Pregnancy: Shared Mechanisms and Clinical Similarities.
Oral contraceptive pill-induced hypertension (OCPIH) and hypertensive disorders in pregnancy (HDP) share common risk factors and pathophysiological mechanisms, yet the bidirectional relationship between these two conditions is not well-established. We review and describe OCPIH and HDP to better understand how hormonal and metabolic imbalances affect hypertension. Oral contraceptive pills continue to be a popular method of contraception, with an incidence of OCPIH ranging from 1-8.5% among OCP users. HDP have an incidence of 5-10% of all pregnancies in the USA and have been shown to be a powerful predictor of lifetime adverse cardiovascular outcomes, including future hypertension. OCPIH and HDP share common risk factors such as age, BMI, past personal and family history of hypertension, as well as pathogenic mechanisms, including alterations in hormonal metabolism and the renin angiotensin aldosterone system; imbalance of vasodilator-vasoconstrictor compounds; and changes in the cardiovascular system. Future research should address additional potential mechanisms that underlie hypertension in these two conditions where endocrine changes, either physiological (pregnancy) or iatrogenic (use of OCP), play a role. This may lead to novel, targeted treatment options to improve hypertension management and overall cardiovascular risk profile management in this subset of young female patients.


Comparative Genomics of Lactobacillus acidipiscis ACA-DC 1533 Isolated From Traditional Greek Kopanisti Cheese Against Species Within the Lactobacillus salivarius Clade.
Lactobacillus acidipiscis belongs to the Lactobacillus salivarius clade and it is found in a variety of fermented foods. Strain ACA-DC 1533 was isolated from traditional Greek Kopanisti cheese and among the available L. acidipiscis genomes it is the only one with a fully sequenced chromosome. L. acidipiscis strains exhibited a high degree of conservation at the genome level. Investigation of the distribution of prophages and Clustered Regularly Interspaced Short Palindromic Repeats (CRISPRs) among the three strains suggests the potential existence of lineages within the species. Based on the presence/absence patterns of these genomic traits, strain ACA-DC 1533 seems to be more related to strain JCM 10692T than strain KCTC 13900. Interestingly, strains ACA-DC 1533 and JCM 10692T which lack CRISPRs, carry two similar prophages. In contrast, strain KCTC 13900 seems to have acquired immunity to these prophages according to the sequences of spacers in its CRISPRs. Nonetheless, strain KCTC 13900 has a prophage that is absent from strains ACA-DC 1533 and JCM 10692T. Furthermore, comparative genomic analysis was performed among L. acidipiscis ACA-DC 1533, L. salivarius UCC118 and Lactobacillus ruminis ATCC 27782. The chromosomes of the three species lack long-range synteny. Important differences were also determined in the number of glycobiome related proteins, proteolytic enzymes, transporters, insertion sequences and regulatory proteins. Moreover, no obvious genomic traits supporting a probiotic potential of L. acidipiscis ACA-DC 1533 were detected when compared to the probiotic L. salivarius UCC118. However, the existence of more than one glycine-betaine transporter within the genome of ACA-DC 1533 may explain the ability of L. acidipiscis to grow in fermented foods containing high salt concentrations. Finally, in silico analysis of the L. acidipiscis ACA-DC 1533 genome revealed pathways that could underpin the production of major volatile compounds during the catabolism of amino acids that may contribute to the typical piquant flavors of Kopanisti cheese.


Coelomocytes express SpBf, a homologue of factor B, the second component in the sea urchin complement system.
A homologue of factor B, SpBf, has been cloned and sequenced from an LPS-activated coelomocyte cDNA library from the purple sea urchin, Strongylocentrotus purpuratus. The deduced amino acid sequence and domain structure show significant similarity to the vertebrate Bf/C2 family proteins. SpBf is a mosaic protein, composed of five short consensus repeats, a von Willebrand Factor domain, and a serine protease domain. It has a deduced molecular mass of 91 kDa, with a conserved cleavage site for a putative factor D protease. It has ten consensus recognition sites for N-linked glycosylation. Amino acids involved in both Mg2+ binding and in serine protease activity in the vertebrate C2/Bf proteins are conserved in SpBf. Phylogenetic analysis of SpBf indicates that it is the most ancient member of the vertebrate Bf/C2 family. Additional phylogenetic analysis of the SCRs indicates that five SCRs in SpBf may be ancestral to three SCRs, which is the typical pattern in the vertebrate Bf/C2 proteins. RNA gel blots show that SpBf transcripts are 5.5 kb and are specifically expressed in coelomocytes. Genome blots suggest that the SpBf gene (Sp152) is single copy gene per haploid genome. This is the second complement component to be identified from the sea urchin, and, with the sea urchin C3 homologue, these two components may be part of a simple complement system that is homologous to the alternative pathway in higher vertebrates.


In-depth mechanistic study on the formation of acrylamide and other vinylogous compounds by the maillard reaction.
The formation of acrylamide was studied in low-moisture Maillard model systems (180 degrees C, 5 min) based on asparagine, reducing sugars, Maillard intermediates, and sugar degradation products. We show evidence that certain glycoconjugates play a major role in acrylamide formation. The N-glycosyl of asparagine generated about 2.4 mmol/mol acrylamide, compared to 0.1-0.2 mmol/mol obtained with alpha-dicarbonyls and the Amadori compound of asparagine. 3-Hydroxypropanamide, the Strecker alcohol of asparagine, generated only low amounts of acrylamide ( approximately 0.23 mmol/mol), while hydroxyacetone increased the acrylamide yields to more than 4 mmol/mol, indicating that alpha-hydroxy carbonyls are much more efficient than alpha-dicarbonyls in converting asparagine into acrylamide. The experimental results are consistent with the reaction mechanism based on (i) a Strecker type degradation of the Schiff base leading to azomethine ylides, followed by (ii) a beta-elimination reaction of the decarboxylated Amadori compound to afford acrylamide. The beta-position on both sides of the nitrogen atom is crucial. Rearrangement of the azomethine ylide to the decarboxylated Amadori compound is the key step, which is favored if the carbonyl moiety contains a hydroxyl group in beta-position to the nitrogen atom. The beta-elimination step in the amino acid moiety was demonstrated by reacting under low moisture conditions decarboxylated model Amadori compounds obtained by synthesis. The corresponding vinylogous compounds were only generated if a beta-proton was available, for example, styrene from the decarboxylated Amadori compound of phenylalanine. Therefore, it is suggested that this thermal pathway may be common to other amino acids, resulting under certain conditions in their respective vinylogous reaction products.


Dopamine D2 receptor activity modulates Akt signaling and alters GABAergic neuron development and motor behavior in zebrafish larvae.
An imbalance in dopamine-mediated neurotransmission is a hallmark physiological feature of neuropsychiatric disorders, such as schizophrenia. Recent evidence demonstrates that dopamine D(2) receptors, which are the main target of antipsychotics, modulate the activity of the protein kinase Akt, which is known to be downregulated in the brain of patients with schizophrenia. Akt has an important role in the regulation of cellular processes that are critical for neurodevelopment, including gene transcription, cell proliferation, and neuronal migration. Thus, it is possible that during brain development, altered Akt-dependent dopamine signaling itself may lead to defects in neural circuit formation. Here, we used a zebrafish model to assess the direct impact of altered dopamine signaling on brain development and larval motor behavior. We demonstrate that D(2) receptor activation acutely suppresses Akt activity by decreasing the level of pAkt(Thr308) in the larval zebrafish brain. This D(2)-dependent reduction in Akt activity negatively regulates larval movement and is distinct from a D(1)-dependent pathway with opposing affects on motor behavior. In addition, we show that D(2)-dependent suppression of Akt activity causes a late onset change in GSK3b activity, a known downstream target of Akt signaling. Finally, altered D(2) receptor signaling, or direct inhibition of Akt activity, causes a significant decrease in the size of the GABAergic neuron population throughout most of the brain. Our observations suggest that D(2) receptor signaling suppresses Akt-GSK3b activity, which regulates GABAergic neuron development and motor behavior.


Training-dependent associative learning induced neocortical structural plasticity: a trace eyeblink conditioning analysis.
Studies utilizing general learning and memory tasks have suggested the importance of neocortical structural plasticity for memory consolidation. However, these learning tasks typically result in learning of multiple different tasks over several days of training, making it difficult to determine the synaptic time course mediating each learning event. The current study used trace-eyeblink conditioning to determine the time course for neocortical spine modification during learning. With eyeblink conditioning, subjects are presented with a neutral, conditioned stimulus (CS) paired with a salient, unconditioned stimulus (US) to elicit an unconditioned response (UR). With multiple CS-US pairings, subjects learn to associate the CS with the US and exhibit a conditioned response (CR) when presented with the CS. Trace conditioning is when there is a stimulus free interval between the CS and the US. Utilizing trace-eyeblink conditioning with whisker stimulation as the CS (whisker-trace-eyeblink: WTEB), previous findings have shown that primary somatosensory (barrel) cortex is required for both acquisition and retention of the trace-association. Additionally, prior findings demonstrated that WTEB acquisition results in an expansion of the cytochrome oxidase whisker representation and synaptic modification in layer IV of barrel cortex. To further explore these findings and determine the time course for neocortical learning-induced spine modification, the present study utilized WTEB conditioning to examine Golgi-Cox stained neurons in layer IV of barrel cortex. Findings from this study demonstrated a training-dependent spine proliferation in layer IV of barrel cortex during trace associative learning. Furthermore, findings from this study showing that filopodia-like spines exhibited a similar pattern to the overall spine density further suggests that reorganization of synaptic contacts set the foundation for learning-induced neocortical modifications through the different neocortical layers.


DNGR-1, a Dendritic Cell-Specific Sensor of Tissue Damage That Dually Modulates Immunity and Inflammation.
DNGR-1 (encoded by CLEC9A) is a C-type lectin receptor (CLR) with an expression profile that is mainly restricted to type 1 conventional dendritic cells (cDC1s) both in mice and humans. This delimited expression pattern makes it appropriate for defining a cDC1 signature and for therapeutic targeting of this population, promoting immunity in mouse models. Functionally, DNGR-1 binds F-actin, which is confined within the intracellular space in healthy cells, but is exposed when plasma membrane integrity is compromised, as happens in necrosis. Upon F-actin binding, DNGR-1 signals through SYK and mediates cross-presentation of dead cell-associated antigens. Cross-presentation to CD8+ T cells promoted by DNGR-1 during viral infections is key for cross-priming tissue-resident memory precursors in the lymph node. However, in contrast to other closely related CLRs such as Dectin-1, DNGR-1 does not activate NFκB. Instead, recent findings show that DNGR-1 can activate SHP-1 to limit inflammation triggered by heterologous receptors, which results in reduced production of inflammatory chemokines and neutrophil recruitment into damaged tissues in both sterile and infectious processes. Hence, DNGR-1 reduces immunopathology associated with tissue damage, promoting disease tolerance to safeguard tissue integrity. How DNGR-1 signals are conditioned by the microenvironment and the detailed molecular mechanisms underlying DNGR-1 function have not been elucidated. Here, we review the expression pattern and structural features of DNGR-1, and the biological relevance of the detection of tissue damage through this CLR.


Capturing a photoexcited molecular structure through time-domain x-ray absorption fine structure.
The determination of the structure of transient molecules, such as photoexcited states, in disordered media (such as in solution) usually requires methods with high temporal resolution. The transient molecular structure of a reaction intermediate produced by photoexcitation of NiTPP-L2 (NiTPP, nickeltetraphenylporphyrin; L, piperidine) in solution was determined by x-ray absorption fine structure (XAFS) data obtained on a 14-nanosecond time scale from a third-generation synchrotron source. The XAFS measurements confirm that photoexcitation leads to the rapid removal of both axial ligands to produce a transient square-planar intermediate, NiTPP, with a lifetime of 28 nanoseconds. The transient structure of the photodissociated intermediate is nearly identical to that of the ground state NiTPP, suggesting that the intermediate adopts the same structure as the ground state in a noncoordinating solvent before it recombines with two ligands to form the more stable octahedrally coordinated NiTPP-L2.


Detection of presymptomatic atherosclerosis: a current perspective.
Atherosclerosis, the pathological process underlying myocardial infarction, stroke and other occlusive vascular disease, is the major cause of death in the Western world. The development of techniques to accurately and reproducibly detect and measure the early changes of atherosclerosis and/or to identify subjects at highest cardiovascular risk may aid in the development of prevention strategies and facilitate a decrease in morbidity and mortality from atherosclerosis. Increasing understanding of the pathophysiology of early atherosclerosis has allowed the development of a number of potential methods for the assessment of the early stages of atherosclerosis in humans. These include techniques for assessing early structural changes in the coronary arteries with electron-beam computed tomography and magnetic resonance imaging. External vascular ultrasound has also been used to image other circulations as a surrogate marker for coronary atherosclerosis, e.g. the measurement of carotid artery intima-media thickness. Early functional changes of atherosclerosis have also been described many years before the development of structural changes. A number of techniques have been developed to measure endothelial dysfunction, one of the earliest changes of atherosclerosis, including non-invasive measurement of endothelial function using external vascular ultrasound. A variety of serum markers have also been described, and may be useful markers of atherosclerosis. We discuss some of the more promising techniques for the detection of early, presymptomatic atherosclerosis.


Polymorphisms in HLA-DPB1 are associated with differences in rubella virus-specific humoral immunity after vaccination.
Vaccination with live attenuated rubella virus induces a strong immune response in most individuals. However, small numbers of subjects never reach or maintain protective antibody levels, and there is a high degree of variability in immune response. We have previously described genetic polymorphisms in HLA and other candidate genes that are associated with interindividual differences in humoral immunity to rubella virus. To expand our previous work, we performed a genome-wide association study (GWAS) to discover single-nucleotide polymorphisms (SNPs) associated with rubella virus-specific neutralizing antibodies. We identified rs2064479 in the HLA-DPB1 genetic region as being significantly associated with humoral immune response variations after rubella vaccination (P = 8.62 × 10(-8)). All other significant SNPs in this GWAS were located near the HLA-DPB1 gene (P ≤ 1 × 10(-7)). These findings demonstrate that polymorphisms in HLA-DPB1 are strongly associated with interindividual differences in neutralizing antibody levels to rubella vaccination and represent a validation of our previous HLA work.


Selective depletion of alloreactive donor T cells leads to elimination of graft-versus-host reactivity and stimulates graft-versus-leukaemia/myeloma effect.
Graft-versus-host disease is a severe complication of allogeneic stem cell transplantation. The major role is played by alloreactive donor T-cell clones leading to host tissue damage. Selective depletion is a strategy to eliminate host-reactive donor T cells from haematopoietic stem cell allografts to prevent graft-versus-host disease while conserving useful donor immune functions. We have used irradiated peripheral blood mononuclear cells from cancer patients and healthy donor cells as responder cells in primary mixed leukocyte reaction. To prepare graft-versus leukaemia/myeloma-specific T cells, alloreactive T cells in primary mixed leukocyte reaction were depleted with anti-CD25 immunotoxin. The remaining T cells had insignificant alloreactivity in secondary mixed leukocyte reaction. Then, allodepleted donor T cells were repeatedly stimulated using purified leukaemia/tumour cells from the same cancer patient. Leukaemia/tumour-reactive donor T cells were purified using cell sorter on the basis of CD4 and CD8 activation. Their specificity was tested in nonradioactive cytotoxicity test. We performed 22 reactions (15 samples with leukemic and 7 samples with multiple myeloma cells). Selective depletion of alloreactive donor T cells with anti-CD25 immunotoxin led to significant depletion (99.2-100 %, median 99.7%). The effect of donor T cells was well preserved, while the graft-versus-host reactivation of donor cells was negligible, even after repeated stimulation with patient's non-tumour cells. Thus, it is possible to selectively deplete donor alloreactive T cells with anti-CD25 immunotoxin. In the cases of leukaemia patients, a strong graft-versus-leukaemia reactivity was noticed in allodepleted donor T cells; in myeloma patients, graft-versus-myeloma reactivity was less significant.


Temperature affects longevity and age-related locomotor and cognitive decay in the short-lived fish Nothobranchius furzeri.
Temperature variations are known to modulate aging and life-history traits in poikilotherms as different as worms, flies and fish. In invertebrates, temperature affects lifespan by modulating the slope of age-dependent acceleration in death rate, which is thought to reflect the rate of age-related damage accumulation. Here, we studied the effects of temperature on aging kinetics, aging-related behavioural deficits, and age-associated histological markers of senescence in the short-lived fish Nothobranchius furzeri. This species shows a maximum captive lifespan of only 3 months, which is tied with acceleration in growth and expression of aging biomarkers. These biological peculiarities make it a very convenient animal model for testing the effects of experimental manipulations on life-history traits in vertebrates. Here, we show that (i) lowering temperature from 25 degrees C to 22 degrees C increases both median and maximum lifespan; (ii) life extension is due to reduction in the slope of the age-dependent acceleration in death rate; (iii) lowering temperature from 25 degrees C to 22 degrees C retards the onset of age-related locomotor and learning deficits; and (iv) lowering temperature from 25 degrees C to 22 degrees C reduces the accumulation of the age-related marker lipofuscin. We conclude that lowering water temperature is a simple experimental manipulation which retards the rate of age-related damage accumulation in this short-lived species.


Antifeedant Activity of Neo-clerodane Diterpenoids from Scutellaria altissima against Colorado Potato Beetle Larvae.
Fourteen neo-clerodane diterpenoids isolated from Scutellaria altissima (Lamiaceae) were tested for insect antifeedant activity against Leptinotarsa decemlineata Say. Potato leaf disks treated with small amounts of the compounds (concentration 1000, 100, 10 ppm) resulted in good to very good antifeedant activity. Clerodin (1), scutecyprin (11) and 11-epi-scutecolumnin C (12) showed strong feeding inhibition at 1000 ppm and exhibited significant antifeedant activity at a concentration of 100 ppm. Activity was established by calculating the feeding ratio (FR) between the consumed areas of treated disks (CTD) and control disks (CCD). For comparison, FR50 values were determined as the FR at a CCD of 50%. Structural features of the compounds associated with the changes in activity and structure-antifeedant activity relationships are discussed. For the first time the anti-feedant activity has been evaluated of neo-clerodane diterpenoids with an unusual R-configuration of the carbon atom C-I 1.


The metastasis-associated proteins 1 and 2 form distinct protein complexes with histone deacetylase activity.
The metastasis-associated protein MTA1 has been shown to express differentially to high levels in metastatic cells. MTA2, which is homologous to MTA1, is a component of the NuRD ATP-dependent chromatin remodeling and histone deacetylase complex. Here we report evidence that although both human MTA1 and MTA2 repress transcription specifically, are located in the nucleus, and contain associated histone deacetylase activity, they exist in two biochemically distinct protein complexes and may perform different functions pertaining to tumor metastasis. Specifically, both MTA1 and MTA2 complexes exert histone deacetylase activity. However, the MTA1 complex contained HDAC1/2, RbAp46/48, and MBD3, but not Sin3 or Mi2, two important components of the MTA2 complex. Moreover, the MTA2 complex is similar to the HDAC1 complex, suggesting a housekeeping role of the MTA2 complex. The MTA1 complex could be further separated, resulting in a core MTA1-HDAC complex, showing that the histone deacetylase activity and transcriptional repression activity were integral properties of the MTA1 complex. Finally, MTA1, unlike MTA2, did not interact with the pleotropic transcription factor YY1 or the immunophilin FKBP25. We suggest that MTA1 associates with a different set of transcription factors from MTA2 and that this property may contribute to the metastatic potential of cells overexpressing MTA1. We also report the finding of human MTA3, which is highly homologous to both MTA1 and MTA2. However, MTA3 does not repress transcription to a significant level and appears to have a diffused pattern of subcellular localization, suggesting a biological role distinct from that of the other two MTA proteins.


Medical abortion: the Tunisian experience.
This paper reports the Tunisian experience of medical abortion. The project started in 1998 with a small introductory study at the obstetric and gynaecology department of a university hospital and was later extended step by step to other family planning and public health centres that provided abortion services. The study was first conducted on 264 women using the modified regimen of 200mg mifepristone, followed 48 hours later by 400 microg misoprostol in women seeking pregnancy of maximum 56 days of amenorrhoea. This gave a success rate of 91.1%. Results from further studies in other locations showed increasing success rates of 94.4% and 95.6%, with high acceptability and satisfaction among users and providers The registration and effective introduction of medical abortion was quite rapid. Following successful conduct of the pilot study, intervention programmes were designed and implemented to improve the capacity of providers in providing safe medical abortion.


BAL1/ARTD9 represses the anti-proliferative and pro-apoptotic IFNγ-STAT1-IRF1-p53 axis in diffuse large B-cell lymphoma.
The B-aggressive lymphoma-1 protein and ADP-ribosyltransferase BAL1/ARTD9 has been recently identified as a risk-related gene product in aggressive diffuse large B-cell lymphoma (DLBCL). BAL1 is constitutively expressed in a subset of high-risk DLBCLs with an active host inflammatory response and has been suggested to be associated with interferon-related gene expression. Here we identify BAL1 as a novel oncogenic survival factor in DLBCL and show that constitutive overexpression of BAL1 in DLBCL tightly associates with intrinsic interferon-gamma (IFNγ) signaling and constitutive activity of signal transducer and activator of transcription (STAT)-1. Remarkably, BAL1 stimulates the phosphorylation of both STAT1 isoforms, STAT1α and STAT1β, on Y701 and thereby promotes the nuclear accumulation of the antagonistically acting and transcriptionally repressive isoform STAT1β. Moreover, BAL1 physically interacts with both STAT1α and STAT1β through its macrodomains in an ADP-ribosylation-dependent manner. BAL1 directly inhibits, together with STAT1β, the expression of tumor suppressor and interferon response factor (IRF)-1. Conversely, BAL1 enhances the expression of the proto-oncogenes IRF2 and B-cell CLL/lymphoma (BCL)-6 in DLBCL. Our results show for the first time that BAL1 represses the anti-proliferative and pro-apoptotic IFNγ-STAT1-IRF1-p53 axis and mediates proliferation, survival and chemo-resistance in DLBCL. As a consequence constitutive IFNγ-STAT1 signaling does not lead to apoptosis but rather to chemo-resistance in DLBCL overexpressing BAL1. Our results suggest that BAL1 may induce an switch in STAT1 from a tumor suppressor to an oncogene in high-risk DLBCL.


Correlation of 18F-FDG PET and MRI Apparent Diffusion Coefficient Histogram Metrics with Survival in Diffuse Intrinsic Pontine Glioma: A Report from the Pediatric Brain Tumor Consortium.
The purpose of this study was to describe baseline 18F-FDG PET voxel characteristics in pediatric diffuse intrinsic pontine glioma (DIPG) and to correlate these metrics with baseline MRI apparent diffusion coefficient (ADC) histogram metrics, progression-free survival (PFS), and overall survival. Methods: Baseline brain 18F-FDG PET and MRI scans were obtained in 33 children from Pediatric Brain Tumor Consortium clinical DIPG trials. 18F-FDG PET images, postgadolinium MR images, and ADC MR images were registered to baseline fluid attenuation inversion recovery MR images. Three-dimensional regions of interest on fluid attenuation inversion recovery MR images and postgadolinium MR images and 18F-FDG PET and MR ADC histograms were generated. Metrics evaluated included peak number, skewness, and kurtosis. Correlation between PET and MR ADC histogram metrics was evaluated. PET pixel values within the region of interest for each tumor were plotted against MR ADC values. The association of these imaging markers with survival was described. Results: PET histograms were almost always unimodal (94%, vs. 6% bimodal). None of the PET histogram parameters (skewness or kurtosis) had a significant association with PFS, although a higher PET postgadolinium skewness tended toward a less favorable PFS (hazard ratio, 3.48; 95% confidence interval [CI], 0.75-16.28 [P = 0.11]). There was a significant association between higher MR ADC postgadolinium skewness and shorter PFS (hazard ratio, 2.56; 95% CI, 1.11-5.91 [P = 0.028]), and there was the suggestion that this also led to shorter overall survival (hazard ratio, 2.18; 95% CI, 0.95-5.04 [P = 0.067]). Higher MR ADC postgadolinium kurtosis tended toward shorter PFS (hazard ratio, 1.30; 95% CI, 0.98-1.74 [P = 0.073]). PET and MR ADC pixel values were negatively correlated using the Pearson correlation coefficient. Further, the level of PET and MR ADC correlation was significantly positively associated with PFS; tumors with higher values of ADC-PET correlation had more favorable PFS (hazard ratio, 0.17; 95% CI, 0.03-0.89 [P = 0.036]), suggesting that a higher level of negative ADC-PET correlation leads to less favorable PFS. A more significant negative correlation may indicate higher-grade elements within the tumor leading to poorer outcomes. Conclusion:18F-FDG PET and MR ADC histogram metrics in pediatric DIPG demonstrate different characteristics with often a negative correlation between PET and MR ADC pixel values. A higher negative correlation is associated with a worse PFS, which may indicate higher-grade elements within the tumor.


Trop2 regulates motility and lamellipodia formation in cultured fetal lung fibroblasts.
Proliferation and migration of fibroblasts are vital for fetal lung development. However, the regulatory mechanisms are poorly understood. We have previously shown that TROP2 gene expression is closely associated with fetal lung cell proliferation in vivo and that TROP2 knockdown decreases proliferation of fetal lung fibroblasts in culture. We hypothesized that the Trop2 protein also regulates the morphology and motility of fetal lung fibroblasts. Fibroblasts isolated from fetal rat lungs (gestational age embryonic day 19) adopted a myofibroblast-like morphology in culture. Trop2 protein was localized to lamellipodia. TROP2 siRNA significantly decreased: TROP2 mRNA levels by 77%, the proportion of cells containing Trop2 protein by 70%, and cell proliferation by 50%. TROP2 siRNA also decreased the degree of motility as determined by the number of gridlines that cells moved across (2.2 ± 0.2 vs. 3.2 ± 0.2; P < 0.001). TROP2 knockdown altered cell morphology, causing a notable absence of lamellipodia and abnormal localization of components of the cell migration apparatus, and it reduced phosphorylated ERK1 and ERK2 levels. In contrast, TROP2 overexpression significantly increased: TROP2 mRNA levels by 40-fold, cell proliferation by 40%, the proportion of cells that were motile by 20%, and the number of gridlines that cells moved across (2.1 ± 0.2 vs. 1.6 ± 0.1; P < 0.001). Our data suggest that Trop2 regulates cell proliferation and motility and that it does so by regulating the ERK pathway and several critical components of the cell migration apparatus.


All that glitters ... dissociating attention and outcome expectancy from prediction errors signals.
Initially reported in dopamine neurons, neural correlates of prediction errors have now been shown in a variety of areas, including orbitofrontal cortex, ventral striatum, and amygdala. Yet changes in neural activity to an outcome or cues that precede it can reflect other processes. We review the recent literature and show that although activity in dopamine neurons appears to signal prediction errors, similar activity in orbitofrontal cortex, basolateral amygdala, and ventral striatum does not. Instead, increased firing in basolateral amygdala to unexpected outcomes likely reflects attention, whereas activity in orbitofrontal cortex and ventral striatum is unaffected by prior expectations and may provide information on outcome expectancy. These results have important implications for how these areas interact to facilitate learning and guide behavior.


Characterization of a tightly controlled promoter of the halophilic archaeon Haloferax volcanii and its use in the analysis of the essential cct1 gene.
A system where archaeal gene expression could be controlled by simple manipulation of growth conditions would enable the construction of conditional lethal mutants in essential genes, and permit the controlled overproduction of proteins in their native host. As tools for the genetic manipulation of Haloferax volcanii are well developed, we set out to identify promoters with a wide dynamic range of expression in this organism. Tryptophan is the most costly amino acid for the cell to make, so we reasoned that tryptophan-regulated promoters might be good candidates. Microarray analysis of H. volcanii gene expression in the presence and absence of tryptophan identified a tryptophanase gene (tna) that showed strong induction in the presence of tryptophan. qRT-PCR revealed a very fast response and an up to 100-fold induction after tryptophan addition. This result has been confirmed using three independent reporter genes (cct1, pyrE2 and bgaH). Vectors containing this promoter will be very useful for investigating gene function in H. volcanii and potentially in other halophilic archaea. To demonstrate this, we used the promoter to follow the consequences of depletion of the essential chaperonin protein CCT1, and to determine the ability of heterologous CCT proteins to function in H. volcanii.


Malaria Stratification Mapping in Thailand to Support Prevention of Reestablishment.
Thailand aims to eliminate malaria by 2026, with 46 of the country's 77 provinces already verified as malaria free. However, these provinces remain susceptible to the reestablishment of indigenous transmission that would threaten the national goal. Thus, the country is prioritizing national and subnational prevention of reestablishment (POR) planning while considering the spatial heterogeneity of the remaining malaria caseload. To support POR efforts, a novel nonmodeling method produced a malaria stratification map at the tambon (subdistrict) level, incorporating malaria case data, demographic data, and environmental factors. The stratification analysis categorized 7,425 tambons into the following four risk strata: Local Transmission (2.9%), At Risk for Transmission (3.1%), High Risk for Reintroduction (2.9%), and Low Risk for Reintroduction (91.1%). The stratification map will support the national program to target malaria interventions in remaining hotspots and mitigate the risk of transmission in malaria-free areas.


Eisenmenger's complex in a Holstein-Friesian cow.
A 4.5-year-old, Holstein-Friesian cow presented with a 1-month history of severe exercise intolerance. Rectal examination and transrectal ultrasonography revealed a large mass in the left retroperitoneum. The heart rate was 70 to 80/min. Premature ventricular complexes and ventricular bigeminy were present on an electrocardiogram. Erythrocytosis was present and blood gas analysis revealed marked hypoxaemia. An echocardiogram demonstrated a large ventricular septal defect, a partially dextroposed aorta, and concentric hypertrophy of the right ventricular free wall. Colour flow Doppler echocardiography and a contrast echocardiographic study demonstrated a right-to-left shunt through the ventricular septal defect. Eisenmenger's complex was diagnosed. The patient was euthanased. Necropsy confirmed the gross cardiac lesions identified by echocardiography and an abscess in the apex of the left ventricle. Severe pulmonary arterial lesions were present, consistent with a marked increased in pulmonary vascular resistance. Actinomyces pyogenes was cultured from abscesses of the retroperitoneum and the ventricular apex.


Infant hydrocephalus: what valve first?
To review the use of different valve types in infants with hydrocephalus, in doing so, determining whether an optimal valve choice exists for this patient cohort. We conducted (1) a literature review for all studies describing valve types used (programmable vs. non-programmable, valve size, pressure) in infants (≤ 2 years) with hydrocephalus, (2) a review of data from the pivotal BASICS trial for infant patients and (3) a separate, institutional cohort study from Alder Hey Children's Hospital NHS Foundation Trust. The primary outcome was any revision not due to infection. The search identified 19 studies that were included in the review. Most did not identify a superior valve choice between programmable and non-programmable, small compared to ultra-small, and differential pressure compared to flow-regulating valves. Five studies investigated a single-valve type without a comparator group. The BASICS data identified 391 infants, with no statistically significant difference between gravitational and programmable subgroups. The institutional data from our tertiary referral centre did not reveal any significant difference in failure rate between valve subtypes. Our review highlights the challenges of valve selection in infant hydrocephalus, reiterating that the concept of an optimal valve choice in this group remains a controversial one. While the infant-hydrocephalic population is at high risk of valve failure, heterogeneity and a lack of direct comparison between valves in the literature limit our ability to draw meaningful conclusions. Data that does exist suggests at present that there is no difference in non-infective failure rate are increasing in number, with the British valve subtypes in infant hydrocephalus, supported by both the randomised trial and institutional data in this study.


Intraoperative techniques to assess cardiac function-feasiblity of strain rate imaging in the perioperative period in children.
The noninvasive assessment of cardiac function during mechanical circulatory support is challenging because conventional markers (like ejection fraction) are significantly load-dependent. Yet loading conditions are abnormal and change during support and weaning process. Tissue Doppler and strain rate imaging are echocardiographic techniques that permit quantitation of regional wall motion. Peak systolic strain rate (SR) is a fairly load-independent marker of ventricular systolic function in experimental validation studies. We hypothesized that SR changes would improve assessment of right and left ventricular function during mechanical circulatory support. Color tissue Doppler images were acquired before surgery, 8 and 24 hours postoperatively in 18 children undergoing open heart surgery. Clinically, all patients were hemodynamically stable and on low doses of inotropics without death or resuscitation events. Wall motion analysis revealed a significant drop of peak systolic velocities and SR postoperatively in both ventricles. On the next day, all parameters improved with regional differences. SR appeared to be more sensitive to changes than velocities. In conclusion, tissue Doppler imaging appears to be a sensitive marker of ventricular mechanics in children and may improve perioperative monitoring. It offers a method to quantitatively assess left and right ventricular performance and may help to compare different cardio-protective strategies.


Cerebrospinal fluid carcinoembryonic antigen in patients with metastatic and nonmetastatic neurological diseases.
Cerebrospinal fluid (CSF) carcinoembryonic antigen (CEA) values were determined in 200 patients suffering from various neurological diseases. We found no relationship between CEA levels and age or sex. A positive test was defined as an upper limit of at least 4.0 ng/mL of CEA. We found raised CSF CEA levels in patients with leptomeningeal spread from carcinoma, but not in patients with leptomeningeal metastases from lymphoma. We also found high values of CSF CEA in three of 21 patients with epidural metastases and in two of 28 patients with cerebral metastases from solid tumors. Comparison was made with the CSF levels of total protein, glucose, and lactate dehydrogenase. The sensitivity of the CSF CEA determination in patients for the presence of leptomeningeal involvement of cancer is 31% and the specificity is 90%.


Assessing measurement invariance of the Personal Growth Initiative Scale-II among Hispanics, African Americans, and European Americans.
This study tested the cross-cultural validity of scores on the Personal Growth Initiative Scale-II (PGIS-II; Robitschek et al., 2012) with Hispanic, African American, and European American community samples. Multigroup confirmatory factor analyses were performed on data from 218 Hispanics, 129 African Americans, and 552 European Americans to examine measurement equivalence among these groups. Measurement invariance of the PGIS-II was established with the original 4 factors of readiness for change, planfulness, using resources, and intentional behavior. These findings suggest the PGIS-II can be administered across these groups and provide meaningful comparisons and interpretations. All samples yielded good internal consistency estimates. The African American sample reported higher means than Hispanic and European American samples for all subscale and total mean scores, and Hispanics scored higher in planfulness, readiness for change, and total score than European Americans, indicating potential cultural factors influencing the scores. Implications for research and clinical practice are discussed.


One-Atom-Thick Crystals as Emerging Proton Sieves.
Two-dimensional (2D) crystals, despite their atomic thickness, have long been considered as impermeable membranes to all molecules and atoms under ambient conditions: even the smallest of atoms, hydrogen, is expected to take billions of years to penetrate the 2D lattice covered with dense electron clouds. Recently it has been found that monolayer graphene, hexagonal boron nitride, and some other one-atom-thick crystals are highly permeable to protons, raising fundamental questions about the details of the transport process. In this Perspective, we review the mechanism of proton transport through 2D crystals and the related room-temperature quantum effects; the potential applications of 2D membranes in proton-related separation and sieving techniques, including proton exchange membranes and hydrogen isotope separation; and factors that enhance proton permeation and in turn influence 2D membrane design.


Ab initio molecular dynamics study of proton transport in imidazolium-based ionic liquids with added imidazole.
Development of efficient anhydrous proton-conducting materials would expand the operational temperature ranges of hydrogen fuels cells (HFCs) and eliminate their dependence on maintaining sufficient hydration levels to function efficiently. Protic ionic liquids (PILs), which have high ionic densities and low vapor pressures, have emerged as a potential material for proton conducting layers in HFCs. In this work, we investigate proton transport via the Grotthuss mechanism in 1-ethylimidazolium bis-(trifluoromethanesulfonyl)imide ([C2HIm][TFSI]) protic ionic liquids with added imidazole (Im0) using ab initio molecular dynamics. In particular, we vary the composition of the systems studied from pure [C2HIm][TFSI] to those where the mole fraction of Im0 is 0.67. Given the large difference in pKa between C2HIm+ and HTFSI, TFSI- does not accept acidic protons from C2HIm+; conversely, imidazolium (HIm+) and C2HIm+ have very similar pKa values, and thus Im0 can readily accept protons. We find that the unprotonated nitrogen on Im0 dominates solvation of the labile protons on C2HIm+ and other Im0 species, resulting in formation of robust imidazole wires. Given the amphoteric nature of Im0, i.e. its ability to accept and donate protons, these wires provide conduits along which protons can rapidly traverse via the Grotthuss mechanism, thereby greatly increasing the proton coefficient of self-diffusion. We find that the average length of the wires increases with added Im0, and thus as the mole fraction of Im0 increases so too does the proton diffusion constant. Lastly, we analyze our trajectories to determine the energy and time scales associated with proton transfer.


The poison-antidote stability system of the broad-host-range Thiobacillus ferrooxidans plasmid pTF-FC2.
In plasmid pTF-FC2, three small open reading frames (ORFs) are situated between the repB (primase) gene and the repA (helicase) gene of its IncQ-type replicon. Disruption of each of the three ORFs followed by tests for plasmid stability and host cell growth indicated that the ORFs encoded a poison-antidote plasmid stability system. The three genes were named pasA, pasB and pasC (plasmid addiction system), in which PasA is the antidote, PasB the toxin and PasC a protein that appears to enhance the ability of the antidote to neutralize the toxin. Disruption of the pasA gene resulted in two different spontaneous deletions, which inactivated the stability system but did not alter the host range or plasmid copy number. This indicated that the three small ORFs were not involved in plasmid replication. When placed behind a tac promoter, induction of pasB was found to be highly lethal to host cells, which suggests that the Pas system acts by killing plasmid-free host cells rather than by retarding the growth of plasmid-free segregants, as occurs in the ParD system of R1. In spite of this, the presence of the Pas poison-antidote system resulted in a relatively modest threefold stabilization of the pTF-FC2 host replicon and a similar increase in the stabilization of an unstable heterologous R1 plasmid replicon. The Pas system is a poison-antidote plasmid stability module, which appears to have become integrated within the pTF-FC2 replicon module.


An operon of three transcriptional regulators controls horizontal gene transfer of the integrative and conjugative element ICEclc in Pseudomonas knackmussii B13.
The integrative and conjugative element ICEclc is a mobile genetic element in Pseudomonas knackmussii B13, and an experimental model for a widely distributed group of elements in Proteobacteria. ICEclc is transferred from specialized transfer competent cells, which arise at a frequency of 3-5% in a population at stationary phase. Very little is known about the different factors that control the transfer frequency of this ICE family. Here we report the discovery of a three-gene operon encoded by ICEclc, which exerts global control on transfer initiation. The operon consists of three consecutive regulatory genes, encoding a TetR-type repressor MfsR, a MarR-type regulator and a LysR-type activator TciR. We show that MfsR autoregulates expression of the operon, whereas TciR is a global activator of ICEclc gene expression, but no clear role was yet found for MarR. Deletion of mfsR increases expression of tciR and marR, causing the proportion of transfer competent cells to reach almost 100% and transfer frequencies to approach 1 per donor. mfsR deletion also caused a two orders of magnitude loss in population viability, individual cell growth arrest and loss of ICEclc. This indicates that autoregulation is an important feature maintaining ICE transfer but avoiding fitness loss. Bioinformatic analysis showed that the mfsR-marR-tciR operon is unique for ICEclc and a few highly related ICE, whereas tciR orthologues occur more widely in a large variety of suspected ICE among Proteobacteria.


The spectrum of neurobehavioural deficits in the Posterior Fossa Syndrome in children after cerebellar tumour surgery.
The Posterior Fossa Syndrome (PFS) may occur in children after resection of cerebellar tumours. The most common feature is mutism, but also oropharyngeal dyspraxia, emotional lability and neuropsychiatric symptoms occur. We analysed the spectrum of behavioural abnormalities, speech and language characteristics during PFS. In order to identify PFS, all children with a cerebellar tumour admitted to our centre in the study period were prospectively assessed before and after tumour surgery. In the case of PFS, children were systematically followed by means of a standard protocol that included a daily neurological examination and assessment of speech behaviour. Speech was recorded on videotape before and immediately after surgery, and in cases of PFS at as short possible intervals for 4 weeks and subsequently every second week until the recurrence of speech and normalisation of behaviour. Data regarding clinical and behavioural features, duration of symptoms and mode of recovery were collected. Pre- and postoperative MRI data were studied. In 13 children with and two children without PFS a (99m)Tc-hexamethylpropyleneamine oxime-Single Photon Emission Tomography (SPECT) scan could be performed. PFS occurred in 41 of 148 children. During recovery all children were dysarthric, but only in a few speech features specific for cerebellar dysarthria occurred. A significant correlation was found between duration of mutism and severity of neurological symptoms. Significant correlations were also found between duration of mutism and abnormalities on SPECT scans of the left temporal lobe, the left and right basal nuclei, and the right frontal lobe. In this study, impairments of higher cognitive functions were observed in the context of PFS. They varied in severity and composition between children with symptoms fitting into the spectrum of the Cerebellar Cognitive Affective Syndrome. SPECT scan findings suggest that these impairments are secondary to supratentorial metabolic hypofunction following cerebellar surgery.


Relationship between acne vulgaris and cosmetic usage in Sri Lankan urban adolescent females.
Acne vulgaris is one of the commonest skin disorders affecting up to 80% of the world population at least during adolescence. Significant psychosocial effects such as depression and poor personality development have been linked with acne, especially in female adolescents. Various causative factors, including cosmetic exposure, have been attributed toward acne. To analyze the association between frequent exposure to cosmetics and severity of acne in adolescent females. A cross-sectional analytical study was performed on 140 girls from three schools in Colombo, Sri Lanka. A self-administered questionnaire was utilized to assess the patterns of cosmetic usage. Grading acne of the participants was performed by the researchers utilizing a standard acne grading scale. The overall prevalence of acne in our study population was 91.4% with a mean acne grade of 3.09. At least one cosmetic type was used by 126 (90%) of the population. A Pearson correlation coefficient (r) value of .452 (P < .001) was obtained between cosmetic exposure and acne grade, which indicates a statistically significant correlation. A chi-square value of 22.875 was obtained at a degree of freedom of 2 (P < .001), enabling us to reject the null hypothesis that there is no significant association between cosmetic usage and acne severity. Our results convey a significant positive association between frequent exposure to cosmetics and severity of acne in adolescent females. Girls of this age group must be made aware that cosmetic usage may be a potential aggravating factor for their facial acne.


Channel interaction in cochlear implant users evaluated using the electrically evoked compound action potential.
One likely determinant of performance with a cochlear implant is the degree of interaction that occurs when overlapping subsets of nerve fibers are stimulated by various electrodes of a multielectrode array. The electrically evoked compound action potential (ECAP) can be used to assess physiological channel interaction. This paper describes results from two different methods of analysis of ECAP channel interaction measures made by the Nucleus neural response telemetry system. Using a forward-masking stimulus paradigm, masker and probe pulses are delivered through different electrodes. The response to the probe is then dependent on the extent of overlap in the stimulated neural populations. The amplitude of response to the probe as a function of masker electrode position then reflects the degree of overlap between the population of neurons responding to the masker and those stimulated by the probe. Results demonstrate large variations across individual implant users as well as across electrodes within an individual. In general, the degree of interaction is shown to be dependent on stimulus level.


Experience of implementing new mental health indicators within information systems in six low- and middle-income countries.
Successful scale-up of integrated primary mental healthcare requires routine monitoring of key programme performance indicators. A consensus set of mental health indicators has been proposed but evidence on their use in routine settings is lacking. To assess the acceptability, feasibility, perceived costs and sustainability of implementing indicators relating to integrated mental health service coverage in six South Asian (India, Nepal) and sub-Saharan African countries (Ethiopia, Nigeria, South Africa, Uganda). A qualitative study using semi-structured key informant interviews (n = 128) was conducted. The 'Performance of Routine Information Systems' framework served as the basis for a coding framework covering three main categories related to the performance of new tools introduced to collect data on mental health indicators: (1) technical; (2) organisation; and (3) behavioural determinants. Most mental health indicators were deemed relevant and potentially useful for improving care, and therefore acceptable to end users. Exceptions were indicators on functionality, cost and severity. The simplicity of the data-capturing formats contributed to the feasibility of using forms to generate data on mental health indicators. Health workers reported increasing confidence in their capacity to record the mental health data and minimal additional cost to initiate mental health reporting. However, overstretched primary care staff and the time-consuming reporting process affected perceived sustainability. Use of the newly developed, contextually appropriate mental health indicators in health facilities providing primary care services was seen largely to be feasible in the six Emerald countries, mainly because of the simplicity of the forms and continued support in the design and implementation stage. However, approaches to implementation of new forms generating data on mental health indicators need to be customised to the specific health system context of different countries. Further work is needed to identify ways to utilise mental health data to monitor and improve the quality of mental health services. None.


Analysis and synthesis of high-amplitude Cis-elements in the mammalian circadian clock.
Mammalian circadian clocks consist of regulatory loops mediated by Clock/Bmal1-binding elements, DBP/E4BP4 binding elements, and RevErbA/ROR binding elements. As a step toward system-level understanding of the dynamic transcriptional regulation of the oscillator, we constructed and used a mammalian promoter/enhancer database (http://promoter.cdb.riken.jp/) with computational models of the Clock/Bmal1-binding elements, DBP/E4BP4 binding elements, and RevErbA/ROR binding elements to predict new targets of the clock and subsequently validated these targets at the level of the cell and organism. We further demonstrated the predictive nature of these models by generating and testing synthetic regulatory elements that do not occur in nature and showed that these elements produced high-amplitude circadian gene regulation. Biochemical experiments to characterize these synthetic elements revealed the importance of the affinity balance between transactivators and transrepressors in generating high-amplitude circadian transcriptional output. These results highlight the power of comparative genomics approaches for system-level identification and knowledge-based design of dynamic regulatory circuits.


[Interaction of homoeotic mutations Antennapedia and aristapedia in Drosophila melanogaster].
Expression of a number of mutant alleles of Antennapedia and aristapedia loci in pairwise combination of the type Antp ssa/+ssa was compared with their expression in initial Antp and ssa stocks. Marked mutual enhancement of homoeotic action of the genes studied was observed up to the formation of well developed antennal legs consisting of coxae, trochanter, femurs, tibiae and five-segment tarsi in some flies (especially, Antp49 ssa/+ssa). Antennapedia-specificity (rather than aristapedia) of the interaction was found. Cellular basis of action and interaction of homoeotic genes is discussed.