When all hypotheses are right: a multifocal account of dyslexia.
Many hypotheses have been proposed about the brain underpinnings of developmental dyslexia, but none of them accommodates the variable deficits observed. To address the issue of anatomical deficits in dyslexia; total and partial volumes, lateralization indices (LI), and local gray matter volumes (LGMV) were measured. Analyses were performed in large samples of control and dyslexic subjects, and in correlation with their performance on phonological, reading, and spelling tests. Results indicate an absence of net differences in terms of volumes but significant continuities and discontinuities between groups in their correlations between LI, LGMV, and performances. Structural connectivity also highlighted correlations between areas showing (dis)continuities between control and dyslexic subjects. Overall, our data put forward the idea of a multifocal brain abnormalities in dyslexia with a major implication of the left superior temporal gyrus, occipital-temporal cortices, and lateral/medial cerebellum, which could account for the diverse deficits predicted by the different theories.


Effects of Electroacupuncture Treatment on Bone Cancer Pain Model with Morphine Tolerance.
Objective. To explore the efficacy of electroacupuncture treatment in cancer induced bone pain (CIBP) rat model with morphine tolerance and explore changes of calcitonin-gene related peptide (CGRP) expression in dorsal root ganglion (DRG). Methods. Forty SD rats were divided into five groups: sham, CIBP (B), CIBP + morphine (BM), CIBP + electroacupuncture (BE), and CIBP + morphine + electroacupuncture (BME). B, BM, BE, and BME groups were prepared CIBP model. The latter three groups then accepted morphine, electroacupuncture, and morphine combined electroacupuncture, separately, nine days consecutively (M1 to M9). Mechanical withdraw threshold (MWT) was evaluated. Results. BE group only had differences in M1, M2, and M3 compared to B group (P < 0.01). From M5, BM group showed significantly decreased MWT. Electroacupuncture could obtain analgesic effects only at early stage (M1 to M5). From M5 to M9, BME had the differences with BM group (P < 0.01). IOD value of CGRP in BM and BME was substantially less than in B group. CGRP in BME was significantly lower than that in BM group (P < 0.01). Conclusion. When used in combination with electroacupuncture, morphine could result in improving analgesic effects and reducing tolerance. CGRP may be associated with pain behaviors.


Gold-catalyzed formation of heterocycles - an enabling new technology for medicinal chemistry.
Gold-catalyzed transformations allow efficient access to a wide scope of heterocyclic structures that serve as building blocks and pharmacophores in medicinal chemistry. Compared with other transition metal and Lewis acid catalysis, gold catalysis presents mechanistic divergence, excellent functional group tolerance and/or operational advantages. Emergent applications of gold catalysis have played a key role in the synthesis of biologically active molecules including a drug candidate.


Stroma-derived IL-6, G-CSF and Activin-A mediated dedifferentiation of lung carcinoma cells into cancer stem cells.
Cancer stem cells (CSCs) are a small population of resistant cells inhabiting the tumors. Although comprising only nearly 3% of the tumor mass, these cells were demonstrated to orchestrate tumorigenesis and differentiation, underlie tumors' heterogeneity and mediate therapy resistance and tumor relapse. Here we show that CSCs may be formed by dedifferentiation of terminally differentiated tumor cells under stress conditions. Using a elegant co-culture cellular system, we were able to prove that nutrients and oxygen deprivation activated non-malignant stromal fibroblasts, which in turn established with tumor cells a paracrine loop mediated by Interleukine-6 (IL-6), Activin-A and Granulocyte colony-stimulating factor (G-CSF), that drove subsequent tumor formation and cellular dedifferentiation. However, by scavenging these cytokines from the media and/or blocking exosomes' mediated communication it was possible to abrogate dedifferentiation thus turning these mechanisms into potential therapeutic targets against cancer progression.


Intercellular communication through extracellular vesicles in cancer and evolutionary biology.
Extracellular vesicles (EVs) are nano-sized membrane enclosed vesicles that are released by cells. While initially thought to be cellular detritus or particles involved in eliminating waste from cells, EVs have been recognised as important mediators of intercellular communication by transferring their bioactive cargoes. Notably, over the last two decades, a substantial research effort has been undertaken to understand the role of EVs in cancer. It is now understood that tumour derived EVs can transfer their contents to influence metastatic behaviour, as well as establish favourable microenvironments and pre-metastatic niches that support cancer development and progression. EV-mediated intercellular communication in cancer will be of importance to understanding the emerging paradigm which views cancer as the establishment of a new species within the host organism. Here, we provide a concise overview of EVs and the current understanding of their role and application in cancer. In addition, we explore the potential wider role of EVs in the transfer of inherited characteristics and evolutionary biology.


Effects of smoking status on immediate treatment outcomes of multidisciplinary pain rehabilitation.
The primary aim of this study was to determine the effects of smoking on treatment outcomes following multidisciplinary pain rehabilitation. A secondary aim was to assess the tobacco use characteristics of smokers with chronic pain. A prospective, nonrandomized, repeated measures design. Multidisciplinary pain rehabilitation center at a tertiary referral medical center. All patients (N = 193) consecutively admitted from August 2005 through February 2006. A 3-week outpatient multidisciplinary pain rehabilitation program. The Multidimensional Pain Inventory (MPI), Short Form-36 Health Status Questionnaire (SF-36), Center for Epidemiologic Studies-Depression scale (CES-D), Pain Anxiety Symptom Scale (PASS-20) and Pain Catastrophizing Scale (PCS) were administered at admission and dismissal. The study involved 49 (83% women) smokers and 144 (83% women) nonsmokers. The mean number of cigarettes smoked daily was 17.5 (SD 11.1) and the mean duration of smoking was 21.5 years (SD 12.1). After adjusting for demographic differences, repeated measures of analysis of covariance showed a main effect of smoking status for MPI affective distress (P = 0.008), CES-D (P = 0.001) and PCS (P = 0.011). An interaction of smoking status and time was found for the PASS-20 (P = 0.028), MPI affective distress (P = 0.033), MPI life control (P = 0.003) and SF-36 role-emotional (P = 0.004) subscale. While the majority of smokers were ready to consider smoking abstinence, 43% declined a brief smoking cessation intervention. In this series of patients undergoing multidisciplinary treatment for chronic pain, immediate treatment effects for a variety of outcome measures were similar or significantly better in smokers compared with nonsmokers.


Engineering the protein dynamics of an ancestral luciferase.
Protein dynamics are often invoked in explanations of enzyme catalysis, but their design has proven elusive. Here we track the role of dynamics in evolution, starting from the evolvable and thermostable ancestral protein AncHLD-RLuc which catalyses both dehalogenase and luciferase reactions. Insertion-deletion (InDel) backbone mutagenesis of AncHLD-RLuc challenged the scaffold dynamics. Screening for both activities reveals InDel mutations localized in three distinct regions that lead to altered protein dynamics (based on crystallographic B-factors, hydrogen exchange, and molecular dynamics simulations). An anisotropic network model highlights the importance of the conformational flexibility of a loop-helix fragment of Renilla luciferases for ligand binding. Transplantation of this dynamic fragment leads to lower product inhibition and highly stable glow-type bioluminescence. The success of our approach suggests that a strategy comprising (i) constructing a stable and evolvable template, (ii) mapping functional regions by backbone mutagenesis, and (iii) transplantation of dynamic features, can lead to functionally innovative proteins.


A major locus for fasting insulin concentrations and insulin resistance on chromosome 6q with strong pleiotropic effects on obesity-related phenotypes in nondiabetic Mexican Americans.
Insulin resistance and hyperinsulinemia are strong correlates of obesity and type 2 diabetes, but little is known about their genetic determinants. Using data on nondiabetics from Mexican American families and a multipoint linkage approach, we scanned the genome and identified a major locus near marker D6S403 for fasting "true" insulin levels (LOD score 4.1, empirical P<.0001), which do not crossreact with insulin precursors. Insulin resistance, as assessed by the homeostasis model using fasting glucose and specific insulin (FSI) values, was also strongly linked (LOD score 3.5, empirical P<.0001) with this region. Two other regions across the genome were found to be suggestively linked to FSI: a location on chromosome 2q, near marker D2S141, and another location on chromosome 6q, near marker D6S264. Since several insulin-resistance syndrome (IRS)-related phenotypes were mapped independently to the regions on chromosome 6q, we conducted bivariate multipoint linkage analyses to map the correlated IRS phenotypes. These analyses implicated the same chromosomal region near marker D6S403 (6q22-q23) as harboring a major gene with strong pleiotropic effects on obesity and on lipid measures, including leptin concentrations (e.g., LOD(eq) for traits-specific insulin and leptin was 4.7). A positional candidate gene for insulin resistance in this chromosomal region is the plasma cell-membrane glycoprotein PC-1 (6q22-q23). The genetic location on chromosome 6q, near marker D6S264 (6q25.2-q26), was also identified by the bivariate analysis as exerting significant pleiotropic influences on IRS-related phenotypes (e.g., LOD(eq) for traits-specific insulin and leptin was 4.1). This chromosomal region harbors positional candidate genes, such as the insulin-like growth factor 2 receptor (IGF2R, 6q26) and acetyl-CoA acetyltransferase 2 (ACAT2, 6q25.3-q26). In sum, we found substantial evidence for susceptibility loci on chromosome 6q that influence insulin concentrations and other IRS-related phenotypes in Mexican Americans.


Fate of injected glucagon taken up by rat liver in vivo. Degradation of internalized ligand in the endosomal compartment.
The uptake and processing of glucagon into liver endosomes were studied in vivo by subcellular fractionation. After injection of [[125I]iodo-Tyr10]glucagon and [[125I]iodo-Tyr13]glucagon to rats, the uptake of radioactivity into the liver was maximum at 2 min (6% of the dose/g of tissue). On differential centrifugation, the radioactivity in the homogenate was recovered mainly in the nuclear (N), microsomal (P) and supernatant (S) fractions, with maxima at 5, 10 and 40 min, respectively; recovery of radioactivity in the mitochondrial-lysosomal (ML) fraction did not exceed 6% and was maximal at 20 min. On density-gradient centrifugation, the radioactivity associated first (2-10 min) with plasma membranes and then (10-40 min) with Golgi-endosomal (GE) fractions, with 2-5-fold and 20-150-fold enrichments respectively. Subfractionation of the GE fractions showed that, unlike the Golgi marker galactosyltransferase, the radioactivity was density-shifted by diaminobenzidine cytochemistry. Subfractionation of the ML fraction isolated at 40 min showed that more than half of the radioactivity was recovered at lower densities than the lysosomal marker acid phosphatase. Throughout the time of study, the [125I]iodoglucagon associated with the P, PM and GE fractions remained at least 80-90% trichloroacetic acid (TCA)-precipitable, whereas that associated with other fractions, especially the S fraction, became progressively TCA-soluble. On gel filtration and h.p.l.c., the small amount of degraded [125I]iodoglucagon associated with GE fractions was found to consist of monoiodotyrosine. Chloroquine treatment of [125I]iodoglucagon-injected rats caused a moderate but significant increase in the late recovery of radioactivity in the ML, P and GE fractions, but had little effect on the association of the ML radioactivity with acid-phosphatase-containing structures. Chloroquine treatment also led to a paradoxical decrease in the TCA-precipitability of the radioactivity associated with the P and GE fractions. Upon h.p.l.c. analysis of GE extracts of chloroquine-treated rats, at least four degradation products less hydrophobic than intact [125I]iodoglucagon were identified. Radio-sequence analysis of four of these products revealed three cleavages, affecting bonds Ser2-Gln3, Thr5-Phe6 and Phe6-Thr7. When GE fractions containing internalized [125I]iodoglucagon were incubated in iso-osmotic KCl at 30 degrees C, a rapid generation of TCA-soluble products was observed, with a maximum at pH 4. We conclude that endosomes are a major site at which internalized glucagon is degraded, endosomal acidification being required for optimum degradation.


Association Between Pesticide Residue Intake From Consumption of Fruits and Vegetables and Pregnancy Outcomes Among Women Undergoing Infertility Treatment With Assisted Reproductive Technology.
Animal experiments suggest that ingestion of pesticide mixtures at environmentally relevant concentrations decreases the number of live-born offspring. Whether the same is true in humans is unknown. To examine the association of preconception intake of pesticide residues in fruits and vegetables (FVs) with outcomes of infertility treatment with assisted reproductive technologies (ART). This analysis included 325 women who completed a diet assessment and subsequently underwent 541 ART cycles in the Environment and Reproductive Health (EARTH) prospective cohort study (2007-2016) at a fertility center at a teaching hospital. We categorized FVs as having high or low pesticide residues using a validated method based on surveillance data from the US Department of Agriculture. Cluster-weighted generalized estimating equations were used to analyze associations of high- and low-pesticide residue FV intake with ART outcomes. Adjusted probabilities of clinical pregnancy and live birth per treatment cycle. In the 325 participants (mean [SD] age, 35.1 [4.0] y; body mass index, 24.1 [4.3]), mean (SD) intakes of high- and low-pesticide residue FVs were 1.7 (1.0) and 2.8 (1.6) servings/d, respectively. Greater intake of high-pesticide residue FVs was associated with a lower probability of clinical pregnancy and live birth. Compared with women in the lowest quartile of high-pesticide FV intake (<1.0 servings/d), women in the highest quartile (≥2.3 servings/d) had 18% (95% CI, 5%-30%) lower probability of clinical pregnancy and 26% (95% CI, 13%-37%) lower probability of live birth. Intake of low-pesticide residue FVs was not significantly related to ART outcomes. Higher consumption of high-pesticide residue FVs was associated with lower probabilities of pregnancy and live birth following infertility treatment with ART. These data suggest that dietary pesticide exposure within the range of typical human exposure may be associated with adverse reproductive consequences.


And now for something completely different: drugs that work!-The patients' perspective.
The result of drug development so far is beyond expectations and also beyond what is possible. The reason for this is probably that the aim is not a better quality of life for the patient and her loved ones but profit. Working together with patients on an equal basis-and in the patients' best interest-will bring better drugs to the market that work and provide better quality of life and with less severe side effects. For the pharmaceutical companies that want to benefit patients, it will bring enough profit. Essential is that we are honest about our interests and respect the interest of one another. And go for the win-win situation instead of the compromise. We can also do better by doing research on combinations of new and existing drugs. This might be faster available for patients and also cheaper. The government can help by making the rules for drug development easier on safety. The cooperation with patients will still make things safe enough. The government has to support the patient advocacy groups financially to make them less dependent on the pharmaceutical companies. And finally, the patient advocacy groups can do a lot to make the patients, doctors, researchers, government and industry more cancer literate.


New Frontiers of Corneal Gene Therapy.
Corneal diseases are among the most prevalent causes of blindness worldwide. The transparency and clarity of the cornea are guaranteed by a delicate physiological, anatomic, and functional balance. For this reason, all the disorders, including those of genetic origin, that compromise this state of harmony can lead to opacity and eventually vision loss. Many corneal disorders have a genetic etiology, and some are associated with rather rare and complex syndromes. Conventional treatments, such as corneal transplantation, are often ineffective, and to date, many of these disorders are still incurable. Gene therapy carries the promise of being a potential cure for many of these diseases, with solutions and strategies that did not seem possible until a few years ago. With its potential to treat genetic disease by means of deletion, replacement, or editing of a defective gene, the challenge can also be extended to corneal disorders in order to achieve long-term, if not definitive, relief. The aim of this paper is to review the state of the art of the different gene therapy approaches as potential treatments for corneal diseases and the future perspectives for the development of personalized gene-based medicine.


miR-19a: an effective regulator of SOCS3 and enhancer of JAK-STAT signalling.
Suppressors of cytokine signalling (SOCS) proteins are classic inhibitors of the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway. Many cytokines and pathogenic mediators induce expression of SOCS, which act in a negative feedback loop to inhibit further signal transduction. SOCS mRNA expression is regulated by DNA binding of STAT proteins, however, their post-transcriptional regulation is poorly understood. microRNAs (miRNAs) are small non-coding RNAs that bind to complementary sequences on target mRNAs, often silencing gene expression. miR-19a has been shown to regulate SOCS1 expression during mutiple myeloma and be induced by the anti-viral cytokine interferon-(IFN)-α, suggesting a role in the regulation of the JAK-STAT pathway. This study aimed to identify targets of miR-19a in the JAK-STAT pathway and elucidate the functional consequences. Bioinformatic analysis identified highly conserved 3'UTR miR-19a target sequences in several JAK-STAT associated genes, including SOCS1, SOCS3, SOCS5 and Cullin (Cul) 5. Functional studies revealed that miR-19a significantly decreased SOCS3 mRNA and protein, while a miR-19a antagomir specifically reversed its inhibitory effect. Furthermore, miR-19a-mediated reduction of SOCS3 enhanced IFN-α and interleukin (IL)-6 signal transduction through STAT3. These results reveal a novel mechanism by which miR-19a may augment JAK-STAT signal transduction via control of SOCS3 expression and are fundamental to the understanding of inflammatory regulation.


Dehalogenation in marine sediments containing natural sources of halophenols.
Halophenols such as 2,4-dibromophenol (DBP) occur naturally in some marine sediments, as a consequence of various animal and algal activities. In an earlier study, DBP was observed in the burrow microenvironment of the hemichordate Saccoglossus kowalewskii. At the concentrations found in the burrow lining, aerobic respiration appeared to be inhibited significantly relative to anaerobic catabolism. This effect, as well as factors contributing to the degradation of DBP, has been documented further here. Results from the addition of radiolabeled DBP to oxic and anoxic sediment slurries and growth experiments with aerobic and anaerobic enrichments suggested that aerobes did not significantly metabolize DBP and that concentrations likely to be encountered on the inner surfaces of the burrow wall were inhibitory. In contrast, only minimal inhibition of growth occurred for anaerobes exposed to 1 mM DBP; in addition, DBP was substantially degraded in both enrichments and sediments under anaerobic conditions. Dehalogenation with the consequent production of phenol appeared to initiate anaerobic degradation. Sulfate-reducing bacteria did not dehalogenate DBP but appeared to degrade phenol. Decreased bacterial numbers and marked differences in the concentration and chemical speciation of iron in sediments from S. kowalewskii burrows may be attributed to toxic effects of DBP on aerobic bacteria.


Conceptual processing is referenced to the experienced location of the self, not to the location of the physical body.
We tested whether an experimentally induced change in the experienced location of the self by means of the Full Body Illusion (FBI) would impact high-level cognitive processing. In an implicit association task, participants saw a landscape where words, conveying spatial ("Near", "Far") or social ("Us", "Them") semantic distance appeared either in a proximal or distal position. Words' "semantic" distance was congruent or incongruent to the words' spatial position. Participants were asked to classify words' spatial position. Implicit association judgements were intermingled with sessions of visuo-tactile stimulation, during which participants were touched on their back, while viewing an avatar in the distal position being touched either synchronously or asynchronously. In a control experiment, participants performed the same task while observing a neutral object being touched, as a control. When subjects self-identified with the avatar presented at the distal position, the facilitation effect of the words' spatial-semantic congruency disappeared. The congruency effect did not disappear in case of asynchronous stimulation as well as in the control experiment with the object, where no change in self-identification was observed. These results demonstrate that conceptual processing is not referenced to the location of the physical body, but to the experienced location of the self.


Inter-Pregnancy Weight Change and the Risk of Recurrent Pregnancy Complications.
Women with specific adverse pregnancy outcomes in their first pregnancy may be receptive to inter-pregnancy weight management guidance aimed at preventing these complications reoccurring in subsequent pregnancies. Thus the association between inter-pregnancy weight change and the risk of recurrent pregnancy complications at the second pregnancy was investigated in a retrospective cohort study of 24,520 women with their first-ever and second consecutive deliveries in Aberdeen using logistic regression. Compared with women who were weight stable, weight loss (>2BMI units) between pregnancies was associated with an increased risk of recurrent small for gestational age (SGA) birth and elective Cesarean-section, and was protective against recurrent pre-eclampsia, placental oversize and large for gestational age (LGA) birth. Conversely weight gain (>2BMI units) between pregnancies increased the risk of recurrent gestational hypertension, placental oversize and LGA birth and was protective against recurrent low placental weight and SGA birth. The relationships between weight gain, and placental and birth weight extremes were evident only in women with a healthy weight at first pregnancy (BMI<25units), while that between weight gain and the increased risk of recurrent gestational hypertension was largely independent of first pregnancy BMI. No relationship was detected between inter-pregnancy weight change and the risk of recurrent spontaneous preterm delivery, labour induction, instrumental delivery, emergency Cesarean-section or postpartum hemorrhage. Therefor inter-pregnancy weight change impacts the risk of recurrent hypertensive disorders, SGA and LGA birth and women with a prior history of these specific conditions may benefit from targeted nutritional advice to either lose or gain weight after their first pregnancy.


Hypokinesia without decrement distinguishes progressive supranuclear palsy from Parkinson's disease.
Repetitive finger tapping is commonly used to assess bradykinesia in Parkinson's disease. The Queen Square Brain Bank diagnostic criterion of Parkinson's disease defines bradykinesia as 'slowness of initiation with progressive reduction in speed and amplitude of repetitive action'. Although progressive supranuclear palsy is considered an atypical parkinsonian syndrome, it is not known whether patients with progressive supranuclear palsy have criteria-defined bradykinesia. This study objectively assessed repetitive finger tap performance and handwriting in patients with Parkinson's disease (n = 15), progressive supranuclear palsy (n = 9) and healthy age- and gender-matched controls (n = 16). The motion of the hand and digits was recorded in 3D during 15-s repetitive index finger-to-thumb tapping trials. The main finding was hypokinesia without decrement in patients with progressive supranuclear palsy, which differed from the finger tap pattern in Parkinson's disease. Average finger separation amplitude in progressive supranuclear palsy was less than half of that in controls and Parkinson's disease (P < 0.001 in both cases). Change in tap amplitude over consecutive taps was computed by linear regression. The average amplitude slope in progressive supranuclear palsy was nearly zero (0.01°/cycle) indicating a lack of decrement, which differed from the negative slope in patients with Parkinson's disease OFF levodopa (-0.20°/cycle, P = 0.002). 'Hypokinesia', defined as <50% of control group's mean amplitude, combined with 'absence of decrement', defined as mean positive amplitude slope, were identified in 87% of finger tap trials in the progressive supranuclear palsy group and only 12% in the Parkinson's disease OFF levodopa group. In progressive supranuclear palsy, the mean amplitude was not correlated with disease duration or other clinimetric scores. In Parkinson's disease, finger tap pattern was compatible with criteria-defined bradykinesia, characterized by slowness with progressive reduction in amplitude and speed and increased variability in speed throughout the tap trial. In Parkinson's disease, smaller amplitude, slower speed and greater speed variability were all associated with a more severe Unified Parkinson's Disease Rating Scale motor score. Analyses of handwriting showed that micrographia, defined as smaller than 50% of the control group's mean script size, was present in 75% of patients with progressive supranuclear palsy and 15% of patients with Parkinson's disease (P = 0.022). Most scripts performed by patients with progressive supranuclear palsy did not exhibit decrements in script size. In conclusion, patients with progressive supranuclear palsy have a specific finger tap pattern of 'hypokinesia without decrement' and they do not have criteria-defined limb bradykinesia. Similarly, 'micrographia' and 'lack of decrement in script size' are also more common in progressive supranuclear palsy than in Parkinson's disease.


Hypnotics and Triazolobenzodiazepines--Best Predictors of High-Dose Benzodiazepine Use: Results from the Luxembourg National Health Insurance Registry.
Benzodiazepines are not all the same concerning their risk of high-dose use. We studied benzodiazepine use from the Luxembourg national records of all insured. We calculated the 12-year prevalence from 1995 to 2007. Benzodiazepine users were divided into 3 groups, short-term with no longer than 3-month intake, intermediate with multiple administration with at least a 1-year interruption, and continuous who never stopped. A high-dose user (HDU) was defined as a patient who received a higher dose than the yearly maximum usual therapeutic dose. An average of 16.0% of the adult insured population received at least 1 benzodiazepine annually, 42.9% were older than 50, 55.9% were women, and 5.4% were HDUs. We found that 32.6% were short-term users, 49.0% intermediate and 18.4% continuous. Compared to diazepam, hypnotics had higher risks for high-dose use in at least 1 age group at first-benzodiazepine intake, the risks being greater in elderly subjects and women, the highest risks being with triazolam (adjusted odds ratio = 215.85; 95% confidence interval = 133.75-348.35) in the 69- to 105-year-old group at first-benzodiazepine intake. Anxiolytics had a low risk except for alprazolam and prazepam in the 69- to 105-year-old group at first-benzodiazepine intake, clonazepam and clobazam had the lowest risk in 18- to 43-year-olds at first-benzodiazepine intake. Alprazolam had dispensed volumes increased by threefold over the 12-year period. All hypnotics had higher risks for high-dose use compared to diazepam in continuous users. Two anxiolytics, clonazepam and clobazam, had the lowest risks. Hypnotics and the triazolobenzodiazepines alprazolam and triazolam were most problematic. Elderly subjects and women are at greater risks.


Characterization and functional allotment of proto-oncogenes belonging to the src family.
Eight proto-oncogenes encode cytoplasmic protein tyrosine kinases whose primary structures are closely related to that of p60proto-src. This group of related genes is called the src-family. Their products share common structures: namely, a glycine residue at position 2 from the N terminus, a unique domain, a modulatory domain (SH2, SH3), a kinase (catalytic) domain, and a regulatory domain. Oncogenic activation of these genes may occur by various mutations such as 1) deletion or substitution of the tyrosine at the C-terminal position, 2) mutation at a defined position in the kinase domain or 3) deletion or mutation in the modulatory domain. The expressions of the proto-oncogenes of this family are tissue specific and are unique for each gene, suggesting functional allotment of these gene products. In the hematopoietic system, the genes appear to be expressed in specific cell lineages. In this paper, the functional allotments of these genes in the hematopoietic system are considered with special reference to the functions of lck, lyn, and fyn in cells of T and B lymphocyte lineages.


The mRNA-binding protein HuR promotes hypoxia-induced chemoresistance through posttranscriptional regulation of the proto-oncogene PIM1 in pancreatic cancer cells.
Previously, it has been shown that pancreatic ductal adenocarcinoma (PDA) tumors exhibit high levels of hypoxia, characterized by low oxygen pressure (pO2) and decreased O2 intracellular perfusion. Chronic hypoxia is strongly associated with resistance to cytotoxic chemotherapy and chemoradiation in an understudied phenomenon known as hypoxia-induced chemoresistance. The hypoxia-inducible, pro-oncogenic, serine-threonine kinase PIM1 (Proviral Integration site for Moloney murine leukemia virus 1) has emerged as a key regulator of hypoxia-induced chemoresistance in PDA and other cancers. Although its role in therapeutic resistance has been described previously, the molecular mechanism behind PIM1 overexpression in PDA is unknown. Here, we demonstrate that cis-acting AU-rich elements (ARE) present within a 38-base pair region of the PIM1 mRNA 3'-untranslated region mediate a regulatory interaction with the mRNA stability factor HuR (Hu antigen R) in the context of tumor hypoxia. Predominantly expressed in the nucleus in PDA cells, HuR translocates to the cytoplasm in response to hypoxic stress and stabilizes the PIM1 mRNA transcript, resulting in PIM1 protein overexpression. A reverse-phase protein array revealed that HuR-mediated regulation of PIM1 protects cells from hypoxic stress through phosphorylation and inactivation of the apoptotic effector BAD and activation of MEK1/2. Importantly, pharmacological inhibition of HuR by MS-444 inhibits HuR homodimerization and its cytoplasmic translocation, abrogates hypoxia-induced PIM1 overexpression and markedly enhances PDA cell sensitivity to oxaliplatin and 5-fluorouracil under physiologic low oxygen conditions. Taken together, these results support the notion that HuR has prosurvival properties in PDA cells by enabling them with growth advantages in stressful tumor microenvironment niches. Accordingly, these studies provide evidence that therapeutic disruption of HuR's regulation of PIM1 may be a key strategy in breaking an elusive chemotherapeutic resistance mechanism acquired by PDA cells that reside in hypoxic PDA microenvironments.


A three-dimensional digital atlas of the starling brain.
Because of their sophisticated vocal behaviour, their social nature, their high plasticity and their robustness, starlings have become an important model species that is widely used in studies of neuroethology of song production and perception. Since magnetic resonance imaging (MRI) represents an increasingly relevant tool for comparative neuroscience, a 3D MRI-based atlas of the starling brain becomes essential. Using multiple imaging protocols we delineated several sensory systems as well as the song control system. This starling brain atlas can easily be used to determine the stereotactic location of identified neural structures at any angle of the head. Additionally, the atlas is useful to find the optimal angle of sectioning for slice experiments, stereotactic injections and electrophysiological recordings. The starling brain atlas is freely available for the scientific community.


Learning pelvic examination with professional patients.
Performing pelvic examination is a vital skill to learn during gynecological and obstetrical training. It's a difficult maneuver to master as there is very little to see and more to feel and interpret. In addition, learning PE in usual clinical set-up has been found to induce lot of stress and anxiety among both the patients and the students. Students fear of hurting the patients and being judged inept, whereas patients feel embarrassed having to expose their most intimate body parts for learning purpose. This hampers effective learning. Learning PE on sedated women before surgery or on mannequins has been practiced as alternative learning models. But, they have been found to miss out on teaching the communication skills, which are as important as the palpation skills. However, there exists another model of learning PE--the professional patients, who are specially trained to act as patients and also guide the students on how to make a proper PE. They provide stress-free environment for the students to learn PE and at the same time, provide immediate feedback on each of their maneuvers. They form a complete learning model and help students to see patients as partner and not just a person seeking help.


High-directional light source using photon recycling with a retro-reflective Dome incorporated with a textured LED die surface.
This paper demonstrates a novel retro-reflective dome that enhances the directionality of a light emitting diode (LED) by recycling photons reflected by a textured LED die surface. A simulation model is developed to describe both the photon recycling process within the dome and the role of specific pyramid patterns on the top surface of the LED die. Advanced simulations showed that a perfectly polished surface with 100% reflectivity potentially enhances the directionality of the dome by 340%, 250%, and 240% using reflective domes with 10°, 20°, and 30° light cones, respectively. In the experiment, the directionality of the domes exhibiting surface imperfections is enhanced by approximately 160%, 150%, and 130% using 10°, 20°, and 30° light cones, respectively. By incorporating a textured top surface on the LED die, the proposed dome effectively increases the directionality of the LED light source.


Immunization with chlamydial type III secretion antigens reduces vaginal shedding and prevents fallopian tube pathology following live C. muridarum challenge.
Chlamydia trachomatis infections in women are often asymptomatic and if left untreated can lead to significant late sequelae including pelvic inflammatory disease and tubal factor infertility. Vaccine development efforts over the past three decades have been unproductive and there is no vaccine approved for use in humans. The existence of serologically distinct strains or serovars of C. trachomatis mandates a vaccine that will provide protection against multiple serovars. Chlamydia spp. use a highly conserved type III secretion system (T3SS) composed of both structural and effector proteins which is an essential virulence factor for infection and intracellular replication. In this study we evaluated a novel fusion protein antigen (BD584) which consists of three T3SS proteins from C. trachomatis (CopB, CopD, and CT584) as a potential chlamydial vaccine candidate. Intranasal immunization with BD584 elicited serum neutralizing antibodies that inhibited C. trachomatis infection in vitro. Following intravaginal challenge with C. muridarum, immunized mice had a 95% reduction in chlamydial shedding from the vagina at the peak of infection and cleared the infection sooner than control mice. Immunization with BD584 also reduced the rate of hydrosalpinx by 87.5% compared to control mice. Together, these results suggest that highly conserved proteins of the chlamydial T3SS may represent good candidates for a Chlamydia vaccine.


[Prevention of stomatitis induced by anti-cancer drugs].
A randomized control trial study was carried out to evaluate the effect of allopurinol mouth wash on stomatitis induced by chemotherapy in gynecologic patients. Chemotherapeutics used consisted of 5-FU+CDDP (PF) given to 10 patients and vincristine and actinomycin-D+cyclophosphamide (VAC) given to 5. Allopurinol mouth wash was prepared for patients to rinse their mouth with the solution 4-5 times daily before and after treatment with anti-cancer drugs. The Japan Society For Cancer Therapy's criteria for stomatitis were used. In the control group, stomatitis occurred in 9 of the 10 patients receiving PF therapy and in all of the 5 receiving VAC. In contrast, stomatitis was observed in only 2 of the 10 patients receiving PF therapy and 2 of the 5 VAC in the allopurinol-treated group. Allopurinol mouth wash showed a marked effect on stomatitis induced by chemotherapy.


Thrombin activatable fibrinolysis inhibitor (TAFI) levels in hypertensive patients and a comparison of the effects of amlodipine and ramipril on TAFI levels.
Hypertension is associated with fibrinolysis abnormality. Thrombin-activatable fibrinolysis inhibitor (TAFI) is a novel molecule-linking coagulation and fibrinolysis. The aim of this study was to investigate the levels of TAFI in primary hypertensive patients and to compare the effects of amlodipine and ramipril on TAFI levels. The study was performed with 58 hypertensive subjects and 27 healthy volunteers. Biochemical and hematological parameters and TAFI levels were measured at baseline and after 1-month follow-up. TAFI concentrations increased in hypertensive patients compared with the controls (P = .030). Additionally, TAFI levels decreased with blood pressure control at 1-month follow-up (P = .026). There was no significant difference between TAFI levels in the amlodipine and ramipril groups at baseline. However, after 1-month follow-up, TAFI levels were decreased in the amlodipine group (P = .037) but not in the ramipril group. Our study is the first in the literature to determine increased TAFI levels in primary hypertension patients. In addition, we determined a decrease in TAFI levels in the amlodipine group after 1 month, but none in the ramipril group.


Predicted effects of nitric oxide and superoxide on the vasoactivity of the afferent arteriole.
We expanded a published mathematical model of an afferent arteriole smooth muscle cell in rat kidney (Edwards A, Layton, AT. Am J Physiol Renal Physiol 306: F34-F48, 2014) to understand how nitric oxide (NO) and superoxide (O(2)(-)) modulate the arteriolar diameter and its myogenic response. The present model includes the kinetics of NO and O(2)(-) formation, diffusion, and reaction. Also included are the effects of NO and its second messenger cGMP on cellular Ca²⁺ uptake and efflux, Ca²⁺-activated K⁺ currents, and myosin light chain phosphatase activity. The model considers as well pressure-induced increases in O(2)(-) production, O(2)(-)-mediated regulation of L-type Ca²⁺ channel conductance, and increased O(2)(-) production in spontaneous hypertensive rats (SHR). Our results indicate that elevated O(2)(-) production in SHR is sufficient to account for observed differences between normotensive and hypertensive rats in the response of the afferent arteriole to NO synthase inhibition, Tempol, and angiotensin II at baseline perfusion pressures. In vitro, whether the myogenic response is stronger in SHR remains uncertain. Our model predicts that if mechanosensitive cation channels are not modulated by O(2)(-), then fractional changes in diameter induced by pressure elevations should be smaller in SHR than in normotensive rats. Our results also suggest that most NO diffuses out of the smooth muscle cell without being consumed, whereas most O(2)(-) is scavenged, by NO and superoxide dismutase. Moreover, the predicted effects of superoxide on arteriolar constriction are not predominantly due to its scavenging of NO.


Current Status of Diagnostic Testing for SARS-CoV-2 Infection and Future Developments: A Review.
The coronavirus disease 2019 (COVID-19) caused by a novel coronavirus, SARS-CoV-2, has infected more than 50.6 million individuals and caused over 1.2 million deaths globally, raising a major health concern. To date, no specific antiviral treatment or vaccine for COVID-19 has been approved by the Food and Drug Administration (FDA). Highly sensitive and specific laboratory diagnostics are therefore critical for controlling the rapidly evolving COVID-19 pandemic and optimizing clinical care, infection control, and public health interventions. The FDA has issued emergency use authorization (EUA) for hundreds of COVID-19 diagnostic tests of different classes. Whereas nucleic acid testing (NAT) such as RT-PCR remains the criterion standard for COVID-19 diagnosis, serological antibody and antigen tests are increasingly being developed. Tests based on the novel RNA sensing techniques (e.g., SHERLOCK, DETECTR, and Toehold Switch) are promising due to their relatively low cost, high accuracy, and rapid detection time. Diagnostic testing results for SARS-CoV-2 should be interpreted with caution, since they depend heavily on factors such as viral load, virus replication, the source and timing of sample collection, sample extraction, and characteristics of various testing methods. This review aims to present the current status of common diagnostic testing for SARS-CoV-2 infection, review the current regulatory requirements, and identify future directions in the development of improved diagnostics that are more accurate, accessible, and rapid.


Exploring genomic dark matter: a critical assessment of the performance of homology search methods on noncoding RNA.
Homology search is one of the most ubiquitous bioinformatic tasks, yet it is unknown how effective the currently available tools are for identifying noncoding RNAs (ncRNAs). In this work, we use reliable ncRNA data sets to assess the effectiveness of methods such as BLAST, FASTA, HMMer, and Infernal. Surprisingly, the most popular homology search methods are often the least accurate. As a result, many studies have used inappropriate tools for their analyses. On the basis of our results, we suggest homology search strategies using the currently available tools and some directions for future development.


Conscientiousness mediates the relation between perceived parental socialisation and self-rated health.
The pathways between parenting behaviours, personality and physical health have all been separately studied. Prior research has paid little attention to the indirect effects of personality in the path between parenting behaviours and better health. The purpose of this study was to explore the mediational effects of conscientiousness on the relationships between parental socialisation of responsibility and self-rated health, and to examine potential age differences in this mediational pathway. In total, 736 female and 749 male members across Japan participated in this study. They were divided into three groups by age category: younger-, middle-aged and older-aged. Conscientiousness and health were concurrently rated, while parental socialisation of responsibility was retrospectively assessed. Our analyses revealed that parental socialisation of responsibility is positively associated with conscientiousness and self-rated health, that conscientiousness is positively associated with self-rated health, and that conscientiousness fully mediated the effect of parental socialisation of responsibility on self-rated health. The mediational links were consistent across younger, middle-aged and older-aged cohorts. Our findings suggest that greater parental socialisation of responsibility relates to higher conscientiousness, and consequently healthier adults. These findings imply that parental behaviours could be a plausible target for intervention to foster the development of conscientiousness and better health.


Safety of Inhalational Anesthesia in Patients with Multiple Drug Allergies Presenting for Major Surgeries under General Anesthesia.
The prevalence of perioperative anaphylaxis is 1 in 1250-20,000 anesthetics. Inhalational anesthesia is considered safe in patients with multiple drug allergies, as there have been no reports of anaphylaxis to volatile inhalational agents. Anesthetic management of six patients with documented allergy to all commonly used anesthetic drugs who underwent major surgeries under general anesthesia is described as a case series. The plan of anesthesia in these patients was an anesthetic gas-based general anesthesia without using muscle relaxants but with the use of intravenous fentanyl if patient was not allergic to it. Sevoflurane 8% in oxygen was used for induction. Following cessation of breathing and on attaining an end-tidal concentration of >4% sevoflurane, direct laryngoscopy and intubation were performed. Anesthesia was maintained with sevoflurane in nitrous oxide and oxygen mixture maintaining a lower end-tidal carbon dioxide. Hypotension and/or bradycardia were managed with intermittent intravenous boluses of adrenaline 20 μg. At the end of surgery, all anesthetic gases were cutoff, and patients were extubated when awake. No muscle relaxant was used in any of the cases. Two patients received fentanyl before induction, whereas others were given oral paracetamol 2 h before induction. Postoperative analgesia was provided with oral paracetamol which was given 2-4 h after surgery. Intraoperative period was uneventful for these patients. In patients with multiple drug allergies, inhalational agent-based general anesthesia can be considered as a safe alternative to regular anesthetic practice involving polypharmacy, with a reduced risk of perioperative adverse events.


From Blame to Punishment: Disrupting Prefrontal Cortex Activity Reveals Norm Enforcement Mechanisms.
The social welfare provided by cooperation depends on the enforcement of social norms. Determining blameworthiness and assigning a deserved punishment are two cognitive cornerstones of norm enforcement. Although prior work has implicated the dorsolateral prefrontal cortex (DLPFC) in norm-based judgments, the relative contribution of this region to blameworthiness and punishment decisions remains poorly understood. Here, we used repetitive transcranial magnetic stimulation (rTMS) and fMRI to determine the specific role of DLPFC function in norm-enforcement behavior. DLPFC rTMS reduced punishment for wrongful acts without affecting blameworthiness ratings, and fMRI revealed punishment-selective DLPFC recruitment, suggesting that these two facets of norm-based decision making are neurobiologically dissociable. Finally, we show that DLPFC rTMS affects punishment decision making by altering the integration of information about culpability and harm. Together, these findings reveal a selective, causal role for DLPFC in norm enforcement: representational integration of the distinct information streams used to make punishment decisions.


Update on genetic markers of quinine resistance in Plasmodium falciparum.
The emergence and spread of antimalarial resistance remain burgeoning issues. Any strategy to slow down or overcome these problems requires an understanding of the genetic changes underlying this resistance. Quinine, the first antimalarial, has been central in the treatment of severe malaria, and has been proposed as second line treatment for uncomplicated malaria in many African countries. Some reports have indicated the emergence of quinine resistance in South East Asia and in Africa, however doubts have been raised about this quinine resistance in Africa. New and interesting data are emerging on the mechanism of quinine reduced susceptibility. In this report, we have reviewed work on the in vivo efficacy and in vitro activity of quinine, and discussed recent data on genetic markers of resistance to this drug. Overall, quinine still remains efficacious in Africa, and pfnhe, the sodium hydrogen exchanger, may be one of the genetic markers underlying quinine in vitro resistance.


Denitrification rates in lake sediments of mountains affected by high atmospheric nitrogen deposition.
During the last decades, atmospheric nitrogen loading in mountain ranges of the Northern Hemisphere has increased substantially, resulting in high nitrate concentrations in many lakes. Yet, how increased nitrogen has affected denitrification, a key process for nitrogen removal, is poorly understood. We measured actual and potential (nitrate and carbon amended) denitrification rates in sediments of several lake types and habitats in the Pyrenees during the ice-free season. Actual denitrification rates ranged from 0 to 9 μmol N2O m-2 h-1 (mean, 1.5 ± 1.6 SD), whereas potential rates were about 10-times higher. The highest actual rates occurred in warmer sediments with more nitrate available in the overlying water. Consequently, littoral habitats showed, on average, 3-fold higher rates than the deep zone. The highest denitrification potentials were found in more productive lakes located at relatively low altitude and small catchments, with warmer sediments, high relative abundance of denitrification nitrite reductase genes, and sulphate-rich waters. We conclude that increased nitrogen deposition has resulted in elevated denitrification rates, but not sufficiently to compensate for the atmospheric nitrogen loading in most of the highly oligotrophic lakes. However, there is potential for high rates, especially in the more productive lakes and landscape features largely govern this.


Unidirectional trans-Atlantic gene flow and a mixed spawning area shape the genetic connectivity of Atlantic bluefin tuna.
The commercially important Atlantic bluefin tuna (Thunnus thynnus), a large migratory fish, has experienced notable recovery aided by accurate resource assessment and effective fisheries management efforts. Traditionally, this species has been perceived as consisting of eastern and western populations, spawning respectively in the Mediterranean Sea and the Gulf of Mexico, with mixing occurring throughout the Atlantic. However, recent studies have challenged this assumption by revealing weak genetic differentiation and identifying a previously unknown spawning ground in the Slope Sea used by Atlantic bluefin tuna of uncertain origin. To further understand the current and past population structure and connectivity of Atlantic bluefin tuna, we have assembled a unique dataset including thousands of genome-wide single-nucleotide polymorphisms (SNPs) from 500 larvae, young of the year and spawning adult samples covering the three spawning grounds and including individuals of other Thunnus species. Our analyses support two weakly differentiated but demographically connected ancestral populations that interbreed in the Slope Sea. Moreover, we also identified signatures of introgression from albacore (Thunnus alalunga) into the Atlantic bluefin tuna genome, exhibiting varied frequencies across spawning areas, indicating strong gene flow from the Mediterranean Sea towards the Slope Sea. We hypothesize that the observed genetic differentiation may be attributed to increased gene flow caused by a recent intensification of westward migration by the eastern population, which could have implications for the genetic diversity and conservation of western populations. Future conservation efforts should consider these findings to address potential genetic homogenization in the species.


Examining Timeliness of Total Knee Replacement Among Patients with Knee Osteoarthritis in the U.S.: Results from the OAI and MOST Longitudinal Cohorts.
Patients with knee osteoarthritis may undergo total knee replacement too early or may delay or underuse this procedure. We quantified these categories of total knee replacement utilization in 2 cohorts of participants with knee osteoarthritis and investigated factors associated with each category. Data were pooled from 2 multicenter cohort studies that collected demographic, patient-reported, radiographic, clinical examination, and total knee replacement utilization information longitudinally on 8,002 participants who had or were at risk for knee osteoarthritis and were followed for up to 8 years. Validated total knee replacement appropriateness criteria were longitudinally applied to classify participants as either potentially appropriate or likely inappropriate for total knee replacement. Participants were further classified on the basis of total knee replacement utilization into 3 categories: timely (indicating that the patient had total knee replacement within 2 years after the procedure had become potentially appropriate), potentially appropriate but knee not replaced (indicating that the knee had remained unreplaced for >2 years after the procedure had become potentially appropriate), and premature (indicating that the procedure was likely inappropriate but had been performed). Utilization rates were calculated, and factors associated with each category were identified. Among 8,002 participants, 3,417 knees fulfilled our inclusion and exclusion criteria and were classified into 1 of 3 utilization categories as follows: 290 knees (8% of the total and 9% of the knees for which replacement was potentially appropriate) were classified as "timely", 2,833 knees (83% of the total and 91% of those for which replacement was potentially appropriate) were classified as "potentially appropriate but not replaced", and 294 knees (comprising 9% of the total and 26% of the 1,114 total knee replacements performed) were considered to be "likely inappropriate" yet underwent total knee replacement and were classified as "premature". Of the knees that were potentially appropriate but were not replaced, 1,204 (42.5%) had severe symptoms. Compared with the patients who underwent timely total knee replacement, the likelihood of being classified as potentially appropriate but not undergoing total knee replacement was greater for black participants and the likelihood of having premature total knee replacement was lower among participants with a body mass index of >25 kg/m and those with depression. In 2 multicenter cohorts of patients with knee osteoarthritis, we observed substantial numbers of patients who had premature total knee replacement as well as of patients for whom total knee replacement was potentially appropriate but had not been performed >2 years after it had become potentially appropriate. Further understanding of these observations is needed, especially among the latter group. Undergoing total knee replacement too early may result in little or no benefit while exposing the patient to the risks of a major operation, whereas waiting too long may cause limitations in physical activity that in turn increase the risk of additional disability and chronic disease; however, little is known about timing of this surgery. We quantified the extent of premature, timely, and delayed use, and found a high prevalence of both premature and delayed use.


How to write a surgical clinical research protocol: literature review and practical guide.
The study protocol is the core document of every clinical research project. Clinical research in studies involving surgical interventions presents some specific challenges, which need to be accounted for and described in the study protocol. The aim of this review is to provide a practical guide for developing a clinical study protocol for surgical interventions with a focus on methodologic issues. On the basis of an in-depth literature search of methodologic literature and on some cardinal published surgical trials and observational studies, the authors provides a 10-step guide for developing a clinical study protocol in surgery. This practical guide outlines key methodologic issues important when planning an ethically and scientifically sound research project involving surgical interventions, with the ultimate goal of providing high-level evidence relevant for health care decision making in surgery.


Whole Grain Intakes Are Associated with Healthcare Cost Savings Following Reductions in Risk of Colorectal Cancer and Total Cancer Mortality in Australia: A Cost-of-Illness Model.
Whole grain consumption has been associated with the reduced risk of several chronic diseases with significant healthcare monetary burden, including cancer. Colorectal cancer (CRC) is one of the most common cancers globally, with the highest rates reported in Australia. Three servings of whole grains provide a 15% reduction in total cancer and 17% reduction in CRC risk; however, 70% of Australians fall short of this level of intake. The aim of this study was to assess the potential savings in healthcare costs associated with reductions in the relative risk of CRC and total cancer mortality following the whole grain Daily Target Intake (DTI) of 48 g in Australia. A three-step cost-of-illness analysis was conducted using input parameters from: (1) estimates of current and targeted whole grain intakes among proportions (5%, 15%, 50%, and 100%) of the Australian adult (≥20 years) population; (2) estimates of reductions in relative risk (with 95% confidence intervals) of CRC and total cancer mortality associated with specific whole grain intake from meta-analysis studies; and (3) estimates of annual healthcare costs of CRC and all cancers from disease expenditure national databases. A very pessimistic (5% of population) through to universal (100% of population) adoption of the recommended DTI in Australia were shown to potentially yield savings in annual healthcare costs equal to AUD 1.9 (95% CI 1.2-2.4) to AUD 37.2 (95% CI 24.1-48.1) million for CRC and AUD 20.3 (95% CI 12.2-27.0) to AUD 405.1 (95% CI 243.1-540.1) million for total cancers. As treatment costs for CRC and other cancers are increasing, and dietary measures exchanging whole grains for refined grains are not cost preclusive nor does the approach increase energy intake, there is an opportunity to facilitate cost-savings along with reductions in disease for Australia. These results suggest specific benefits of encouraging Australians to swap refined grains for whole grains, with greater overall adherence to suggestions in dietary guidelines.


Advanced glycation end products increase retinal vascular endothelial growth factor expression.
Advanced glycation end products (AGEs) are linked with the development of diabetic retinopathy; however, the pathogenic mechanisms are poorly defined. Vascular endothelial growth factor (VEGF) levels are increased in ischemic and nonischemic diabetic retina, and VEGF is required for the development of retinal and iris neovascularization. Moreover, VEGF alone can induce much of the concomitant pathology of diabetic retinopathy. In this study, we found that AGEs increased VEGF mRNA levels in the ganglion, inner nuclear, and retinal pigment epithelial (RPE) cell layers of the rat retina. In vitro, AGEs increased VEGF mRNA and secreted protein in human RPE and bovine vascular smooth muscle cells. The AGE-induced increases in VEGF expression were dose- and time-dependent, inhibited by antioxidants, and additive with hypoxia. Use of an anti-VEGF antibody blocked the capillary endothelial cell proliferation induced by the conditioned media of AGE-treated cells. AGEs may participate in the pathogenesis of diabetic retinopathy through their ability to increase retinal VEGF gene expression.


Attenuation of cortisol across development for victims of sexual abuse.
Inconsistencies exist in literature examining hypothalamic-pituitary-adrenal (HPA) axis activity in children and adults who have experienced childhood abuse. Hence, the extent and manner to which childhood abuse may disrupt HPA axis development is largely unknown. To address these inconsistencies, the developmental course of nonstress cortisol in a long-term longitudinal study was assessed at six time points from childhood through adolescence and into young adulthood to determine whether childhood abuse results in disrupted cortisol activity. Nonstress, morning cortisol was measured in 84 females with confirmed familial sexual abuse and 89 nonabused, comparison females. Although dynamically controlling for co-occurring depression and anxiety, hierarchical linear modeling (HLM) showed that relative to comparison females, the linear trend for abused females was significantly less steep when cortisol was examined across development from age 6 to age 30, t (1, 180) = -2.55, p < .01, indicating attenuation in cortisol activity starting in adolescence with significantly lower levels of cortisol by early adulthood, F (1, 162) = 4.78, p < .01. As a more direct test of the attenuation hypothesis, supplemental HLM analyses of data arrayed by time since the disclosure of abuse indicated that cortisol activity was initially significantly higher, t (1, 425) = 2.18, p < .05, and slopes were significantly less steep t (1, 205) = -2.66, p < .01, for abused females. These findings demonstrate how the experience of childhood abuse might disrupt the neurobiology of stress, providing some support for the attenuation hypothesis that victims of abuse may experience cortisol hyposecretion subsequent to a period of heightened secretion.


First Report of Fire Blight Disease on Blackberry in Turkey.
During 2008 and 2009, a new disease on blackberry (Rubus fruticosus cv. Chester) causing leaf and shoot blight and cankers with brown discoloration of necrotic tissues on mature branches was observed in Isparta and Konya provinces of Turkey. Disease incidence was estimated to be 4% for the two years. Isolations were made from lesions on leaves and shoots on nutrient sucrose agar (NSA) medium. Bacteria consistently isolated from the diseased tissues were identified on the basis of biochemical, physiological (2), and molecular tests (1). Eleven representative bacterial strains were gram-negative, rod-shaped, mucoid, fermentative, yellow-orange on Miller and Scroth (MS) medium, positive for levan formation and acetoin production, no growth at 36°C, positive for gelatin hydrolysis, and negative for esculin hydrolysis, indole, urease, catalase, oxidase, arginine dehydrolase, reduction of nitrate, acid production from lactose, and inositol. Two reference strains of Erwinia amylovora (EaP28 and NCPPB 2791) obtained from the culture collection unit of Selcuk University were used as positive controls. All strains induced a hypersensitive response in tobacco (Nicotiana tobaccum cv White Burley) 24 h after inoculation with a 108 CFU/ml bacterial suspension in water. All strains were identified as E. amylovora using the species-specific primers set A/B (1), which amplified a 1-kb DNA fragment in PCR, and fatty acid methyl ester (FAME) profiles determined by Sherlock Microbial Identification System software (TSBA 6 v. 6.00; Microbial ID, Newark, DE) with similarity indices ranging from of 79 to 99%. Pathogenicity was confirmed by injecting bacterial suspensions (108 CFU/ml-1) in sterile distilled water into the shoot tips of 2-year-old R. fruticosus cv. Chester and the first blighting symptoms were observed on leaves within 3 days and also 10 days later after inoculation on shoots. Sterile distilled water was used as a negative control. No symptoms were observed on control plants. All tests were repeated three times. The bacterium was reisolated from inoculated plants and identified as. E. amylovora. To our knowledge, this is the first report of E. amylovora on blackberry in Turkey. Phytosanitary measures are needed to prevent any further spread of the bacterium to new blackberry areas. References: (1) S. Bereswill et al. App. Environ. Microbiol. 58:3522, 1992. (2) A. L. Jones and K. Geider. Lab. Guide for Identification of Plant Pathological Bacteria, 40, 2001.


Child-level evaluation of a web-based intervention to improve dietary guideline implementation in childcare centers: a cluster-randomized controlled trial.
Although it is recommended that childcare centers provide foods consistent with dietary guidelines, the impact of implementing sector-specific guidelines on child outcomes is largely unknown. This study aims to examine the impact of a web-based program and support to implement dietary guidelines in childcare centers on children's 1) diet; 2) BMI z scores; and 3) child health-related quality of life (HRQoL). This study was a cluster-randomized controlled trial utilizing a Type-3 Hybrid implementation-effectiveness design conducted between October 2016 and March 2018. This study reports on child outcomes. Fifty-four childcare centers in New South Wales, Australia were randomly assigned to the intervention (a web-based menu-planning tool and support) or control group (usual care). The intervention was designed to address barriers and enablers to dietary guideline implementation according to the Theoretical Domains Framework. A quota of 35 consenting childcare centers undertook child-level evaluation of dietary intake where 522 parents consented to completing ≥1 component of data collection for their child. Child consumption of core and discretionary (unhealthy) foods while in care was assessed via dietary observations by blinded research assistants, childcare diet quality was assessed via educator-completed questionnaires, BMI z scores were assessed via measured weight and height, and child HRQoL was assessed via parent report at baseline and 12-mo follow-up. There was a significant increase in mean child consumption of fruit (0.39 servings; 95% CI: 0.12, 0.65 servings) and dairy foods (0.38 servings; 95% CI: 0.19, 0.57 servings) and a significant reduction in consumption of discretionary foods (-0.40 servings; 95% CI: -0.64, -0.16 servings) in care in the intervention group, relative to control at 12-mo follow-up. No significant differences were observed in diet quality, BMI z scores, or HRQoL. A web-based intervention to support planning of childcare menus consistent with dietary guidelines can improve child consumption of healthier foods in daycare. This trial was registered at www.anzctr.org.au as ACTRN12616000974404.


Stem cell mobilization by hyperbaric oxygen.
We hypothesized that exposure to hyperbaric oxygen (HBO(2)) would mobilize stem/progenitor cells from the bone marrow by a nitric oxide (*NO) -dependent mechanism. The population of CD34(+) cells in the peripheral circulation of humans doubled in response to a single exposure to 2.0 atmospheres absolute (ATA) O(2) for 2 h. Over a course of 20 treatments, circulating CD34(+) cells increased eightfold, although the overall circulating white cell count was not significantly increased. The number of colony-forming cells (CFCs) increased from 16 +/- 2 to 26 +/- 3 CFCs/100,000 monocytes plated. Elevations in CFCs were entirely due to the CD34(+) subpopulation, but increased cell growth only occurred in samples obtained immediately posttreatment. A high proportion of progeny cells express receptors for vascular endothelial growth factor-2 and for stromal-derived growth factor. In mice, HBO(2) increased circulating stem cell factor by 50%, increased the number of circulating cells expressing stem cell antigen-1 and CD34 by 3.4-fold, and doubled the number of CFCs. Bone marrow *NO concentration increased by 1,008 +/- 255 nM in association with HBO(2). Stem cell mobilization did not occur in knockout mice lacking genes for endothelial *NO synthase. Moreover, pretreatment of wild-type mice with a *NO synthase inhibitor prevented the HBO(2)-induced elevation in stem cell factor and circulating stem cells. We conclude that HBO(2) mobilizes stem/progenitor cells by stimulating *NO synthesis.


The first cleavage furrow demarcates the dorsal-ventral axis in Xenopus embryos.
To determine the relationship between the first cleavage furrow and the dorsal-ventral axis of the Xenopus embryo, a heritable intracellular marker was injected into one blastomere at the two-cell stage. Embryos were selected in which the cleavage furrow bisected the crescent-shaped region of pale pigmentation or in which it formed 45-90 degrees from this region. This region, which is located in the animal hemisphere of the Xenopus embryo, meets the criteria of the grey crescent as defined in other amphibian species. At tailbud stages the interface between the labeled and unlabeled halves was always coincident with the midsagittal plane. This correlation shows that the first cleavage furrow demarcates the dorsal-ventral axis. The labeling pattern was the same whether the first cleavage furrow bisected the region of pale pigmentation or whether it formed 90 degrees from it. However, when this region was bisected (70% of embryos) it always was located on the dorsal side of the embryo. Thus the region of pale pigmentation indicates the dorsal side of the embryo only when it is bisected by the first cleavage furrow.


The impact of 'on-pack' pictorial health warning labels and calorie information labels on drink choice: A laboratory experiment.
Sugar-sweetened beverages (SSBs) are one of the largest added sugar sources to diets in the UK and USA. Health warning labels reduce hypothetical selection of SSBs in online studies but uncertainty surrounds their impact on selection of drinks for consumption. Calorie information labels are also promising but their impact on SSB selection is unclear. This laboratory study assessed the impact on SSB selection of 'on-pack' labels placed directly on physical products: i.a pictorial health warning label depicting an adverse health consequence of excess sugar consumption; and ii.calorie information labels. Potential moderation of any effects by socio-economic position (SEP) was also examined. Participants - 401 adults, resident in England, approximately half of whom were of lower SEP and half of higher SEP, were asked to select a drink from a range of two non-SSBs and four SSBs (subsequent to completing a separate study assessing the effects of food availability on snack selection). The drinks included 'on-pack' labels according to randomisation: Group 1: pictorial health warning label on SSBs; Group 2: calorie information label on all drinks; Group 3: no additional label. The primary outcome was the proportion of participants selecting an SSB. Compared to not having additional labels (39%), neither the pictorial health warning label (40%) nor calorie information labels (43%) affected the proportion of participants selecting an SSB. Lower SEP participants (45%) were more likely to select an SSB compared to those of higher SEP (35%), but SEP did not moderate the impact of labels on drink selection. In conclusion, pictorial health warning labels may be less effective in reducing SSB selection in lab-based compared with online settings, or depending on label design and placement. Findings suggest that effects might be absent when choosing from real products with actual 'on-pack' labels, positioned in a 'realistic' manner. Field studies are needed to further assess the impact of 'on-pack' SSB warning labels in real-world settings to rule out the possible contribution of study design factors.


Four-component relativistic 31P NMR calculations for trans-platinum(ii) complexes: importance of the solvent and dynamics in spectral simulations.
We report a combined experimental-theoretical study on the 31P NMR chemical shift for a number of trans-platinum(ii) complexes. Validity and reliability of the 31P NMR chemical shift calculations are examined by comparing with the experimental data. A successful computational protocol for the accurate prediction of the 31P NMR chemical shifts was established for trans-[PtCl2(dma)PPh3] (dma = dimethylamine) complexes. The reliability of the computed values is shown to be critically dependent on the level of relativistic effects (two-component vs. four component), choice of density functionals, dynamical averaging, and solvation effects. Snapshots obtained from ab initio molecular dynamics simulations were used to identify those solvent molecules which show the largest interactions with the platinum complex, through inspection by using the non-covalent interaction program. We observe satisfactory accuracy from the full four-component matrix Dirac-Kohn-Sham method (mDKS) based on the Dirac-Coulomb Hamiltonian, in conjunction with the KT2 density functional, and dynamical averaging with explicit solvent molecules.


Spatial predictions at the community level: from current approaches to future frameworks.
A fundamental goal of ecological research is to understand and model how processes generate patterns so that if conditions change, changes in the patterns can be predicted. Different approaches have been proposed for modelling species assemblage, but their use to predict spatial patterns of species richness and other community attributes over a range of spatial and temporal scales remains challenging. Different methods emphasize different processes of structuring communities and different goals. In this review, we focus on models that were developed for generating spatially explicit predictions of communities, with a particular focus on species richness, composition, relative abundance and related attributes. We first briefly describe the concepts and theories that span the different drivers of species assembly. A combination of abiotic processes and biotic mechanisms are thought to influence the community assembly process. In this review, we describe four categories of drivers: (i) historical and evolutionary, (ii) environmental, (iii) biotic, and (iv) stochastic. We discuss the different modelling approaches proposed or applied at the community level and examine them from different standpoints, i.e. the theoretical bases, the drivers included, the source data, and the expected outputs, with special emphasis on conservation needs under climate change. We also highlight the most promising novelties, possible shortcomings, and potential extensions of existing methods. Finally, we present new approaches to model and predict species assemblages by reviewing promising 'integrative frameworks' and views that seek to incorporate all drivers of community assembly into a unique modelling workflow. We discuss the strengths and weaknesses of these new solutions and how they may hasten progress in community-level modelling.


Cytomegalovirus Reactivation after Allogeneic Hematopoietic Stem Cell Transplantation is Associated with a Reduced Risk of Relapse in Patients with Acute Myeloid Leukemia Who Survived to Day 100 after Transplantation: The Japan Society for Hematopoietic Cell Transplantation Transplantation-related Complication Working Group.
Cytomegalovirus (CMV) infection is a major infectious complication after allogeneic hematopoietic cell transplantation (allo-HSCT). Recently, it was reported that CMV reactivation is associated with a decreased risk of relapse in patients with acute myeloid leukemia (AML). The aim of this study was to evaluate the impact of early CMV reactivation on the incidence of disease relapse after allo-HSCT in a large cohort of patients. The Japan Society for Hematopoietic Cell Transplantation's Transplantation-Related Complication Working Group retrospectively surveyed the database of the Transplant Registry Unified Management Program at the Japan Society for Hematopoietic Cell Transplantation. Patients with AML (n = 1836), acute lymphoblastic leukemia (ALL, n = 911), chronic myeloid leukemia (CML, n = 223), and myelodysplastic syndrome (MDS, n = 569) who underwent their first allo-HSCT from HLA-matched related or unrelated donors between 2000 and 2009 and who survived without disease relapse until day 100 after transplantation were analyzed. Patients who received umbilical cord blood transplantation were not included. Patients underwent surveillance by pp65 antigenemia from the time of engraftment, and the beginning of preemptive therapy was defined as CMV reactivation. Cox proportional hazards models were used to evaluate the risk factors of relapse, nonrelapse, and overall mortality. CMV reactivation and acute/chronic graft-versus-host disease (GVHD) were evaluated as time-dependent covariates. CMV reactivation was associated with a decreased incidence of relapse in patients with AML (20.3% versus 26.4%, P = .027), but not in patients with ALL, CML, or MDS. Among 1836 patients with AML, CMV reactivation occurred in 795 patients (43.3%) at a median of 42 days, and 436 patients (23.7%) relapsed at a median of 221 days after allo-HSCT. Acute GVHD grades II to IV developed in 630 patients (34.3%). By multivariate analysis considering competing risk factors, 3 factors were significantly associated with a decreased risk of AML relapse and 1 factor with an increased risk of AML relapse: CMV reactivation (hazard ratio [HR], .77; 95% confidence interval [CI], .59 to .99), unrelated donor compared with related donor (HR, .59; 95% CI, .42 to .84), development of chronic GVHD (HR, .77; 95% CI, .60 to .99), and pretransplantation advanced disease status compared with standard disease status (HR, 1.99; 95% CI, 1.56 to 2.52). However, CMV reactivation was associated with increased nonrelapse mortality (HR, 1.60; 95% CI, 1.18 to 2.17) and overall mortality (HR, 1.37; 95% CI, 1.11 to 1.69). A beneficial effect of CMV reactivation on subsequent risk of relapse was observed in patients with AML but not in those with other hematological malignancies. However, this benefit was nullified by the increased nonrelapse mortality. The underlying mechanism is unclear; however, immunological activation against CMV reactivation plays an essential role in this association. Thus, immune augmentation treatment options, including vaccination and adoptive T cell transfer, may be useful to take advantage of the efficacy of CMV reactivation with minimal increase in nonrelapse mortality.


Genome-wide association study for age at puberty and resumption of cyclicity in a crossbred dairy cattle population.
Fertility is of primary economic importance in dairy cattle and the most common reason for involuntary culling. However, standard fertility traits have very low heritability that renders genetic selection slow and difficult. In this study, we explored fertility from an endocrine standpoint. A total of 1,163 crossbred Holstein-Normande females in a 3-generation familial design were studied for progesterone level measured every 10 d to determine age at puberty (PUB) and commencement of postpartum luteal activity (CPLA). Genetic parameters were estimated using REML with WOMBAT software. The heritability estimates were 0.38 ± 0.10 and 0.16 ± 0.07 for PUB and CPLA, respectively. Moreover, the 2 traits were genetically correlated (0.45 ± 0.23), suggesting a partially common determinism. Because of the family structure, a linkage disequilibrium and linkage analysis approach was preferred over standard genome-wide association study to map genomic regions associated with these traits. Ten quantitative trait loci (QTL) were detected for PUB on chromosomes 1, 3, 11, 13, 14, 21, and 29, whereas 3 QTL were associated with CPLA on chromosomes 21 and 26. Only the QTL on chromosome 21 was common to both traits. Four functional candidate genes (NCOA2, GAS2, OVOL1, and FOSL1) were identified in the detected regions. These findings will contribute to a clearer understanding of fertility determinism and enhance the value of introducing endocrinological data in fertility studies.


On scattered waves and lipid domains: detecting membrane rafts with X-rays and neutrons.
In order to understand the biological role of lipids in cell membranes, it is necessary to determine the mesoscopic structure of well-defined model membrane systems. Neutron and X-ray scattering are non-invasive, probe-free techniques that have been used extensively in such systems to probe length scales ranging from angstroms to microns, and dynamics occurring over picosecond to millisecond time scales. Recent developments in the area of phase separated lipid systems mimicking membrane rafts will be presented, and the underlying concepts of the different scattering techniques used to study them will be discussed in detail.


Toxicological evaluation and metal bioavailability in pregnant rats following exposure to clay minerals in the diet.
Silicate clays are frequently added to animal feeds to bind and reduce the bioavailability of mycotoxins in the gastrointestinal tract. However, the bioavailability of trace metals in these clay feed additives has not been thoroughly investigated. Clays that act nonselectively may interact with nutrients, minerals, and other feedborne chemicals to pose significant hidden risks. In this study, a calcium montmorillonite clay (Novasil Plus, NSP) commonly used as an enterosorbent for aflatoxins and a sodium montmorillonite clay (Swy-2) (Source Clay Minerals Repository, Columbia, MO) were examined. Clays were supplemented in the balanced diet of Sprague-Dawley rats during pregnancy at a level of 2% (w/w). Evaluations of toxicity were performed on gestation d 16 and included maternal body weights, maternal feed intakes, litter weights, and embryonic resorptions. Liver, kidneys, tibia, brain, uterus, pooled placentas, and pooled embryonic mass were collected and weighed. Tissues were lyophilized and neutron activation analysis (NAA) was performed. Elements considered by NAA included Al, Ba, Br, Ca, Ce, Co, Cr, Cs, Cu, Dy, Eu, Fe, Hf, K, La, Lu, Mg, Mn, Na, Nd, Ni, Rb, S, Sb, Sc, Se, Sm, Sr, Ta, Tb, Te, Th, Ti, Tl, U, V, Yb, Zn, and Zr. Inductively coupled plasma-mass spectroscopy further confirmed that Al was below detection limits (<0.5 ppm) in the brain. Animals supplemented with either NSP or Swy-2 were similar to controls with respect to toxicity evaluations and metal analysis, with the exception of decreased brain Rb following clay supplementation. Overall, the results of this study suggest that neither NSP nor Swy-2, at relatively high dietary concentrations, influences mineral uptake or utilization in the pregnant rat.


A combined proteomics and metabolomics approach to assess the effects of gold nanoparticles in vitro.
Omics technologies, such as proteomics or metabolomics, have to date been applied in the field of nanomaterial safety assessment to a limited extent. To address this dearth, we developed an integrated approach combining the two techniques to study the effects of two sizes, 5 and 30 nm, of gold nanoparticles (AuNPs) in Caco-2 cells. We observed differences in cells exposed for 72 h to each size of AuNPs: 61 responsive (up/down-regulated) proteins were identified and 35 metabolites in the cell extract were tentatively annotated. Several altered biological pathways were highlighted by integrating the obtained multi-omics data with bioinformatic tools. This provided a unique set of molecular information on the effects of nanomaterials at cellular level. This information was supported by complementary data obtained by immunochemistry, microscopic analysis, and multiplexed assays. A part from increasing our knowledge on how the cellular processes and pathways are affected by nanomaterials (NMs), these findings could be used to identify specific biomarkers of toxicity or to support the safe-by-design concept in the development of new nanomedicines.


In vitro quantification of the performance of model-based mono-planar and bi-planar fluoroscopy for 3D joint kinematics estimation.
Model-based mono-planar and bi-planar 3D fluoroscopy methods can quantify intact joints kinematics with performance/cost trade-off. The aim of this study was to compare the performances of mono- and bi-planar setups to a marker-based gold-standard, during dynamic phantom knee acquisitions. Absolute pose errors for in-plane parameters were lower than 0.6 mm or 0.6° for both mono- and bi-planar setups. Mono-planar setups resulted critical in quantifying the out-of-plane translation (error < 6.5 mm), and bi-planar in quantifying the rotation along bone longitudinal axis (error < 1.3°). These errors propagated to joint angles and translations differently depending on the alignment of the anatomical axes and the fluoroscopic reference frames. Internal-external rotation was the least accurate angle both with mono- (error < 4.4°) and bi-planar (error < 1.7°) setups, due to bone longitudinal symmetries. Results highlighted that accuracy for mono-planar in-plane pose parameters is comparable to bi-planar, but with halved computational costs, halved segmentation time and halved ionizing radiation dose. Bi-planar analysis better compensated for the out-of-plane uncertainty that is differently propagated to relative kinematics depending on the setup. To take its full benefits, the motion task to be investigated should be designed to maintain the joint inside the visible volume introducing constraints with respect to mono-planar analysis.


Job stress and depression symptoms in middle-aged workers--prospective results from the Belstress study.
The aim of this study was to explore the prospective relation between job stress and symptoms of depression within a cohort study. Altogether 2821 workers were involved in the longitudinal Belstress study (Belgian job stress study); there were two measurements with a mean follow-up time of 6.6 years. Job stress was assessed by the Job Content Questionnaire. Depression symptoms were assessed by the Iowa form of the Center for Epidemiological Studies-Depression Scale. Baseline and repeated exposures to job stress were related to the development of high levels of depression symptoms through logistic regression analysis. Within a population free of high depression scores at baseline, job stress increased the risk of developing high levels of depression symptoms after a mean follow-up time of 6.6 years. Independent associations were found for low decision latitude, high job strain, and isolated strain among women, but not among men. The adjusted association with high job strain among men was borderline significant. Repeated high job strain was associated with a more elevated risk of developing high levels of depression symptoms among both the women and the men. The results of this study confirm that job stress is a risk factor for developing symptoms of depression. Stronger associations were found for women. The impact of high job strain among both men and women was more harmful when there was repeated exposure.


Comparison of Different Convolutional Neural Network Activation Functions and Methods for Building Ensembles for Small to Midsize Medical Data Sets.
CNNs and other deep learners are now state-of-the-art in medical imaging research. However, the small sample size of many medical data sets dampens performance and results in overfitting. In some medical areas, it is simply too labor-intensive and expensive to amass images numbering in the hundreds of thousands. Building Deep CNN ensembles of pre-trained CNNs is one powerful method for overcoming this problem. Ensembles combine the outputs of multiple classifiers to improve performance. This method relies on the introduction of diversity, which can be introduced on many levels in the classification workflow. A recent ensembling method that has shown promise is to vary the activation functions in a set of CNNs or within different layers of a single CNN. This study aims to examine the performance of both methods using a large set of twenty activations functions, six of which are presented here for the first time: 2D Mexican ReLU, TanELU, MeLU + GaLU, Symmetric MeLU, Symmetric GaLU, and Flexible MeLU. The proposed method was tested on fifteen medical data sets representing various classification tasks. The best performing ensemble combined two well-known CNNs (VGG16 and ResNet50) whose standard ReLU activation layers were randomly replaced with another. Results demonstrate the superiority in performance of this approach.


Cellular and molecular events leading to mitochondrial toxicity of 1-(2-deoxy-2-fluoro-1-beta-D-arabinofuranosyl)-5-iodouracil in human liver cells.
We have explored the mechanism(s) related to FIAU-induced liver toxicity, particularly focusing on its effect on mitochondrial function in a human hepatoma cell line-HepG2. The potential role of FMAU and FAU, metabolites detected in FIAU-treated patients were also ascertained. FIAU and FMAU inhibited cell growth and were effectively phosphorylated. A substantial increase in lactic acid production in medium of cells incubated with 1-10 microM FIAU or FMAU was consistent with mitochondrial dysfunction. Slot blot analysis demonstrated that a two week exposure to 10 microM FIAU or FMAU was not associated with a decrease in total mitochondrial (mt) DNA content. However, FIAU and FMAU were incorporated into nuclear and mtDNA and relative values suggest that both compounds incorporate at a much higher rate into mtDNA. Electron micrographs of cells incubated with 10 microM FIAU or FMAU revealed the presence of enlarged mitochondria with higher cristae density and lipid vesicles. In conclusion, these data suggest that despite the lack of inhibition of mtDNA content, incorporation of FIAU and FMAU into mtDNA of HepG2 cells leads to marked mitochondrial dysfunction as evidenced by disturbance in cellular energy metabolism and detection of micro- and macrovesicular steatosis.


Suppression of rain and snow by urban and industrial air pollution
Direct evidence demonstrates that urban and industrial air pollution can completely shut off precipitation from clouds that have temperatures at their tops of about -10 degrees C over large areas. Satellite data reveal plumes of reduced cloud particle size and suppressed precipitation originating from major urban areas and from industrial facilities such as power plants. Measurements obtained by the Tropical Rainfall Measuring Mission satellite reveal that both cloud droplet coalescence and ice precipitation formation are inhibited in polluted clouds.


Understanding the Prevalence of Prediabetes and Diabetes in Patients With Cancer in Clinical Practice: A Real-World Cohort Study.
This study aimed to understand the prevalence of prediabetes (preDM) and diabetes mellitus (DM) in patients with cancer overall and by tumor site, cancer treatment, and time point in the cancer continuum. This cohort study was conducted at Huntsman Cancer Institute at the University of Utah. Patients with a first primary invasive cancer enrolled in the Total Cancer Care protocol between July 2016 and July 2018 were eligible. Prevalence of preDM and DM was based on ICD code, laboratory tests for hemoglobin A1c, fasting plasma glucose, nonfasting blood glucose, or insulin prescription. The final cohort comprised 3,512 patients with cancer, with a mean age of 57.8 years at cancer diagnosis. Of all patients, 49.1% (n=1,724) were female. At cancer diagnosis, the prevalence of preDM and DM was 6.0% (95% CI, 5.3%-6.8%) and 12.2% (95% CI, 11.2%-13.3%), respectively. One year after diagnosis the prevalence was 16.6% (95% CI, 15.4%-17.9%) and 25.0% (95% CI, 23.6%-26.4%), respectively. At the end of the observation period, the prevalence of preDM and DM was 21.2% (95% CI, 19.9%-22.6%) and 32.6% (95% CI, 31.1%-34.2%), respectively. Patients with myeloma (39.2%; 95% CI, 32.6%-46.2%) had the highest prevalence of preDM, and those with pancreatic cancer had the highest prevalence of DM (65.1%; 95% CI, 57.0%-72.3%). Patients who underwent chemotherapy, radiotherapy, or immunotherapy had a higher prevalence of preDM and DM compared with those who did not undergo these therapies. Every second patient with cancer experiences preDM or DM. It is essential to foster interprofessional collaboration and to develop evidence-based practice guidelines. A better understanding of the impact of cancer treatment on the development of preDM and DM remains critical.


Water-resistant perovskite nanodots enable robust two-photon lasing in aqueous environment.
Owing to their large absorption cross-sections and high photoluminescence quantum yields, lead halide perovskite quantum dots (PQDs) are regarded as a promising candidate for various optoelectronics applications. However, easy degradation of PQDs in water and in a humid environment is a critical hindrance for applications. Here we develop a Pb-S bonding approach to synthesize water-resistant perovskite@silica nanodots keeping their emission in water for over six weeks. A two-photon whispering-gallery mode laser device made of these ultra-stable nanodots retain 80% of its initial emission quantum yield when immersed in water for 13 h, and a two-photon random laser based on the perovskite@silica nanodots powder could still operate after the nanodots were dispersed in water for up to 15 days. Our synthetic approach opens up an entirely new avenue for utilizing PQDs in aqueous environment, which will significantly broaden their applications not only in optoelectronics but also in bioimaging and biosensing.


Unmet demand for training among mature age Australians: Prevalence, differentials and perceived causes.
To explore the prevalence of unmet demand for training by mature age Australians and to identify the main barriers to accessing training. A total of 3007 Australians aged 45-74 years were surveyed using Computer Assisted Telephone Interviewing. The sample frame was randomly selected and stratified based on the capital city and the rest of the state, and data were weighted to be nationally representative. Over one-third (37%) of respondents who had worked in the past five years reported wanting to attend some form of training but were unable to; these were most likely women and those aged 45-54 year. Commonly cited reasons for not being able to attend training included not being able to fit it in with work commitments, affordability and employer reluctance. Reduction of these barriers to workplace training can improve mature age people's ability to remain engaged in the workforce.


Can surgery improve neurological function in penetrating spinal injury? A review of the military and civilian literature and treatment recommendations for military neurosurgeons.
Penetrating spinal injury (PSI), although an infrequent injury in the civilian population, is not an infrequent injury in military conflicts. Throughout military history, the role of surgery in the treatment of PSI has been controversial. The US is currently involved in 2 military campaigns, the hallmark of both being the widespread use of various explosive devices. The authors reviewed the evidence for or against the use of decompressive laminectomy to treat PSI to provide a triservice (US Army, Navy, and Air Force) consensus and treatment recommendations for military neurosurgeons and spine surgeons. A US National Library of Medicine PubMed database search that identified all literature dealing with acute management of PSI from military conflicts and civilian urban trauma centers in the post-Vietnam War period was undertaken. Nineteen retrospective case series (11 military and 8 civilian) met the study criteria. Eleven military articles covered a 20-year time span that included 782 patients who suffered either gunshot or blast-related projectile wounds. Four papers included sufficient data that analyzed the effectiveness of surgery compared with nonoperative management, 6 papers concluded that surgery was of no benefit, 2 papers indicated that surgery did have a role, and 3 papers made no comment. Eight civilian articles covered a 9-year time span that included 653 patients with spinal gunshot wounds. Two articles lacked any comparative data because of treatment bias. Two papers concluded that decompressive laminectomy had a beneficial role, 1 paper favored the removal of intracanal bullets between T-12 and L-4, and 5 papers indicated that surgery was of no benefit. Based on the authors' military and civilian PubMed literature search, most of the evidence suggests that decompressive laminectomy does not improve neurological function in patients with PSI. However, there are serious methodological shortcomings in both literature groups. For this and other reasons, neurosurgeons from the US Air Force, Army, and Navy collectively believe that decompression should still be considered for any patient with an incomplete neurological injury and continued spinal canal compromise, ideally within 24-48 hours of injury; the patient should be stabilized concurrently if it is believed that the spinal injury is unstable. The authors recognize the highly controversial nature of this topic and hope that this literature review and the proposed treatment recommendations will be a valuable resource for deployed neurosurgeons. Ultimately, the deployed neurosurgeon must make the final treatment decision based on his or her opinion of the literature, individual abilities, and facility resources available.