Phytochemicals - A Novel and Prominent Source of Anti-cancer Drugs Against Colorectal Cancer.
Colorectal cancer (CRC) is a malignant disease whose incidence and mortality rates are greatly influenced by environmental factors. Under-treatment of CRC such as a poor diagnostic evaluation, less aggressive surgery, less intensive chemotherapy results in metastasizing of the primary tumor cells and recurrence of cancer. Prolonged chemotherapy treatment against cancer is hazardous to the patients, which also limits its use in cancer therapy. Current research in developing a novel anti-cancer agent, direct towards finding a better antimetastatic and an anti-invasive drug with reduced side effects. In this direction, plant derived chemical compounds or phytochemical act as a prominent source of new compounds for drug development. Phytochemicals have a multi-action and a multi-target capacity, and has gained attention among the research communities from last two decades. Epidemiological study shows a direct relationship between a diet and CRC development. A diet rich in plant based products such as vegetables, fruits and cereals is known to prevent CRC development. This review is an effort to explore more about the potential phytochemicals in CRC prevention and also in CRC treatment. Here, we have discussed few phytochemicals actively used in CRC research and are in clinical trials against CRC. We have explored more on some of these phytochemicals which can act as a source for new drug or can act as a lead compound for further modifications during the drug development against cancer.


Antibiotic Use, Its Resistance in Nepal and Recommendations for Action: A Situation Analysis.
Antibiotics are crucial, life-saving medicines in the fight against infectious disease, but resistance to these drugs is growing all over. This article presents key findings from a detailed situation analysis produced by the Global Antibiotic Resistance Partnership (GARP)-Nepal working group. In the absence of nationally-representative surveillance, it is not possible to fully describe antibiotic resistance in the country, but many important bacterial pathogens are highly resistant to most first-line and some second-line antibiotics, according to available reports. In credible studies, more than half of Escherichia coli, Klebsiella pneumoniae and Streptococcus pneumoniae isolates tested, and over 30 percent of some Shigella spp. and Vibrio cholerae isolates were resistant to first-line antibiotics. The findings for Neisseria gonorrheae and hospital-acquired Staphylococcus aureus are similar. Antibiotic use in animal food is poorly documented in Nepal, but it is commonly acknowledged to be widespread, contributing to the overall antibiotic resistance burden. The volume of veterinary antibiotic sales in Nepal rose over 50 percent from 2008 to 2012, most through retailers without veterinarian prescription. Antibiotics are necessary to treat infections in animals, but they are also used extensively for preventing disease, a use that can be restricted without jeopardizing animal or human health. They may also be used for promoting animal growth, which can be eliminated with no health consequences. Nepal has made important advances in reducing mortality and morbidity and increasing health coverage, but has not yet taken steps to address antibiotic resistance. The GARP-Nepal working group outlines the components of a national strategy on antibiotic resistance, consistent with the recent call by the World Health Organization for national action plans, to be developed collaboratively with stakeholders and partners from government and all relevant sectors.


Elevated frequencies of self-reactive CD8+ T cells following immunization with a xenoantigen are due to the presence of a heteroclitic CD4+ T-cell helper epitope.
Immunization of mice with human dopachrome tautomerase (hDCT) provides greater protection against melanoma than immunization with the murine homologue (mDCT). We mapped the CD8(+) and CD4(+) T-cell epitopes in both proteins to better understand the mechanisms of the enhanced protection. The dominant CD8(+) T-cell epitopes were fully conserved between both proteins, yet immunization with hDCT produced frequencies of CD8(+) T cells that were 5- to 10-fold higher than immunization with mDCT. This difference was not intrinsic to the two proteins because comparable frequencies of CD8(+) T cells were elicited by both antigens in DCT-deficient mice. Strikingly, only hDCT elicited a significant level of specific CD4(+) T cells in wild-type (WT) mice. The murine protein was not devoid of CD4(+) T-cell epitopes because immunization of DCT-deficient mice with mDCT resulted in robust CD4(+) T-cell immunity directed against two epitopes that were not identified in WT mice. These results suggested that the reduced immunogenicity of mDCT in WT mice may be a function of insufficient CD4(+) T-cell help. To address this possibility, the dominant CD4(+) T-cell epitope from hDCT was introduced into mDCT. Immunization with the mutated mDCT evoked CD8(+) T-cell frequencies and protective immunity comparable with hDCT. These results reveal a novel mechanism by which xenoantigens overcome tolerance. Our data also suggest that immunologic tolerance is more stringent for CD4(+) T cells than CD8(+) T cells, providing a mechanism of peripheral tolerance where autoreactive CD8(+) T cells fail to be activated due to a lack of autoreactive CD4(+) T cells specific for the same antigen.


Cardiac applications of 123I-mIBG imaging.
Cardiac autonomic innervation plays a key role in maintaining hemodynamic and electrophysiologic harmony. Cardiac sympathetic function is adversely altered in many disease states, such as congestive heart failure, myocardial ischemia, and diabetes. (123)I-mIBG, a sympathetic neurotransmitter radionuclide analog, aids in the detection of sympathetic innervation abnormalities and can be imaged with planar and single-photon emission computed tomographic techniques. Cardiac (123)I-mIBG uptake can be assessed by the heart mediastinal ratio (H/M), tracer washout rate, and focal uptake defects. These parameters have been widely studied and shown to correlate strongly and independently with congestive heart failure progression, cardiac arrhythmias, cardiac death, and all-cause mortality. There is accumulating evidence that (123)I-mIBG imaging can help to monitor a patient's clinical course and response to therapy. The ability to predict potentially lethal ventricular arrhythmias promises to help more accurately select patients for implantable cardioverter defibrillators, limiting unnecessary devices and identifying additional patients at risk who do not meet current guidelines. (123)I-mIBG shows potential to help determine whether greater risk and usually more expensive ventricular assist device therapies or cardiac transplantation might be needed. Although more investigation in larger populations is needed to strengthen previous findings, cardiac (123)I-mIBG imaging shows promise as a new technique for recognizing and following potentially life-threatening cardiac conditions.


Identification of Glycoproteins Isolated from Extracellular Polymeric Substances of Full-Scale Anammox Granular Sludge.
ANaerobic AMMonium OXidation (anammox) is an established process for efficient nitrogen removal from wastewater, relying on anammox bacteria to form stable biofilms or granules. To understand the formation, structure, and stability of anammox granules, it is important to determine the composition of the extracellular polymeric substances (EPS). The aim of this research was to elucidate the nature of the proteins, which are the major fraction of the EPS and were suspected to be glycosylated. EPS were extracted from full-scale anammox granular sludge, dominated by " Candidatus Brocadia", and subjected to denaturing polyacrylamide gel electrophoresis. By further analysis with mass spectrometry, a high abundant glycoprotein, carrying a heterogeneous O-glycan structure, was identified. The potential glycosylation sequence motif was identical to that proposed for the surface layer protein of " Candidatus Kuenenia stuttgartiensis". The heavily glycosylated protein forms a large fraction of the EPS and was also located by lectin staining. Therefore, we hypothesize an important role of glycoproteins in the structuring of anammox granules, comparable to the importance of glycans in the extracellular matrix of multicellular organisms. Furthermore, different glycoconjugates may have distinct roles in the matrix of granular sludge, which requires more in-depth characterization of different glycoconjugates in future EPS studies.


Chitosan-Based Extrafibrillar Demineralization for Dentin Bonding.
Instability of resin-dentin bonds is the Achilles' heel of adhesive dentistry. To address this problem, a chelate-and-rinse extrafibrillar dentin demineralization strategy has been developed that keeps intrafibrillar minerals within collagen fibrils intact to prevent activation of endogenous proteases that are responsible for collagen degradation within hybrid layers. The objective of the present study was to evaluate the potential of using chitosan >40 kDa as an antimicrobial extrafibrillar dentin-chelating agent to enhance bond durability. Transmission electron microscopy provided evidence for retention of intrafibrillar minerals and smear plugs in dentin conditioned with 1 wt% chitosan. Analyzed by Kruskal-Wallis analysis of variance, Dunn's statistic, and separate Mann-Whitney tests, tensile bond strengths to wet- and dry-bonded dentin indicated that chelating dentin with chitosan for 60 s prior to bonding did not result in a significant decline in resin-dentin bond strength when compared with that of phosphoric acid etching ( P > 0.05). Gelatinolytic activity within the hybrid layers was examined via in situ zymography after 24-h storage or after thermomechanical cycling and analyzed with 3-factor analysis of variance. After 24 h, enzymatic activity was detected only within completely demineralized phosphoric acid-etched dentin, with values derived from dry bonding significantly higher than those derived from wet bonding ( P < 0.05). Negligible fluorescence was detected within hybrid layers when dentin was conditioned with chitosan, even after thermomechanical cycling, as compared with the controls. Reduction in water permeability in chitosan-conditioned dentin, attributed to smear plug retention, also fostered long-term bond stability. Antibacterial testing performed with live/dead staining indicated that the acetic acid-solubilized chitosan possessed antibacterial activities against 3 single-species biofilms: Streptococcus mutans, Actinomyces naeslundii, and Enterococcus faecalis. Taken together, the new chitosan-based extrafibrillar demineralization strategy retains intrafibrillar minerals, reduces endogenous protease-initiated collagen degradation, prevents water permeation within hybrid layers, and kills bacteria on dentin surfaces, which are crucial factors for enhancing resin-dentin bond durability.


Recurrent and second primary squamous cell carcinoma of the head and neck: when and how to reirradiate.
Local and/or regional recurrence and metachronous primary tumor arising in a previously irradiated area are rather frequent events in patients with head and neck squamous cell carcinoma (HNSCC). Re-treatment is associated with an increased risk of serious toxicity and impaired quality of life (QOL) with an uncertain survival advantage. We analyzed the literature on the efficacy and toxicity of photon/electron-based external beam reirradiation for previously irradiated patients with HNSCC of non-nasopharyngeal origin. Studies were grouped according to the radiotherapy technique used for reirradiation. Patient selection criteria, target volume identification method, tumor dose, fractionation schedule, systemic therapy administration, and toxicities were reviewed. In addition to disease-related factors, current comorbidities and preexisting organ dysfunction must be considered when selecting patients for reirradiation. As morbidity from re-treatment may be considerable and differ depending on which mode of re-treatment is used, it is important to give patients information on potential morbidity outcomes so that an informed choice can be made within a shared decision-making context. With improved dose distribution and adequate imaging support, including positron emission tomography-CT, modern radiotherapy techniques may improve local control and reduce toxicity of reirradiation. A reirradiation dose of ≥60 Gy and a volume encompassing the gross tumor with up to a 5-mm margin are recommended. Concomitant administration of systemic therapeutics and reirradiation is likely to be of similar benefit as observed in large randomized studies of upfront therapy. Reirradiation, administered either with or without concurrent systemic therapy, is feasible and tolerable in properly selected patients with recurrent or a new primary tumor in a previously irradiated area of the head and neck, offering a meaningful survival (in the range of 10% to 30% at 2 years). Whenever feasible, salvage surgery is the method of choice for curative intent; patients at high-risk for local recurrence should be advised that postoperative reirradiation is expected to increase locoregional control at the expense of higher toxicity and without survival advantage compared to salvage surgery without reirradiation. © 2014 Wiley Periodicals, Inc. Head Neck 37: 134-150, 2015.


Atypical antipsychotic drugs perturb AMPK-dependent regulation of hepatic lipid metabolism.
Dysregulation of lipid metabolism is a key feature of metabolic disorder related to side effects of antipsychotic drugs. Here, we investigated the molecular mechanism by which second-generation atypical antipsychotic drugs (AAPDs) affect hepatic lipid metabolism in liver. AAPDs augmented hepatic lipid accumulation by activating expression of sterol regulatory element-binding protein (SREBP) transcription factors, with subsequent induction of downstream target genes involved in lipid and cholesterol synthesis in hepatocytes. We confirmed the direct involvement of SREBPs on AAPD-induced expression of lipogenic and cholesterogenic genes by utilization of adenovirus for dominant negative SREBP (Ad-SREBP-DN). Interestingly, AAPDs significantly decreased phosphorylation of AMPKα and expression of fatty acid oxidation genes. Treatment of constitutive active AMPK restored AAPD-mediated dysregulation of genes involved in both lipid synthesis and fatty acid oxidation. Moreover, AAPDs decreased transcriptional activity of PPARα, a critical transcriptional regulator for controlling hepatic fatty acid oxidation, via an AMPK-dependent manner. Close investigations revealed that mutations at the known p38 MAPK phosphorylation sites (S6/12/21A), but not mutations at the putative AMPKα phosphorylation sites (S167/373/453A), block AAPD-dependent reduction of PPARα transcriptional activity, suggesting that p38 MAPK might be also involved in the regulatory pathway as a downstream effector of AAPDs/AMPK. Taken together, these data suggest that AAPD-stimulated hepatic dysregulation of lipid metabolism could result from the inhibition of AMPK activity, and pharmaceutical means to potentiate AMPK activity would contribute to restore hepatic lipid homeostasis that occurs during AAPD treatment.


Comparison of q-Space Reconstruction Methods for Undersampled Diffusion Spectrum Imaging Data.
To compare different q-space reconstruction methods for undersampled diffusion spectrum imaging data. We compared the quality of three methods: Mean Apparent Propagator (MAP); Compressed Sensing using Identity (CSI) and Compressed Sensing using Dictionary (CSD) with simulated data and in vivo acquisitions. We used retrospective undersampling so that the fully sampled reconstruction could be used as ground truth. We used the normalized mean squared error (NMSE) and the Pearson's correlation coefficient as reconstruction quality indices. Additionally, we evaluated two propagator-based diffusion indices: mean squared displacement and return to zero probability. We also did a visual analysis around the centrum semiovale. All methods had reconstruction errors below 5% with low undersampling factors and with a wide range of noise levels. However, the CSD method had at least 1-2% lower NMSE than the other reconstruction methods at higher noise levels. MAP was the second-best method when using a sufficiently high number of q-space samples. MAP reconstruction showed better propagator-based diffusion indices for in vivo acquisitions. With undersampling factors greater than 4, MAP and CSI have noticeably more reconstruction error than CSD. Undersampled data were best reconstructed by means of CSD in simulations and in vivo. MAP was more accurate in the extraction of propagator-based indices, particularly for in vivo data.


Genetic testing and Alzheimer disease: recommendations of the Stanford Program in Genomics, Ethics, and Society.
Several genes associated with Alzheimer disease (AD) have been localized and cloned; two genetic tests are already commercially available, and new tests are being developed. Genetic testing for AD--either for disease prediction or for diagnosis--raises critical ethical concerns. The multidisciplinary Alzheimer Disease Working Group of the Stanford Program in Genomics, Ethics, and Society (PGES) presents comprehensive recommendations on genetic testing for AD. The Group concludes that under current conditions, genetic testing for AD prediction or diagnosis is only rarely appropriate. Criteria for judging the readiness of a test for introduction into routine clinical practice typically rely heavily on evaluation of technical efficacy. PGES recommends a broader and more comprehensive approach, considering: 1) the unique social and historical meanings of AD; 2) the availability of procedures to promote good surrogate decision making for incompetent patients and to safeguard confidentiality; 3) access to sophisticated genetic counselors able to communicate complex risk information and effectively convey the social costs and psychological burdens of testing, such as unintentional disclosure of predictive genetic information to family members; 4) protection from inappropriate advertising and marketing of genetic tests; and 5) recognition of the need for public education about the meaning and usefulness of predictive and diagnostic tests for AD. In this special issue of Genetic Testing, the PGES recommendations are published along with comprehensive background papers authored by Working Group members.


Immunogenicity and Efficacy of Zika Virus Envelope Domain III in DNA, Protein, and ChAdOx1 Adenoviral-Vectored Vaccines.
The flavivirus envelope protein domain III (EDIII) was an effective immunogen against dengue virus (DENV) and other related flaviviruses. Whether this can be applied to the Zika virus (ZIKV) vaccinology remains an open question. Here, we tested the efficacy of ZIKV-EDIII against ZIKV infection, using several vaccine platforms that present the antigen in various ways. We provide data demonstrating that mice vaccinated with a ZIKV-EDIII as DNA or protein-based vaccines failed to raise fully neutralizing antibodies and did not control viremia, following a ZIKV challenge, despite eliciting robust antibody responses. Furthermore, we showed that ZIKV-EDIII encoded in replication-deficient Chimpanzee adenovirus (ChAdOx1-EDIII) elicited anti-ZIKV envelope antibodies in vaccinated mice but also provided limited protection against ZIKV in two physiologically different mouse challenge models. Taken together, our data indicate that contrary to what was shown for other flaviviruses like the dengue virus, which has close similarities with ZIKV-EDIII, this antigen might not be a suitable vaccine candidate for the correct induction of protective immune responses against ZIKV.


Transient, selective factor X deficiency and acute liver failure following chest infection treated with erythromycin BP.
A 57-year-old man developed symptoms of a respiratory tract infection which was treated with erythromycin BP. He subsequently went into acute liver failure. Investigation of a very prolonged prothrombin time revealed a marked, selective factor X deficiency (1% of normal activity). He later recovered virtually normal liver function and completely normal factor X activity.


A study of abbreviations in MEDLINE abstracts.
Abbreviations are widely used in writing, and the understanding of abbreviations is important for natural language processing applications. Abbreviations are not always defined in a document and they are highly ambiguous. A knowledge base that consists of abbreviations with their associated senses and a method to resolve the ambiguities are needed. In this paper, we studied the UMLS coverage, textual variants of senses, and the ambiguity of abbreviations in MEDLINE abstracts. We restricted our study to three-letter abbreviations which were defined using parenthetical expressions. When grouping similar expansions together and representing senses using groups, we found that after ignoring senses where the total number of occurrences within the corresponding group was less than 100, 82.8% of the senses matched the UMLS, covered over 93% of occurrences that were considered, and had an average of 7.74 expansions for each sense. Abbreviations are highly ambiguous: 81.2% of the abbreviations were ambiguous, and had an average of 16.6 senses. However, after ignoring senses with occurrences of less than 5, 64.6% of the abbreviations were ambiguous, and had an average of 4.91 senses.


Acute pulmonary oedema: not always cardiogenic.
A patient presented with fulminant pulmonary oedema and required acute intubation and ventilation. There was no history of a prior cardiac disorder. As he was weaned from sedation, following stabilisation of his pulmonary status, neurological signs suggestive of brainstem dysfunction became apparent. Investigations showed infarcts in the posterior cerebral circulation secondary to a vertebral artery dissection. Neurogenic pulmonary oedema needs to be considered in any patient with fulminant pulmonary oedema without overt evidence or history of cardiac disease.


Study of plating efficiency of bacteriophages of thermophilic lactic acid bacteria on different media.
The qualitative and quantitative abilities of phages of 13 strains of thermophilic lactic bacteria (lactobacilli and streptococci) to produce plaques on six different media were studied. The influence of the addition of calcium on the one hand, and of incubation conditions (aero-anaerobiosis), on the other hand, was also examined. For the phages of lactobacilli, the best results were obtained with the medium of de Man, Rogosa, and Sharpe (1960), whereas for the phages of streptococci the medium of Hogg and Jago (1970) appeared to be the best. Calcium and incubation conditions play a role which is variable in importance, but rarely negligible.


Motor Learning Improvement Remains 3 Months After a Multisession Anodal tDCS Intervention in an Aging Population.
Healthy aging is associated with decline of motor function that can generate serious consequences on the quality of life and safety. Our studies aim to explore the 3-month effects of a 5-day multisession anodal transcranial direct current stimulation (a-tDCS) protocol applied over the primary motor cortex (M1) during motor sequence learning in elderly. The present sham-controlled aging study investigated whether tDCS-induced motor improvements previously observed 1 day after the intervention persist beyond 3 months. A total of 37 cognitively-intact aging participants performed five consecutive daily 20-min sessions of the serial-reaction time task (SRTT) concomitant with either anodal (n = 18) or sham (n = 19) tDCS over M1. All participants performed the Purdue Pegboard Test and transcranial magnetic stimulation (TMS) measures of cortical excitability were collected before, 1 day after and 3 months after the intervention. The last follow-up session also included the execution of the trained SRTT. The main findings are the demonstration of durable effects of a 5-day anodal tDCS intervention at the trained skill, while the active intervention did not differ from the sham intervention at both the untrained task and on measures of M1-disinhibition. Thus, the current article revealed for the first time the durability of functional effects of a-tDCS combined with motor training after only 5 days of intervention in an aging population. This finding provides evidence that the latter treatment alternative is effective in achieving our primary motor rehabilitation goal, that is to allow durable motor training effects in an aging population.


Evidence of fuels management and fire weather influencing fire severity in an extreme fire event.
Following changes in vegetation structure and pattern, along with a changing climate, large wildfire incidence has increased in forests throughout the western United States. Given this increase, there is great interest in whether fuels treatments and previous wildfire can alter fire severity patterns in large wildfires. We assessed the relative influence of previous fuels treatments (including wildfire), fire weather, vegetation, and water balance on fire-severity in the Rim Fire of 2013. We did this at three different spatial scales to investigate whether the influences on fire severity changed across scales. Both fuels treatments and previous low to moderate-severity wildfire reduced the prevalence of high-severity fire. In general, areas without recent fuels treatments and areas that previously burned at high severity tended to have a greater proportion of high-severity fire in the Rim Fire. Areas treated with prescribed fire, especially when combined with thinning, had the lowest proportions of high severity. The proportion of the landscape burned at high severity was most strongly influenced by fire weather and proportional area previously treated for fuels or burned by low to moderate severity wildfire. The proportion treated needed to effectively reduce the amount of high severity fire varied by spatial scale of analysis, with smaller spatial scales requiring a greater proportion treated to see an effect on fire severity. When moderate and high-severity fire encountered a previously treated area, fire severity was significantly reduced in the treated area relative to the adjacent untreated area. Our results show that fuels treatments and low to moderate-severity wildfire can reduce fire severity in a subsequent wildfire, even when burning under fire growth conditions. These results serve as further evidence that both fuels treatments and lower severity wildfire can increase forest resilience.


An overview and management of osteoporosis.
Osteoporosis -related to various factors including menopause and aging- is the most common chronic metabolic bone disease, which is characterized by increased bone fragility. Although it is seen in all age groups, gender, and races, it is more common in Caucasians (white race), older people, and women. With an aging population and longer life span, osteoporosis is increasingly becoming a global epidemic. Currently, it has been estimated that more than 200 million people are suffering from osteoporosis. According to recent statistics from the International Osteoporosis Foundation, worldwide, 1 in 3 women over the age of 50 years and 1 in 5 men will experience osteoporotic fractures in their lifetime. Every fracture is a sign of another impending one. Osteoporosis has no clinical manifestations until there is a fracture. Fractures cause important morbidity; in men, in particular, they can cause mortality. Moreover, osteoporosis results in a decreased quality of life, increased disability-adjusted life span, and big financial burden to health insurance systems of countries that are responsible for the care of such patients. With an early diagnosis of this disease before fractures occur and by assessing the bone mineral density and with early treatment, osteoporosis can be prevented. Therefore, increasing awareness among doctors, which, in turn, facilitates increase awareness of the normal populace, will be effective in preventing this epidemic.


A photoaffinity-labeled allosteric site in Escherichia coli ribonucleotide reductase.
The B1 subunit of Escherichia coli ribonucleotide reductase is coded for by the nrdA gene, of determined structure. Protein B1 contains two types of allosteric binding sites. One type (h-sites) determines the substrate specificity while the other type (l sites) governs the overall activity. The effectors dGTP and dTTP bind only to the h-sites while dATP and ATP bind to both the h- and the l-sites. Protein B1 has been photoaffinity-labeled with radioactive dTTP and dATP using direct UV irradiation. Following tryptic digestion of labeled protein B1 only one peptide labeled with dTTP was found, while several peptides were labeled with dATP. One of the dATP-labeled peptides had chromatographic properties very similar to that labeled with dTTP and this peptide most likely forms part of the h-site of protein B1. Labeling of the l-site could not be conclusively shown since substantial non-specific labeling occurred with dATP. CNBr fragments of dTTP-labeled protein B1 were used to localize the region of nucleotide binding in the deduced primary structure of the nrdA gene. The dTTP label was further localized to a tryptic octapeptide with the sequence Ser-X-Ser-Gln-Gly-Gly-Val-Arg. The labeled amino acid was found at position 2, but the residue itself could not be directly identified. Unexpectedly, this sequence was not found in the earlier reported primary structure of the nrdA gene. However, a recent revised structure of the gene identifies the labeled residue as Cys-289 and fully confirms the rest of the peptide sequence. Thus the present result clearly defines one of the allosteric binding sites in ribonucleotide reductase.


COL4A1 Mutations Cause Neuromuscular Disease with Tissue-Specific Mechanistic Heterogeneity.
Collagen type IV alpha 1 and alpha 2 chains form heterotrimers ([α1(IV)]2α2(IV)) that represent a fundamental basement membrane constituent. Dominant COL4A1 and COL4A2 mutations cause a multisystem disorder that is marked by clinical heterogeneity and variable expressivity and that is generally characterized by the presence of cerebrovascular disease with ocular, renal, and muscular involvement. Despite the fact that muscle pathology is reported in up to one-third of individuals with COL4A1 and COL4A2 mutations and in animal models with mutations in COL4A1 and COL4A2 orthologs, the pathophysiological mechanisms underlying COL4A1-related myopathy are unknown. In general, mutations are thought to impair [α1(IV)]2α2(IV) secretion. Whether pathogenesis results from intracellular retention, extracellular deficiency, or the presence of mutant proteins in basement membranes represents an important gap in knowledge and a major obstacle for developing targeted interventions. We report that Col4a1 mutant mice develop progressive neuromuscular pathology that models human disease. We demonstrate that independent muscular, neural, and vascular insults contribute to neuromyopathy and that there is mechanistic heterogeneity among tissues. Importantly, we provide evidence of a COL4A1 functional subdomain with disproportionate significance for tissue-specific pathology and demonstrate that a potential therapeutic strategy aimed at promoting [α1(IV)]2α2(IV) secretion can ameliorate or exacerbate myopathy in a mutation-dependent manner. These data have important translational implications for prediction of clinical outcomes based on genotype, development of mechanism-based interventions, and genetic stratification for clinical trials. Collectively, our data underscore the importance of the [α1(IV)]2α2(IV) network as a multifunctional signaling platform and show that allelic and tissue-specific mechanistic heterogeneities contribute to the variable expressivity of COL4A1 and COL4A2 mutations.


Stimulus-driven and strategic neural responses to fearful and happy facial expressions in humans.
The human amygdala responds selectively to consciously and unconsciously perceived facial expressions, particularly those that convey potential threat such as fear and anger. In many social situations, multiple faces with varying expressions confront observers yet little is known about the neural mechanisms involved in encoding several faces simultaneously. Here we used event-related fMRI to measure neural activity in pre-defined regions of interest as participants searched multi-face arrays for a designated target expression (fearful or happy). We conducted separate analyses to examine activations associated with each of the four multi-face arrays independent of target expression (stimulus-driven effects), and activations arising from the search for each of the target expressions, independent of the display type (strategic effects). Comparisons across display types, reflecting stimulus-driven influences on visual search, revealed activity in the amygdala and superior temporal sulcus (STS). By contrast, strategic demands of the task did not modulate activity in either the amygdala or STS. These results imply an interactive threat-detection system involving several neural regions. Crucially, activity in the amygdala increased significantly when participants correctly detected the target expression, compared with trials in which the identical target was missed, suggesting that the amygdala has a limited capacity for extracting affective facial expressions.


Tracking changes following spinal cord injury: insights from neuroimaging.
Traumatic spinal cord injury is often disabling and recovery of function is limited. As a consequence of damage, both spinal cord and brain undergo anatomical and functional changes. Besides clinical measures of recovery, biomarkers that can detect early anatomical and functional changes might be useful in determining clinical outcome-during the course of rehabilitation and recovery-as well as furnishing a tool to evaluate novel treatment interventions and their mechanisms of action. Recent evidence suggests an interesting three-way relationship between neurological deficit and changes in the spinal cord and of the brain and that, importantly, noninvasive magnetic resonance imaging techniques, both structural and functional, provide a sensitive tool to lay out these interactions. This review describes recent findings from multimodal imaging studies of remote anatomical changes (i.e., beyond the lesion site), cortical reorganization, and their relationship to clinical disability. These developments in this field may improve our understanding of effects on the nervous system that are attributable to the injury itself and will allow their distinction from changes that result from rehabilitation (i.e., functional retraining) and from interventions affecting the nervous system directly (i.e., neuroprotection or regeneration).


Molecular phylogeny and biogeography of Picea (Pinaceae): implications for phylogeographical studies using cytoplasmic haplotypes.
The center of diversity is not necessarily the place of origin, as has been established by many plant molecular phylogenies. Picea is a complicated but very important genus in coniferous forests of the Northern Hemisphere, with a high species diversity in Asia. Its phylogeny and biogeography were investigated here using sequence analysis of the paternally inherited chloroplast trnC-trnD and trnT-trnF regions and the maternally inherited mitochondrial nad5 intron 1. We found that the North American P. breweriana and P. sitchensis were basal to the other spruces that were further divided into three clades in the cpDNA phylogeny, and that the New World species harbored four of five mitotypes detected, including two ancestral ones and three endemics. These results, combined with biogeographic analyses using DIVA and MacClade and fossil evidence, suggest that Picea originated in North America, and that its present distribution could stem from two times of dispersal from North America to Asia by the Beringian land bridge, and then from Asia to Europe. Most of the northeastern Asian species and the European P. abies could arise from a recent radiation given the very low interspecific genetic differentiation and pure mitotype of them. Considering that the ancestral mtDNA polymorphism can be preserved in many descendant species, even distantly related ones, we suggest that more species, at least the closely related ones, should be sampled in the phylogeographical study using cytoplasmic haplotypes if possible. In addition, we also discussed the evolution and phylogenetic utility of morphological characters in Picea.


Tumorigenicity of adenovirus-transformed rodent cells is influenced by at least two regions of adenovirus type 12 early region 1A.
Chimeric adenovirus type 5 (Ad5)/Ad12 early region 1A (E1A) genes were used to transform primary baby rat kidney cells in cooperation with Ad12 E1B, and the resulting cell lines were assayed for tumorigenicity in syngeneic rats. It was found that lines were nontumorigenic when transformed by hybrid E1A genes consisting of the amino-terminal 80 amino acids from Ad12 including conserved region 1 (CR1), with the remaining portion from Ad5. In contrast, cell lines transformed by hybrids containing Ad12 E1A sequences from the amino terminus to the leftmost border of CR3 or beyond were tumorigenic. To extend these results, sequences spanning CR2 and CR3 of Ad5 E1A were replaced with the homologous regions of Ad12 E1A and additional transformed cell lines were established. These lines were weakly-to-moderately tumorigenic, suggesting that Ad12 E1A sequences between CR2 and CR3 may be involved in tumorigenicity but are not the sole factors influencing it. Interestingly, examination of an E1A sequence alignment indicated that the region between CR2 and CR3 of Ad12 E1A is also conserved in the corresponding sequence of simian adenovirus type 7, which, like Ad12, is highly oncogenic. This region is characterized by the presence of a stretch of several alanine residues and is similar to a motif present in a number of proteins with transcriptional repression activity. The possibility that this region may influence tumorigenicity by means of a transcriptional regulatory mechanism is discussed.


Evidence for a single non-arachidonic acid-specific fatty acyl-CoA synthetase in heart which is regulated by Mg2+.
Previous reports indicated that arachidonic acid is incorporated into the isolated perfused rabbit heart in preference to other fatty acids, and that incorporation of arachidonic acid, but not other fatty acids, is inhibited during Mg2+ depletion. In this study, we have not been able to demonstrate an arachidonic acid-specific fatty acyl-CoA synthetase in rat or rabbit heart by hydroxyapatite chromatography. Kinetic evidence was consistent with a single enzyme, as the slopes of pseudo-Hill plots were not significantly different from -1. The single fatty acyl-CoA synthetase present appears to prefer C18:0 unsaturated fatty acids to arachidonate, and had about the same affinity for C10:0 -C14:0 saturated fatty acids as for arachidonate. At 35 microM arachidonate, enzyme velocity increased as the total Mg2+ was increased from 3 to 80 mM. Calculated [MgATP] indicated that the MgATP complex was not rate-limiting. At low concentrations, Mn2+ and Ni2+ supported activity, but Cu2+ and Zn2+ did not. Low Ca2+ concentrations activated only oleic acid conversion. Kinetic analysis indicated that the Vmax of the enzyme was increased with increasing concentrations of ionized Mg2+ for both oleic acid and arachidonic acid. The data are constant with the hypothesis that Mg2+ has a direct effect on fatty acyl-CoA synthetase activity, and suggest that preference for oleic acid and arachidonic acid can be influenced by the ionic milieu.


Prognostic significance of depression in blacks with heart failure: insights from Heart Failure: a Controlled Trial Investigating Outcomes of Exercise Training.
Although studies have shown that depression is associated with worse outcomes in patients with heart failure, most studies have been in white patients. The impact of depression on outcomes in blacks with heart failure has not been studied. We analyzed 747 blacks and 1420 whites enrolled in Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training, which randomized 2331 patients with ejection fraction ≤35% to usual care with or without exercise training. We examined the association between depressive symptoms assessed by the Beck Depression Inventory-II (BDI-II) at baseline and after 3 months with all-cause mortality/hospitalization. A race by baseline BDI-II interaction was observed (P=0.003) in which elevated baseline scores were associated with worse outcomes in blacks versus whites. In blacks, the association was nonlinear with a hazard ratio of 1.44 (95% confidence interval, 1.24-1.68) when comparing the 75th and 25th percentile of BDI-II (score of 15 and 5, respectively). No race interaction was observed for mortality (P=0.34). There was no differential association between BDI-II change and outcomes in blacks versus whites. In blacks, an increase in BDI-II score from baseline to 3 months was associated with increased mortality/hospitalization (hazard ratio, 1.33; 95% confidence interval, 1.12-1.57 per 10 point increase), whereas a decrease was not related to outcomes. In blacks with heart failure, baseline symptoms of depression and worsening of symptoms over time are associated with increased all-cause mortality/hospitalization. Routine assessment of depressive symptoms in blacks with heart failure may help guide management. URL: http://www.clinicaltrials.gov. Unique identifier: NCT00047437.


Towards a model-based integration of co-registered electroencephalography/functional magnetic resonance imaging data with realistic neural population meshes.
Brain activity can be measured with several non-invasive neuroimaging modalities, but each modality has inherent limitations with respect to resolution, contrast and interpretability. It is hoped that multimodal integration will address these limitations by using the complementary features of already available data. However, purely statistical integration can prove problematic owing to the disparate signal sources. As an alternative, we propose here an advanced neural population model implemented on an anatomically sound cortical mesh with freely adjustable connectivity, which features proper signal expression through a realistic head model for the electroencephalogram (EEG), as well as a haemodynamic model for functional magnetic resonance imaging based on blood oxygen level dependent contrast (fMRI BOLD). It hence allows simultaneous and realistic predictions of EEG and fMRI BOLD from the same underlying model of neural activity. As proof of principle, we investigate here the influence on simulated brain activity of strengthening visual connectivity. In the future we plan to fit multimodal data with this neural population model. This promises novel, model-based insights into the brain's activity in sleep, rest and task conditions.


Silicon tissue assays: a comparison of nonaugmented cadaveric and augmented patient levels.
Tissue silicon assays were performed on 10 nonaugmented cadavers and 25 augmented women to confirm our previous cadaveric data and to establish silicon levels at local and distant sites in augmented women undergoing explant and further reconstruction. All assays were performed by inductively coupled plasma atomic emissions spectroscopy (ICP-AES). Cadaveric tissues were sampled from six sites: liver, spleen, breast, nipple, axilla (soft tissue and nodes), and subcutaneous tissue (abdominal). Augmented women undergoing explant surgery had a portion of their implant capsule, breast tissue, and for those undergoing autogenous reconstruction, a portion of the autogenous donor site or distant tissue sampled. Twenty-four women had silicone implants; one had saline. Results revealed baseline silicon levels in all 10 non-augmented cadavers. These results were equivalent to our previous data, confirming the validity of these baseline data. Silicon tissue levels in the 25 augmented women revealed elevated levels within the implant capsule and surrounding breast tissue. However, silicon levels obtained from distant sites in augmented women were equivalent to the baseline nonaugmented cadaveric levels. There was no correlation between intact or ruptured implants and symptoms of collagen-vascular disease. In conclusion, study validates our original data of baseline silicon levels in nonaugmented cadavers. Contrary to what some may perceive as silicone floating throughout the body, we have found elevated levels around the implant only, and levels at distant tissue sites were equivalent to the baseline cadaveric data.


Can the sociology of social problems help us to understand and manage 'lifestyle drift'?
Lifestyle drift is increasingly seen as a barrier to broad action on the social determinants of health. The term is currently used in the population health literature to describe how broad policy initiatives for tackling inequalities in health that start off with social determinants (upstream) approach drift downstream to largely individual lifestyle factors, as well as the general trend of investing a the individual level. Lifestyle drift occurs despite the on-going efforts of public health advocates, such as anti-obesity campaigners, to draw attention to the social factors which shape health behavior and outcomes. In this article, we explore whether the sociology of social problems can help understand lifestyle drift in the context of obesity. Specifically, we apply Jamrozik and Nocella's residualist conversion model to the problem of obesity in order to explore whether such an approach can provide greater insight into the processes that underpin lifestyle drift and inform our attempts to mitigate it.


PEGylation of interleukin-6 effectively increases its thrombopoietic potency.
The in vivo thrombopoietic activity of polyethylene glycol-modified interleukin-6 (MPEG-IL-6), in which 54% of the 14 lysine amino groups of IL-6 were coupled with PEG, was compared to that of native IL-6. Native IL-6 and MPEG-IL-6, which showed about 51% of the specific bioactivity of native IL-6, were administered subcutaneously to mice every 2 days for 7 days. Native IL-6 increased not only the peripheral platelet count, but also the plasma-IgG1 level in a dose-dependent manner. MPEG-IL-6 showed about 500 times higher thrombopoietic potency than native IL-6. Further, in comparison to native IL-6, MPEG-IL-6 did not enhance IgG1 production as much as it enhanced platelet production. MPEG-IL-6 significantly stimulated platelet recovery in mice treated with 5-fluorouracil, whereas the administration of native IL-6 had a negligible effect. The plasma half-life of MPEG-IL-6 was about 100-fold longer than that of native IL-6. The decrease in the plasma clearance of MPEG-IL-6 was thought to be due, in part, to the shielding of the proteolytic sites in the IL-6 molecule by the PEG chain. The uptake of IL-6 by the reticuloendothelial system, such as the liver and spleen, was markedly limited by PEGylation. The PEGylation of IL-6 markedly enhanced the blood-residency of IL-6, resulting in effective augmentation of its thrombopoietic activity and a marked decrease in its side-effects. These findings suggest that MPEG-IL-6 may be a potential candidate for thrombopoietic agent.


Ryanodine receptor 2 inhibition reduces dispersion of cardiac repolarization, improves contractile function, and prevents sudden arrhythmic death in failing hearts.
Sudden cardiac death (SCD) from ventricular tachycardia/fibrillation (VT/VF) is a leading cause of death, but current therapies are limited. Despite extensive research on drugs targeting sarcolemmal ion channels, none have proven sufficiently effective for preventing SCD. Sarcoplasmic ryanodine receptor 2 (RyR2) Ca2+ release channels, the downstream effectors of sarcolemmal ion channels, are underexplored in this context. Recent evidence implicates reactive oxygen species (ROS)-mediated oxidation and hyperactivity of RyR2s in the pathophysiology of SCD. We tested the hypothesis that RyR2 inhibition of failing arrhythmogenic hearts reduces sarcoplasmic Ca2+ leak and repolarization lability, mitigates VT/VF/SCD and improves contractile function. We used a guinea pig model that replicates key clinical aspects of human nonischemic HF, such as a prolonged QT interval, a high prevalence of spontaneous arrhythmic SCD, and profound Ca2+ leak via a hyperactive RyR2. HF animals were randomized to receive dantrolene (DS) or placebo in early or chronic HF. We assessed the incidence of VT/VF and SCD (primary outcome), ECG heart rate and QT variability, echocardiographic left ventricular (LV) structure and function, immunohistochemical LV fibrosis, and sarcoplasmic RyR2 oxidation. DS treatment prevented VT/VF and SCD by decreasing dispersion of repolarization and ventricular arrhythmias. Compared to placebo, DS lowered resting heart rate, preserved chronotropic competency during transient β-adrenergic challenge, and improved heart rate variability and cardiac function. Inhibition of RyR2 hyperactivity with dantrolene mitigates the vicious cycle of sarcoplasmic Ca2+ leak-induced increases in diastolic Ca2+ and ROS-mediated RyR2 oxidation, thereby reducing repolarization lability and protecting against VT/VF/SCD. Moreover, the consequent increase in sarcoplasmic Ca2+ load improves contractile function. These potentially life-saving effects of RyR2 inhibition warrant further investigation, such as clinical studies of repurposing dantrolene as a potential new therapy for heart failure and/or SCD.


Angina pectoris and intensive intravenous iron treatment in hemodialysis patients.
Intravenous iron and erythropoietin are commonly used for the treatment of anemia in end stage renal disease (ESRD) patients. Even though i.v. iron is proven to be very effective, there is great concern regarding its possible toxic effects. The aim of our study was to evaluate the possible correlation between iron administration and the incidence of angina pectoris in hemodialysis patients. The study sample consisted of 10 stable coronary heart disease patients, receiving chronic hemodialysis treatment. The patients followed consecutively three different i.v. iron dose regimens according to their needs. Their standard monthly laboratory measurements were correlated with the incidence of angina pectoris and i.v. iron treatment. Hematocrit, ferritin, serum iron and mean rhEPO dose were related to the total amount of administered iron. Angina pectoris was related to intensive iron treatment, age and platelet count. Total white blood cell count were related to hemodialysis duration, platelet count and serum triglycerides. It is suggested that the intensive intravenous iron treatment (300 mg/week) is associated with the increased incidence of angina pectoris in stable coronary heart disease patients receiving hemodialysis.


Influence of stochastic gene expression on the cell survival rheostat after traumatic brain injury.
Experimental evidence suggests that random, spontaneous (stochastic) fluctuations in gene expression have important biological consequences, including determination of cell fate and phenotypic variation within isogenic populations. We propose that fluctuations in gene expression represent a valuable tool to explore therapeutic strategies for patients who have suffered traumatic brain injury (TBI), for which there is no effective drug therapy. We have studied the effects of TBI on the hippocampus because TBI survivors commonly suffer cognitive problems that are associated with hippocampal damage. In our previous studies we separated dying and surviving hippocampal neurons by laser capture microdissection and observed unexplainable variations in post-TBI gene expression, even though dying and surviving neurons were adjacent and morphologically identical. We hypothesized that, in hippocampal neurons that subsequently are subjected to TBI, randomly increased pre-TBI expression of genes that are associated with neuroprotection predisposes neurons to survival; conversely, randomly decreased expression of these genes predisposes neurons to death. Thus, to identify genes that are associated with endogenous neuroprotection, we performed a comparative, high-resolution transcriptome analysis of dying and surviving hippocampal neurons in rats subjected to TBI. We found that surviving hippocampal neurons express a distinct molecular signature--increased expression of networks of genes that are associated with regeneration, cellular reprogramming, development, and synaptic plasticity. In dying neurons we found decreased expression of genes in those networks. Based on these data, we propose a hypothetical model in which hippocampal neuronal survival is determined by a rheostat that adds injury-induced genomic signals to expression of pro-survival genes, which pre-TBI varies randomly and spontaneously from neuron to neuron. We suggest that pharmacotherapeutic strategies that co-activate multiple survival signals and enhance self-repair mechanisms have the potential to shift the cell survival rheostat to favor survival and therefore improve functional outcome after TBI.


New York City young adults' psychological reactions to 9/11: findings from the Reach for Health longitudinal study.
This research examines psychological distress among 955 economically disadvantaged New York City residents surveyed during high school and again after the September 11th terrorist attacks (9/11), when they were young adults. As part of the longitudinal Reach for Health study, young adult surveys were conducted from 6-19 months post-9/11 (average 8 months), providing opportunity to assess types of exposures and psychological distress, including symptoms of post-traumatic stress disorder (PTSD), depression, hopelessness, and anger. Regressions of psychological distress on 9/11 exposure were performed, controlling for high school distress, prior exposure to violence victimization, and socio-demographic characteristics. Exposure to 9/11 was positively associated with anger, hopelessness, and PTSD symptoms and a measure of global distress. The relationship was greater among women for PTSD symptoms. Although those who reported high school distress also reported more distress in young adulthood, prior psychological distress did not moderate the relationship between exposure and psychological outcomes. Greater exposure is related to distress among those who, during high school, reported lower distress, as well as among those who reported prior greater distress.


Ultrastructural and immunohistochemical study of the basal apparatus of solitary cilia in the human oviduct epithelium.
The basal apparatus of the solitary cilium is composed of the basal body, an associated centriole and the basal body-associated structures. To see the connection between the basal body and the centriole, we studied the basal apparatus of solitary cilia in human oviductal secretory cells by electron microscopy and immunohistochemistry. A single centriole was present in the vicinity of the basal body of a solitary cilium. The basal body and the single centriole were interconnected by one or two bundles of thin filaments with a few periodic striations. We have called these bundles the striated connector. The periodicity of striations in the striated connector measured 55 +/- 6 nm, about 15 nm shorter than that of striated rootlets. The striated connector was immunolabelled with R67 antibody specific to striated rootlets, indicating that they are composed of common molecule(s). Although the true function of the connector is unknown as yet, it could play an important role for stabilising the basal body in the apical cytoplasm.


Functional assessment of the lumbar spine through the optoelectronic ZooMS system. Clinical application.
The radiographic method remains the main imaging technique for the physiological, anatomical and possibly pathological analysis of the spine thanks to its ease of use, precision and reliability. Despite this, the technique is inadequate for functional and dynamic studies. This paper aims to apply a dedicated noninvasive methodology based on optoelectronic techniques for the functional evaluation of the lumbar spine. A reference data set for typical movements (i.e. flexion/extension, lateral bending, axial rotation) of the lumbar spine has been developed. Twenty healthy subjects have been recruited (10 males and 10 females) to create the databases of healthy subjects; one subject who suffers from lumbar spine diseases has been analyzed and his mobility has been compared to healthy subjects. Two databases have been created: in the former, the entire movement is normalized in time with respect to its duration; in the latter, all movements are classified in characteristic phases and each single phase is normalized to a defined duration. These databases include both the global movement of the lumbar tract of the spine and the movement of the single functional units (2 vertebrae, the intervertebral disk and the intervening surrounding soft tissues). Moreover, these databases are divided into male and female databases according to the natural differences in range of motion and pattern of movement. A clinical application for pathologic subjects is shown demonstrating the applicability and usability of this protocol. This method allows to assess both the quality and the quantity of lumbar spine movement (both global and metameric level) of the subject and to distinguish the patient from the healthy subject.


The apolipoprotein E (APOE) gene appears functionally monomorphic in chimpanzees (Pan troglodytes).
The human apolipoprotein E (APOE) gene is polymorphic, with three primary alleles (E2, E3, E4) that differ at two key non-synonymous sites. These alleles are functionally different in how they bind to lipoproteins, and this genetic variation is associated with phenotypic variation for several medical traits, including cholesterol levels, cardiovascular health, Alzheimer's disease risk, and longevity. The relative frequencies of these alleles vary across human populations, and the evolution and maintenance of this diversity is much debated. Previous studies comparing human and chimpanzee APOE sequences found that the chimpanzee sequence is most similar to the human E4 allele, although the resulting chimpanzee protein might function like the protein coded for by the human E3 allele. However, these studies have used sequence data from a single chimpanzee and do not consider whether chimpanzees, like humans, show intra-specific and subspecific variation at this locus. To examine potential intraspecific variation, we sequenced the APOE gene of 32 chimpanzees. This sample included 20 captive individuals representing the western subspecies (P. troglodytes verus) and 12 wild individuals representing the eastern subspecies (P. t. schweinfurthii). Variation in our resulting sequences was limited to one non-coding, intronic SNP, which showed fixed differences between the two subspecies. We also compared APOE sequences for all available ape genera and fossil hominins. The bonobo APOE protein is identical to that of the chimpanzee, and the Denisovan APOE exhibits all four human-specific, non-synonymous changes and appears functionally similar to the human E4 allele. We found no coding variation within and between chimpanzee populations, suggesting that the maintenance of functionally diverse APOE polymorphisms is a unique feature of human evolution.


The local field potential reflects surplus spike synchrony.
While oscillations of the local field potential (LFP) are commonly attributed to the synchronization of neuronal firing rate on the same time scale, their relationship to coincident spiking in the millisecond range is unknown. Here, we present experimental evidence to reconcile the notions of synchrony at the level of spiking and at the mesoscopic scale. We demonstrate that only in time intervals of significant spike synchrony that cannot be explained on the basis of firing rates, coincident spikes are better phase locked to the LFP than predicted by the locking of the individual spikes. This effect is enhanced in periods of large LFP amplitudes. A quantitative model explains the LFP dynamics by the orchestrated spiking activity in neuronal groups that contribute the observed surplus synchrony. From the correlation analysis, we infer that neurons participate in different constellations but contribute only a fraction of their spikes to temporally precise spike configurations. This finding provides direct evidence for the hypothesized relation that precise spike synchrony constitutes a major temporally and spatially organized component of the LFP.


Patterns of Alcohol Consumption and Associated Factors in a Population-Based Sample of 70-Year-Olds: Data from the Gothenburg H70 Birth Cohort Study 2014-16.
Older adults of today consume more alcohol, yet knowledge about the factors associated with different consumption levels is limited in this age group. Based on the data from a population-based sample (n = 1156, 539 men and 617 women) in The Gothenburg H70 Birth Cohort Study 2014−16, we examined sociodemographic, social, and health-related factors associated with alcohol consumption levels in 70-year-olds, using logistic regression. Total weekly alcohol intake was calculated based on the self-reported amount of alcohol consumed. Alcohol consumption was categorized as lifetime abstention, former drinking, moderate consumption (≤98 g/week), and at-risk consumption (>98 g/week). At-risk consumption was further categorized into lower at-risk (98−196 g/week), medium at-risk (196−350 g/week), and higher at-risk (≥350 g/week). We found that among the 1156 participants, 3% were lifetime abstainers, 3% were former drinkers, 64% were moderate drinkers, and 30% were at-risk drinkers (20% lower, 8% medium, 2% higher). Among several factors, former drinking was associated with worse general self-rated health (OR 1.65, 95% CI 1.08−2.51) and lower health-related quality of life (measured by physical component score) (OR 0.94, 95% CI 0.91−0.97), higher illness burden (OR 1.16, 95% CI 1.07−1.27), and weaker grip strength (OR 0.96, 95% CI 0.94−0.98). Higher at-risk drinkers more often had liver disease (OR 11.41, 95% CI 3.48−37.37) and minor depression (OR 4.57, 95% CI 1.40−14.95), but less contacts with health care (OR 0.32, 95% CI 0.11−0.92). Our findings demonstrate the importance of classifications beyond abstinence and at-risk consumption, with implications for both the prevention and clinical management of unhealthy consumption patterns in older adults.


A test for comparing two groups of samples when analyzing multiple omics profiles.
A number of statistical models has been proposed for studying the association between gene expression and copy number data in integrated analysis. The next step is to compare association patterns between different groups of samples. We propose a method, named dSIM, to find differences in association between copy number and gene expression, when comparing two groups of samples. Firstly, we use ridge regression to correct for the baseline associations between copy number and gene expression. Secondly, the global test is applied to the corrected data in order to find differences in association patterns between two groups of samples. We show that dSIM detects differences even in small genomic regions in a simulation study. We also apply dSIM to two publicly available breast cancer datasets and identify chromosome arms where copy number led gene expression regulation differs between positive and negative estrogen receptor samples. In spite of differing genomic coverage, some selected arms are identified in both datasets. We developed a flexible and robust method for studying association differences between two groups of samples while integrating genomic data from different platforms. dSIM can be used with most types of microarray/sequencing data, including methylation and microRNA expression. The method is implemented in R and will be made part of the BioConductor package SIM.


Nucleation process of a fibril precursor in the C-terminal segment of amyloid-β.
By extended atomistic simulations in explicit solvent and bias-exchange metadynamics, we study the aggregation process of 18 chains of the C-terminal segment of amyloid-β, an intrinsically disordered protein involved in Alzheimer's disease and prone to form fibrils. Starting from a disordered aggregate, we are able to observe the formation of an ordered nucleus rich in beta sheets. The rate limiting step in the nucleation pathway involves crossing a barrier of approximately 40 kcal/mol and is associated with the formation of a very specific interdigitation of the side chains belonging to different sheets. This structural pattern is different from the one observed experimentally in a microcrystal of the same system, indicating that the structure of a "nascent" fibril may differ from the one of an "extended" fibril.


Auditing the UMLS for redundant classifications.
The UMLS's Semantic Network (SN) serves as a valuable abstraction for the underlying concept repository called the Metathesaurus (META). Specifically, the SN forms a classification layer for the META, with each of the META's constituent concepts assigned to one or more semantic types in the SN. The rule in the design of the SN is to have concepts explicitly assigned to the lowest possible semantic types in the SN's IS-A hierarchy. Implicit assignment to higher semantic types can be inferred via the IS-A relationships. However, in subsequent versions of the UMLS, unnecessary, simultaneous assignments to descendant and ancestor semantic types have been discovered (e.g., 8,622 in the UMLS 1998 version and 12,657 in the 2001 version). The assignment of concepts to such ancestor semantic types is called redundant classification. There is a need for an automated auditing tool that can identify all these redundant classifications. In this paper, an efficient algorithm for this auditing task is introduced. Details of its application to the current (2001) version of the UMLS are presented and the results are discussed.


Resonant SPP modes supported by discrete metal nanoparticles on high-index substrates.
We provide a new physical interpretation of scattering from plasmonic nanoparticles on high-index substrates. We demonstrate the excitation of different types of resonant modes on disk-shaped, Ag nanoparticles. At short wavelengths, the resonances are localised at the top of the particle, while at longer wavelengths they are localised at the Ag/substrate interface. We attribute the long wavelength resonances to geometric resonances of surface plasmon polaritons (SPPs) at the Ag/substrate interface. We show that particles that support resonant SPP modes have enhanced scattering cross-sections when placed directly on a high-index substrate; up to 7.5 times larger than that of a dipole scatterer with an equivalent free-space resonance. This has implications for designing scattering nanostructures for light trapping solar cells.


Complex roads from genotype to phenotype in dilated cardiomyopathy: scientific update from the Working Group of Myocardial Function of the European Society of Cardiology.
Dilated cardiomyopathy (DCM) frequently affects relatively young, economically, and socially active adults, and is an important cause of heart failure and transplantation. DCM is a complex disease and its pathological architecture encounters many genetic determinants interacting with environmental factors. The old perspective that every pathogenic gene mutation would lead to a diseased heart, is now being replaced by the novel observation that the phenotype depends not only on the penetrance-malignancy of the mutated gene-but also on epigenetics, age, toxic factors, pregnancy, and a diversity of acquired diseases. This review discusses how gene mutations will result in mutation-specific molecular alterations in the heart including increased mitochondrial oxidation (sarcomeric gene e.g. TTN), decreased calcium sensitivity (sarcomeric genes), fibrosis (e.g. LMNA and TTN), or inflammation. Therefore, getting a complete picture of the DCM patient will include genomic data, molecular assessment by preference from cardiac samples, stratification according to co-morbidities, and phenotypic description. Those data will help to better guide the heart failure and anti-arrhythmic treatment, predict response to therapy, develop novel siRNA-based gene silencing for malignant gene mutations, or intervene with mutation-specific altered gene pathways in the heart.This article is part of the Mini Review Series from the Varenna 2017 meeting of the Working Group of Myocardial Function of the European Society of Cardiology.


A giant comet-like cloud of hydrogen escaping the warm Neptune-mass exoplanet GJ 436b.
Exoplanets orbiting close to their parent stars may lose some fraction of their atmospheres because of the extreme irradiation. Atmospheric mass loss primarily affects low-mass exoplanets, leading to the suggestion that hot rocky planets might have begun as Neptune-like, but subsequently lost all of their atmospheres; however, no confident measurements have hitherto been available. The signature of this loss could be observed in the ultraviolet spectrum, when the planet and its escaping atmosphere transit the star, giving rise to deeper and longer transit signatures than in the optical spectrum. Here we report that in the ultraviolet the Neptune-mass exoplanet GJ 436b (also known as Gliese 436b) has transit depths of 56.3 ± 3.5% (1σ), far beyond the 0.69% optical transit depth. The ultraviolet transits repeatedly start about two hours before, and end more than three hours after the approximately one hour optical transit, which is substantially different from one previous claim (based on an inaccurate ephemeris). We infer from this that the planet is surrounded and trailed by a large exospheric cloud composed mainly of hydrogen atoms. We estimate a mass-loss rate in the range of about 10(8)-10(9) grams per second, which is far too small to deplete the atmosphere of a Neptune-like planet in the lifetime of the parent star, but would have been much greater in the past.


Cognitive coping and goal adjustment in people with Peripheral Arterial Disease: relationships with depressive symptoms.
The aim was to study relationships between cognitive coping strategies, goal adjustment processes (goal disengagement and re-engagement) and symptoms of depression in people with Peripheral Arterial Disease (PAD). The sample consisted of 88 patients with PAD. Strategies of cognitive coping, goal disengagement, goal re-engagement, and depression were measured by written questionnaires. The main statistical methods were Pearson correlations and Multiple Regression Analyses. The results showed that a ruminative and catastrophizing way of coping in response to the disabilities was related to more depressive symptoms in this group. In contrast, coping by seeking and re-engaging in alternative, meaningful goals was related to less depressive symptoms. These findings suggest that improvements in cognitive and goal-related coping strategies might reduce the level or risk of depressive symptomatology. This confirms the need for specific intervention programs that bring about effective changes in the coping strategies of people suffering from PAD. As both cognitive and goal-related coping are generally assumed to be mechanisms that are subject to potential influence and change, the results of this study provide important targets for such an intervention.


Tetraethylammonium-sensitive apical K+ channels mediating K+ secretion by turtle colon.
1. Apical membrane K+ channels in turtle colon were identified and characterized using current fluctuation analysis. 2. Under short-circuit conditions in NaCl-Ringer solution, the power density spectrum (PDS) of the short-circuit current (Isc) sometimes exhibited a clearly discernible Lorentzian component, indicating spontaneous fluctuations produced by a population of apical ion channels. The Lorentzian component had a characteristic corner frequency (fc) which averaged 10.2 +/- 0.9 Hz (mean +/- S.E.M., n = 20). 3. The power of the spontaneous fluctuations was enhanced (So increased) by manoeuvres that depolarize the apical membrane electrical potential (Va). Discernible fluctuations were enhanced or induced by raising the serosal K+ concentration ([K+]s = 50-115 mM, Na+ replacement), by clamping the transepithelial potential (Vt) to serosa-positive values, or by blocking basolateral K+ channels with Ba2+. 4. Mucosal amiloride (100 microM) attenuated the spontaneous fluctuations observed in NaCl-Ringer solution but had no effect in the presence of serosal high K+, indicating that amiloride did not block the K(+)-permeable channels but these channels resided in the same cells as the amiloride-sensitive Na+ channels. 5. Raising the mucosal K+ concentration attenuated spontaneous fluctuations. 6. In the presence of serosal high K+ and mucosal amiloride, the spontaneous fluctuations were often accompanied by a reversed Isc consistent with K+ secretion. These conditions were used to test the effects of putative channel blockers. 7. Mucosal Ba2+ and tetraethylammonium (TEA+) were effective inhibitors of the spontaneous fluctuations and the reversed Isc. At a concentration of 10 mM, TEA+ was maximally effective but the TEA+ analogues tetramethylammonium (TMA+) and tetrapropylammonium (TPrA+) were much less effective. Mucosal Rb+ or Cs+ did not inhibit at a concentration of 10 mM. 8. Mucosal lidocaine (200 microM), quinidine (200 microM), or diphenylamine-2-carboxylate (DPC, 1 mM) had little or no effect on the spontaneous fluctuations and reversed Isc. Quinine (100 microM), 4-aminopyridine (1 mM), and apamin (100 nM) were also without effect. 9. Mucosal TEA+ (10 mM) abolished the active secretory K+ flux measured in the presence of serosa-positive transepithelial potentials. 10. These experiments identified a population of TEA(+)-sensitive, apical K+ channels which mediate active K+ secretion in turtle colon. Sensitivity to external TEA+ distinguishes these channels from basolateral K+ channels in turtle colon and demonstrates similarity to apical K+ channels in mammalian colon.


2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference.
In 1991, the American College of Chest Physicians (ACCP) and the Society of Critical Care Medicine (SCCM) convened a "Consensus Conference," the goals of which were to "provide a conceptual and a practical framework to define the systemic inflammatory response to infection, which is a progressive injurious process that falls under the generalized term 'sepsis' and includes sepsis-associated organ dysfunction as well. The general definitions introduced as a result of that conference have been widely used in practice, and have served as the foundation for inclusion criteria for numerous clinical trials of therapeutic interventions. Nevertheless, there has been an impetus from experts in the field to modify these definitions to reflect our current understanding of the pathophysiology of these syndromes. Several North American and European intensive care societies agreed to revisit the definitions for sepsis and related conditions. This conference was sponsored by the Society of Critical Care Medicine (SCCM), The European Society of Intensive Care Medicine (ESICM), The American College of Chest Physicians (ACCP), the American Thoracic Society (ATS), and the Surgical Infection Society (SIS). 29 participants attended the conference from Europe and North America. In advance of the conference, subgroups were formed to evaluate the following areas: signs and symptoms of sepsis, cell markers, cytokines, microbiologic data, and coagulation parameters. The present manuscript serves as the final report of the 2001 International Sepsis Definitions Conference. 1. Current concepts of sepsis, severe sepsis and septic shock remain useful to clinicians and researchers. 2. These definitions do not allow precise staging or prognostication of the host response to infection. 3. While SIRS remains a useful concept, the diagnostic criteria for SIRS published in 1992 are overly sensitive and non-specific. 4. An expanded list of signs and symptoms of sepsis may better reflect the clinical response to infection. 6. PIRO, a hypothetical model for staging sepsis is presented, which, in the future, may better characterize the syndrome on the basis of predisposing factors and premorbid conditions, the nature of the underlying infection, the characteristics of the host response, and the extent of the resultant organ dysfunction.


Biodiversity simultaneously enhances the production and stability of community biomass, but the effects are independent.
To predict the ecological consequences of biodiversity loss, researchers have spent much time and effort quantifying how biological variation affects the magnitude and stability of ecological processes that underlie the functioning of ecosystems. Here we add to this work by looking at how biodiversity jointly impacts two aspects of ecosystem functioning at once: (1) the production of biomass at any single point in time (biomass/area or biomass/ volume), and (2) the stability of biomass production through time (the CV of changes in total community biomass through time). While it is often assumed that biodiversity simultaneously enhances both of these aspects of ecosystem functioning, the joint distribution of data describing how species richness regulates productivity and stability has yet to be quantified. Furthermore, analyses have yet to examine how diversity effects on production covary with diversity effects on stability. To overcome these two gaps, we reanalyzed the data from 34 experiments that have manipulated the richness of terrestrial plants or aquatic algae and measured how this aspect of biodiversity affects community biomass at multiple time points. Our reanalysis confirms that biodiversity does indeed simultaneously enhance both the production and stability of biomass in experimental systems, and this is broadly true for terrestrial and aquatic primary producers. However, the strength of diversity effects on biomass production is independent of diversity effects on temporal stability. The independence of effect sizes leads to two important conclusions. First, while it may be generally true that biodiversity enhances both productivity and stability, it is also true that the highest levels of productivity in a diverse community are not associated with the highest levels of stability. Thus, on average, diversity does not maximize the various aspects of ecosystem functioning we might wish to achieve in conservation and management. Second, knowing how biodiversity affects productivity gives no information about how diversity affects stability (or vice versa). Therefore, to predict the ecological changes that occur in ecosystems after extinction, we will need to develop separate mechanistic models for each independent aspect of ecosystem functioning.


Temporal changes in inflammatory mediator concentrations in an adjuvant model of temporomandibular joint inflammation.
To determine temporal changes in the concentrations found in the temporomandibular joint (TMJ) and trigeminal ganglion of 3 specific classes of inflammatory mediators commonly linked with conditions of joint inflammation. The intent was to determine whether concentrations of the neuropeptide calcitonin gene-related peptide (CGRP), the neurotrophin nerve growth factor (NGF), and the proinflammatory cytokines interleukin-1beta (IL1beta) and tumor necrosis factor-alpha (TNF-alpha) are altered in the trigeminal ganglion and TMJ tissues during various stages of adjuvant-induced inflammation of the rat TMJ. Adult male rats received bilateral TMJ injection of complete Freund's adjuvant (CFA), while control rats did not receive CFA treatment. The trigeminal ganglion and TMJ tissues were collected at 2 days, and 2, 4, and 6 weeks postinjection and analyzed using either radioimmunoassay or enzyme-linked immunosorbent assay. In the trigeminal ganglion, both CGRP and NGF concentrations were significantly elevated in comparison to controls from 2 days to 4 weeks; however, the patterns of increase differed. Concentrations of each inflammatory mediator were significantly elevated in the TMJ tissues of CFA-injected animals at 2 days and continued to be significantly elevated throughout the 6-week period. CGRP content remained at peak levels from 2 days through 6 weeks, while peak content for NGF, IL-1beta, and TNF-alpha was found at 2 days through 2 weeks. The results suggest that the development of CFA-induced inflammation of the TMJ was accompanied by a variable increase in the concentration of different classes of inflammatory mediators in both the trigeminal ganglion and TMJ tissues, which implies that each class of inflammatory mediator may play a significant role during different stages in the onset and exacerbation of the inflammatory process.


Nonimaging optical designs for maximum-power-density remote irradiation.
Designs for flexible, high-power-density, remote irradiation systems are presented. Applications include industrial infrared heating such as in semiconductor processing, alternatives to laser light for certain medical procedures, and general remote high-brightness lighting. The high power densities in herent to the small active radiating regions of conventional metal-halide, halogen, xenon, microwave-sulfur, and related lamps can be restored with nonimaging concentrators with little loss of power. These high fluxlevels can then be transported at high transmissivity with light channels such as optical fibers or lightpipes, and reshaped into luminaires that can deliver prescribed angular and spatial flux distributions onto desired targets. Details for nominally two- and three-dimensional systems are developed, along with estimates ofoptical performance.


Biofilm Structure Promotes Coexistence of Phage-Resistant and Phage-Susceptible Bacteria.
Encounters among bacteria and their viral predators (bacteriophages) are among the most common ecological interactions on Earth. These encounters are likely to occur with regularity inside surface-bound communities that microbes most often occupy in natural environments. Such communities, termed biofilms, are spatially constrained: interactions become limited to near neighbors, diffusion of solutes and particulates can be reduced, and there is pronounced heterogeneity in nutrient access and physiological state. It is appreciated from prior theoretical work that phage-bacteria interactions are fundamentally different in spatially structured contexts, as opposed to well-mixed liquid culture. Spatially structured communities are predicted to promote the protection of susceptible host cells from phage exposure, and thus weaken selection for phage resistance. The details and generality of this prediction in realistic biofilm environments, however, are not known. Here, we explore phage-host interactions using experiments and simulations that are tuned to represent the essential elements of biofilm communities. Our simulations show that in biofilms, phage-resistant cells-as their relative abundance increases-can protect clusters of susceptible cells from phage exposure, promoting the coexistence of susceptible and phage-resistant bacteria under a large array of conditions. We characterize the population dynamics underlying this coexistence, and we show that coexistence is recapitulated in an experimental model of biofilm growth measured with confocal microscopy. Our results provide a clear view into the dynamics of phage resistance in biofilms with single-cell resolution of the underlying cell-virion interactions, linking the predictions of canonical theory to realistic models and in vitro experiments of biofilm growth.IMPORTANCE In the natural environment, bacteria most often live in communities bound to one another by secreted adhesives. These communities, or biofilms, play a central role in biogeochemical cycling, microbiome functioning, wastewater treatment, and disease. Wherever there are bacteria, there are also viruses that attack them, called phages. Interactions between bacteria and phages are likely to occur ubiquitously in biofilms. We show here, using simulations and experiments, that biofilms will in most conditions allow phage-susceptible bacteria to be protected from phage exposure, if they are growing alongside other cells that are phage resistant. This result has implications for the fundamental ecology of phage-bacteria interactions, as well as the development of phage-based antimicrobial therapeutics.


Non-invasive imaging of cartilage in early osteoarthritis.
Treatment for osteoarthritis (OA) has traditionally focused on joint replacement for end-stage disease. An increasing number of surgical and pharmaceutical strategies for disease prevention have now been proposed. However, these require the ability to identify OA at a stage when it is potentially reversible, and detect small changes in cartilage structure and function to enable treatment efficacy to be evaluated within an acceptable timeframe. This has not been possible using conventional imaging techniques but recent advances in musculoskeletal imaging have been significant. In this review we discuss the role of different imaging modalities in the diagnosis of the earliest changes of OA. The increasing number of MRI sequences that are able to non-invasively detect biochemical changes in cartilage that precede structural damage may offer a great advance in the diagnosis and treatment of this debilitating condition.


A structural signature of the breakdown of the Stokes-Einstein relation in metallic liquids.
The breakdown of the Stokes-Einstein relation (SER) in three model metallic liquids is investigated via molecular dynamics simulations. It is found that the breakdown of SER is closely correlated with the clustering behavior of well-packed atoms. When the SER breaks down, many cluster properties have almost the same value in these metallic liquids. At the breakdown temperature of SER, the temperature dependence of the number of clusters begins to deviate from a linear increase and the average number of well-packed atoms in the clusters reaches about 2, which indicates an increase in structure heterogeneity. Moreover, the size of the largest cluster shows a direct correlation with the SER. Therefore, our study provides a possible structural origin for the breakdown of SER in metallic liquids.


Advice from the health insurer as a channelling strategy: a natural experiment at a Dutch health insurance company.
In a health care system based on managed competition it is important that health insurers are able to channel their enrolees to preferred care providers. However, enrolees are often very negative about financial incentives and any limitations in their choice of care provider. Therefore, a Dutch health insurance company conducted an experiment to study the effectiveness of a new method of channelling their enrolees. This method entails giving enrolees advise on which physiotherapists to choose when they call customer service. Offering this advice as an extra service is supposed to improve service quality ratings. Objective of this study is to evaluate this channelling method on effectiveness and the impact on service quality ratings. In this experiment, one of the health insurer's customer service call teams (pilot team) began advising enrolees on their choice of physiotherapist. Three data sources were used. Firstly, all enrolees who called customer service received an online questionnaire in order to measure their evaluation of the quality of service. Enrolees who were offered advice received a slightly different questionnaire which, in addition, asked about whether they intended to follow the advice they were offered. Multilevel regression analysis was conducted to analyse the difference in service quality ratings between the pilot team and two comparable customer service teams before and after the implementation of the channelling method. Secondly, employees logged each call, registering, if they offered advice, whether the enrolee accepted it, and if so, which care provider was advised. Thirdly, data from the insurance claims were used to see if enrolees visited the recommended physiotherapist. The results of the questionnaire show that enrolees responded favorably to being offered advice on the choice of physiotherapist. Furthermore, 45% of enrolees who received advice and then went on to visit a care provider, followed the advice. The service quality ratings were higher compared to control groups. However, it could not be determined whether this effect was entirely due to the intervention. Channelling enrolees towards preferred care providers by offering advice on their choice of care provider when they call customer service is successful. The effect on service quality seems positive, although a causal relationship could not be determined.


Patterns and interpretation of mercury exposure in freshwater avian communities in northeastern north America.
A large data set of over 4,700 records of avian mercury (Hg) levels in northeastern North America was compiled and evaluated. As Hg emissions remain poorly regulated in the United States and Canada, atmospheric deposition patterns and associated ecological responses continue to elicit interest by landscape managers, conservation biologists, policy makers, and the general public. How avian Hg exposure is interpreted greatly influences decision-making practices. The geographic extent and size of this data set is valuable in understanding the factors that affect the exposure of Hg to birds. Featured are differences found among tissues, major aquatic habitats and geographic areas, between age class and gender, and among species. While Hg concentrations in egg and blood reflect short-term Hg exposure, Hg concentrations in liver and feather provide insight into long-term Hg exposure. Blood is a particularly important matrix for relating site-specific exposure to methylmercury (MeHg). The level of MeHg is generally 5-10x greater in adults compared to nestlings. Age also influences MeHg bioaccumulation, particularly for individuals where MeHg intake exceeds elimination. Gender is of interpretive concern when evaluating Hg exposure for species exhibiting sexual dimorphism and niche partitioning. Based on two indicator species, the belted kingfisher (Ceryle alcyon) and bald eagle (Haliaeetus leucocephalus), we found MeHg availability increased from marine, to estuarine and riverine systems, and was greatest in lake habitats. A large sample of > 1,800 blood and egg Hg levels from the common loon (Gavia immer) facilitated a suitable comparison of geographic differences. Although some clusters of highly elevated Hg exposure (i.e., blood levels > 3.0 microg/g, ww and egg levels > 1.3 microg/g, ww) were associated with hydrological and biogeochemical factors known to increase MeHg production and availability, others were not. Geographic areas without a relationship between Hg exposure and biogeochemical processes were associated with emission or waterborne point sources. Differences in Hg exposure among species are primarily correlated with trophic position and availability of MeHg. Although piscivorous species were repeatedly shown to have some of the highest MeHg levels of the 38 species analyzed, insectivorous birds in both aquatic and terrestrial habitats (such as montane areas) were also found with elevated MeHg levels. A better understanding of the factors confounding interpretation of Hg exposure provides an effective basis for choice of indicator species and tissues according to 12 selected scenarios. This and the national need for spatiotemporal monitoring of MeHg availability require careful consideration of indicator species choice. Only then will local, regional, continental, and even global monitoring efforts be effective.


Locus coeruleus: From global projection system to adaptive regulation of behavior.
The brainstem nucleus locus coeruleus (LC) is a major source of norepinephrine (NE) projections throughout the CNS. This important property was masked in very early studies by the inability to visualize endogenous monoamines. The development of monoamine histofluorescence methods by Swedish scientists led to a plethora of studies, including a paper published in Brain Research by Loizou in 1969. That paper was highly cited (making it a focal point for the 50th anniversary issue of this journal), and helped to spark a large and continuing set of investigations to further refine our understating of the LC-NE system and its contribution to brain function and behavior. This paper very briefly reviews the ensuing advances in anatomical, physiological and behavioral aspects of the LC-NE system. Although its projections are ubiquitously present throughout the CNS, recent studies find surprising specificity within the organizational and operational domains of LC neurons. These and other findings lead us to expect that future work will unmask additional features of the LC-NE system and its roles in normative and pathological brain and behavioral processes. This article is part of a Special Issue entitled SI:50th Anniversary Issue.


Concatenation and Species Tree Methods Exhibit Statistically Indistinguishable Accuracy under a Range of Simulated Conditions.
Phylogeneticists have long understood that several biological processes can cause a gene tree to disagree with its species tree. In recent years, molecular phylogeneticists have increasingly foregone traditional supermatrix approaches in favor of species tree methods that account for one such source of error, incomplete lineage sorting (ILS). While gene tree-species tree discordance no doubt poses a significant challenge to phylogenetic inference with molecular data, researchers have only recently begun to systematically evaluate the relative accuracy of traditional and ILS-sensitive methods. Here, we report on simulations demonstrating that concatenation can perform as well or better than methods that attempt to account for sources of error introduced by ILS. Based on these and similar results from other researchers, we argue that concatenation remains a useful component of the phylogeneticist's toolbox and highlight that phylogeneticists should continue to make explicit comparisons of results produced by contemporaneous and classical methods.


MicroRNA-regulated gene networks during mammary cell differentiation are associated with breast cancer.
MicroRNAs (miRNAs) play pivotal roles in stem cell biology, differentiation and oncogenesis and are of high interest as potential breast cancer therapeutics. However, their expression and function during normal mammary differentiation and in breast cancer remain to be elucidated. In order to identify which miRNAs are involved in mammary differentiation, we thoroughly investigated miRNA expression during functional differentiation of undifferentiated, stem cell-like, murine mammary cells using two different large-scale approaches followed by qPCR. Significant changes in expression of 21 miRNAs were observed in repeated rounds of mammary cell differentiation. The majority, including the miR-200 family and known tumor suppressor miRNAs, was upregulated during differentiation. Only four miRNAs, including oncomiR miR-17, were downregulated. Pathway analysis indicated complex interactions between regulated miRNA clusters and major pathways involved in differentiation, proliferation and stem cell maintenance. Comparisons with human breast cancer tumors showed the gene profile from the undifferentiated, stem-like stage clustered with that of poor-prognosis breast cancer. A common nominator in these groups was the E2F pathway, which was overrepresented among genes targeted by the differentiation-induced miRNAs. A subset of miRNAs could further discriminate between human non-cancer and breast cancer cell lines, and miR-200a/miR-200b, miR-146b and miR-148a were specifically downregulated in triple-negative breast cancer cells. We show that miR-200a/miR-200b can inhibit epithelial-mesenchymal transition (EMT)-characteristic morphological changes in undifferentiated, non-tumorigenic mammary cells. Our studies propose EphA2 as a novel and important target gene for miR-200a. In conclusion, we present evidentiary data on how miRNAs are involved in mammary cell differentiation and indicate their related roles in breast cancer.


Does marriage protect against hospitalization with pneumonia? A population-based case-control study.
To reduce the increasing burden of pneumonia hospitalizations, we need to understand their determinants. Being married may decrease the risk of severe infections, due to better social support and healthier lifestyle. In this population-based case-control study, we identified all adult patients with a first-time pneumonia-related hospitalization between 1994 and 2008 in Northern Denmark. For each case, ten sex- and age-matched population controls were selected from Denmark's Civil Registration System. We performed conditional logistic regression analysis to estimate the odds ratios (ORs) for pneumonia hospitalization among persons who were divorced, widowed, or never married, as compared with married persons, adjusting for age, sex, 19 different comorbidities, alcoholism-related conditions, immunosuppressant use, urbanization, and living with small children. The study included 67,162 patients with a pneumonia-related hospitalization and 671,620 matched population controls. Compared with controls, the pneumonia patients were more likely to be divorced (10% versus 7%) or never married (13% versus 11%). Divorced and never-married patients were much more likely to have previous diagnoses of alcoholism-related conditions (18% and 11%, respectively) compared with married (3%) and widowed (6%) patients. The adjusted OR for pneumonia-related hospitalization was increased, at 1.29 (95% confidence interval [CI]: 1.25-1.33) among divorced; 1.15 (95% CI: 1.12-1.17) among widowed; and 1.33 (95% CI: 1.29-1.37) among never-married individuals as compared with those who were married. Married individuals have a decreased risk of being hospitalized with pneumonia compared with never-married, divorced, and widowed patients.