Protein and peptides in pictures: imaging with MALDI mass spectrometry.
Imaging using MS has the potential to deliver highly parallel, multiplexed data on the specific localization of molecular ions in tissue samples directly, and to measure and map the variations of these ions during development and disease progression or treatment. There is an intrinsic potential to be able to identify the biomarkers in the same experiment, or by relatively simple extension of the technique. Unlike many other imaging techniques, no a priori knowledge of the markers being sought is necessary. This review concentrates on the use of MALDI-MS for MS imaging (MSI) of proteins and peptides, with an emphasis on mammalian tissue. We discuss the methodologies used, their potential limitations, overall experimental considerations and progress that has been made towards establishing MALDI-MSI as a routine technique for the spatially resolved measurement of peptides and proteins. As well as determining the local abundance of individual molecular ions, there is the potential to determine their identity within the same experiment using relatively simple extensions of the basic techniques. In this way MSI offers an important opportunity for biomarker discovery and identification.


Identification of Aspergillus fumigatus Surface Components That Mediate Interaction of Conidia and Hyphae With Human Platelets.
Platelets were recently identified as a part of innate immunity. They are activated by contact with Aspergillus fumigatus; putative consequences include antifungal defense but also thrombosis, excessive inflammation, and thrombocytopenia. We aimed to identify those fungal surface structures that mediate interaction with platelets. Human platelets were incubated with Aspergillus conidia and hyphae, isolated wall components, or fungal surface mutants. Interaction was visualized microscopically; activation was quantified by flow cytometry of specific markers. The capacity of A. fumigatus conidia to activate platelets is at least partly due to melanin, because this effect can be mimicked with "melanin ghosts"; a mutant lacking melanin showed reduced platelet stimulating potency. In contrast, conidial hydrophobin masks relevant structures, because an A. fumigatus mutant lacking the hydrophobin protein induced stronger platelet activation than wild-type conidia. A. fumigatus hyphae also contain surface structures that interact with platelets. Wall proteins, galactomannan, chitin, and β-glucan are not the relevant hyphal components; instead, the recently identified fungal polysaccharide galactosaminogalactan potently triggered platelet activation. Conidial melanin and hydrophobin as well as hyphal galactosaminogalactan represent important pathogenicity factors that modulate platelet activity and thus might influence immune responses, inflammation, and thrombosis in infected patients.


The Association of Statin Use with Age-Related Macular Degeneration Progression: The Age-Related Eye Disease Study 2 Report Number 9.
To evaluate the association of statin use with progression of age-related macular degeneration (AMD). Preplanned, prospective cohort study within a controlled clinical trial of oral supplementation for age-related eye diseases. Age-Related Eye Disease Study 2 (AREDS2) participants, aged 50 to 85 years. Factors, including age, gender, smoking status, aspirin use, and history of diabetes, hypertension, heart disease, angina, and stroke-all known to be associated with statin use-were included in a logistic regression model to estimate propensity scores for each participant. Age-adjusted proportional hazards regression models, with and without propensity score matching, were performed to evaluate the association of statin use with progression to late AMD. Analyses adjusting for the competing risk of death were also performed. Baseline and annual stereoscopic fundus photographs were assessed centrally by masked graders for the development of late AMD, either neovascular AMD or geographic atrophy (GA). Of the 3791 participants (2462 with bilateral large drusen and 1329 with unilateral late AMD at baseline), 1659 (43.8%) were statin users. The overall analysis, with no matching of propensity scores and no adjustment for death as a competing risk, showed that statin use was not associated with progression to late AMD (hazard ratio [HR], 1.08; 95% confidence interval [CI], 0.83-1.41; P = 0.56). When matched for propensity scores and adjusted for death as a competing risk, the result was not statistically significant (HR, 0.81; 95% CI, 0.55-1.20; P = 0.29). Furthermore, subgroup analyses of persons with or without late AMD at baseline and the various components of late AMD (neovascular AMD, central GA, or any GA) also showed no statistically significant association of statin use with progression to AMD. Statin use was not statistically significantly associated with progression to late AMD in the AREDS2 participants, and these findings are consistent with findings in the majority of previous studies. Statins have been demonstrated to reduce the risk of cardiovascular disease, but our data do not provide evidence of a beneficial effect on slowing AMD progression.


Efficacy of intravitreal bevacizumab combined with pan retinal photocoagulation versus panretinal photocoagulation alone in treatment of proliferative diabetic retinopathy.
To compare effectiveness of pan-retinal photocoagulation alone versus panretinal photocoagulation combined with intravitreal bevacizumab on visual acuity and central macular thickness in patients presenting with proliferative diabetic retinopathy. This Randomized controlled trial was carried out at Armed Forces Institute of ophthalmology, Pakistan from Jan 2016 to Aug 2016. Seventy six eyes of 50 patients having proliferative diabetic retinopathy and diabetic macular edema were included in the study. All the patients were subjected to detailed clinical examination that included Uncorrected visual acuity (UCVA), best corrected visual acuity (BCVA), slit lamp examination of anterior and posterior segments. Optical coherence tomography (OCT) and fundus fluorescein angiography (FFA) were carried out and patients were divided in two groups (GP and GI). Three monthly sessions of Pan retinal photocoagulation (PRP) using Pattern Scan Laser (PASCAL) alone was performed in group GP while PRP along with three monthly intravitreal bevacizumab (IVB) was performed in group GI. BCVA and CMT was recorded 04 weeks after the third PRP session in both the groups. Seventy six eyes of 50 patients (38 in each group) were treated with three sessions of PRP alone and PRP with IVB in Group GP and GI respectively. Mean age of the patient in group GP was 57.47± 6.08 years while that in group GI was 55.69 ±6.58. The magnitude of induced change in BCVA was 0.09 ± 0.15 in GP while 0.22 + 0.04 in GI groups while mean induced change in CMT after treatment was 77.44 ± 92.30 um and 117.50 ± 93.82 um in group GP and GI. Laser PRP combined with IVB has superior visual and anatomical outcome than PRP alone in patients with combined presentation of PDR and DME.


Exploring the combinatorial space of complete pathways to chemicals.
Computational pathway design tools often face the challenges of balancing the stoichiometry of co-metabolites and cofactors, and dealing with reaction rule utilization in a single workflow. To this end, we provide an overview of two complementary stoichiometry-based pathway design tools optStoic and novoStoic developed in our group to tackle these challenges. optStoic is designed to determine the stoichiometry of overall conversion first which optimizes a performance criterion (e.g. high carbon/energy efficiency) and ensures a comprehensive search of co-metabolites and cofactors. The procedure then identifies the minimum number of intervening reactions to connect the source and sink metabolites. We also further the pathway design procedure by expanding the search space to include both known and hypothetical reactions, represented by reaction rules, in a new tool termed novoStoic. Reaction rules are derived based on a mixed-integer linear programming (MILP) compatible reaction operator, which allow us to explore natural promiscuous enzymes, engineer candidate enzymes that are not already promiscuous as well as design de novo enzymes. The identified biochemical reaction rules then guide novoStoic to design routes that expand the currently known biotransformation space using a single MILP modeling procedure. We demonstrate the use of the two computational tools in pathway elucidation by designing novel synthetic routes for isobutanol.


Population level assessment of hospital based outcomes following laparoscopic versus open partial nephrectomy during the adoption of minimally invasive surgery.
The comparative outcomes of laparoscopic and open partial nephrectomy remain incompletely defined. Therefore, we used population based data to examine resource use and short-term outcomes among patients with kidney cancer treated with laparoscopic vs open partial nephrectomy. Using linked SEER (Surveillance, Epidemiology, and End Results)-Medicare data we identified patients with kidney cancer treated with laparoscopic or open partial nephrectomy from 2000 through 2007. We then used Medicare claims to identify several postoperative outcomes including intensive care unit care, length of stay, rehospitalizations, operative mortality and postoperative complications. We fit multivariate logistic regression models to estimate the association between each outcome and surgical approach (ie laparoscopic partial nephrectomy vs open partial nephrectomy), adjusting for patient and tumor characteristics. We identified 651 (28%) and 1,670 (72%) patients treated with laparoscopic partial nephrectomy and open partial nephrectomy, respectively. Compared to those who underwent open partial nephrectomy, patients treated with laparoscopic partial nephrectomy had a 34% lower probability of requiring intensive care unit time (20.0% vs 30.2%, p <0.001) and shorter median length of stay (3 vs 5 days, p <0.001), with no differences observed in the likelihood of rehospitalization or operative mortality. While the frequency of postoperative complications was similar (35.5% vs 36.1%, p = 0.829), patients treated with laparoscopic partial nephrectomy had a nearly twofold greater probability of genitourinary complications and postoperative hemorrhage (p <0.001). At a population level the patients with kidney cancer treated with laparoscopic partial nephrectomy experienced a shorter and less intense hospitalization, supporting the benefits of laparoscopy. However, the greater likelihood of procedure related complications highlights the need for continued efforts aimed at ensuring the safe adoption and application of this advanced surgical technique.


Soil biodiversity and soil community composition determine ecosystem multifunctionality.
Biodiversity loss has become a global concern as evidence accumulates that it will negatively affect ecosystem services on which society depends. So far, most studies have focused on the ecological consequences of above-ground biodiversity loss; yet a large part of Earth's biodiversity is literally hidden below ground. Whether reductions of biodiversity in soil communities below ground have consequences for the overall performance of an ecosystem remains unresolved. It is important to investigate this in view of recent observations that soil biodiversity is declining and that soil communities are changing upon land use intensification. We established soil communities differing in composition and diversity and tested their impact on eight ecosystem functions in model grassland communities. We show that soil biodiversity loss and simplification of soil community composition impair multiple ecosystem functions, including plant diversity, decomposition, nutrient retention, and nutrient cycling. The average response of all measured ecosystem functions (ecosystem multifunctionality) exhibited a strong positive linear relationship to indicators of soil biodiversity, suggesting that soil community composition is a key factor in regulating ecosystem functioning. Our results indicate that changes in soil communities and the loss of soil biodiversity threaten ecosystem multifunctionality and sustainability.


Differential fate of erythromycin and beta-lactam resistance genes from swine lagoon waste under different aquatic conditions.
The attenuation and fate of erythromycin-resistance-methylase (erm) and extended-spectrum beta-lactamse (bla) genes were quantified over time in aquatic systems by adding 20-L swine waste to 11,300-L outdoor mesocosms that simulated receiving water conditions below intensive agricultural operations. The units were prepared with two different light-exposure scenarios and included artificial substrates to assess gene movement into biofilms. Of eleven genes tested, only erm(B), erm(F), bla(SHV) and bla(TEM) were found in sufficient quantity for monitoring. The genes disappeared rapidly from the water column and first-order water-column disappearance coefficients were calculated. However, detected gene levels became elevated in the biofilms within 2 days, but then disappeared over time. Differences were observed between sunlight and dark treatments and among individual genes, suggesting that ecological and gene-specific factors play roles in the fate of these genes after release into the environment. Ultimately, this information will aid in generating better predictive models for gene fate.


A network-based kernel machine test for the identification of risk pathways in genome-wide association studies.
Biological pathways provide rich information and biological context on the genetic causes of complex diseases. The logistic kernel machine test integrates prior knowledge on pathways in order to analyze data from genome-wide association studies (GWAS). In this study, the kernel converts the genomic information of 2 individuals into a quantitative value reflecting their genetic similarity. With the selection of the kernel, one implicitly chooses a genetic effect model. Like many other pathway methods, none of the available kernels accounts for the topological structure of the pathway or gene-gene interaction types. However, evidence indicates that connectivity and neighborhood of genes are crucial in the context of GWAS, because genes associated with a disease often interact. Thus, we propose a novel kernel that incorporates the topology of pathways and information on interactions. Using simulation studies, we demonstrate that the proposed method maintains the type I error correctly and can be more effective in the identification of pathways associated with a disease than non-network-based methods. We apply our approach to genome-wide association case-control data on lung cancer and rheumatoid arthritis. We identify some promising new pathways associated with these diseases, which may improve our current understanding of the genetic mechanisms.


Base-displaced intercalated structure of the food mutagen 2-amino-3-methylimidazo[4,5-f]quinoline in the recognition sequence of the NarI restriction enzyme, a hotspot for -2 bp deletions.
The solution structure of the oligodeoxynucleotide 5'-d(CTCGGCXCCATC)-3'.5'-d(GATGGCGCCGAG)-3' containing the heterocyclic amine 8-[(3-methyl-3H-imidazo[4,5-f]quinolin-2-yl)amino]-2'-deoxyguanosine adduct (IQ) at the third guanine in the NarI restriction sequence, a hot spot for -2 bp frameshifts, is reported. Molecular dynamics calculations restrained by distances derived from 24 (1)H NOEs between IQ and DNA, and torsion angles derived from (3)J couplings, yielded ensembles of structures in which the adducted guanine was displaced into the major groove with its glycosyl torsion angle in the syn conformation. One proton of its exocyclic amine was approximately 2.8 A from an oxygen of the 5' phosphodiester linkage, suggesting formation of a hydrogen bond. The carcinogen-guanine linkage was defined by torsion angles alpha' [N9-C8-N(IQ)-C2(IQ)] of 159 +/- 7 degrees and beta' [C8-N(IQ)-C2(IQ)-N3(IQ)] of -23 +/- 8 degrees . The complementary cytosine was also displaced into the major groove. This allowed IQ to intercalate between the flanking C.G base pairs. The disruption of Watson-Crick hydrogen bonding was corroborated by chemical-shift perturbations for base aromatic protons in the complementary strand opposite to the modified guanine. Chemical-shift perturbations were also observed for (31)P resonances corresponding to phosphodiester linkages flanking the adduct. The results confirmed that IQ adopted a base-displaced intercalated conformation in this sequence context but did not corroborate the formation of a hydrogen bond between the IQ quinoline nitrogen and the complementary dC [Elmquist, C. E.; Stover, J. S.; Wang, Z.; Rizzo, C. J. J. Am. Chem. Soc. 2004, 126, 11189-11201].


Recovery from DSM-IV alcohol dependence: United States, 2001-2002.
To investigate the prevalence and correlates of recovery from Diagnostic and Statistical Manual version IV (DSM-IV) alcohol dependence by examining the past-year status of individuals who met the criteria for prior-to-past-year (PPY) dependence. Cross-sectional, retrospective survey of a nationally representative sample of US adults 18 years of age and over (first wave of a planned longitudinal survey). This analysis is based on data from the 2001-02 National Epidemiologic Survey on Alcohol and Related Conditions (NESARC), in which data were collected in personal interviews conducted with one randomly selected adult in each sample household. A subset of the NESARC sample (total n = 43 093), consisting of 4422 US adults 18 years of age and over classified with PPY DSM-IV alcohol dependence, were evaluated with respect to their past-year recovery status: past-year dependence, partial remission, full remission, asymptomatic risk drinking, abstinent recovery (AR) and non-abstinent recovery (NR). Correlates of past-year status were examined in bivariate analyses and using multivariate logistic regression models. Of people classified with PPY alcohol dependence, 25.0% were still classified as dependent in the past year; 27.3% were classified as being in partial remission; 11.8% were asymptomatic risk drinkers who demonstrated a pattern of drinking that put them at risk of relapse; 17.7% were low-risk drinkers; and 18.2% were abstainers. Only 25.5% of people with PPY dependence ever received treatment. Being married was associated positively with the odds of both AR and NR, and ethanol intake was negatively associated with both. Severity of dependence increased the odds of AR but decreased the odds of NR. The odds of AR (but not NR) increased with age and female gender but were decreased by the presence of a personality disorder. Treatment history modified the effects of college attendance/graduation, age at onset and interval since onset on the odds of recovery. There is a substantial level of recovery from alcohol dependence. Information on factors associated with recovery may be useful in targeting appropriate treatment modalities.


Mycobacterium tuberculosis resistance to rifampicin and ethambutol: a clinical survey.
Ninety-seven cultures of Myco, tuberculosis referred to the Tuberculosis Reference Laboratory, Cardiff during 1972-73 and found to be resistant to rifampicin or ethambutol were studied. Resistance to each drug appeared equally common. Few lower grades of rifampicin resistance occurred, cultures tending to be either fully sensitive or highly resistant. Intermediate grades of ethambutol resistance, however, were common, and a majority of highly resistant cultures were preceded by cultures showing lower grades of resistance. Case-notes were obtained on 84 patients (87%) and revealed no cases of primary resistance. In the three years since first developing resistance 36% of patients died: in the majority tuberculosis was a major cause of death. Half the patients had been prescribed unsatisfactory drug regimens containing rifampicin or ethambutol by their physicians, and only a small minority were considered to have co-operated well. One-third had discharged themselves from hospital against medical advice and only 21% attended clinics regularly. These two factors probably accounted for the development of resistance in most cases.


GaInAsP/InP MZI waveguide optical isolator integrated with spot size converter.
We fabricated a waveguide optical isolator with a GaInAsP guiding layer integrated with spot size converters (SSCs) for efficient coupling to optical fibers. The isolator is constructed with a Mach-Zehnder interferometer (MZI), which is composed of multi-mode interference (MMI) couplers, as well as nonreciprocal and reciprocal phase shifters. The nonreciprocal phase shifter is constructed with a magneto-optical cladding layer directly bonded to a semiconductor guiding layer. The performance of the GaInAsP waveguide optical isolator was demonstrated with a maximum optical isolation of 28.3 dB at a wavelength of 1558 nm for the TM mode.


A Capable Surgeon and a Willing Electrologist: Challenges to the Expansion of Transgender Surgical Care in the United States.
Since 2014, public and private insurance coverage for transgender Americans' surgical care has increased exponentially. Training clinicians and equipping institutions to meet the surge in demand has not been as rapid. Through ethnographic research at a surgical workshop focused on trans- genital reconstruction and in a U.S. hospital working to grow its transgender health program, this article shows that effects of the decades-long insurance exclusion of trans- surgery are not easily remedied through the recent event of its inclusion because patient access is not the only thing that has been restricted by coverage denial. Decades of excluding coverage for trans- genital reconstructive surgery have limited the development and circulation of technical skills required to perform these procedures, as well as the administrative processes needed to integrate them into existing clinical workflows. One surgeon estimates that turning expanded access into realized care is "a five or six-year problem."


Cellular pathology within the anterior cingulate cortex of patients with late-life depression: a morphometric study.
Previous imaging and morphometric studies have identified volumetric and cellular abnormalities in prefrontal areas in late-life depression. This study aimed to examine cellular morphology using stereological methodology in the supragenual region of the anterior cingulate cortex in late-life depressed patients compared with age-matched controls. Post-mortem tissue was acquired from nine patients with depression and 11 control patients and analyzed using the optical disector and nucleator methods. No changes were found in glial, non-pyramidal and pyramidal cell density, or in non-pyramidal or pyramidal cell volume within individual layers (2-5) or the supragenual anterior cortex as a whole. This study, therefore, does not provide further evidence for cellular abnormalities in late-life depression.


Local CXCR4 Upregulation in the Injured Arterial Wall Contributes to Intimal Hyperplasia.
CXCR4 is a stem/progenitor cell surface receptor specific for the cytokine stromal cell-derived factor-1 (SDF-1α). There is evidence that bone marrow-derived CXCR4-expressing cells contribute to intimal hyperplasia (IH) by homing to the arterial subintima which is enriched with SDF-1α. We have previously found that transforming growth factor-β (TGFβ) and its signaling protein Smad3 are both upregulated following arterial injury and that TGFβ/Smad3 enhances the expression of CXCR4 in vascular smooth muscle cells (SMCs). It remains unknown, however, whether locally induced CXCR4 expression in SM22 expressing vascular SMCs plays a role in neointima formation. Here, we investigated whether elevated TGFβ/Smad3 signaling leads to the induction of CXCR4 expression locally in the injured arterial wall, thereby contributing to IH. We found prominent CXCR4 upregulation (mRNA, 60-fold; protein, 4-fold) in TGFβ-treated, Smad3-expressing SMCs. Chromatin immunoprecipitation assays revealed a specific association of the transcription factor Smad3 with the CXCR4 promoter. TGFβ/Smad3 treatment also markedly enhanced SDF-1α-induced ERK1/2 phosphorylation as well as SMC migration in a CXCR4-dependent manner. Adenoviral expression of Smad3 in balloon-injured rat carotid arteries increased local CXCR4 levels and enhanced IH, whereas SMC-specific depletion of CXCR4 in the wire-injured mouse femoral arterial wall produced a 60% reduction in IH. Our results provide the first evidence that upregulation of TGFβ/Smad3 in injured arteries induces local SMC CXCR4 expression and cell migration, and consequently IH. The Smad3/CXCR4 pathway may provide a potential target for therapeutic interventions to prevent restenosis. Stem Cells 2016;34:2744-2757.


The genomic and phenotypic diversity of Schizosaccharomyces pombe.
Natural variation within species reveals aspects of genome evolution and function. The fission yeast Schizosaccharomyces pombe is an important model for eukaryotic biology, but researchers typically use one standard laboratory strain. To extend the usefulness of this model, we surveyed the genomic and phenotypic variation in 161 natural isolates. We sequenced the genomes of all strains, finding moderate genetic diversity (π = 3 × 10(-3) substitutions/site) and weak global population structure. We estimate that dispersal of S. pombe began during human antiquity (∼340 BCE), and ancestors of these strains reached the Americas at ∼1623 CE. We quantified 74 traits, finding substantial heritable phenotypic diversity. We conducted 223 genome-wide association studies, with 89 traits showing at least one association. The most significant variant for each trait explained 22% of the phenotypic variance on average, with indels having larger effects than SNPs. This analysis represents a rich resource to examine genotype-phenotype relationships in a tractable model.


DNA-templated silver nanoclusters: structural correlation and fluorescence modulation.
12 years after the introduction of DNA-templated silver nanoclusters (DNA-AgNCs), exciting progress has been made and yet we are still in the midst of trying to fully understand this nanomaterial. The prominent excellence of DNA-AgNCs is undoubtedly its modulatable emission property, of which how variation in DNA templates causes emission tuning remains elusive. Based on the up-to-date DNA-AgNCs, we aim to establish the correlation between the structure/sequence of DNA templates and emission behaviour of AgNCs. Herein, we systematically present a wide-range of DNA-AgNCs based on the structural complexity of the DNA templates, including single-stranded DNA (ssDNA), double-stranded DNA (dsDNA), triple-stranded DNA (tsDNA) and DNA nanostructures. For each DNA category, we discuss the emission property, quantum yield and synthesis condition of the respective AgNCs, before cross-comparing the impact of different DNA scaffolds on the properties of AgNCs. A future outlook for this area is given as a conclusion. By putting the information together, this review may shed new light on understanding DNA-AgNCs while we are expecting continuous breakthroughs in this field.


Stacking disorder in ice I.
Traditionally, ice I was considered to exist in two well-defined crystalline forms at ambient pressure: stable hexagonal ice (ice Ih) and metastable cubic ice (ice Ic). However, it is becoming increasingly evident that what has been called cubic ice in the past does not have a structure consistent with the cubic crystal system. Instead, it is a stacking-disordered material containing cubic sequences interlaced with hexagonal sequences, which is termed stacking-disordered ice (ice Isd). In this article, we summarise previous work on ice with stacking disorder including ice that was called cubic ice in the past. We also present new experimental data which shows that ice which crystallises after heterogeneous nucleation in water droplets containing solid inclusions also contains stacking disorder even at freezing temperatures of around -15 °C. This supports the results from molecular simulations, that the structure of ice that crystallises initially from supercooled water is always stacking-disordered and that this metastable ice can transform to the stable hexagonal phase subject to the kinetics of recrystallization. We also show that stacking disorder in ice which forms from water droplets is quantitatively distinct from ice made via other routes. The emerging picture of ice I is that of a very complex material which frequently contains stacking disorder and this stacking disorder can vary in complexity depending on the route of formation and thermal history.


Efficacy and Tolerability of First-Line Cetuximab Plus Leucovorin, Fluorouracil, and Oxaliplatin (FOLFOX-4) Versus FOLFOX-4 in Patients With RAS Wild-Type Metastatic Colorectal Cancer: The Open-Label, Randomized, Phase III TAILOR Trial.
Cetuximab in combination with chemotherapy is a standard-of-care first-line treatment regimen for patients with RAS wild-type (wt) metastatic colorectal cancer (mCRC); however, the efficacy of cetuximab plus leucovorin, fluorouracil, and oxaliplatin (FOLFOX) has never before been proven in a controlled and randomized phase III trial. To our knowledge, the TAILOR trial ( ClinicalTrials.gov identifier: NCT01228734) is the first randomized, multicenter, phase III study of the addition of cetuximab to first-line FOLFOX prospectively choosing a RAS wt population and thus providing confirmative data for the efficacy and safety of cetuximab plus FOLFOX versus FOLFOX alone. TAILOR is an open-label, randomized (1:1), multicenter, phase III trial in patients from China comparing FOLFOX-4 with or without cetuximab in RAS wt (KRAS/NRAS, exons 2 to 4) mCRC. The primary end point of TAILOR was progression-free survival time; secondary end points included overall survival time, overall response rate, and safety and tolerability. In the modified intent-to-treat population of 393 patients with RAS wt mCRC, adding cetuximab to FOLFOX-4 significantly improved the primary end point of progression-free survival time compared with FOLFOX-4 alone (hazard ratio, 0.69; 95% CI, 0.54 to 0.89; P = .004; median, 9.2 v 7.4 months, respectively), as well as the secondary end points of overall survival time (current assessment after 300 events: hazard ratio, 0.76; 95% CI, 0.61 to 0.96; P = .02; median, 20.7 v 17.8 months, respectively) and overall response rate (odds ratio, 2.41; 95% CI, 1.61 to 3.61; P < .001; 61.1% v 39.5%, respectively). Treatment was well tolerated, and there were no new or unexpected safety findings. The TAILOR study met all of its objectives and relevant clinical end points, confirming cetuximab in combination with FOLFOX as an effective standard-of-care first-line treatment regimen for patients with RAS wt mCRC.


Water quality indices based on bioassessment: the biotic indices.
Water quality indices (WQIs), which translate numerical values of several water quality characteristics of a sample into a single value, play a very important role in the monitoring, comparison and control of water quality. The WQIs of modern and post-modern times have been almost exclusively based on physical and chemical characteristics, and have seldom included 'biological' characteristics other than biochemical oxygen demand (BOD) and faecal coliforms. During the last three decades of the 20th century, indices based on bioassessment have been increasingly used in some developed countries, besides South Africa and Serbia, to complement the conventional WQIs, but the rest of the world continues to base its WQIs predominantly on physical and chemical characteristics. The serious drawbacks of this approach have been elucidated in this paper and, against that background, the state-of-the-art of biotic indices has been summarized. The paper makes a strong case for greater reliance on bioassessment-based WQls, especially by developing countries, to strengthen the diagnostic value of the conventional WQls.


Projection of the Grüneberg ganglion to the mouse olfactory bulb.
In mammals, sensory neurons from the main olfactory and vomeronasal systems project their axons to the olfactory bulbs in the brain. We here report that a cluster of neurons, distinct from these two systems, located at the very tip of the mouse nose and called the Grüneberg ganglion expresses the mature olfactory-sensory neuron-specific marker olfactory marker protein (OMP), but is unlikely to express known odorant or pheromone receptors. The ganglion is present at birth and maintained during adult life. Tracing experiments indicate that these neurons target ipsilaterally to a specific set of glomeruli located on the caudal part of the olfactory bulb, and that this connection is necessary for the survival of the ganglion. The glomerular targets are structures previously proposed to be associated with suckling behaviour. These observations strongly suggest that this peculiar olfactory neuronal population plays a sensory role, possibly linked to chemoperception.


MiR-210 promotes a hypoxic phenotype and increases radioresistance in human lung cancer cell lines.
The resistance of hypoxic cells to radiotherapy and chemotherapy is a major problem in the treatment of cancer. Recently, an additional mode of hypoxia-inducible factor (HIF)-dependent transcriptional regulation, involving modulation of a specific set of micro RNAs (miRNAs), including miR-210, has emerged. We have recently shown that HIF-1 induction of miR-210 also stabilizes HIF-1 through a positive regulatory loop. Therefore, we hypothesized that by stabilizing HIF-1 in normoxia, miR-210 may protect cancer cells from radiation. We developed a non-small cell lung carcinoma (NSCLC)-derived cell line (A549) stably expressing miR-210 (pmiR-210) or a control miRNA (pmiR-Ctl). The miR-210-expressing cells showed a significant stabilization of HIF-1 associated with mitochondrial defects and a glycolytic phenotype. Cells were subjected to radiation levels ranging from 0 to 10 Gy in normoxia and hypoxia. Cells expressing miR-210 in normoxia had the same level of radioresistance as control cells in hypoxia. Under hypoxia, pmiR-210 cells showed a low mortality rate owing to a decrease in apoptosis, with an ability to grow even at 10 Gy. This miR-210 phenotype was reproduced in another NSCLC cell line (H1975) and in HeLa cells. We have established that radioresistance was independent of p53 and cell cycle status. In addition, we have shown that genomic double-strand breaks (DSBs) foci disappear faster in pmiR-210 than in pmiR-Ctl cells, suggesting that miR-210 expression promotes a more efficient DSB repair. Finally, HIF-1 invalidation in pmiR-210 cells removed the radioresistant phenotype, showing that this mechanism is dependent on HIF-1. In conclusion, miR-210 appears to be a component of the radioresistance of hypoxic cancer cells. Given the high stability of most miRNAs, this advantage could be used by tumor cells in conditions where reoxygenation has occurred and suggests that strategies targeting miR-210 could enhance tumor radiosensitization.


Chemotherapy for high-grade glioma.
Trials on the effect of systemic chemotherapy on survival and recurrence in adults with high-grade glioma have had inconclusive results. We undertook a systematic review and meta-analysis to assess the effects of such treatment on survival and recurrence. To compare radiotherapy plus chemotherapy with radiotherapy alone in completely resected adults with high-grade glioma. To investigate whether or not pre-defined patient subgroups benefit more or less from chemotherapy. MEDLINE and CancerLit searches were supplemented with information from trial registers and by hand searching relevant meeting proceedings and by discussion with relevant trialists and organisations. These searches were carried out in June 1997, June 1999 and December 2000. Trials comparing radiotherapy versus radiotherapy + chemotherapy were eligible for inclusion provided that they randomized adult patients using a method which precluded prior knowledge of treatment assignment. A quantitative meta-analysis using updated information from individual patients from all available randomized trials was carried out. Data from all patients randomized in all eligible trials were sought directly from those responsible. Updated information on survival and date of follow-up were obtained, as were details of treatment allocation, date of randomization, age, sex, histological cell type, stage and performance status. To avoid potential bias, information was requested for all randomized patients including those who had been excluded from the investigators' original analyses. All analyses were done on an intention to treat basis on the endpoint of survival. For trials using cisplatin-based regimens, subgroup analyses by age, sex, histological cell type, tumour stage and performance status were also done. Data from 12 randomized trials and 3004 patients were included. The results show a significant prolongation of survival associated with chemotherapy, with a hazard ratio of 0.85 (95% CI 0.78-0.91, p=0.00004) or 15% relative decrease in the risk of death. This is equivalent to an absolute increase in one year survival rate of 6% (95% confidence interval 3% to 9%) from 40% to 46% and a two-month increase in median survival time (95% confidence interval one month to three months). There was no evidence that the effect of chemotherapy was different in any group of patients defined by age, sex, histology, performance status or extent of resection. This small but clear improvement in survival from chemotherapy encourages further study of drug treatment of these tumours


Should I stay or should I go? How the human brain manages the trade-off between exploitation and exploration.
Many large and small decisions we make in our daily lives-which ice cream to choose, what research projects to pursue, which partner to marry-require an exploration of alternatives before committing to and exploiting the benefits of a particular choice. Furthermore, many decisions require re-evaluation, and further exploration of alternatives, in the face of changing needs or circumstances. That is, often our decisions depend on a higher level choice: whether to exploit well known but possibly suboptimal alternatives or to explore risky but potentially more profitable ones. How adaptive agents choose between exploitation and exploration remains an important and open question that has received relatively limited attention in the behavioural and brain sciences. The choice could depend on a number of factors, including the familiarity of the environment, how quickly the environment is likely to change and the relative value of exploiting known sources of reward versus the cost of reducing uncertainty through exploration. There is no known generally optimal solution to the exploration versus exploitation problem, and a solution to the general case may indeed not be possible. However, there have been formal analyses of the optimal policy under constrained circumstances. There have also been specific suggestions of how humans and animals may respond to this problem under particular experimental conditions as well as proposals about the brain mechanisms involved. Here, we provide a brief review of this work, discuss how exploration and exploitation may be mediated in the brain and highlight some promising future directions for research.


The development of video game enjoyment in a role playing game.
This study examines the development of video game enjoyment over time. The results of a longitudinal study (N=62) show that enjoyment increases over several sessions. Moreover, results of a multilevel regression model indicate a causal link between the dependent variable video game enjoyment and the predictor variables exploratory behavior, spatial presence, competence, suspense and solution, and simulated experiences of life. These findings are important for video game research because they reveal the antecedents of video game enjoyment in a real-world longitudinal setting. Results are discussed in terms of the dynamics of video game enjoyment under real-world conditions.


Accelerated intermittent theta burst stimulation in major depression induces decreases in modularity: A connectome analysis.
Accelerated intermittent theta burst stimulation (aiTBS) is a noninvasive neurostimulation technique that shows promise for improving clinical outcome in patients suffering from treatment-resistant depression (TRD). Although it has been suggested that aiTBS may evoke beneficial neuroplasticity effects in neuronal circuits, the effects of aiTBS on brain networks have not been investigated until now. Fifty TRD patients were enrolled in a randomized double-blind sham-controlled crossover trial involving aiTBS, applied to the left dorsolateral prefrontal cortex. Diffusion-weighted MRI data were acquired at each of three time points (T1 at baseline; T2 after the first week of real/sham aiTBS stimulation; and T3 after the second week of treatment). Graph analysis was performed on the structural connectivity to examine treatment-related changes in the organization of brain networks. Changes in depression severity were assessed using the Hamilton Depression Rating Scale (HDRS). Baseline data were compared with 60 healthy controls. We observed a significant reduction in depression symptoms over time (p < 0.001). At T1, both TRD patients and controls exhibited a small-world topology in their white matter networks. More importantly, the TRD patients demonstrated a significantly shorter normalized path length (p AUC = 0.01), and decreased assortativity (p AUC = 0.035) of the structural networks, compared with the healthy control group. Within the TRD group, graph analysis revealed a less modular network configuration between T1 and T2 in the TRD group who received real aiTBS stimulation in the first week (p < 0.013). Finally, there were no significant correlations between changes on HDRS scores and reduced modularity. Application of aiTBS in TRD is characterized by reduced modularity, already evident 4 days after treatment. These findings support the potential clinical application of such noninvasive brain stimulation in TRD.


Poly(ethylene glycol) adlayers immobilized to metal oxide substrates through catechol derivatives: influence of assembly conditions on formation and stability.
We have investigated five different poly(ethylene glycol) (PEG, 5 kDa) catechol derivatives in terms of their spontaneous surface assembly from aqueous solution, adlayer stability, and resistance to nonspecific blood serum adsorption as a function of the type of catechol-based anchor, assembly conditions (temperature, pH), and type of substrate (SiO(2), TiO(2), Nb(2)O(5)). Variable-angle spectroscopic ellipsometry (VASE) was used for layer thickness evaluation, X-ray photoelectron spectroscopy (XPS) for layer composition, and ultraviolet-visible optical spectroscopy (UV-vis) for cloud point determination. Polymer surface coverage was influenced by the type of catechol anchor, type of the substrate, as well as pH and temperature (T) of the assembly solution. Furthermore, it was found to be highest for T close to the cloud point (T(CP)) and pH of the assembly solution close to pK(a1) (dissociation constant of the first catechol hydroxy group) of the polymer and to the isoelectric point (IEP) of the substrate. T(CP) turned out to depend on not only the ionic strength of the assembly solution, but also the type of catechol derivative and pH. PEG-coating dry thickness above 10 A correlated with low serum adsorption. We therefore conclude that optimum coating protocols for catechol-based polymer assembly at metal oxide interfaces have to take into account specific physicochemical properties of the polymer, anchor, and substrate.


What can rhythm control therapy contribute to prognosis in atrial fibrillation?
Atrial fibrillation (AF) is a global healthcare problem of growing prevalence and major significance. The consequences of AF include an increased rate of death, stroke and heart failure. Theoretically, a therapeutic strategy aiming at restoration and maintenance of sinus rhythm should offset the prognosis impairment associated with AF. However, these expectations were disproven in large randomised controlled trials comparing conventional antiarrhythmic drugs for rhythm control with conventional rate control. These apparently contradictory findings suggest that rhythm control strategies require better therapeutic instruments. These improvements may involve drugs and/or interventions with optimised risk-benefit profile and which also appreciate the specific atrial pathology and the patient's comorbidities. This article addresses important aspects of rhythm control strategies, which may have the potential of a beneficial contribution to the prognosis of AF patients.


Array comparative genomic hybridization analysis of colorectal cancer cell lines and primary carcinomas.
Array comparative genomic hybridization, with a genome-wide resolution of approximately 1 Mb, has been used to investigate copy number changes in 48 colorectal cancer (CRC) cell lines and 37 primary CRCs. The samples were divided for analysis according to the type of genomic instability that they exhibit, microsatellite instability (MSI) or chromosomal instability (CIN). Consistent copy number changes were identified, including gain of chromosomes 20, 13, and 8q and smaller regions of amplification such as chromosome 17q11.2-q12. Loss of chromosome 18q was a recurrent finding along with deletion of discrete regions such as chromosome 4q34-q35. The overall pattern of copy number change was strikingly similar between cell lines and primary cancers with a few obvious exceptions such as loss of chromosome 6 and gain of chromosomes 15 and 12p in the former. A greater number of aberrations were detected in CIN+ than MSI+ samples as well as differences in the type and extent of change reported. For example, loss of chromosome 8p was a common event in CIN+ cell lines and cancers but was often found to be gained in MSI+ cancers. In addition, the target of amplification on chromosome 8q appeared to differ, with 8q24.21 amplified frequently in CIN+ samples but 8q24.3 amplification a common finding in MSI+ samples. A number of genes of interest are located within the frequently aberrated regions, which are likely to be of importance in the development and progression of CRC.


Bipolar hemiarthroplasty for primary osteoarthritis of the hip: a review of 41 cases with 8 to 10 years of follow-up.
This article reports the results of 41 hips in 36 patients who underwent bipolar hemiarthroplasty for primary osteoarthritis of the hip. Surgical technique included a complete capsulectomy and light reaming of the acetabulum in all patients. The average follow-up was 8.9 years with a minimum of 8 years. Harris hip scores improved from 49 preoperatively to 93 at the latest follow-up, with 95% of the hips rated as excellent or good. Two patients had mild, intermittent groin pain, while a third developed recalcitrant pain necessitating revision. Migration of the bipolar cup was minimal with an average of 2.3 mm superior and 2.1 mm medial migration. Survivorship analysis demonstrated an 89.5% survival rate at 10 years.


Fabrication imperfection analysis and statistics generation using precision and reliability optimization method.
This paper applies a recently proposed dominant point detection method - precision and reliability optimization (PRO) - for representing shapes in the microscopy images of fabricated structures. This method uses both the local and the global nature of fit for dominant point detection. A smaller value of its control parameter better represents the local curvature properties of the shape while a larger value better indicates the global curvature properties. The applicability of this method to a wide range of microscopy images is demonstrated using four microscopy examples of brightness enhancement films, electromagnetic and photonic band gap materials, and aspherical mirror alignments. It is shown that PRO can clearly highlight several image effects and imperfections which may not be easily identifiable by human eye or may be difficult to analyze and assess. Further, for large scale arrays, it can be used to generate useful fabrication accuracy statistics and detect features with low fidelity or more imperfections.


Taenia crassiceps upper limb fasciitis in a patient with untreated acquired immunodeficiency syndrome and chronic hepatitis C infection--the role of surgical debridement.
We report a rare case of human Taenia crassiceps infection in a 47-year-old female patient with untreated acquired immunodeficiency syndrome and chronic hepatitis C infection. Little experience exists regarding the appropriate treatment of this infection. Usually, a combination of anthelmintic drugs is applied. Whether surgical measures are indicated have not been clarified. In our patient, initial surgery showed an abscess and fluid collection with numerous transparent cysts localised in the subcutaneous tissue of the cubital fossa. Parasitological and pathological examinations identified these structures as larvae of the cestode T. crassiceps. After treatment with anthelmintic medications, the patient was discharged in good condition. However, the patient presented with the clinical symptoms of an acute fasciitis of the right upper extremity 7 days later. The deteriorating general condition entailing a pre-septical state demanded emergency debridement and fasciectomy of the right arm. After the surgery, the patient recovered fully. Surgical treatment appears to be an important measure to reduce the tissue parasite load in patients with severe immunodeficiency. It also has to be questioned whether the bioavailability and the penetration of the drugs commonly administered is sufficiently high to treat such a fulminant infection alone.


Burkitt Lymphoma International Prognostic Index.
Burkitt lymphoma (BL) has unique biology and clinical course but lacks a standardized prognostic model. We developed and validated a novel prognostic index specific for BL to aid risk stratification, interpretation of clinical trials, and targeted development of novel treatment approaches. We derived the BL International Prognostic Index (BL-IPI) from a real-world data set of adult patients with BL treated with immunochemotherapy in the United States between 2009 and 2018, identifying candidate variables that showed the strongest prognostic association with progression-free survival (PFS). The index was validated in an external data set of patients treated in Europe, Canada, and Australia between 2004 and 2019. In the derivation cohort of 633 patients with BL, age ≥ 40 years, performance status ≥ 2, serum lactate dehydrogenase > 3× upper limit of normal, and CNS involvement were selected as equally weighted factors with an independent prognostic value. The resulting BL-IPI identified groups with low (zero risk factors, 18% of patients), intermediate (one factor, 36% of patients), and high risk (≥ 2 factors, 46% of patients) with 3-year PFS estimates of 92%, 72%, and 53%, respectively, and 3-year overall survival estimates of 96%, 76%, and 59%, respectively. The index discriminated outcomes regardless of HIV status, stage, or first-line chemotherapy regimen. Patient characteristics, relative size of the BL-IPI groupings, and outcome discrimination were consistent in the validation cohort of 457 patients, with 3-year PFS estimates of 96%, 82%, and 63% for low-, intermediate-, and high-risk BL-IPI, respectively. The BL-IPI provides robust discrimination of survival in adult BL, suitable for use as prognostication and stratification in trials. The high-risk group has suboptimal outcomes with standard therapy and should be considered for innovative treatment approaches.


Microbe Profile: Listeria monocytogenes: a paradigm among intracellular bacterial pathogens.
Listeria monocytogenes is a food-borne bacterial pathogen that is responsible for listeriosis, a disease characterized by occasional febrile gastroenteritis in immunocompetent individuals, abortions in pregnant women, meningitis in the newborn and fatal bacteraemia in immunocompromised individuals or the elderly. The ability of L. monocytogenes to produce disease is intimately associated with its potential to traverse several human barriers (including the intestinal, placental and blood/brain barriers), to promote its internalization within diverse populations of epithelial cells and to proliferate in the intra-ic environment while escaping host immune responses. L. monocytogenes is often regarded as a paradigm for intracellular parasitism.


Improved tolerance for enteral nutrition after serial transverse enteroplasty (STEP) in infants and children with short bowel syndrome--a seven-year single-center experience.
Serial transverse enteroplasty (STEP) was designed to lengthen and taper the small intestine in patients with short bowel syndrome (SBS) and dilated small bowel. We hypothesized that tolerance for enteral nutrition (EN) improves after STEP. Patients who underwent STEP between March 2004 and January 2011 were identified. Candidates for STEP had radiographic evidence of dilated small bowel and either failed to advance EN or demonstrated deterioration in tolerance for EN. Clinical and nutritional data were analyzed pre- and post-STEP. EN was defined as the percentage of calories administered enterally. Statistical analysis employed the signed rank test with significance assumed when p<0.05. Twenty STEPs were performed at a median age of 13.7 months. Median pre-STEP bowel length was 30 cm with a median increase in bowel length of 42%. Five patients achieved enteral autonomy at a median of 6.5 months post-STEP. EN increased in 75%, while 25% exhibited unchanged or decreased EN post-STEP. In aggregate, median EN tolerance increased from 22% at one month pre-STEP to 61% at six months post-STEP (p=0.003). The STEP is an effective adjunct in the treatment of patients with intestinal failure. While enteral autonomy is eventually possible in some patients, improved enteral tolerance can be achieved in a majority of cases.


The Pseudomonas syringae avrRpt2 gene product promotes pathogen virulence from inside plant cells.
Several bacterial avr genes have been shown to contribute to virulence on susceptible plants lacking the corresponding resistance (R) gene. The mechanisms by which avr genes promote parasitism and disease, however, are not well understood. We investigated the role of the Pseudomonas syringae pv. tomato avrRpt2 gene in pathogenesis by studying the interaction of P. syringae pv. tomato strain PstDC3000 expressing avrRpt2 with several Arabidopsis thaliana lines lacking the corresponding R gene, RPS2. We found that PstDC3000 expressing avrRpt2 grew to significantly higher levels and often resulted in the formation of more severe disease symptoms in ecotype No-0 plants carrying a mutant RPS2 allele, as well as in two Col-0 mutant lines, cpr5 rps2 and coil rps2, that exhibit enhanced resistance. We also generated transgenic A. thaliana lines expressing avrRpt2 and demonstrated, by using several different assays, that expression of avrRpt2 within the plant also promotes virulence of PstDC3000. Thus, AvrRpt2 appears to promote pathogen virulence from within the plant cell.


The proportion of childhood leukaemia incidence in Great Britain that may be caused by natural background ionizing radiation.
The aetiology of childhood leukaemia remains generally unknown, although exposure to moderate and high levels of ionizing radiation, such as those experienced during the atomic bombings of Japan or from radiotherapy, is an established cause. Risk models based primarily on studies of the Japanese atomic bomb survivors imply that low-level exposure to ionizing radiation, including ubiquitous natural background radiation, also raises the risk of childhood leukaemia. Using two sets of recently published leukaemia risk models and estimates of natural background radiation red-bone-marrow doses received by children, about 20% of the cases of childhood leukaemia in Great Britain are predicted to be attributable to this source. However, for one of these sets of risk models this attributable fraction is materially dependent on how the radiation-induced risk is assumed to be transferred between the Japanese atomic bomb survivors and Western children. Over a range of annual doses representing the range (0.5-2.5 mSv/year) experienced by most populations, the attributable proportion for the preferred risk-transfer model varies between 8 and 30%, with small deviations from a linear relationship that are largely due to the saturation of the model, although again this range of attributable fractions depends on the assumed transfer of risk between populations.


Developing models of how cognitive improvements change functioning: mediation, moderation and moderated mediation.
Cognitive remediation (CRT) affects functioning but the extent and type of cognitive improvements necessary are unknown. To develop and test models of how cognitive improvement transfers to work behaviour using the data from a current service. Participants (N49) with a support worker and a paid or voluntary job were offered CRT in a Phase 2 single group design with three assessments: baseline, post therapy and follow-up. Working memory, cognitive flexibility, planning and work outcomes were assessed. Three models were tested (mediation - cognitive improvements drive functioning improvement; moderation - post treatment cognitive level affects the impact of CRT on functioning; moderated mediation - cognition drives functioning improvements only after a certain level is achieved). There was evidence of mediation (planning improvement associated with improved work quality). There was no evidence that cognitive flexibility (total Wisconsin Card Sorting Test errors) and working memory (Wechsler Adult Intelligence Scale III digit span) mediated work functioning despite significant effects. There was some evidence of moderated mediation for planning improvement if participants had poorer memory and/or made fewer WCST errors. The total CRT effect on work quality was d=0.55, but the indirect (planning-mediated CRT effect) was d=0.082 Planning improvements led to better work quality but only accounted for a small proportion of the total effect on work outcome. Other specific and non-specific effects of CRT and the work programme are likely to account for some of the remaining effect. This is the first time complex models have been tested and future Phase 3 studies need to further test mediation and moderated mediation models.


4-Acetoxyphenol Prevents RPE Oxidative Stress-Induced Necrosis by Functioning as an NRF2 Stabilizer.
Oxidative stress has been suggested to be a major risk factor for the pathogenesis of AMD. Retinal pigment epithelial (RPE) cells are essential for maintaining the homeostasis of the retina, and RPE cell death and the resultant photoreceptor apoptosis have been observed in dry AMD, especially in geographic atrophy. The purpose of this article was to identify and repurpose the Food and Drug Administration-approved natural compound 4-Acetoxyphenol (4-AC), and to evaluate its effect and mechanism in protecting against oxidative stress-induced RPE necrosis. We exposed ARPE-19 cells to tert-Butyl hydroperoxide (tBHP) after pretreatment with 4-AC, and measured cell viability by MTT assay. Aggregation of RIPK3 and HMGB1 nuclear release were analyzed by transfected reporter genes. Reactive oxygen species (ROS) were measured using a commercially available ROS detection system. The importance of the NRF2/NQO1/HO-1 pathway in mediating 4-AC function was corroborated by siRNA studies, qRT-PCR, and immunostaining. We have identified a natural antioxidant, 4-AC, which demonstrates strong abilities to protect RPE cells from oxidative stress-induced necrosis. Mechanistically, 4-AC blocked the increase of cellular ROS induced by oxidative stress, and upregulated NQO1 and HO-1 genes by stabilizing and inducing the nuclear translocation of NRF2 transcription factor. The NQO1, HO-1, and NRF2 were further shown to be required for 4-AC protection of RPE cells from death induced by tBHP. The tBHQ, an NRF2 stabilizer, consistently mimicked the protective effect of 4-AC against tBHP-induced RPE death. The compound 4-AC protects ARPE-19 cells from oxidative stress-induced necrosis through upregulation of NQO1 and HO-1 genes by stabilization of NRF2.


Molecular epidemiology of infectious bursal disease virus in Zambia.
Nucleotide sequences of the VP2 hypervariable region (VP2-HVR) of 10 infectious bursal disease viruses detected in indigenous and exotic chickens in Zambia from 2004 to 2005 were determined. Phylogenetic analysis showed that the viruses diverged into two genotypes and belonged to the African very virulent types (VV1 and VV2). In the phylogenetic tree, strains in one genotype clustered in a distinct group and were closely related to some strains isolated in western Africa (VV1), with nucleotide similarities of 95.7%- 96.5%. Strains in the other genotype were clustered within the eastern African VV type (VV2), with nucleotide similarities of 97.3%- 98.5%. Both genotypes were distributed in the southern parts of Zambia and had a unique conserved amino acid substitution at 300 (E→A) in addition to the putative virulence marker at positions 222(A), 242(I), 256(I), 294(I) and 299(S). These findings represent the first documentation of the existence of the African VV-IBDV variants in both indigenous and exotic chickens in Zambia.


De novo truncation of chromosome 16p and healing with (TTAGGG)n in the alpha-thalassemia/mental retardation syndrome (ATR-16).
We have previously described a series of patients in whom the deletion of 1-2 megabases (Mb) of DNA from the tip of the short arm of chromosome 16 (band 16p13.3) is associated with alpha-thalassemia/mental retardation syndrome (ATR-16). We now show that one of these patients has a de novo truncation of the terminal 2 Mb of chromosome 16p and that telomeric sequence (TTAGGG)n has been added at the site of breakage. This suggests that the chromosomal break, which is paternal in origin and which probably arose at meiosis, has been stabilized in vivo by the direct addition of the telomeric sequence. Sequence comparisons of this breakpoint with that of a previously described chromosomal truncation (alpha alpha)TI do not reveal extensive sequence homology. However, both breakpoints show minimal complementarity (3-4 bp) to the proposed RNA template of human telomerase at the site at which telomere repeats have been added. Unlike previously characterized individuals with ATR-16, the clinical features of this patient appear to be solely due to monosomy for the terminal portion of 16p13.3. The identification of further patients with "pure" monosomy for the tip of chromosome 16p will be important for defining the loci contributing to the phenotype of this syndrome.


Sequence analysis of European maize inbred line F2 provides new insights into molecular and chromosomal characteristics of presence/absence variants.
Maize is well known for its exceptional structural diversity, including copy number variants (CNVs) and presence/absence variants (PAVs), and there is growing evidence for the role of structural variation in maize adaptation. While PAVs have been described in this important crop species, they have been only scarcely characterized at the sequence level and the extent of presence/absence variation and relative chromosomal landscape of inbred-specific regions remain to be elucidated. De novo genome sequencing of the French F2 maize inbred line revealed 10,044 novel genomic regions larger than 1 kb, making up 88 Mb of DNA, that are present in F2 but not in B73 (PAV). This set of maize PAV sequences allowed us to annotate PAV content and to analyze sequence breakpoints. Using PAV genotyping on a collection of 25 temperate lines, we also analyzed Linkage Disequilibrium in PAVs and flanking regions, and PAV frequencies within maize genetic groups. We highlight the possible role of MMEJ-type double strand break repair in maize PAV formation and discover 395 new genes with transcriptional support. Pattern of linkage disequilibrium within PAVs strikingly differs from this of flanking regions and is in accordance with the intuition that PAVs may recombine less than other genomic regions. We show that most PAVs are ancient, while some are found only in European Flint material, thus pinpointing structural features that may be at the origin of adaptive traits involved in the success of this material. Characterization of such PAVs will provide useful material for further association genetic studies in European and temperate maize.


Effect of Probiotic Supplementation on Cognitive Function and Metabolic Status in Alzheimer's Disease: A Randomized, Double-Blind and Controlled Trial.
Alzheimer's disease (AD) is associated with severe cognitive impairments as well as some metabolic defects. Scant studies in animal models indicate a link between probiotics and cognitive function. This randomized, double-blind, and controlled clinical trial was conducted among 60 AD patients to assess the effects of probiotic supplementation on cognitive function and metabolic status. The patients were randomly divided into two groups (n = 30 in each group) treating with either milk (control group) or a mixture of probiotics (probiotic group). The probiotic supplemented group took 200 ml/day probiotic milk containing Lactobacillus acidophilus, Lactobacillus casei, Bifidobacterium bifidum, and Lactobacillus fermentum (2 × 109 CFU/g for each) for 12 weeks. Mini-mental state examination (MMSE) score was recorded in all subjects before and after the treatment. Pre- and post-treatment fasting blood samples were obtained to determine the related markers. After 12 weeks intervention, compared with the control group (-5.03% ± 3.00), the probiotic treated (+27.90% ± 8.07) patients showed a significant improvement in the MMSE score (P <0.001). In addition, changes in plasma malondialdehyde (-22.01% ± 4.84 vs. +2.67% ± 3.86 μmol/L, P <0.001), serum high-sensitivity C-reactive protein (-17.61% ± 3.70 vs. +45.26% ± 3.50 μg/mL, P <0.001), homeostasis model of assessment-estimated insulin resistance (+28.84% ± 13.34 vs. +76.95% ± 24.60, P = 0.002), Beta cell function (+3.45% ± 10.91 vs. +75.62% ± 23.18, P = 0.001), serum triglycerides (-20.29% ± 4.49 vs. -0.16% ± 5.24 mg/dL, P = 0.003), and quantitative insulin sensitivity check index (-1.83 ± 1.26 vs. -4.66 ± 1.70, P = 0.006) in the probiotic group were significantly varied compared to the control group. We found that the probiotic treatment had no considerable effect on other biomarkers of oxidative stress and inflammation, fasting plasma glucose, and other lipid profiles. Overall, the current study demonstrated that probiotic consumption for 12 weeks positively affects cognitive function and some metabolic statuses in the AD patients. http://www.irct.ir/, IRCT201511305623N60.


The separation of vanillate O-demethylase from protocatechuate 3,4-oxygenase by ultracentrifugation.
1. Protocatechuate 3,4-oxygenase in the soluble part of a cell-free extract of Pseudomonas fluorescens (strain T) sedimented more rapidly than vanillate O-demethylase under specified conditions in a preparative ultracentrifuge. 2. The supernatant from this process contained vanillate O-demethylase and formaldehyde dehydrogenase, and when supplemented with NADH oxidized vanillate with an uptake of 1 mole of oxygen/mole of substrate and accumulation of protocatechuate. 3. This uptake was decreased to 0.5mole/mole of substrate in the presence of semicarbazide as trapping agent for formaldehyde. 4. Reasons are presented for the process of methyl group removal from vanillate being oxidative demethylation.


Cell-autonomous regulation of brown fat identity gene UCP1 by unliganded vitamin D receptor.
White adipose tissue stores energy in the form of lipids, and brown adipose tissue expends energy via uncoupled fatty acid oxidation, which leads to the generation of heat. Obesity reflects an imbalance between energy storage and energy expenditure and is strongly associated with metabolic and cardiovascular disease. Therefore, there are important medical and biological implications for elucidating the mechanisms that promote energy expenditure in humans. Animal models with altered vitamin D receptor (VDR) expression have changes in energy expenditure. However, the specific mechanism for this effect has not been elucidated and the relevance for humans is unclear. Here we show, using human patient samples from individuals with hereditary vitamin D resistant rickets, that the VDR directly inhibits the expression of uncoupling protein-1 (UCP1), the critical protein for uncoupling fatty acid oxidation in brown fat and burning energy. The inhibition is enforced by VDR occupancy of a negative response element in the promoter proximal region of the UCP1 gene. Deletion of VDR increases UCP1 expression and results in a "browning" of adipocytes. Importantly, we found that this process occurs cell autonomously and is independent of the physiologic VDR hormone ligand, 1,25-dihydroxyvitamin D. These results identify a mechanism for modulating energy balance in humans.


Galectin-3 up-regulation in hypoxic and nutrient deprived microenvironments promotes cell survival.
Galectin-3 (gal-3) is a β-galactoside binding protein related to many tumoral aspects, e.g. angiogenesis, cell growth and motility and resistance to cell death. Evidence has shown its upregulation upon hypoxia, a common feature in solid tumors such as glioblastoma multiformes (GBM). This tumor presents a unique feature described as pseudopalisading cells, which accumulate large amounts of gal-3. Tumor cells far from hypoxic/nutrient deprived areas express little, if any gal-3. Here, we have shown that the hybrid glioma cell line, NG97ht, recapitulates GBM growth forming gal-3 positive pseudopalisades even when cells are grafted subcutaneously in nude mice. In vitro experiments were performed exposing these cells to conditions mimicking tumor areas that display oxygen and nutrient deprivation. Results indicated that gal-3 transcription under hypoxic conditions requires previous protein synthesis and is triggered in a HIF-1α and NF-κB dependent manner. In addition, a significant proportion of cells die only when exposed simultaneously to hypoxia and nutrient deprivation and demonstrate ROS induction. Inhibition of gal-3 expression using siRNA led to protein knockdown followed by a 1.7-2.2 fold increase in cell death. Similar results were also found in a human GBM cell line, T98G. In vivo, U87MG gal-3 knockdown cells inoculated subcutaneously in nude mice demonstrated decreased tumor growth and increased time for tumor engraftment. These results indicate that gal-3 protected cells from cell death under hypoxia and nutrient deprivation in vitro and that gal-3 is a key factor in tumor growth and engraftment in hypoxic and nutrient-deprived microenvironments. Overexpression of gal-3, thus, is part of an adaptive program leading to tumor cell survival under these stressing conditions.


Social Interactions of Clerks: The Role of Engagement, Imagination, and Alignment as Sources for Professional Identity Formation.
Participating in clinical practice shapes students' identities, but it is unclear how students build meaningful relationships while "dipping into" various social contexts. This study explored with whom students interacted, which social relationships they built, and how these relationships contributed to the formation of a professional identity. In this longitudinal study at University Medical Center Groningen, University of Groningen, the Netherlands, 9 undergraduate medical students recorded experiences of thinking about themselves as future professionals (September 2015 to March 2017). The authors conducted template analysis using both open coding and a priori themes derived from Wenger's modes of belonging to communities of practice: engagement, imagination, and alignment. The authors received 205 recorded experiences. While rotating, students used engagement, imagination, and alignment to give meaning to clinical workplace social interactions. Participants considered relationships with doctors, patients, and peers as preconditions for engaging in meaningful experiences. Although imagination and alignment were less represented, discussing imagination with peers and physicians stimulated a deeper understanding of what it means to become a physician. Explicitly being invited "to the table" and awareness of the benefits of being a clerk were instances of alignment that stimulated the development of identities as future doctors. To understand the nature of professional identity formation, Wenger's modes of belonging must be considered. Where engagement is very prevalent, imagination and alignment are less spontaneously mentioned and therefore more difficult to foster. Looking for ways to support imagination and alignment is important for students' sensemaking process of becoming a doctor.


Adoption of hip resurfacing arthroplasty at hospital for special surgery: a cohort study.
Hip resurfacing arthroplasty (HRA) is an alternative to traditional total hip replacement (THR) that allows for the preservation of femoral bone. It is a more technically difficult procedure that has led some researchers to report an unsatisfactory learning curve (Berend et al., J Bone Joint Surg Am Suppl 2:89-92, 2011; Mont et al., Clin Orthop Relat Res 465:63-70, 2007). The purpose of this study was to investigate the adoption of HRA at our institution, examining the clinical results, revision rate, and modes of failure. Additionally, a comparison of three different implant systems was performed. A retrospective review of a consecutive series of HRA performed at our institution between the years 2004 and 2009 was carried out. A total of 820 HRA with a minimum of 2 years of follow-up were included in the study. The majority of included patients were males (70%), with osteoarthritis (92%). The average age was 49.8 years, and the mean BMI was 27.5 kg/m(2). The average Harris hip score improved from 61 to 96.5 postoperatively. Thirteen revisions (1.6%) were performed for femoral neck fracture, femoral head osteonecrosis, acetabular loosening, metal reactivity/metallosis, and metal allergy. The overall Kaplan-Meier survival curve with revision surgery as an endpoint showed 98.5% survival at 5 years. There were no observable differences in clinical scores or revision rates between the different implant systems. HRA can be successfully adopted with a low complication rate, given careful patient selection, specialized surgical training, and use of good implant design.


Mutations in heat shock protein beta-1 (HSPB1) are associated with a range of clinical phenotypes related to different patterns of motor neuron dysfunction: A case series.
Heat shock protein beta-1 (HSPB1) is a ubiquitously expressed molecular chaperone that is important in protecting cells against cellular injury. Mutations in this protein are known to cause autosomal dominant hereditary distal axonal neuropathies, including Charcot Marie Tooth disease type 2F (CMT2F) and distal hereditary motor neuropathy (dHMN). However, patients with HSPB1 mutations have also been described with upper motor neuron signs. We present five patients with mutations in HSPB1 who presented with a range of clinical phenotypes related to different patterns of motor neuron dysfunction. Three of these mutations have not been previously reported. Patients were seen at our neuromuscular or amyotrophic lateral sclerosis (ALS) clinics. Gene sequencing was carried out as part of diagnostic investigations. Detailed clinical and electrophysiologic data was collected. Five patients had variants of HSPB1. Three patients had a hereditary length-dependent sensori-motor axonal neuropathy consistent with Charcot Marie Tooth type 2 (CMT2); two of these patients carried novel mutations in the C-terminal region (p.Glu186* and p.Pro170Thr). One patient had the clinical picture of ALS and a novel missense mutation (p.Arg27Leu) in the N-terminal region. Another patient had the phenotype of hereditary spastic paraparesis (HSP) associated with a missense mutation (p.Gly84Arg) already described in families with CMT or dHMN. This study describes three novel mutations of HSPB1 and describes two patients with upper motor neurone signs associated with HSPB1 mutations.


"At Least They're Workin' on My Case?" Victim Notification in Sexual Assault "Cold" Cases.
Sexual assault is a significantly under-reported, -investigated, and -prosecuted crime in the United States, which criminal justice and advocacy actors across the country are working to address. Law enforcement procedures often involve providing crime victims, including sexual assault victims, with written notification by mail about the status of their case, but little is known about the best practices for victim notification in sexual assault "cold" cases. This qualitative research explored whether this standard law enforcement practice was appropriate for sexual assault victims in "cold cases" particularly when there had been no contact from law enforcement, despite forensic evidence having been tested. The research questions were what do sexual assault victims in cold cases have to say about victim notification protocols and practices? and What do sexual assault victims in cold cases have to say about hypothetical written victim notification protocols? Twenty-three sexual assault victims were asked in focus groups and individual interviews to respond to hypothetical written notification letters for content and the sending authority and to give input on alternative modes of communication. The data were analyzed using grounded theory. Themes related to trust, personal agency, and decision making from notification examples emerged. Recommendations on notification included respecting privacy, including specifics, identifying next steps, normalizing, translating, and providing resources. Implications for developing notification protocols include use of emerging evidence about neurobiology of trauma, use of victim input, and patience for the varying reactions and needs of sexual assault victims.


Survey of pest infestation, asthma, and allergy in low-income housing.
Low-income housing often has multiple indoor health risks. Among them, pest infestation, pesticide use, and pest allergens are recognized as common risks which affect residents' health. Cockroach and rodent allergens are associated with morbidity and mortality of asthmatics. To characterize the levels of pest infestation, residents' attitudes toward pest control, and the relationships among cockroaches, mice, cockroach allergen level, asthma and allergy rate in public housing, we interviewed residents from 358 randomly selected apartments in Gary, Indiana and assessed the environmental conditions. Dust samples were collected from 101 apartment kitchen floors to analyze for cockroach allergen (Bla g 1 and Bla g 2) levels. Eighty one percent of the apartments were found infested by cockroaches, mice, ants, spiders, or flies. In the 101 apartments evaluated, 98% of the kitchen dust samples had detectable levels of Bla g 1 allergen (>or=0.4 U/g), 52% had >or=2 U/g, and 33% had >or=8 U/g of Bla g 1. Among the 1,173 residents, 13% and 9% had physician-diagnosed asthma and allergy, respectively. Existence of diagnosed asthmatic was positively correlated with mouse infestations.


The potential impact of male circumcision on HIV in Sub-Saharan Africa.
A randomized controlled trial (RCT) has shown that male circumcision (MC) reduces sexual transmission of HIV from women to men by 60% (32%-76%; 95% CI) offering an intervention of proven efficacy for reducing the sexual spread of HIV. We explore the implications of this finding for the promotion of MC as a public health intervention to control HIV in sub-Saharan Africa. Using dynamical simulation models we consider the impact of MC on the relative prevalence of HIV in men and women and in circumcised and uncircumcised men. Using country level data on HIV prevalence and MC, we estimate the impact of increasing MC coverage on HIV incidence, HIV prevalence, and HIV-related deaths over the next ten, twenty, and thirty years in sub-Saharan Africa. Assuming that full coverage of MC is achieved over the next ten years, we consider three scenarios in which the reduction in transmission is given by the best estimate and the upper and lower 95% confidence limits of the reduction in transmission observed in the RCT. MC could avert 2.0 (1.1-3.8) million new HIV infections and 0.3 (0.1-0.5) million deaths over the next ten years in sub-Saharan Africa. In the ten years after that, it could avert a further 3.7 (1.9-7.5) million new HIV infections and 2.7 (1.5-5.3) million deaths, with about one quarter of all the incident cases prevented and the deaths averted occurring in South Africa. We show that a) MC will increase the proportion of infected people who are women from about 52% to 58%; b) where there is homogenous mixing but not all men are circumcised, the prevalence of infection in circumcised men is likely to be about 80% of that in uncircumcised men; c) MC is equivalent to an intervention, such as a vaccine or increased condom use, that reduces transmission in both directions by 37%. This analysis is based on the result of just one RCT, but if the results of that trial are confirmed we suggest that MC could substantially reduce the burden of HIV in Africa, especially in southern Africa where the prevalence of MC is low and the prevalence of HIV is high. While the protective benefit to HIV-negative men will be immediate, the full impact of MC on HIV-related illness and death will only be apparent in ten to twenty years.


Benefit from decline: the primary transcriptome of Alteromonas macleodii str. Te101 during Trichodesmium demise.
Interactions between co-existing microorganisms deeply affect the physiology of the involved organisms and, ultimately, the function of the ecosystem as a whole. Copiotrophic Alteromonas are marine gammaproteobacteria that thrive during the late stages of phytoplankton blooms in the marine environment and in laboratory co-cultures with cyanobacteria such as Trichodesmium. The response of this heterotroph to the sometimes rapid and transient changes in nutrient supply when the phototroph crashes is not well understood. Here, we isolated and sequenced the strain Alteromonas macleodii str. Te101 from a laboratory culture of Trichodesmium erythraeum IMS101, yielding a chromosome of 4.63 Mb and a single plasmid of 237 kb. Increasing salinities to ≥43 ppt inhibited the growth of Trichodesmium but stimulated growth of the associated Alteromonas. We characterized the transcriptomic responses of both microorganisms and identified the complement of active transcriptional start sites in Alteromonas at single-nucleotide resolution. In replicate cultures, a similar set of genes became activated in Alteromonas when growth rates of Trichodesmium declined and mortality was high. The parallel activation of fliA, rpoS and of flagellar assembly and growth-related genes indicated that Alteromonas might have increased cell motility, growth, and multiple biosynthetic activities. Genes with the highest expression in the data set were three small RNAs (Aln1a-c) that were identified as analogs of the small RNAs CsrB-C in E. coli or RsmX-Z in pathogenic bacteria. Together with the carbon storage protein A (CsrA) homolog Te101_05290, these RNAs likely control the expression of numerous genes in responding to changes in the environment.


Difference in spin crossover pathways among saddle-shaped six-coordinated iron(III) porphyrin complexes.
The electronic states of a series of saddle-shaped porphyrin complexes [Fe(OMTPP)L(2)](+) and [Fe(TBTXP)L(2)](+) have been examined in solution by (1)H NMR, (13)C NMR, and EPR spectroscopy and by magnetic measurements. While [Fe(OMTPP)(DMAP)(2)](+) and [Fe(TBTXP)(DMAP)(2)](+) maintain the low-spin (S = (1)/(2)) state, [Fe(OMTPP)(THF)(2)](+) and [Fe(TBTXP)(THF)(2)](+) exhibit an essentially pure intermediate-spin (S = (3)/(2)) state over a wide range of temperatures. In contrast, the Py and 4-CNPy complexes of OMTPP and TBTXP exhibit a spin transition from S = (3)/(2) to S = (1)/(2) as the temperature was decreased from 300 to 200 K. Thus, the magnetic behavior of these complexes is similar to that of [Fe(OETPP)Py(2)](+) reported in our previous paper (Ikeue, T.; Ohgo, Y.; Yamaguchi, T.; Takahashi, M.; Takeda, M.; Nakamura, M. Angew. Chem., Int. Ed. 2001, 40, 2617-2620) in the context that all these complexes exhibit a novel spin crossover phenomenon in solution. Close examination of the NMR and EPR data of [Fe(OMTPP)L(2)](+) and [Fe(TBTXP)L(2)](+) (L = Py, 4-CNPy) revealed, however, that these complexes adopt the less common (d(xz), d(yz))(4)(d(xy))(1) electron configuration at low temperature in contrast to [Fe(OETPP)Py(2)](+) which shows the common (d(xy))(2)(d(xz), d(yz))(3) electron configuration. These observations have been attributed to the flexible nature of the OMTPP and TBTXP cores as compared with that of OETPP; the relatively flexible OMTPP and TBTXP cores can ruffle the porphyrin ring and adopt the (d(xz), d(yz))(4)(d(xy))(1) electron configuration at low temperature. Therefore, this study reveals that the rigidity of porphyrin cores is an important factor in determining the spin crossover pathways.


Inheritance pattern of Beckwith-Wiedemann syndrome is heterogeneous in 291 families with an affected proband.
Beckwith-Wiedemann syndrome (BWS) is congenital disorder whose molecular etiology is related to genetic and epigenetic mutations on 11p15. The majority of cases of BWS are sporadic, but a substantial proportion are familial, with an unknown inheritance pattern, although autosomal dominant and sex-dependent inheritance have been proposed. We tested the hypothesis that in familial BWS, autosomal dominant inheritance is the primary mode of transmission underlying familial instances. Segregation analysis was performed in 291 families ascertained with an affected child. Individuals were considered to have BWS if they had two of five major features: macroglossia, macrosomia, hypoglycemia at birth, abdominal wall defect, and ear pits or creases. Models of inheritance were tested using pedigree analysis package (PAP) parameterized for a discrete trait. A total of 291 families of an affected proband were included in the study. The analysis was based on a revised general model that included a boundary solution. Sporadic and environmental models were rejected. Overall, the results suggested Mendelian inheritance but under recessive or additive mode of inheritance, which fit the data equally well rather than dominant inheritance. However, the presence of families in the cohort consistent with dominant and sex-dependent inheritance suggest familial BWS may be a heterogeneous group comprised of different inheritance patterns. Familial BWS does not appear to be consistent with autosomal dominant transmission, and is likely a complex mixture of different inheritance patterns.


Have some guidelines for the treatment of acute bipolar depression gone too far in the restriction of antidepressants?
This paper gives a critical review of recommendations concerning the drug treatment of acute bipolar depression. The suggestions of different guidelines and consensus papers, especially in US-American and Canadian psychiatry, have a strong tendency against antidepressants in bipolar depression; they prefer mono-therapy with mood stabilizers and, in the case of co-medication with mood stabilizers and antidepressants in severe depression, to withdraw the antidepressant as early as possible. The intention of this restrictive use is to avoid the risk of mania and the risk of rapid cycling induced by antidepressants. However, apparently the risk of suicidal acts, which is as prominent in bipolar depression as in unipolar depression, has been totally neglected. Furthermore, the fact that none of the mood stabilizers have proven their antidepressive efficacy leads not only to the risk of depression-related suicidal behavior but also to the risk of chronicity of depressive symptoms due to undertreatment. Altogether the view expressed in some guidelines and consensus papers appears not well balanced. Furthermore, the fact that apparently the selective serotonin re-uptake inhibitors and possibly some other modern antidepressants have only a low risk of inducing a switch to mania should stimulate a rewriting of the guidelines on drug treatment in acute bipolar depression in a less restrictive way concerning the use of antidepressants.


Aberrant base excision repair pathway of oxidatively damaged DNA: Implications for degenerative diseases.
In cellular organisms composition of DNA is constrained to only four nucleobases A, G, T and C, except for minor DNA base modifications such as methylation which serves for defence against foreign DNA or gene expression regulation. Interestingly, this severe evolutionary constraint among other things demands DNA repair systems to discriminate between regular and modified bases. DNA glycosylases specifically recognize and excise damaged bases among vast majority of regular bases in the base excision repair (BER) pathway. However, the mismatched base pairs in DNA can occur from a spontaneous conversion of 5-methylcytosine to thymine and DNA polymerase errors during replication. To counteract these mutagenic threats to genome stability, cells evolved special DNA repair systems that target the non-damaged DNA strand in a duplex to remove mismatched regular DNA bases. Mismatch-specific adenine- and thymine-DNA glycosylases (MutY/MUTYH and TDG/MBD4, respectively) initiated BER and mismatch repair (MMR) pathways can recognize and remove normal DNA bases in mismatched DNA duplexes. Importantly, in DNA repair deficient cells bacterial MutY, human TDG and mammalian MMR can act in the aberrant manner: MutY and TDG removes adenine and thymine opposite misincorporated 8-oxoguanine and damaged adenine, respectively, whereas MMR removes thymine opposite to O6-methylguanine. These unusual activities lead either to mutations or futile DNA repair, thus indicating that the DNA repair pathways which target non-damaged DNA strand can act in aberrant manner and introduce genome instability in the presence of unrepaired DNA lesions. Evidences accumulated showing that in addition to the accumulation of oxidatively damaged DNA in cells, the aberrant DNA repair can also contribute to cancer, brain disorders and premature senescence. For example, the aberrant BER and MMR pathways for oxidized guanine residues can lead to trinucleotide expansion that underlies Huntington's disease, a severe hereditary neurodegenerative syndrome. This review summarises the present knowledge about the aberrant DNA repair pathways for oxidized base modifications and their possible role in age-related diseases.


The clinical spectrum of pulmonary aspergillosis.
The clinical presentation of Aspergillus lung disease is determined by the interaction between fungus and host. Invasive aspergillosis develops in severely immunocompromised patients, including those with neutropenia, and increasingly in the non-neutropenic host, including lung transplant recipients, the critically ill patients and patients on steroids. A high index of suspicion is required in patients without the classical risk factors as early presentation is usually silent and non-specific, pyrexia uncommon and timely treatment is crucial for survival. Invasive aspergillosis has also been diagnosed in normal hosts after massive exposure to fungal spores. Chronic pulmonary aspergillosis affects patients without obvious immune compromise, but with an underlying lung condition such as COPD or sarcoidosis, prior or concurrent TB or non-tuberculous mycobacterial disease. Aspergillus bronchitis may be responsible for persistent respiratory symptoms in patients with Aspergillus detected repeatedly in sputum without evidence of parenchymal Aspergillus disease, especially in patients with bronchiectasis and cystic fibrosis. Allergic bronchopulmonary aspergillosis affects patients with asthma and cystic fibrosis, and is important to recognise as permanent lung or airways damage may accrue if untreated. Changes in the classification of Aspergillus allergic lung disease have been proposed recently. Cases of extrinsic allergic alveolitis and chronic pulmonary aspergillosis have been observed after Aspergillus exposure. Asymptomatic colonisation of the respiratory tract needs close monitoring as it can lead to clinical disease especially with ongoing immunosuppression. The various syndromes should be viewed as a semicontinuous spectrum of disease and one form may evolve into another depending on the degree of ongoing immunosuppression.


The role of somatic and germline mutations in aging and a mutation interaction model of aging.
Mutations with a deleterious effect that is expressed after the average reproductive period are not effectively selected against and can accumulate in the germline. A conservative estimate is that at least 1-2% of new deleterious mutations affect some aspect of DNA replication, repair, or chromosome segregation. Since deleterious mutations can have an effect even as heterozygotes, this mutation accumulation can create an inherited background of late-acting mutations that themselves enhance mutation rate. This can have an interactive effect, in that it may increase the rate of somatic mutation during an individual's lifetime. The aging individual therefore becomes increasingly mosaic for somatic mutations, which in turn could potentially contribute to the gradual deterioration of biological processes and influence what we experience as senescence. Interventions that reduce somatic and germ cell mutations should, therefore, reduce the aging process in present and future generations.


Populations of Pacific oysters Crassostrea gigas respond variably to elevated CO2 and predation by Morula marginalba.
Ocean acidification is anticipated to decrease calcification and increase dissolution of shelled molluscs. Molluscs with thinner and weaker shells may be more susceptible to predation, but not all studies have measured negative responses of molluscs to elevated pCO2. Recent studies measuring the response of molluscs have found greater variability at the population level than first expected. Here we investigate the impact of acidification on the predatory whelk Morula marginalba and genetically distinct subpopulations of the Pacific oyster Crassostrea gigas. Whelks and eight family lines of C. gigas were separately exposed to ambient (385 ppm) and elevated (1000 ppm) pCO2 for 6 weeks. Following this period, individuals of M. marginalba were transferred into tanks with oysters at ambient and elevated pCO2 for 17 days. The increase in shell height of the oysters was on average 63% less at elevated compared to ambient pCO2. There were differences in shell compression strength, thickness, and mass among family lines of C. gigas, with sometimes an interaction between pCO2 and family line. Against expectations, this study found increased shell strength in the prey and reduced shell strength in the predator at elevated compared to ambient pCO2. After 10 days, the whelks consumed significantly more oysters regardless of whether C. gigas had been exposed to ambient or elevated CO2, but this was not dependent on the family line and the effect was not significant after 17 days. Our study found an increase in predation after exposure of the predator to predicted near-future levels of estuarine pCO2.


Developing Creativity to Enhance Human Potential in Sport: A Wicked Transdisciplinary Challenge.
The challenge of developing creativity to enhance human potential is conceptualized as a multifaceted wicked problem due to the countless interactions between people and environments that constitute human development, athletic skill, and creative moments. To better comprehend the inter-relatedness of ecologies and human behaviors, there have been increasing calls for transdisciplinary approaches and holistic ecological models. In this paper we explore an ecological dynamics rationale for creativity, highlighting the conceptual adjacency of key concepts from transdisciplinarity, dynamic systems theory, ecological psychology and social-cognitive psychology. Our aim is to extend the scope of ecological dynamics and contextualize the application of non-linear pedagogy in sport. Foregrounding the role of sociocultural constraints on creative behaviors, we characterize the athlete-environment system as an ecological niche that arises from, and simultaneously co-creates, a form of life. We elaborate the notion that creative moments, skill and more generally talent in sport, are not traits possessed by individuals alone, but rather can be conceived as properties of the athlete-environment system shaped by changing constraints. This re-conceptualization supports a pedagogical approach predicated on notions of athletes and sports teams as complex adaptive systems. In such systems, continuous non-linear interactions between system components support the exploration of fluent and flexibly creative performance solutions by athletes and sports teams. The implications for practice suggest that cultivating a constellation of constraints can facilitate adaptive exploration of novel affordances (opportunities/invitation for action), fostering creative moments and supporting creative development in athletes. Future models or frameworks for practice contend that pedagogies should emerge from, and evolve in, interaction with the sociocultural context in which practitioners and athletes are embedded.