Elevated levels of FMRP-target MAP1B impair human and mouse neuronal development and mouse social behaviors via autophagy pathway.

Fragile X messenger ribonucleoprotein 1 protein (FMRP) binds many mRNA targets in the brain. The contribution of these targets to fragile X syndrome (FXS) and related autism spectrum disorder (ASD) remains unclear. Here, we show that FMRP deficiency leads to elevated microtubule-associated protein 1B (MAP1B) in developing human and non-human primate cortical neurons. Targeted MAP1B gene activation in healthy human neurons or MAP1B gene triplication in ASD patient-derived neurons inhibit morphological and physiological maturation. Activation of Map1b in adult male mouse prefrontal cortex excitatory neurons impairs social behaviors. We show that elevated MAP1B sequesters components of autophagy and reduces autophagosome formation. Both MAP1B knockdown and autophagy activation rescue deficits of both ASD and FXS patients' neurons and FMRP-deficient neurons in ex vivo human brain tissue. Our study demonstrates conserved FMRP regulation of MAP1B in primate neurons and establishes a causal link between MAP1B elevation and deficits of FXS and ASD.

101 Dothideomycetes genomes: A test case for predicting lifestyles and emergence of pathogens.

Dothideomycetes is the largest class of kingdom Fungi and comprises an incredible diversity of lifestyles, many of which have evolved multiple times. Plant pathogens represent a major ecological niche of the class Dothideomycetes and they are known to infect most major food crops and feedstocks for biomass and biofuel production. Studying the ecology and evolution of Dothideomycetes has significant implications for our fundamental understanding of fungal evolution, their adaptation to stress and host specificity, and practical implications with regard to the effects of climate change and on the food, feed, and livestock elements of the agro-economy. In this study, we present the first large-scale, whole-genome comparison of 101 Dothideomycetes introducing 55 newly sequenced species. The availability of whole-genome data produced a high-confidence phylogeny leading to reclassification of 25 organisms, provided a clearer picture of the relationships among the various families, and indicated that pathogenicity evolved multiple times within this class. We also identified gene family expansions and contractions across the Dothideomycetes phylogeny linked to ecological niches providing insights into genome evolution and adaptation across this group. Using machine-learning methods we classified fungi into lifestyle classes with >95 % accuracy and identified a small number of gene families that positively correlated with these distinctions. This can become a valuable tool for genome-based prediction of species lifestyle, especially for rarely seen and poorly studied species.

Better soils for healthier lives? An econometric assessment of the link between soil nutrients and malnutrition in Sub-Saharan Africa.

Malnutrition, the suboptimal consumption of essential nutrients like zinc, severely affects human health. This burden of malnutrition falls disproportionally heavy on developing countries, directly increasing child mortality and childhood stunting, or reducing people's ability mending diseases. One option to combat malnutrition is to blend missing nutrients in crop fertilizers, thereby increasing crop yields and possibly the nutrient density in harvested crop products, thus enriching crop products destined for human consumption. But, the effectiveness of so-called agronomic fortification remains ill-understood, primarily due to a paucity of field trials. We hypothesize that, if at all this is an effective strategy, there should exist a causal link between malnutrition and natural variation in the quality of soils to begin with. Until now, data limitations prevented the establishment of such a link, but new soil micronutrient maps for Sub-Saharan Africa allow for a detailed assessment. In doing so, we find statistically significant relations between soil nutrients and child mortality, stunting, wasting and underweight. For instance, a simultaneous increase in soil densities of copper, manganese and zinc by one standard deviation reduces child mortality by 4-6 per mille points, but only when malaria pressure is modest. The effects of soil nutrients on health dissipate when malaria pressure increases. Yet, the effects are fairly small in magnitude suggesting that except for a few regions, agronomic fortification is a relatively cost ineffective means to combat malnutrition.

Factors Affecting the Response of Pomegranate Fruit to Alternaria alternata, the Causal Agent of Heart Rot.

Heart rot, caused by Alternaria alternata, is a major pomegranate disease that impacts production worldwide; most fruits in orchards are colonized by A. alternata but, nevertheless, symptoms are apparent on only a small proportion of the colonized fruits. During the years of our previous research it was noticed that within individual orchards, the incidence of pomegranate fruits exhibiting heart rot symptoms was related to the visual appearance of the trees: trees that appeared visually frail bore more diseased fruits than robust trees. Furthermore, it was noticed that the disease responses of different pomegranate accessions and possibly of different variants of the same cultivar varied markedly. The specific objectives of the present study were: (i) to characterize the relationship between the visual appearance of pomegranate plants or individual stems and the incidence of heart rot and their vulnerability to heart rot; and (ii) to elucidate factors affecting the response of pomegranate fruit to A. alternata. Analysis of heart rot incidence in four orchards in 2014 revealed large differences in heart rot incidence among trees growing side by side in the same orchard; these differences were related to the visual appearance of the pomegranate trees. There were significant differences among germination rates of A. alternata spores in juice prepared from asymptomatic fruits originating from these trees, and comparable differences were found among the acidity levels (pH) of the juices. These differences may reflect differences among the physiological responses of pomegranate trees to heart rot. Fruits collected from the pomegranate collection located in Newe Ya'ar, which comprised 95 accessions in 2015 and 110 accessions in 2016, were also examined. There were differences among the acidity levels (pH) of the juices produced from these fruits and among the germination rates of A. alternata spores in the juices. These differences may reflect variances among the genetic responses of pomegranate accessions to heart rot. Results of studying the relationship between the acidity levels of pomegranate juice and the germination rates of A. alternata spores supported the hypothesis that, apart from pH, a compound(s) present in the juice regulates the germination of A. alternata spores in the juice.

Diaporthe diversity and pathogenicity revealed from a broad survey of grapevine diseases in Europe.

Species of Diaporthe are considered important plant pathogens, saprobes, and endophytes on a wide range of plant hosts. Several species are well-known on grapevines, either as agents of pre- or post-harvest infections, including Phomopsis cane and leaf spot, cane bleaching, swelling arm and trunk cankers. In this study we explore the occurrence, diversity and pathogenicity of Diaporthe spp. associated with Vitis vinifera in major grape production areas of Europe and Israel, focusing on nurseries and vineyards. Surveys were conducted in Croatia, Czech Republic, France, Hungary, Israel, Italy, Spain and the UK. A total of 175 Diaporthe strains were isolated from asymptomatic and symptomatic shoots, branches and trunks. A multi-locus phylogeny was established based on five genomic loci (ITS, tef1, cal, his3 and tub2), and the morphological characters of the isolates were determined. Preliminary pathogenicity tests were performed on green grapevine shoots with representative isolates. The most commonly isolated species were D. eres and D. ampelina. Four new Diaporthe species described here as D. bohemiae, D. celeris, D. hispaniae and D. hungariae were found associated with affected vines. Pathogenicity tests revealed D. baccae, D. celeris, D. hispaniae and D. hungariae as pathogens of grapevines. No symptoms were caused by D. bohemiae. This study represents the first report of D. ambigua and D. baccae on grapevines in Europe. The present study improves our understanding of the species associated with several disease symptoms on V. vinifera plants, and provides useful information for effective disease management.

Erratum to: Outcome of HIV-associated lymphoma in a resource-limited setting of Jos, Nigeria.

[This corrects the article DOI: 10.1186/s13027-017-0144-7.].

Outcome of HIV-associated lymphoma in a resource-limited setting of Jos, Nigeria.

BACKGROUND: Lymphoma is a leading cause of cancer-related death among human immunodeficiency virus (HIV)-infected individuals in the current era of potent anti-retroviral therapy (ART). Globally, mortality after HIV-associated lymphoma has profound regional variation. Little is known about HIV-associated lymphoma mortality in Nigeria and other resource-limited setting in sub-Saharan Africa. Therefore, we evaluated the all-cause mortality after lymphoma and associated risk factors including HIV at the Jos University Teaching Hospital (JUTH) Nigeria. METHODS: We conducted a ten-year retrospective cohort study of lymphoma patients managed in JUTH. The main outcome measured was all-cause mortality and HIV infection was the main exposure variable. Overall death rate was estimated using the total number of death events and cumulative follow up time from lymphoma diagnosis to death. Cox proportional hazard regression was used to assess factors associated with mortality after lymphoma diagnosis. RESULTS: Out of 40 lymphoma patients evaluated, 8(20.0%) were HIV positive and 32(80.0%) were HIV negative. After 127.63 person- years of follow-up, there were 16 deaths leading to a crude mortality rate of 40.0 per 100 person-years. The 2-year probability of survival was 30% for HIV-infected patients and 74% for HIV-uninfected. Median survival probability for HIV-infected patients was 2.1 years and 7.6 years for those without HIV. Unadjusted hazard of death was associated with late stage, HR 11.33(95% CI 2.55, 50.26,p = 0.001); low cumulative cycles of chemotherapy, HR 6.43(95% CI 1.80, 22.89,p = 0.004); greater age, HR 5.12(95% CI 1.45,18.08,p = 0.01); presence of comorbidity, HR 3.43(95% CI 1.10,10.78,p = 0.03); and HIV-infection, HR 3.32(95% CI 1.05, 10.51,p = 0.04). In an adjusted model only stage was significantly associated with death, AHR 5.45(1.14-26.06, p = 0.03). CONCLUSION: Our findings suggest that HIV- infection accounted for three times probability of death in lymphoma patients compared to their HIV-uninfected counterparts due to late stage of lymphoma presentation in this population. Also initiation of chemotherapy was associated with lower probability of death among lymphoma patients managed at JUTH, Nigeria. Earlier stage at lymphoma diagnosis and prompt therapeutic intervention is likely to improve survival in these patients. Future research should undertake collaborative studies to obtain comprehensive regional data and identify unique risk factors of poor outcomes among HIV-infected patients with lymphoma in Nigeria.

Management of thyroid eye disease in the United Kingdom: A multi-centre thyroid eye disease audit.

This article aims to provide baseline data and highlight any major deficiencies in the current level of care provided for adult patients with thyroid eye disease (TED). We undertook a prospective, nonrandomized cross-sectional multicenter observational study. During a 3-month period June-August 2014, consecutive adult patients with TED who presented to nominated specialist eye clinics in the United Kingdom, completed a standardized questionnaire. Main outcome measures were: demographics, time from diagnosis to referral to tertiary centre, time from referral to review in specialist eye clinic, management of thyroid dysfunction, radioiodine and provision of steroid prophylaxis, smoking, and TED classification. 91 patients (mean age 47.88 years) were included. Female-to-male ratio was 6:1. Mean time since first symptoms of TED = 27.92 (73.71) months; from first visit to any doctor with symptoms to diagnosis = 9.37 (26.03) months; from hyperthyroidism diagnosis to euthyroidism 12.45 (16.81) months. First, 13% had received radioiodine. All those with active TED received prophylactic steroids. Seven patients who received radioiodine and did not have TED at the time went on to develop it. Then, 60% patients were current or ex-smokers. 63% current smokers had been offered smoking cessation advice. 65% patients had active TED; 4% had sight-threatening TED. A large proportion of patients (54%) were unaware of their thyroid status. Not enough patients are being provided with smoking cessation advice and information on the impact of smoking on TED and control of thyroid function.

Strategies for Human Tumor Virus Discoveries: From Microscopic Observation to Digital Transcriptome Subtraction.

Over 20% of human cancers worldwide are associated with infectious agents, including viruses, bacteria, and parasites. Various methods have been used to identify human tumor viruses, including electron microscopic observations of viral particles, immunologic screening, cDNA library screening, nucleic acid hybridization, consensus PCR, viral DNA array chip, and representational difference analysis. With the Human Genome Project, a large amount of genetic information from humans and other organisms has accumulated over the last decade. Utilizing the available genetic databases, Feng et al. (2007) developed digital transcriptome subtraction (DTS), an in silico method to sequentially subtract human sequences from tissue or cellular transcriptome, and discovered Merkel cell polyomavirus (MCV) from Merkel cell carcinoma. Here, we review the background and methods underlying the human tumor virus discoveries and explain how DTS was developed and used for the discovery of MCV.

Does strabismus surgery improve quality and mood, and what factors influence this?

AimsTo establish the impact of adult strabismus surgery on clinical and psychosocial well-being and determine who experiences the greatest benefit from surgery and how one could intervene to improve quality of life post-surgery.MethodsA longitudinal study, with measurements taken pre-surgery and at 3 and 6 months post-surgery. All participants completed the AS-20 a disease specific quality of life scale, along with measures of mood, strabismus and appearance-related beliefs and cognitions and perceived social support. Participants also underwent a full orthoptic assessment at their preoperative visit and again 3 months postoperatively. Clinical outcomes of surgery were classified as success, partial success or failure, using the largest angle of deviation, diplopia and requirement for further therapy.Results210 participants took part in the study. Strabismus surgery led to statistically significant improvements in psychosocial and functional quality of life. Those whose surgery was deemed a partial success did however experience a deterioration in quality of life. A combination of clinical variables, high expectations, and negative beliefs about the illness and appearance pre-surgery were significant predictors of change in quality of life from pre- to post-surgery.ConclusionsStrabismus surgery leads to significant improvements in quality of life up to 6 months postoperatively. There are however a group of patients who do not experience these benefits. A series of clinical and psychosocial factors have now been identified, which will enable clinicians to identify patients who may be vulnerable to poorer outcomes post-surgery and allow for the development of interventions to improve quality of life after surgery.

Which factors are associated with quality of life in patients with Graves' orbitopathy presenting for orbital decompression surgery?

PURPOSE: Graves' orbitopathy (GO) is associated with changes in the appearance of the eyes and visual dysfunction. Patients report feeling socially isolated and unable to continue with day-to-day activities. This study aimed at investigating the demographic, clinical, and psychosocial factors associated with quality of life in patients presenting for orbital decompression surgery. METHODS: One-hundred and twenty-three adults with GO due for orbital decompression at Moorfields Eye Hospital London were recruited prospectively. Clinical measures including treatment history, exophthalmos, optic neuropathy, and diplopia were taken by an ophthalmologist. Participants completed psychosocial questionnaires, including the Graves' Ophthalmopathy Quality of Life Scale (GO-QOL), the Hospital Anxiety and Depression Scale, and the Derriford Appearance Scale. Hierarchical multiple regression analyses were used to identify predictors of quality of life. RESULTS: Higher levels of potential cases of clinical anxiety (37%) and depression (26%) were found in this study sample than in patients with other chronic diseases or facial disfigurements. A total of 55% of the variance in GO-QOL visual function scores was explained by the regression model; age, asymmetrical GO and depressed mood were significant unique contributors. In all, 75% of the variance in GO-QOL appearance scores was explained by the regression model; gender, appearance-related cognitions and depressed mood were significant unique contributors. CONCLUSION: Appearance-related quality of life and mood were particularly affected in this sample. Predominantly psychosocial characteristics were associated with quality of life. It is important when planning surgery for patients that clinicians be aware of factors that could potentially influence outcomes.

First Report of Internal Black Rot Caused by Neoscytalidium dimidiatum on Hylocereus undatus (Pitahaya) Fruit in Israel.

Pitahaya (Hylocereus undatus [Haw.] Britton & Rose) was introduced to Israel in 1994, and is grown throughout the country. In the summer of 2009, fruit with internal black rot was collected from a field in central Israel. Symptomatic tissue from the black rot was placed on potato dextrose agar (PDA) plates amended with 12 µg/ml tetracycline and incubated at 25°C for 3 days. A dark, gray to black, fast-growing fungus was isolated from all samples (10 fruits). For identification, single-spore cultures were grown on PDA at 25°C for 5 days, and colonies with gray to black, wooly mycelium were formed. The mycelia were branched and septate (4 to 8 µm wide). The arthroconidia were dark brown, thick-walled, and one-celled, 6.3 to 14.2 × 2.0 to 4.5 µm (n = 5), and ovate to rectangular. Based on these characteristics, the fungus was identified as Neoscytalidium dimidiatum (Penz.) Crous & Slippers (1). The internal transcribed spacer (ITS) region of rDNA and ß-tubulin gene were amplified using ITS1 and ITS4, T121 (2), and Bt1b (3) primers, respectively, and then sequenced (GenBank Accessions KF000372 and KF020895, respectively). Both sequences were identical to sequences previously deposited in GenBank. The ITS (561 bp) and ß-tubulin (488 bp) sequences exhibited 99% and 100% identity, and 100% and 84% coverage, respectively, to N. dimidiatum (JX524168 and FM211185, respectively). Thus, the results of the molecular identifications confirmed the morphological characterization. To establish fungal pathogenicity and the mechanism of infection, 60 flowers in a disease-free orchard were marked to form three different treatments (15 flowers per treatment): inoculations of the flower tube by inserting PDA plugs (0.5 × 0.5 cm) from a 5-day-old culture to the base of the flower, inoculations of the flower stigma by placing the fungus plug on intact, or pre-wounded flower stigma. The wounds were made by scratching the stigma with a sterile scalpel. For each treatment, five additional flowers were used as negative controls in which the PDA plugs did not contain any fungus. All flowers were hand-pollinated and left to grow for a month until the fruit had ripened. Only flowers inoculated by insertion of the fungus into the flower tube developed black rot in the fruit (8 of 15 fruit) 3 to 4 weeks post inoculation, suggesting involvement of the flower tube in the mechanism of infection. All other treatments and controls failed to develop any detectable disease symptoms. N. dimidiatum was reisolated from the rot, fulfilling Koch's postulates. Flowers with wounded stigma developed significantly smaller fruit. Interestingly, diseased fruit changed color about a week before ripening from the flower opening downwards, whereas healthy fruit changed color from the attachment point to the stem upwards. These results indicate that N. dimidiatum is the pathogen of pitahaya internal black rot disease. Recently, this pathogen was reported to cause brown spot disease and stem canker disease of pitahaya in China (4) and Taiwan (5), respectively. To date, the disease can be detected in all orchards in Israel, with up to 50% of the fruit being infected. Since the disease symptoms of the Israeli isolate are located in the fruit, the commercial loss due to pathogen attack is significant. To our knowledge, this is the first report of internal black rot caused by N. dimidiatum on pitahaya fruit in Israel. References: (1) P. W. Crous et al. Stud. Mycol. 55:235, 2006. (2) K. O'Donnell and E. Cigelnik. Mol. Phylo, Evol. 7:103, 1997. (3) N. L. Glass and G. C. Donaldson. Appl. Environ. Microiol. 61:1323, 1995. (4) G. B. Lan and Z. F. He. Plant Dis. 96:1702, 2012. (5) M. F. Chuang et al. Plant Dis. 96:906, 2012.

Mechanisms and management of vision loss following orbital and facial trauma.

PURPOSE OF REVIEW: To examine the proposed mechanisms of vision-threatening injuries occurring secondary to orbital and facial trauma: traumatic optic neuropathy (TON), retrobulbar haemorrhage (RBH) and penetrating eye injury. To evaluate the evidence supporting different management options for traumatic vision-threatening injury. RECENT FINDINGS: Despite considerable debate over the roles of surgical decompression and systemic steroid therapy for TON, these interventions have not been proved to be more effective than conservative management and there is limited evidence that the use of steroids may be associated with an adverse outcome. Lateral canthotomy and inferior cantholysis have been proven to be effective treatments for RBH. Orbital exploration and surgical evacuation of haematoma remains a second line intervention. Open globe injuries require immediate primary surgical exploration and repair. Irretrievable devastating globe injuries require either enucleation or evisceration. There is no consensus as to which is the best treatment with recent surveys indicating that enucleation is preferred in the USA and evisceration in the United Kingdom. SUMMARY: Conservative management is the first line treatment for TON. The evidence strongly supports lateral canthotomy and inferior cantholysis as best treatment for RBH. There is no consensus as to whether enucleation or evisceration is the best treatment for irretrievable devastating globe injury. The choice of management is currently determined by surgeon preference.

Appearance concerns in ophthalmic patients.

AIMS: This study aimed to determine the psychosocial and appearance-related concerns of a sample of ophthalmic patients by measuring a range of psychological, social, and demographic factors. METHODS: Standardized psychological measures including anxiety, depression, appearance-related distress, self-discrepancy, appearance salience and valence were administered to 98 participants attending ophthalmic outpatient clinics in either London, Bristol, Sheffield or Bradford. Differences between groups were explored using t-tests and ANOVA, relationships between all variables were investigated using Pearson's correlation coefficient. RESULTS: Although mean scores for psychological adjustment were within the normal range, some participants were experiencing considerable levels of generalized anxiety. Being older, male, and married or living with a partner was related to significantly better adjustment. Better adjustment was also related to a less visible area of concern, greater disguisability of the affected area, a more positive evaluation of their own appearance, less engagement in comparing themselves with others, greater feelings of being accepted by others, appearance being less important to their self-concept, and a smaller discrepancy between the persons ideal and actual appearance. CONCLUSIONS: A majority of ophthalmic patients adjust positively to the demands placed on them. By identifying the variables that are associated with successful adaptation, the specific psychological interventions and appropriate systems of support can be put in place to help those who are adversely affected.

Infectious agents in cutaneous T-cell lymphoma.

Infectious agents have long been suspected as potential causative agents in cutaneous T-cell lymphoma (CTCL). Tissues of patients with CTCL have been evaluated for evidence of infection with a number of agents, including Staphylococcus aureus, retroviruses, and herpesviruses. These studies have failed to reveal a consistent association of CTCL with investigated agents. However, there is substantial evidence suggesting a potential role of a yet unidentified virus in CTCL. This article will review the findings of studies exploring potential roles of infectious agents in CTCL. In addition, we investigated CTCL tissues for evidence of infection with Merkel cell polyomavirus, a novel polyomavirus that was recently discovered as a probable carcinogenic agent in Merkel cell carcinoma. Cutaneous lesions demonstrating mycosis fungoides were stained with a monoclonal antibody against the Merkel cell polyomavirus T antigen, along with appropriate positive and negative controls. Immunohistochemical stains produced negative results in all examined mycosis fungoides specimens. These findings, which suggest a lack of association of CTCL with Merkel cell polyomavirus, add to the current body of knowledge regarding infectious agents and CTCL.

Cutaneous reactions to epidermal growth factor receptor inhibitors.

Cutaneous toxicities are the most common adverse effects of antineoplastic therapy with epidermal growth factor receptor (EGFR) inhibitors. Skin reactions to this class of agents usually present as papular and/or pustular follicular eruptions developing within two weeks of treatment onset. Other manifestations include generalized xerosis and pruritus, as well as abnormalities of the hair and nails. For most EGFR inhibitors, the incidence and severity of cutaneous toxicity are associated with clinical benefit. At the same time, cutaneous toxic effects may detract substantially from health-related quality of life, leading to interruption, discontinuation or dose reduction of EGFR inhibitor therapy in significantly affected patients. Current recommendations for treatment of EGFR inhibitor-induced eruptions are based primarily on anecdotal evidence from published case series and physicians' own experiences, and include antibiotics, corticosteroids and retinoids. Randomized controlled trials are needed to enable the development of evidence-based paradigms for the treatment of EGFR inhibitor-induced skin eruptions.