A deep learning method for replicate-based analysis of chromosome conformation contacts using Siamese neural networks.

The organisation of the genome in nuclear space is an important frontier of biology. Chromosome conformation capture methods such as Hi-C and Micro-C produce genome-wide chromatin contact maps that provide rich data containing quantitative and qualitative information about genome architecture. Most conventional approaches to genome-wide chromosome conformation capture data are limited to the analysis of pre-defined features, and may therefore miss important biological information. One constraint is that biologically important features can be masked by high levels of technical noise in the data. Here we introduce a replicate-based method for deep learning from chromatin conformation contact maps. Using a Siamese network configuration our approach learns to distinguish technical noise from biological variation and outperforms image similarity metrics across a range of biological systems. The features extracted from Hi-C maps after perturbation of cohesin and CTCF reflect the distinct biological functions of cohesin and CTCF in the formation of domains and boundaries, respectively. The learnt distance metrics are biologically meaningful, as they mirror the density of cohesin and CTCF binding. These properties make our method a powerful tool for the exploration of chromosome conformation capture data, such as Hi-C capture Hi-C, and Micro-C.

Integrative genomic analyses in adipocytes implicate DNA methylation in human obesity and diabetes.

DNA methylation variations are prevalent in human obesity but evidence of a causative role in disease pathogenesis is limited. Here, we combine epigenome-wide association and integrative genomics to investigate the impact of adipocyte DNA methylation variations in human obesity. We discover extensive DNA methylation changes that are robustly associated with obesity (N = 190 samples, 691 loci in subcutaneous and 173 loci in visceral adipocytes, P < 1 × 10-7). We connect obesity-associated methylation variations to transcriptomic changes at >500 target genes, and identify putative methylation-transcription factor interactions. Through Mendelian Randomisation, we infer causal effects of methylation on obesity and obesity-induced metabolic disturbances at 59 independent loci. Targeted methylation sequencing, CRISPR-activation and gene silencing in adipocytes, further identifies regional methylation variations, underlying regulatory elements and novel cellular metabolic effects. Our results indicate DNA methylation is an important determinant of human obesity and its metabolic complications, and reveal mechanisms through which altered methylation may impact adipocyte functions.

Chromatin jets define the properties of cohesin-driven in vivo loop extrusion.

Complex genomes show intricate organization in three-dimensional (3D) nuclear space. Current models posit that cohesin extrudes loops to form self-interacting domains delimited by the DNA binding protein CTCF. Here, we describe and quantitatively characterize cohesin-propelled, jet-like chromatin contacts as landmarks of loop extrusion in quiescent mammalian lymphocytes. Experimental observations and polymer simulations indicate that narrow origins of loop extrusion favor jet formation. Unless constrained by CTCF, jets propagate symmetrically for 1-2 Mb, providing an estimate for the range of in vivo loop extrusion. Asymmetric CTCF binding deflects the angle of jet propagation as experimental evidence that cohesin-mediated loop extrusion can switch from bi- to unidirectional and is controlled independently in both directions. These data offer new insights into the physiological behavior of in vivo cohesin-mediated loop extrusion and further our understanding of the principles that underlie genome organization.

Training to Improve Pro-Agility Performance: A Systematic Review.

Effective directional change in sport is imperative to success in key game situations. Change of direction (COD) ability is underpinned by various athletic qualities which can be developed through specific and non-specific training methods. This review examined the effect of specific and non-specific training methods on pro-agility performance, by analysing the intervention type and resulting magnitude of training effects on pro-agility shuttle performance. A total of 20 studies were included for review. Data from 638 subjects and 29 intervention groups involving seven different training methods were extracted and analysed in relation to training method classification and primary outcome measures. Interventions involving sprint training, plyometric training, resistance training, and combined resistance, plyometric, and sprint training were found to produce statistically significant positive change on pro-agility performance per session (p < 0.05). Sprint training (0.108 ES), plyometric training (0.092 ES), resistance training (0.087 ES), and combined resistance, plyometric, and sprint training (0.078 ES) methods were found to have the highest per session training effect. While total time is the typical unit of measure for this test, different types of training may lead to preferential improvements in either acceleration, deceleration, or COD phases of the pro-agility shuttle. Specifically, resisted or inclined sprinting may develop the linear acceleration phases, unilateral resistance training may promote increased strength to overcome the imposed forces during the deceleration and COD phases, multiplanar plyometrics can help enhance stretch-shortening cycle capabilities across different force vectors, and a combination of two or more of these methods may enable simultaneous development of each of these qualities.

Safety and effectiveness of amoxicillin in the treatment of inflammatory acne.

Acne is a common skin disease that predominantly affects teenagers and young adults. Systemic antibiotic therapy, including tetracyclines, macrolides, and trimethoprim-sulfamethoxazole, is indicated in moderate-to-severe inflammatory disease. However, in certain cases, these antibiotics and other commonly prescribed treatments including oral contraceptives, spironolactone, and isotretinoin may be prohibited, especially in cases of pregnancy and drug intolerance. In this retrospective study, we assessed the safety and efficacy of systemic amoxicillin, which has a favorable tolerability profile and compatibility with pregnancy in the treatment of inflammatory acne.

Conserved non-coding elements: developmental gene regulation meets genome organization.

Comparative genomics has revealed a class of non-protein-coding genomic sequences that display an extraordinary degree of conservation between two or more organisms, regularly exceeding that found within protein-coding exons. These elements, collectively referred to as conserved non-coding elements (CNEs), are non-randomly distributed across chromosomes and tend to cluster in the vicinity of genes with regulatory roles in multicellular development and differentiation. CNEs are organized into functional ensembles called genomic regulatory blocks-dense clusters of elements that collectively coordinate the expression of shared target genes, and whose span in many cases coincides with topologically associated domains. CNEs display sequence properties that set them apart from other sequences under constraint, and have recently been proposed as useful markers for the reconstruction of the evolutionary history of organisms. Disruption of several of these elements is known to contribute to diseases linked with development, and cancer. The emergence, evolutionary dynamics and functions of CNEs still remain poorly understood, and new approaches are required to enable comprehensive CNE identification and characterization. Here, we review current knowledge and identify challenges that need to be tackled to resolve the impasse in understanding extreme non-coding conservation.

Spironolactone for the treatment of acne in women, a retrospective study of 110 patients.

BACKGROUND: There is limited evidence on the safety and efficacy of spironolactone in the treatment of women with acne. Thus, for many dermatologists spironolactone remains an alternative rather than a mainstay treatment for female patients with acne. METHODS: An electronic medical records search tool was used to select data from a group of women who received spironolactone to treat acne and were evaluated with the comprehensive acne severity scale (CASS) before treatment and at all follow-up visits. Data points were collected for CASS scores at each follow-up visit, concurrent and previous treatments, and side effects. These data points were used to draw conclusions about the safety and efficacy of spironolactone in this patient population. RESULTS: There were 110 patients that met all eligibility requirements. Of these, 94 patients saw an improvement in their CASS score and 61 patients completely cleared their score to 0. There were 16 patients who did not improve and six who relapsed after initial improvement. The women saw an average improvement in their acne by 73.1% for the face, 75.9% for the chest, and 77.6% for the back. Fifty-one women experienced side effects, but only six found them bothersome enough to stop taking spironolactone. CONCLUSION: A majority of women in this study saw a dramatic improvement in their acne while treated with spironolactone. There were low rates of relapse or discontinuation of the medication. To further promote the use of spironolactone as a first-line systemic treatment for women with acne, there must be more prospective controlled trials.

Metarhizium anisopliae pathogenesis of mosquito larvae: a verdict of accidental death.

Metarhizium anisopliae, a fungal pathogen of terrestrial arthropods, kills the aquatic larvae of Aedes aegypti, the vector of dengue and yellow fever. The fungus kills without adhering to the host cuticle. Ingested conidia also fail to germinate and are expelled in fecal pellets. This study investigates the mechanism by which this fungus adapted to terrestrial hosts kills aquatic mosquito larvae. Genes associated with the M. anisopliae early pathogenic response (proteinases Pr1 and Pr2, and adhesins, Mad1 and Mad2) are upregulated in the presence of larvae, but the established infection process observed in terrestrial hosts does not progress and insecticidal destruxins were not detected. Protease inhibitors reduce larval mortality indicating the importance of proteases in the host interaction. The Ae. aegypti immune response to M. anisopliae appears limited, whilst the oxidative stress response gene encoding for thiol peroxidase is upregulated. Cecropin and Hsp70 genes are downregulated as larval death occurs, and insect mortality appears to be linked to autolysis through caspase activity regulated by Hsp70 and inhibited, in infected larvae, by protease inhibitors. Evidence is presented that a traditional host-pathogen response does not occur as the species have not evolved to interact. M. anisopliae retains pre-formed pathogenic determinants which mediate host mortality, but unlike true aquatic fungal pathogens, does not recognise and colonise the larval host.

Perceptions of risk factors of cardiovascular disease and cardiac rehabilitation: a cross-sectional study targeting the Chinese population in the Midlands, UK.

OBJECTIVES: To find out and explore the knowledge and opinion of Chinese people on cardiovascular disease and awareness of cardiac rehabilitation. DESIGN: A cross-sectional study using 14-item bilingual (Chinese and English) questionnaires that include information on demographics, health status, cardiovascular disease related knowledge and perception, and awareness and understanding of the cardiac rehabilitation programme. SETTING: Chinese community groups in the Midlands, UK from January to April 2008. PARTICIPANTS: 436 questionnaires from Chinese adults over 18 were obtained. MAIN OUTCOME MEASURES: Current knowledge and attitude towards cardiovascular disease and awareness of cardiac rehabilitation. RESULTS: Obesity was the most common risk factor identified by 80.7% of participants. Those originated from China had significantly less knowledge compared with subjects from other countries (p<0.001). People who have had exposure or experience of cardiac disease rated a higher risk of cardiac disease for Chinese living in the UK than people without experience. A majority (81.7%) used orthodox medicine and perceived it to be most effective against cardiac disease. Only 30% of participants were aware of cardiac rehabilitation. CONCLUSION: The coronary artery disease (CAD) risk factors of Chinese population have increased significantly in the last decade. Cardiac rehabilitation awareness was poor among the sample population of this study and language barrier is still a problem. More large studies on Chinese population assessing CAD risk should be done to provide more evidence on CAD prevention for this growing population in the Western world.

Differential improvements in lipid profiles and Framingham recurrent risk score in patients with and without diabetes mellitus undergoing long-term cardiac rehabilitation.

OBJECTIVE: To determine whether lipid profiles and recurrent coronary heart disease (CHD) risk could be modified in patients with and without diabetes mellitus undergoing long-term cardiac rehabilitation (CR). DESIGN: Retrospective analysis of patient case records. SETTING: Community-based phase 4 CR program. PARTICIPANTS: Patients without diabetes (n=154; 89% men; mean ± SD age, 59.6 ± 8.5y; body mass index [BMI], 27.0 ± 3.5 kg/m²) and patients with diabetes (n=20; 81% men; mean age, 63.0 ± 8.7y; BMI, 28.7 ± 3.3 kg/m²) who completed 15 months of CR. INTERVENTIONS: Exercise testing and training, risk profiling, and risk-factor education. MAIN OUTCOME MEASURES: Cardiometabolic risk factors and 2- to 4-year Framingham recurrent CHD risk scores were assessed. RESULTS: At follow up, a significant main effect for time was evident for decreased body mass and waist circumference and improved low-density lipoprotein cholesterol (LDL-C) level and submaximal cardiorespiratory fitness (all P<.05), showing the benefits of CR in both groups. However, a significant group-by-time interaction effect was evident for high-density lipoprotein cholesterol (HDL-C) level and total cholesterol (TC)/HDL-C ratio (both P<.05). TC/HDL-C ratio improved (5.0 ± 1.5 to 4.4 ± 1.3) in patients without diabetes, but showed no improvement in patients with diabetes (4.8 ± 1.6 v 4.9 ± 1.6). CONCLUSIONS: We showed that numerous anthropometric, submaximal fitness, and cardiometabolic risk variables (especially LDL-C level) improved significantly after long-term CR. However, some aspects of cardiometabolic risk (measures incorporating TC and HDL-C) improved significantly in only the nondiabetic group.

Ratiometric analysis of subcellular recruitment of Fc receptors during phagocytosis.

Numerous immune receptors have the ability to mediate phagocytosis of large particles by triggering dynamic local rearrangement of the cytoskeleton and cell membrane. Different receptors can be differentially recruited to sites of particle binding, which in turn can have important functional consequences with respect to engulfment and downstream signaling. Using Fcγ receptor-mediated phagocytosis of IgG-coated particles as a model, we describe a method for analyzing nascent phagocytic cups and quantifying relative receptor levels at sites of phagocytosis. This technique is based on a ratiometric analysis of subcellular localization of exogenously expressed receptors carrying different fluorescent protein tags. This approach could be applied more generally to the analysis of surface membrane protein localization in the context of any dynamic cellular process.

Capecitabine induced inflammation of actinic keratoses.

Capecitabine, an oral prodrug of 5-fluorouracil, is a systemic chemotherapeutic agent used in the treatment of metastatic breast and colon cancer. Patients undergoing capecitabine therapy may experience inflammation and irritation of existing actinic keratoses. Oncologists and dermatologists alike should be aware of this side effect.

Topical nitrogen mustard ointment with occlusion for Langerhans' cell histiocytosis of the scalp.

BACKGROUND: Topical nitrogen mustard solution has been used as an effective alternative to corticosteroids for the treatment of cutaneous eruptions of Langerhans' cell histiocytosis (LCH). When used as an ointment under occlusion, nitrogen mustard may still be effective and possess less risk of unwanted side effects. METHODS: A patient with scalp LCH was treated topically with nitrogen mustard ointment 0.01% under occlusion. RESULTS: The lesions cleared in 3 weeks without irritation. CONCLUSION: Topical nitrogen mustard ointment 0.01% under occlusion is a well-tolerated, non-irritating treatment for scalp LCH.

Newer skin signs of systemic disease.

The skin is a well-known reflection of internal disease states. It provides the astute clinician with clues that lead to the diagnosis of systemic illness. While skin disease is rarely life-threatening, serious morbidity and mortality may be avoided by early recognition of subtle cutaneous signs signaling internal problems. The recent literature was reviewed to glean new findings that either added new associations to older syndromes or described completely new diseases. While entire books are written regarding the "Skin Signs of Internal Disease", this article focuses only on the newest of such findings.

Contact dermatitis due to printer's ink in a milk industry employee: case report and review of the allergen paraphenylenediamine.

Paraphenylenediamine is a common cause of occupational dermatoses in hairdressers, metallurgy workers, and others. Hand dermatitis developed in an employee of a milk packaging facility. The employee's hands were exposed to milk cartons embossed with wet printer's ink on a daily basis for 2 years. The worker was evaluated through a history, physical examination, and patch testing with 50 standard allergens. Patch testing revealed a positive reaction to paraphenylenediamine. The hand dermatitis resolved once the patient instituted protective measures. The worker's reaction might represent a delayed-type hypersensitivity reaction to printer's ink that contained this agent. More likely, the inciting agent was some other ingredient of the printer's ink that cross-reacts with paraphenylenediamine.

Aquagenic palmoplantar keratoderma.

Aquagenic palmoplantar keratoderma is an acquired condition characterized by burning and edema limited to the hands after brief immersion in water. The 3 patients described possess a striking similarity to those with transient reactive papulotranslucent acrokeratoderma. All 3 patients manifested the "hand-in-the-bucket" sign, having presented to a physician with a hand immersed in a bucket of water to more promptly demonstrate the physical findings. Aluminum chloride hexahydrate represents a potentially valuable therapeutic option for this unusual condition.

Great cases from the University of Pennsylvania.

New skin diseases are reported yearly. Some well-known conditions may develop unusual manifestations. Other cutaneous findings are simply rare. While patients with such diseases represent only a small fraction of our practice they are an important subset of our experience. Many of these diseases are treatable, pinpoint the discovery of internal disease, or simply allow for a diagnosis and prognosis to be given to a concerned patient who had previously escaped classification. Such cases expand our knowledge and provide excitement to our day. Several patients from whom I have learned the most in the last few years are detailed for your enjoyment.

Imported skin diseases in dermatology.

Millions of afflicted people suffer from conditions which Japanese dermatologists may rarely encounter. Many of our patients travel extensively either as part of work-related business trips or during vacationing. From three to ten percent of travelers experience skin, hair or nail disorders. With worldwide travel heightening exposure to the causative agents, there is an increasing likelihood that a patient with leishmaniasis, Boutonneuse fever, onchocerciasis, loaiasis, dengue fever, cutaneous larva migrans or other recently acquired skin conditions from a far away land will visit your office for diagnosis and treatment. The clinical characteristics, diagnostic tests and therapeutic options for such imported tropical diseases will be discussed.