bluuebunny/crossref_metadata_2025 huggingface dataset:
Educational Gaps in Molecular Diagnostics, Genomics, and Personalized Medicine in Dermatopathology Training: A Survey of U.S. Dermatopathology Fellowship Program Directors
Authors: Torre Kristin , Russomanno Kristen , Ferringer Tammie , Elston Dirk , Murphy Michael J.
Published: May 2017

Background:

Molecular technologies offer clinicians the tools to provide high-quality, cost-effective patient care. We evaluated education focused on molecular diagnostics, genomics, and personalized medicine in dermatopathology fellowship training.

Design:

A 20-question online survey was emailed to all (n = 53) Accreditation Council for Graduate Medical Education (ACGME)-accredited dermatopathology training programs in the United States.

Results:

Thirty-one of 53 program directors responded (response rate = 58%). Molecular training is undertaken in 74% of responding dermatopathology fellowships, with levels of instruction varying among dermatology-based and pathology-based programs. Education differed for dermatology- and pathology-trained fellows in approximately one-fifth (19%) of programs. Almost half (48%) of responding program directors believe that fellows are not currently receiving adequate molecular education, although the majority (97%) expect to incorporate additional instruction in the next 2–5 years. Factors influencing the incorporation of relevant education include perceived clinical utility and Accreditation Council for Graduate Medical Education/residency review committee (RRC) requirements. Potential benefits of molecular education include increased medical knowledge, improved patient care, and promotion of effective communication with other healthcare professionals. More than two-thirds (68%) of responding program directors believe that instruction in molecular technologies should be required in dermatopathology fellowship training.

Conclusions:

Although all responding dermatopathology fellowship program directors agreed that molecular education is important, only a little over half of survey participants believe that their fellows receive adequate instruction. This represents an important educational gap. Discussion among those who oversee fellow education is necessary to best integrate and evaluate teaching of molecular dermatopathology.
Development of glucose-responsive ‘smart’ insulin systems
Authors: Rege Nischay K. , Phillips Nelson F.B. , Weiss Michael A.
Published: May 2017

Purpose of review

The complexity of modern insulin-based therapy for type I and type II diabetes mellitus and the risks associated with excursions in blood–glucose concentration (hyperglycemia and hypoglycemia) have motivated the development of ‘smart insulin’ technologies (glucose-responsive insulin, GRI). Such analogs or delivery systems are entities that provide insulin activity proportional to the glycemic state of the patient without external monitoring by the patient or healthcare provider. The present review describes the relevant historical background to modern GRI technologies and highlights three distinct approaches: coupling of continuous glucose monitoring (CGM) to deliver devices (algorithm-based ‘closed-loop’ systems), glucose-responsive polymer encapsulation of insulin, and molecular modification of insulin itself.

Recent findings

Recent advances in GRI research utilizing each of the three approaches are illustrated; these include newly developed algorithms for CGM-based insulin delivery systems, glucose-sensitive modifications of existing clinical analogs, newly developed hypoxia-sensitive polymer matrices, and polymer-encapsulated, stem-cell-derived pancreatic β cells.

Although GRI technologies have yet to be perfected, the recent advances across several scientific disciplines that are described in this review have provided a path towards their clinical implementation.
Short article: Stool cytomegalovirus polymerase chain reaction for the diagnosis of cytomegalovirus-related gastrointestinal disease
Authors: Prachasitthisak Noparat , Tanpowpong Pornthep , Lertudomphonwanit Chatmanee , Treepongkaruna Suporn , Boonsathorn Sophida , Angkathunyakul Napat , Sornmayura Pattana , Chantratita Wasun
Published: May 2017

Objectives

The diagnosis of cytomegalovirus-related gastrointestinal disease (CMV-GI disease) still requires histopathology, but biopsy is considered invasive. Stool CMV PCR has been reported in adults as an alternative method to diagnose this condition; hence, the results between studies are discrepant. Moreover, no pediatric studies on stool CMV real-time PCR in CMV-GI disease have been carried out. Here, we evaluate the value of stool CMV real-time PCR in detecting CMV-GI disease among immunocompromised children.

Methods

We enrolled immunocompromised patients aged younger than 20 years who presented with gastrointestinal symptoms at a teaching hospital during January 2015–March 2016. Stool samples were analyzed for CMV real-time PCR. All patients underwent esophagogastroduodenoscopy and colonoscopy with mucosal biopsy.

Results

We performed stool CMV real-time PCR in 31 patients, but two could not undergo endoscopy. Therefore, 29 patients were analyzed. Two additional stool samples showed inhibitors that interfere with the PCR testing and were precluded from the final analysis. Among 27 patients, we found CMV-GI disease in seven (26%) patients. The sensitivity, specificity, and accuracy of stool CMV real-time PCR were 71, 85, and 82%, respectively. We also found that all patients with CMV-GI disease had positive plasma CMV real-time PCR (>150 copies/ml). A significant association between stool and plasma CMV real-time PCR was also noted (P<0.001).

Conclusion

Stool CMV real-time PCR may be used as a noninvasive tool in the diagnosis of CMV-GI disease. Plasma CMV real-time PCR shows a significant correlation with stool CMV real-time PCR and also represents high diagnostic values.
Utility of SOFA and Δ-SOFA scores for predicting outcome in critically ill patients from the emergency department
Authors: García-Gigorro Renata , Sáez-de la Fuente Ignacio , Marín Mateos Helena , Andrés-Esteban Eva M. , Sanchez-Izquierdo Jose A. , Montejo-González Juan C.
Published: May 2017

Objective

The condition of critically ill patients in the emergency department (ED) varies from moment to moment. The aims of this study are to quantify sequential organ failure assessment (SOFA) and changes in SOFA scores over time and determine its prognostic impact.

Patients and methods

This is a prospective observational cohort study. We included 269 patients consecutively admitted to the ICU from the ED over 18 months. The SOFA scores at ED admission (ED-SOFA) and ICU admission (ICU-SOFA) were obtained. Relative changes in SOFA scores were calculated as follows: Δ-SOFA=ICU-SOFA−ED-SOFA. Patients were divided into two groups depending on the Δ-SOFA score: (a) Δ-SOFA=0–1; and (b) Δ-SOFA more than or equal to 2.

Results

The median ED-SOFA score was two points (interquartile range: 1–4.5) and the Δ-SOFA score was 2 points (interquartile range: 0–3). The Δ-SOFA score was more powerful (area under the curve: 0.81) than the ED-SOFA score (area under the curve: 0.75) in predicting hospital mortality. Sixteen (6%) patients had a Δ-SOFA score less than 0, 116 (43%) patients had a Δ-SOFA=0–1, and 137 (51%) patients had a Δ-SOFA of at least 2 points. The probability of being alive at hospital discharge was 51 and 86.5% in Δ-SOFA of at least 2 and Δ-SOFA=0–1 groups, respectively (P<0.001). Risk factors for an increase of two or more SOFA points were age, cirrhosis, a diagnosis of sepsis, and a prolonged ED stay.

Conclusion

SOFA and changes in the SOFA score over time are potentially useful tools for risk stratification when applied to critically ill patients admitted to ICUs from the ED.
Celiac Disease Symptom Resolution
Authors: Sansotta Naire , Amirikian Karine , Guandalini Stefano , Jericho Hilary
Published: May 2017

Objective:

The aim of the study was to evaluate the efficacy of the gluten‐free diet (GFD) on gastrointestinal (GI) and extra‐intestinal (EI) symptom resolution and identify predictors for persistence of symptoms in all celiac patients at the University of Chicago.

Methods:

We conducted a retrospective chart review from 2002 to 2015. GI symptoms included abdominal pain, bloating, constipation, diarrhea, failure to thrive/weight loss, nausea, reflux, and vomiting. EI symptoms included abnormal liver enzymes, arthralgia/arthritis, dermatitis herpetiformis, alopecia, fatigue, headache, anemia, stomatitis, myalgia, psychiatric disorders, rashes, seizures, neuropathy, short stature, delayed puberty, osteoporosis, and infertility.

Results:

A total of 554 patients (227 children) with celiac disease (CeD) were included. Abdominal pain, diarrhea and failure to thrive were the most common GI symptoms in children whereas diarrhea, bloating, and abdominal pain were most common in adults. Short stature, fatigue, and headache were the most common EI symptoms in children whereas iron deficiency anemia, fatigue, and headache/psychiatric disorders were most common in adults. Children had significantly higher rates of EI and GI symptom resolution as compared to adults, with greater rates of improvements in GI versus EI symptoms at more than 24 months. Long duration of symptoms, female sex, and non‐adherence to a GFD were the most important significant predictors of failure to clinically improve.

Conclusions:

On a strict GFD, children report greater rates of both GI and EI symptom resolution as compared to adults with greater rates of improvement in GI over EI symptoms. Early recognition of CeD and close attention to diet adherence may help in symptom resolution.
Psychotherapy Technique Related to Changes in Anxiety Symptoms With a Transdiagnostic Sample
Authors: Pitman Seth R. , Hilsenroth Mark J. , Weinberger Joel , Conway Francine , Owen Jesse
Published: May 2017

The current study examined how techniques in a psychodynamic model of therapy (Blagys and Hilsenroth, Clin Psychol Sci Pract. 7, 167–188, 2000) were related to changes in anxiety symptoms across early treatment process among a transdiagnostic sample of patients with primary anxiety disorder, subclinical anxiety disorder, and no anxiety disorder. Secondary analyses examined the use of specific psychodynamic techniques in relation to symptom change. Results revealed that therapists' use of psychodynamic-interpersonal (PI) techniques were significantly and directly related to changes in anxiety symptoms, in line with previous findings (Pitman, Slavin-Mulford, and Hilsenroth, J Nerv Ment Dis. 202, 391–396, 2014). In addition, patients with co-occurring axis I and II disorders demonstrated positive changes in anxiety symptoms regardless of level of PI technique used, whereas patients without co-occurring disorders experienced greater improvement with more PI. Implications for transdiagnostic treatment protocols for anxiety, notably Leichsenring and Salzer's (Psychotherapy 51, 224, 2104) Unified Psychodynamic Protocol for Anxiety Disorders, are discussed in relation to the current findings.
Sugar Price Supports and Taxation
Authors: Dilk Abby , Savaiano Dennis A.
Published: May 2017

Domestic US sugar production has been protected by government policy for the past 82 years, resulting in elevated domestic prices and an estimated annual (2013) $1.4 billion dollar “tax” on consumers. These elevated prices and the simultaneous federal support for domestic corn production have ensured a strong market for high-fructose corn syrup. Americans have dramatically increased their consumption of caloric sweeteners during the same period. Consumption of “empty” calories (ie, foods with low-nutrient/high-caloric density)—sugar and high-fructose corn syrup being the primary sources—is considered by most public health experts to be a key contributing factor to the rise in obesity. There have been substantial efforts to tax sugar-sweetened beverages (SSBs) to both reduce consumption and provide a source of funds for nutrition education, thereby emulating the tobacco tax model. Volume-based SSB taxes levy the tax rate per ounce of liquid, where some are only imposed on beverages with added sugar content exceeding a set threshold. Nonetheless, volume-based taxes have significant limitations in encouraging consumers to reduce their caloric intake due to a lack of transparency at the point of purchase. Thus, it is hypothesized that point-of-purchase, nutrient-specific excise taxes on SSBs would be more effective at reducing sugar consumption. However, all SSB taxes are limited by the possibility that consumers may compensate their decreased intake from SSBs with other high-calorie junk foods. Furthermore, there are no existing studies to provide evidence on how SSB taxes will impact obesity rates in the long term. The paradox of sugar prices is that Americans have paid higher prices for sugar to protect domestic production for more than 80 years, and now, Americans are being asked to pay even more to promote public health. The effective use of sugar taxes should be considered based on their merits in reducing sugar consumption and making available a new source of funds to support nutrition education, not on lobbying efforts by the food industry or sugar and corn producers.
The Safety of Soft Contact Lenses in Children
Authors: Bullimore Mark A.
Published: May 2017

Purpose

There is increasing interest in fitting children with soft contact lenses. This review collates data from a range of studies to estimate the incidence of complications, specifically corneal infiltrative events and microbial keratitis, in patients under the age of 18 years.

Methods

Peer-review papers were identified using PubMed and the Web of Science. A broad range of studies are summarized including large-scale epidemiological studies of contact lens–related complications, hospital-based case series, long- and short-term prospective studies, and multicenter retrospective studies.

Results

Nine prospective studies representing 1800 patient years of wear in 7- to 19-year-olds include safety outcomes. In three large prospective studies representing between 159 and 723 patient years of soft contact lens wear in patients 8 to 14 years, the incidence of corneal infiltrative events is up to 136 per 10,000 years. Data from a large retrospective study show similar rates of corneal infiltrative events: 97 per 10,000 years in 8- to 12-year-olds (based on 411 patient years of wear) and 335 per 10,000 years in 13- to 17-year-olds (based on 1372 patient years of wear). None of the prospective studies report any cases of microbial keratitis. Five clinical studies where safety data are not reported constitute a further 493 patient years. One retrospective study found no cases of microbial keratitis occurred in 8- to 12-year-olds (411 patient years) and an incidence of 15 per 10,000 patient years in 13- to 17-year-olds (1372 patient years)—no higher than the incidence of microbial keratitis in adults wearing soft contact lenses on an overnight basis.

Conclusions

The overall picture is that the incidence of corneal infiltrative events in children is no higher than in adults, and in the youngest age range of 8 to 11 years, it may be markedly lower.
Penis Transplantation
Authors: Cetrulo Curtis L. , Li Kai , Salinas Harry M. , Treiser Matthew D. , Schol Ilse , Barrisford Glen W. , McGovern Francis J. , Feldman Adam S. , Grant Michael T. , Tanrikut Cigdem , Lee Jeffrey H. , Ehrlichman Richard J. , Holzer Paul W. , Choy Garry M. , Liu Raymond W. , Ng Zhi Yang , Lellouch Alexandre G. , Kurtz Josef M. , Austen William G. , Winograd Jonathan M. , Bojovic Branko , Eberlin Kyle R. , Rosales Ivy A. , Colvin Robert B. , Ko Dicken S. C.
Published: May 2017

Objective:

We describe the first successful penis transplant in the United States in a patient with a history of subtotal penectomy for penile cancer.

Background:

Penis transplantation represents a new paradigm in restoring anatomic appearance, urine conduit, and sexual function after genitourinary tissue loss. To date, only 2 penis transplants have been performed worldwide.

Methods:

After institutional review board approval, extensive medical, surgical, and radiological evaluations of the patient were performed. His candidacy was reviewed by a multidisciplinary team of surgeons, physicians, psychiatrists, social workers, and nurse coordinators. After appropriate donor identification and recipient induction with antithymocyte globulin, allograft procurement and recipient preparation took place concurrently. Anastomoses of the urethra, corpora, cavernosal and dorsal arteries, dorsal vein, and dorsal nerves were performed, and also inclusion of a donor skin pedicle as the composite allograft. Maintenance immunosuppression consisted of mycophenolate mofetil, tacrolimus, and methylprednisolone.

Results:

Intraoperative, the allograft had excellent capillary refill and strong Doppler signals after revascularization. Operative reinterventions on postoperative days (PODs) 2 and 13 were required for hematoma evacuation and skin eschar debridement. At 3 weeks, no anastomotic leaks were detected on urethrogram, and the catheter was removed. Steroid resistant-rejection developed on POD 28 (Banff I), progressed by POD 32 (Banff III), and required a repeat course of methylprednisolone and antithymocyte globulin. At 7 months, the patient has recovered partial sensation of the penile shaft and has spontaneous penile tumescence. Our patient reports increased overall health satisfaction, dramatic improvement of self-image, and optimism for the future.

Conclusions:

We have shown that it is feasible to perform penile transplantation with excellent results. Furthermore, this experience demonstrates that penile transplantation can be successfully performed with conventional immunosuppression. We propose that our successful penile transplantation pilot experience represents a proof of concept for an evolution in reconstructive transplantation.
Neuroimaging as a tool to study the sources of phenotypic heterogeneity in Huntington's disease
Authors: Garcia-Gorro Clara , Camara Estela , de Diego-Balaguer Ruth
Published: May 2017

Purpose of review

Huntington's disease is a neurodegenerative disorder characterized by a triad of motor, cognitive and psychiatric disturbances. There is great variability regarding the prominence and evolution of each type of clinical sign. One possible source of phenotypic heterogeneity could be the more prominent degeneration of specific brain circuits. The scope of this review is to highlight the most recent neuroimaging studies that have analysed the relationship between brain changes and motor, cognitive and psychiatric alterations in Huntington's disease.

Recent findings

The results from recent neuroimaging studies are heterogeneous. Although there is a great overlap between the different regions associated with each symptomatic domain, there is some degree of differentiation. For example, the motor network is associated with motor impairment, whereas the ventral striatum is especially involved in emotional deficits related with psychiatric problems.

Motor, cognitive and psychiatric impairments are associated with structural and functional brain biomarkers. However, the specificity of the regions involved remains unknown, because these studies focused on specific regions and symptoms. In order to tease apart the neural substrates that underlie the phenotypic heterogeneity in Huntington's disease, multivariate approaches combining brain and behavioural measures related to all symptomatic domains should be considered in the future.
Spread of competing viruses on heterogeneous networks
Authors: Chen Shanshan , Wang Kaihua , Sun Mengfeng , Fu Xinchu
Published: May 2017

In this paper, we propose a model where two strains compete with each other at the expense of common susceptible individuals on heterogeneous networks by using pair-wise approximation closed by the probability-generating function (PGF). All of the strains obey the susceptible–infected–recovered (SIR) mechanism. From a special perspective, we first study the dynamical behaviour of an SIR model closed by the PGF, and obtain the basic reproduction number via two methods. Then we build a model to study the spreading dynamics of competing viruses and discuss the conditions for the local stability of equilibria, which is different from the condition obtained by using the heterogeneous mean-field approach. Finally, we perform numerical simulations on Barabási–Albert networks to complement our theoretical research, and show some dynamical properties of the model with competing viruses.

This article is part of the themed issue ‘Mathematical methods in medicine: neuroscience, cardiology and pathology’.
Computational design of treatment strategies for proactive therapy on atopic dermatitis using optimal control theory
Authors: Christodoulides Panayiotis , Hirata Yoshito , Domínguez-Hüttinger Elisa , Danby Simon G. , Cork Michael J. , Williams Hywel C. , Aihara Kazuyuki , Tanaka Reiko J.
Published: May 2017

Atopic dermatitis (AD) is a common chronic skin disease characterized by recurrent skin inflammation and a weak skin barrier, and is known to be a precursor to other allergic diseases such as asthma. AD affects up to 25% of children worldwide and the incidence continues to rise. There is still uncertainty about the optimal treatment strategy in terms of choice of treatment, potency, duration and frequency. This study aims to develop a computational method to design optimal treatment strategies for the clinically recommended ‘proactive therapy’ for AD. Proactive therapy aims to prevent recurrent flares once the disease has been brought under initial control. Typically, this is done by using an anti-inflammatory treatment such as a potent topical corticosteroid intensively for a few weeks to ‘get control’, followed by intermittent weekly treatment to suppress subclinical inflammation to ‘keep control’. Using a hybrid mathematical model of AD pathogenesis that we recently proposed, we computationally derived the optimal treatment strategies for individual virtual patient cohorts, by recursively solving optimal control problems using a differential evolution algorithm. Our simulation results suggest that such an approach can inform the design of optimal individualized treatment schedules that include application of topical corticosteroids and emollients, based on the disease status of patients observed on their weekly hospital visits. We demonstrate the potential and the gaps of our approach to be applied to clinical settings.

This article is part of the themed issue ‘Mathematical methods in medicine: neuroscience, cardiology and pathology’.
Dynamics of the cell-mediated immune response to tumour growth
Authors: López Álvaro G. , Seoane Jesús M. , Sanjuán Miguel A. F.
Published: May 2017

Using a hybrid cellular automaton, we investigate the transient and asymptotic dynamics of the cell-mediated immune response to tumour growth. We analyse the correspondence between this dynamics and the three phases of the theory of immunoedition: elimination, equilibrium and escape. Our results demonstrate that the immune system can keep a tumour dormant for long periods of time, but that this dormancy is based on a frail equilibrium between the mechanisms that spur the immune response and the growth of the tumour. Thus, we question the capacity of the cell-mediated immune response to sustain long periods of dormancy, as those appearing in recurrent disease. We suggest that its role might be rather to synergize with other types of tumour dormancy.

This article is part of the themed issue ‘Mathematical methods in medicine: neuroscience, cardiology and pathology’.
Multiscale ordinal network analysis of human cardiac dynamics
Authors: McCullough M. , Small M. , Iu H. H. C. , Stemler T.
Published: May 2017

In this study, we propose a new information theoretic measure to quantify the complexity of biological systems based on time-series data. We demonstrate the potential of our method using two distinct applications to human cardiac dynamics. Firstly, we show that the method clearly discriminates between segments of electrocardiogram records characterized by normal sinus rhythm, ventricular tachycardia and ventricular fibrillation. Secondly, we investigate the multiscale complexity of cardiac dynamics with respect to age in healthy individuals using interbeat interval time series and compare our findings with a previous study which established a link between age and fractal-like long-range correlations. The method we use is an extension of the symbolic mapping procedure originally proposed for permutation entropy. We build a Markov chain of the dynamics based on order patterns in the time series which we call an ordinal network, and from this model compute an intuitive entropic measure of transitional complexity. A discussion of the model parameter space in terms of traditional time delay embedding provides a theoretical basis for our multiscale approach. As an ancillary discussion, we address the practical issue of node aliasing and how this effects ordinal network models of continuous systems from discrete time sampled data, such as interbeat interval time series.

This article is part of the themed issue ‘Mathematical methods in medicine: neuroscience, cardiology and pathology’.
Pulsatile flow in ventricular catheters for hydrocephalus
Authors: Giménez Á. , Galarza M. , Thomale U. , Schuhmann M. U. , Valero J. , Amigó J. M.
Published: May 2017

The obstruction of ventricular catheters (VCs) is a major problem in the standard treatment of hydrocephalus, the flow pattern of the cerebrospinal fluid (CSF) being one important factor thereof. As a first approach to this problem, some of the authors studied previously the CSF flow through VCs under time-independent boundary conditions by means of computational fluid dynamics in three-dimensional models. This allowed us to derive a few basic principles which led to designs with improved flow patterns regarding the obstruction problem. However, the flow of the CSF has actually a pulsatile nature because of the heart beating and blood flow. To address this fact, here we extend our previous computational study to models with oscillatory boundary conditions. The new results will be compared with the results for constant flows and discussed. It turns out that the corrections due to the pulsatility of the CSF are quantitatively small, which reinforces our previous findings and conclusions.

This article is part of the themed issue ‘Mathematical methods in medicine: neuroscience, cardiology and pathology’.
Mathematical methods in medicine: neuroscience, cardiology and pathology
Authors: Amigó José M. , Small Michael
Published: May 2017

The application of mathematics, natural sciences and engineering to medicine is gaining momentum as the mutual benefits of this collaboration become increasingly obvious. This theme issue is intended to highlight the trend in the case of mathematics. Specifically, the scope of this theme issue is to give a general view of the current research in the application of mathematical methods to medicine, as well as to show how mathematics can help in such important aspects as understanding, prediction, treatment and data processing. To this end, three representative specialties have been selected: neuroscience, cardiology and pathology. Concerning the topics, the 12 research papers and one review included in this issue cover biofluids, cardiac and virus dynamics, computational neuroscience, functional magnetic resonance imaging data processing, neural networks, optimization of treatment strategies, time-series analysis and tumour growth. In conclusion, this theme issue contains a collection of fine contributions at the intersection of mathematics and medicine, not as an exercise in applied mathematics but as a multidisciplinary research effort that interests both communities and our society in general.

This article is part of the themed issue ‘Mathematical methods in medicine: neuroscience, cardiology and pathology’.
KKL-35 exhibits potent antibiotic activity againstLegionellaspecies independently of trans-translation inhibition
Authors: Brunel Romain , Descours Ghislaine , Durieux Isabelle , Doublet Patricia , Jarraud Sophie , Charpentier Xavier
Published: May 2017

Trans-translation is a ribosome rescue system that is ubiquitous in bacteria. Small molecules defining a new family of oxadiazole compounds that inhibit trans-translation have been found to have broad-spectrum antibiotic activity. We sought to determine the activity of KKL-35, a potent member of the oxadiazole family, against the human pathogenLegionella pneumophilaand other related species that can also cause Legionnaires disease (LD). Consistent with the essential nature of trans-translation inL. pneumophila, KKL-35 inhibits growth of all tested strains at sub-micromolar concentrations. KKL-35 is also active against other LD-causingLegionellaspecies. KKL-35 remains equally active againstL. pneumophilamutants that have evolved resistance to macrolides. KKL-35 inhibits multiplication ofL. pneumophilain human macrophages at several stages of infection. No resistant mutants could be obtained, even during extended and chronic exposure. Surprisingly, KKL-35 is not synergistic with other ribosome-targeting antibiotics and does not induce the filamentation phenotype observed in cells defective for trans-translation. Importantly, KKL-35 remains active againstL. pneumophilamutants expressing an alternate ribosome-rescue system and lacking tmRNA, the essential component of trans-translation. These results indicate that the antibiotic activity of KKL-35 is not related to the specific inhibition of trans-translation and its mode of action remains to be identified. In conclusion, KKL-35 is an effective antibacterial agent against the intracellular pathogenL. pneumophilaand with no detectable resistance. However, further studies are needed to better understand its mechanism of action and to assess further the potential of oxadiazoles in treatment.
Gene expression variability across cells and species shapes innate immunity
Authors: Hagai Tzachi , Chen Xi , Miragaia Ricardo J , Gomes Tomás , Rostom Raghd , Kunowska Natalia , Proserpio Valentina , Donati Giacomo , Bossini-Castillo Lara , Naamati Guy , Emerton Guy , Trynka Gosia , Kondova Ivanela , Denis Mike , Teichmann Sarah A
Published: May 2017

As the first line of defence against pathogens, cells mount an innate immune response, which is highly variable from cell to cell. The response must be potent yet carefully controlled to avoid self-damage. How these constraints have shaped the evolution of innate immunity remains poorly understood. Here, we characterise this programme’s transcriptional divergence between species and expression variability across cells. Using bulk and single-cell transcriptomics in primate and rodent fibroblasts challenged with an immune stimulus, we reveal a striking architecture of the innate immune response. Rapidly diverging genes, including cytokines and chemokines, also vary across cells and have distinct promoter structures. Conversely, genes involved in response regulation, such as transcription factors and kinases, are conserved between species and display low cell-to-cell variability. We suggest that this unique expression pattern, observed across species and conditions, has evolved as a mechanism for fine-tuned regulation, to achieve an effective but balanced response.
High-quality rice RNA-seq-based co-expression network for predicting gene function and regulation
Authors: Yu Hua , Jiao Bingke , Liang Chengzhi
Published: May 2017

Inferring the genome-scale gene co-expression network is important for understanding genetic architecture underlying the complex and various biological phenotypes. The recent availability of large-scale RNA-seq sequencing-data provides great potential for co-expression network inference. In this study, for the first time, we presented a novel heterogeneous ensemble pipeline integrating three frequently used inference methods, to build a high-quality RNA-seq-based Gene Co-expression Network (GCN) in rice, an important monocot species. The quality of the network obtained by our proposed method was first evaluated and verified with the curated positive and negative gene functional link datasets, which obviously outperformed each single method. Secondly, the powerful capability of this network for associating unknown genes with biological functions and agronomic traits was showed by enrichment analysis and case studies. Particularly, we demonstrated the potential applications of our proposed method to predict the biological roles of long non-coding RNA (lncRNA) and circular RNA (circRNA) genes. Our results provided a valuable data source for selecting candidate genes to further experimental validation during rice genetics research and breeding. To enhance identification of novel genes regulating important biological processes and agronomic traits in rice and other crop species, we released the source code of constructing high-quality RNA-seq-based GCN and rice RNA-seq-based GCN, which can be freely downloaded online athttps://github.com/czllab/NetMiner.
Predicting drug resistance evolution: insights from antimicrobial peptides and antibiotics
Authors: Yu Guozhi , Baeder Desiree Y , Regoes Roland R , Rolff Jens
Published: May 2017

Antibiotic resistance constitutes one of the most pressing public health concerns. Antimicrobial peptides of multicellular organisms are considered part of a solution to this problem, and AMPs produced by bacteria such as colistin are last resort drugs. Importantly, antimicrobial peptides differ from many antibiotics in their pharmacodynamic characteristics. Here we implement these differences within a theoretical framework to predict the evolution of resistance against antimicrobial peptides and compare it to antibiotic resistance. Our analysis of resistance evolution finds that pharmacodynamic differences all combine to produce a much lower probability that resistance will evolve against antimicrobial peptides. The finding can be generalized to all drugs with pharmacodynamics similar to AMPs. Pharmacodynamic concepts are familiar to most practitioners of medical microbiology, and data can be easily obtained for any drug or drug combination. Our theoretical and conceptual framework is therefore widely applicable and can help avoid resistance evolution if implemented in antibiotic stewardship schemes or the rational choice of new drug candidates.
Mitochondrial genetic effects on reproductive success: signatures of positive intra-sexual, but negative inter-sexual pleiotropy
Authors: Camus M. Florencia , Dowling Damian K.
Published: May 2017

Mitochondria contain their own DNA, and numerous studies have reported that genetic variation in this (mt)DNA sequence modifies the expression of life-history phenotypes. Maternal inheritance of mitochondria adds a layer of complexity to trajectories of mtDNA evolution, because theory predicts the accumulation of mtDNA mutations that are male-biased in effect. While it is clear that mitochondrial genomes routinely harbor genetic variation that affects components of reproductive performance, the extent to which this variation is sex-biased, or even sex-specific in effect, remains elusive. This is because nearly all previous studies have failed to examine mitochondrial genetic effects on both male and female reproductive performance within the one-and-the-same study. Here, we show that variation across naturally-occurring mitochondrial haplotypes affects components of reproductive success in both sexes, inDrosophila melanogaster. However, while we uncovered evidence for positive pleiotropy, across haplotypes, in effects on separate components of reproductive success when measured within the same sex, such patterns were not evident across sexes. Rather, we found a pattern of sexual antagonism across haplotypes on some reproductive parameters. This suggests the pool of polymorphisms that delineate global mtDNA haplotypes is likely to have been partly shaped by maternal transmission of mtDNA and its evolutionary consequences.
Regulation of DNA demethylation by the XPC DNA repair complex in somatic and pluripotent stem cells
Authors: Ho Jaclyn J. , Cattoglio Claudia , McSwiggen David T. , Tjian Robert , Fong Yick W.
Published: May 2017

Faithful resetting of the epigenetic memory of a somatic cell to a pluripotent state during cellular reprogramming requires DNA methylation to silence somatic gene expression and dynamic DNA demethylation to activate pluripotency gene transcription. The removal of methylated cytosines requires the base excision repair enzyme TDG, but the mechanism by which TDG-dependent DNA demethylation occurs in a rapid and site-specific manner remains unclear. Here we show that the XPC DNA repair complex is a potent accelerator of global and locus-specific DNA demethylation in somatic and pluripotent stem cells. XPC cooperates with TDG genome-wide to stimulate the turnover of essential intermediates by overcoming slow TDG–abasic product dissociation during active DNA demethylation. We further establish that DNA demethylation induced by XPC expression in somatic cells overcomes an early epigenetic barrier in cellular reprogramming and facilitates the generation of more robust induced pluripotent stem cells, characterized by enhanced pluripotency-associated gene expression and self-renewal capacity. Taken together with our previous studies establishing the XPC complex as a transcriptional coactivator, our findings underscore two distinct but complementary mechanisms by which XPC influences gene regulation by coordinating efficient TDG-mediated DNA demethylation along with active transcription during somatic cell reprogramming.
Focus on cutaneous and uveal melanoma specificities
Authors: Pandiani Charlotte , Béranger Guillaume E. , Leclerc Justine , Ballotti Robert , Bertolotto Corine
Published: May 2017

Cutaneous melanoma (CM) and uveal melanoma (UM) derive from cutaneous and uveal melanocytes that share the same embryonic origin and display the same cellular function. However, the etiopathogenesis and biological behaviors of these melanomas are very different. CM and UM display distinct landscapes of genetic alterations and show different metastatic routes and tropisms. Hence, therapeutic improvements achieved in the last few years for the treatment of CM have failed to ameliorate the clinical outcomes of patients with UM. The scope of this review is to discuss the differences in tumorigenic processes (etiologic factors and genetic alterations) and tumor biology (gene expression and signaling pathways) between CM and UM. We develop hypotheses to explain these differences, which might provide important clues for research avenues and the identification of actionable vulnerabilities suitable for the development of new therapeutic strategies for metastatic UM.
Long-term sensitization training in Aplysia decreases the excitability of a decision-making neuron through a sodium-dependent mechanism
Authors: Hernandez John S. , Wainwright Marcy L. , Mozzachiodi Riccardo
Published: May 2017

In Aplysia, long-term sensitization (LTS) occurs concurrently with a suppression of feeding. At the cellular level, the suppression of feeding is accompanied by decreased excitability of decision-making neuron B51. We examined the contribution of voltage-gated Na+ and K+ channels to B51 decreased excitability. In a pharmacologically isolated Na+ channels environment, LTS training significantly increased B51 firing threshold, compared with untrained controls. Conversely, in a pharmacologically isolated K+ channels environment, no differences were observed between trained and untrained animals in either amplitude or area of B51 K+-dependent depolarizations. These findings suggest that Na+ channels contribute to the decrease in B51 excitability induced by LTS training.
α2* Nicotinic acetylcholine receptors influence hippocampus-dependent learning and memory in adolescent mice
Authors: Lotfipour Shahrdad , Mojica Celina , Nakauchi Sakura , Lipovsek Marcela , Silverstein Sarah , Cushman Jesse , Tirtorahardjo James , Poulos Andrew , Elgoyhen Ana Belén , Sumikawa Katumi , Fanselow Michael S. , Boulter Jim
Published: May 2017

The absence of α2* nicotinic acetylcholine receptors (nAChRs) in oriens lacunosum moleculare (OLM) GABAergic interneurons ablate the facilitation of nicotine-induced hippocampal CA1 long-term potentiation and impair memory. The current study delineated whether genetic mutations of α2* nAChRs (Chrna2L9′S/L9′S and Chrna2KO) influence hippocampus-dependent learning and memory and CA1 synaptic plasticity. We substituted a serine for a leucine (L9′S) in the α2 subunit (encoded by the Chrna2 gene) to make a hypersensitive nAChR. Using a dorsal hippocampus-dependent task of preexposure-dependent contextual fear conditioning, adolescent hypersensitive Chrna2L9′S/L9′S male mice exhibited impaired learning and memory. The deficit was rescued by low-dose nicotine exposure. Electrophysiological studies demonstrated that hypersensitive α2 nAChRs potentiate acetylcholine-induced ion channel flux in oocytes and acute nicotine-induced facilitation of dorsal/intermediate CA1 hippocampal long-term potentiation in Chrna2L9′S/L9′S mice. Adolescent male mice null for the α2 nAChR subunit exhibited a baseline deficit in learning that was not reversed by an acute dose of nicotine. These effects were not influenced by locomotor, sensory or anxiety-related measures. Our results demonstrated that α2* nAChRs influenced hippocampus-dependent learning and memory, as well as nicotine-facilitated CA1 hippocampal synaptic plasticity.
Response-specific sex difference in the retention of fear extinction
Authors: Voulo Meagan E. , Parsons Ryan G.
Published: May 2017

Fear conditioning studies in rodents allow us to assess vulnerability factors which might underlie fear-based psychopathology such as post-traumatic stress disorder (PTSD). Despite PTSD being more prevalent in females than males, very few fear conditioning studies in rodents have tested females. Our study assessed fear conditioning and extinction in male and female rats using both fear-potentiated startle and freezing behavior as measures. Rats were trained to fear cues that predicted the occurrence of shock and then subsequently exposed to an extinction training procedure where the cue was presented repeatedly in the absence of shock. Retention of the extinction memory was assessed the next day. Our results showed that females exhibited less retention of fear extinction, but only when measured by fear-potentiated startle. Our results highlight the importance of using multiple indices of fear behavior, particularly when comparing sexes on measures of extinction learning.
Epitaxial Ni nanoparticles on CaF2(001), (110) and (111) surfaces studied by three-dimensional RHEED, GIXD and GISAXS reciprocal-space mapping techniques
Authors: Suturin S. M. , Fedorov V. V. , Korovin A. M. , Sokolov N. S. , Nashchekin A. V. , Tabuchi M.
Published: May 2017

The development of growth techniques aimed at the fabrication of nanoscale heterostructures with layers of ferroic 3d metals on semiconductor substrates is very important for their potential usage in magnetic media recording applications. A structural study is presented of single-crystal nickel island ensembles grown epitaxially on top of CaF2/Si insulator-on-semiconductor heteroepitaxial substrates with (111), (110) and (001) fluorite surface orientations. The CaF2 buffer layer in the studied multilayer system prevents the formation of nickel silicide, guides the nucleation of nickel islands and serves as an insulating layer in a potential tunneling spin injection device. The present study, employing both direct-space and reciprocal-space techniques, is a continuation of earlier research on ferromagnetic 3d transition metals grown epitaxially on non-magnetic and magnetically ordered fluorides. It is demonstrated that arrays of stand-alone faceted nickel islands with a face-centered cubic lattice can be grown controllably on CaF2 surfaces of (111), (110) and (001) orientations. The proposed two-stage nickel growth technique employs deposition of a thin seeding layer at low temperature followed by formation of the islands at high temperature. The application of an advanced three-dimensional mapping technique exploiting reflection high-energy electron diffraction (RHEED) has proved that the nickel islands tend to inherit the lattice orientation of the underlying fluorite layer, though they exhibit a certain amount of {111} twinning. As shown by scanning electron microscopy, grazing-incidence X-ray diffraction (GIXD) and grazing-incidence small-angle X-ray scattering (GISAXS), the islands are of similar shape, being faceted with {111} and {100} planes. The results obtained are compared with those from earlier studies of Co/CaF2 epitaxial nanoparticles, with special attention paid to the peculiarities related to the differences in lattice structure of the deposited metals: the dual-phase hexagonal close-packed/face-centered cubic lattice structure of cobalt as opposed to the single-phase face-centered cubic lattice structure of nickel.
Synthesis and crystal structures of a 3-acetylated (20S,24S)-ocotillol-type saponin and its C-24 epimer
Authors: Liu Juan , Xu Yang-Rong , An Xing-Si , Hou Gui-Ge , Meng Qing-Guo
Published: May 2017

In order to study the in vivo protective effect on myocardial ischemia, (20S,24R)-epoxydammarane-12β,25-diol, (V), and (20S,24S)-epoxydammarane-12β,25-diol, (VI), were synthesized through a novel synthetic route. Two key intermediates, namely (20S,24R)-3-acetyl-20,24-epoxydammarane-3β,12β,25-triol, (III) [obtained as the hemihydrate, C32H54O5·0.5H2O, (IIIa), and the ethanol hemisolvate, C32H54O5·0.5C2H5OH, (IIIb), with identical conformations but different crystal packings], and (20S,24S)-3-acetyl-20,24-epoxydammarane-3β,12β,25-triol, C32H54O5, (IV), were obtained during the synthesis. The structures were confirmed by 1H NMR, 13C NMR and HRMS analyses, and single-crystal X-ray diffraction. Molecules of (IIIa) are extended into a two-dimensional network constructed with water molecules linked alternately through intermolecular O—H...O hydrogen bonds, which are further stacked into a three-dimensional network. Compound (IIIb) contains two completely asymmetric molecules, which are linked in a disordered manner through intermolecular C—H...O hydrogen bonds. While the crystal stacks in compound (IV) are linked via weak C—H...O hydrogen bonds, the hydrogen-bonded chains extend helically along the crystallographic b axis.
Optical properties of (Z)-2-(2-phenylhydrazinylidene)acenaphthen-1(2H)-one: a potential electron donor in organic solar cells
Authors: Su Yan-Xiao , Zhang Chao-Zhi , Song Ming-Xia
Published: May 2017

Electron-donating molecules play an important role in the development of organic solar cells. (Z)-2-(2-Phenylhydrazinylidene)acenaphthen-1(2H)-one (PDAK), C18H12N2O, was synthesized by a Schiff base reaction. The crystal structure shows that the molecules are planar and are linked together forming `face-to-face' assemblies held together by intermolecular C—H...O, π–π and C—H...π interactions. PDAK exhibits a broadband UV–Vis absorption (200–648 nm) and a low HOMO–LUMO energy gap (1.91 eV; HOMO is the highest occupied molecular orbital and LUMO is the lowest unoccupied molecular orbital), while fluorescence quenching experiments provide evidence for electron transfer from the excited state of PDAK to C60. This suggests that the title molecule may be a suitable donor for use in organic solar cells.
2-(1-Hexyl-2-oxo-2,3-dihydro-1H-indol-3-ylidene)propanedinitrile
Authors: Rayni Ibtissam , El Bakri Youness , Sebhaoui Jihad , El Bourakadi Khadija , Essassi El Mokhtar , Mague Joel T.
Published: May 2017

In the title compound, C17H17N3O, the indolone ring system is almost planar, with an angle of 0.76 (14)° between the five- and six-membered rings. The dicyanomethylidene substituent lies close to the indolene plane. In the crystal, offset π-stacking interactions between five- and six-membered rings of indolene stack the molecules along thec-axis direction.