bluuebunny/crossref_metadata_2025 huggingface dataset:
An Unusual Presentation of Pyemotes ventricosus Dermatitis Presenting With Umbilicated Papules Mimicking Poxvirus Infection
Authors: Henning Ania , Torok Helen , Weaver Joshua
Published: June 2019

Pyemotes ventricosus mites are an uncommon cause of pruritic dermatitis seen most commonly in occupational exposure, prominently found in professionals such as farmers, landscapers, and factory workers who work with grains, wheat, dried beans, or grasses. The clinical description of the rash has typically been described as papular, erythematous, with a central vesicular lesion. We describe a case of Pyemotes dermatitis with an atypical clinical presentation. A 30-year-old man presented with pruritic, umbilicated papules, which involved his right lateral trunk and upper thigh leading to the submitted clinical impression of molloscum contagiosum. A biopsy of the skin was taken, and fragments of arthropod consistent with P. ventricosus were identified within umbilicated indentations of skin. The patient subsequently admitted to the onset of the rash immediately after carrying bales of straw while supporting each bale with his right side. The possibility of Pyemotes dermatitis mimicking a poxvirus–like eruption should be considered when encountering an unusual umbilicated papular eruption in the appropriate patient with occupational exposure.
Risk Factors for Fistula Development Following Palatoplasty
Authors: Aldaghir Osamah Mohammed , AlQuisi Ahmed Fadhel , Aljumaily Hassanien A.
Published: June 2019

Purpose:

The aim of this study is to assess the influence of some risks factors on the fistula development after palatoplasty to improve the outcome of the patients

Patients and Methods:

A total of 48 patients (the males were 22, The females were 26) were included in this study. All the patients were examined weekly for the first month postoperatively to assess any breakdown in the wound by inspection and by asking the parents for any nasal regurgitation during fluids feeding.

Results:

The incidence of palatal fistula development after primary palatoplasty in this study was 12.5% (6\48). Occurrence of fistula was unrelated to the gender (P >0.5), but it was directly related to the age of patients (r = 0.98) and to the size of the cleft (r = 1). Fistula had occurred most likely in cases of Baradach 2 flap palatoplasty (83.3%) this was occurred especially when it was used for isolated cleft palate, but it was not associated with the type of the cleft (P >0.4). The surgeons experience and the use of prophylactic antibiotic were associated with the development of the fistula (P = 0.01 for both).

Conclusion:

knowledge of the expected risk factors for fistula after different protocols of palatoplasty can improve the experience of the surgeon and improve the outcome on the patients.
The Familial Rhino Tooth: Two Mesiodentes
Authors: Sadeghzadeh-Araghi Ariyan , Vassiliou Leandros
Published: June 2019

The authors herein report on 2 cases of patients who had supernumerary teeth. The 2 cases outline how 1 was managed sub-optimally and other managed efficiently. The patients were direct relatives with a very similar clinical problem. This case report explores the genetic relevance of mesiodentes. This case report aims to outline the importance in examination, diagnosis and surgical removal of supernumerary teeth. It also describes several lessons that all members of the dental and wider surgical team can learn from, with regards to supernumerary teeth and more specifically mesiodentes.
Frequency and Implications of Paratracheal Lymph Node Metastases in Resectable Esophageal or Gastroesophageal Junction Adenocarcinoma
Authors: Harada Kazuto , Hwang Hyunsoo , Wang Xuemei , Abdelhakeem Ahmed , Iwatsuki Masaaki , Blum Murphy Mariela A. , Maru Dipen M. , Weston Brian , Lee Jeffrey H. , Rogers Jane E. , Thomas Irene , Shanbhag Namita , Zhao Meina , Bhutani Manoop S. , Nguyen Quynh-Nhu , Swisher Stephen G. , Ikoma Naruhiko , Badgwell Brian D. , Hofstetter Wayne L. , Ajani Jaffer A.
Published: June 2019

Objective:

We aimed to evaluate the frequency of paratracheal lymph nodes (LN) metastases and their prognostic influence.

Summary Background Data:

Paratracheal LNs are considered regional nodes in the esophageal cancer classification, but their metastatic rate and influence on survival remain unclear.

Methods:

One thousand one hundred ninety-nine patients with resectable esophageal or gastroesophageal junction adenocarcinoma (EAC) (January 2002 and December 2016) in our Gastrointestinal Medical Oncology Database were analyzed. Paratracheal LNs were defined as1R, 1L, 2R, 2L, 4R, and 4L, according to the 8th American Joint Committee on Cancer classification.

Results:

Of 1199 patients, 73 (6.1%) had positive paratracheal LNs at diagnosis. The median overall survival (OS) of 73 patients with initial paratracheal LN involvement was 2.10 years (range 0.01–10.1, 5-yrs OS 24.2%). Of 1071 patients who were eligible for recurrence evaluation, 70 patients (6.5%) developed paratracheal LN metastases as the first recurrence. The median time to recurrence was 1.28 years (range 0.28–5.96 yrs) and the median OS following recurrence was only 0.95 year (range 0.03–7.88). OS in 35 patients who had only paratracheal LN recurrence was significantly longer than in patients who had other recurrences (median OS 2.26 vs 0.51 yrs, 5-yrs OS; 26.8% vs 0%, P < 0.0001). Higher T stage (T3/T4) was an independently risk factor for paratracheal LN recurrence (odds ratio 5.10, 95% confidence interval 1.46–17.89). We segregated patients in 3 groups based on the distance of tumor's proximal edge to esophagogastric junction (low; ≤2 cm, medium; 2.0–7.0 cm, and high; >7.0 cm). Paratracheal LN metastases were more frequent with the proximal tumors (low, 4.2%; medium, 12.0%; high, 30.3%; Cochran–Armitage Trend test, P < 0.001).

Conclusion:

Paratracheal LN metastases were associated with a shorter survival in resectable EAC patients. Alternate approaches to prolong survival of this group of patients are warranted.
Driver Gene Mutations and Epigenetics in Colorectal Cancer
Authors: Raskov Hans , Søby Jacob H. , Troelsen Jesper , Bojesen Rasmus D. , Gögenur Ismail
Published: June 2019

Objective:

The majority of patients with colorectal cancer are diagnosed with locally advanced and/or disseminated disease, and treatment options include surgery in combination with cytotoxic chemotherapy regimens, biologics, and/or radiotherapy. Thus, colorectal cancer remains a heavy burden on society and health care systems.

Mounting evidence show that driver gene mutations play only part of the role in carcinogenesis. Epigenetics are strongly implicated in initiation and progression of colorectal cancer along with major players such as intestinal microbiotic dysbiosis and chronic mucosal inflammation.

To assess phenotypic changes in proteins and gene expression, multigene expression signatures based on sequencing techniques have been developed to hopefully improve predictors of the tumor profile, immune response, and therapeutic outcomes. Our objective was to review current advances in the field and to update surgeons and academics on driver gene mutations and epigenetics in colorectal cancer.

Background and methods:

This is a narrative review studying relevant research published in the PUBMED database from 2012–2018.

Results and conclusion:

Increased understanding of the molecular biology will improve options to characterize colorectal cancer with regard to mutations and molecular pathways, including microsatellite instability, epigenetics, microbiota, and microenvironment. Research will inevitably improve risk group stratification and targeted treatment approaches.

Epigenetic profiling and epigenetic modulating drugs will increase risk stratification, increase accessibility for DNA targeting chemotherapeutics and reduce cytotoxic drug resistance.

New generation antibiotics such as biofilm inhibitors and quorum sensing inhibitors are being developed to target the carcinogenetic impact of colonic dysbiosis and inflammation.
Pain in Parkinson's disease: new concepts in pathogenesis and treatment
Authors: Rukavina Katarina , Leta Valentina , Sportelli Carolina , Buhidma Yazead , Duty Susan , Malcangio Marzia , Ray Chaudhuri Kallol
Published: June 2019

Purpose of review

In this review, we discuss the most recent evidence on mechanisms underlying pathological nociceptive processing in Parkinson's disease patients, as well as novel treatment strategies.

Recent findings

In Parkinson's disease, specific neurodegenerative changes may cause alterations in nociceptive processing at multiple levels. Optimization of dopaminergic therapies should always be the first step in the management of Parkinson's disease pain. Reportedly, rotigotine transdermal patch, a monoamine oxidase type B inhibitor safinamide (as an add-on therapy to levodopa), subcutaneous apomorphine and intrajejunal levodopa infusion therapy may have a beneficial effect on pain sensations in Parkinson's disease patients. Among the nondopaminergic pharmacological therapies, prolonged-release oxycodone/naloxone and duloxetine may be effective in the treatment of chronic pain in Parkinson's disease. Botulinum toxin (BTX) injections should be considered for the treatment of dystonic Parkinson's disease pain. Deep brain stimulation (DBS) may lead to pain relief with a long-lasting effect in Parkinson's disease patients. Physiotherapy and physical activity in general are essential for Parkinson's disease patients suffering from pain.

Pain in Parkinson's disease is not simply a consequence of motor complainants. The management of Parkinson's disease-related pain implicates maintenance of stable levels of dopaminergic drugs. Nondopaminergic pharmacological therapies (prolonged-release oxycodone/naloxone, duloxetine, BTX) and nonpharmacological interventions (DBS, physiotherapie) may also be beneficial in treatment of Parkinson's disease pain.
Understanding intellectual disability and autism spectrum disorders from common mouse models: synapses to behaviour
Authors: Verma Vijaya , Paul Abhik , Amrapali Vishwanath Anjali , Vaidya Bhupesh , Clement James P.
Published: June 2019

Normal brain development is highly dependent on the timely coordinated actions of genetic and environmental processes, and an aberration can lead to neurodevelopmental disorders (NDDs). Intellectual disability (ID) and autism spectrum disorders (ASDs) are a group of co-occurring NDDs that affect between 3% and 5% of the world population, thus presenting a great challenge to society. This problem calls for the need to understand the pathobiology of these disorders and to design new therapeutic strategies. One approach towards this has been the development of multiple analogous mouse models. This review discusses studies conducted in the mouse models of five major monogenic causes of ID and ASDs:Fmr1, Syngap1, Mecp2, Shank2/3andNeuroligins/Neurnexins.These studies reveal that, despite having a diverse molecular origin, the effects of these mutations converge onto similar or related aetiological pathways, consequently giving rise to the typical phenotype of cognitive, social and emotional deficits that are characteristic of ID and ASDs. This convergence, therefore, highlights common pathological nodes that can be targeted for therapy. Other than conventional therapeutic strategies such as non-pharmacological corrective methods and symptomatic alleviation, multiple studies in mouse models have successfully proved the possibility of pharmacological and genetic therapy enabling functional recovery.
Ecosystem services and ecological degradation of communal wetlands in a South African biodiversity hotspot
Authors: Owethu Pantshwa A. , Buschke Falko T.
Published: June 2019

Wetlands provide important ecosystem services to rural communities. However, wetlands are often on communal land, so they may become degraded when individual users act to maximize their personal benefit from ecosystem services without bearing the full environmental costs of their actions. Although it is possible to manage communal resources sustainably, this depends on the dynamics of the socio-ecological system. In this study, we used a structured questionnaire to examine whether demographic characteristics of a rural community and the propensity for partaking in damage-causing activities affected the benefits obtained from the wetlands. Responses from 50 households in the rural Hlabathi administrative area within the Maputo-Albany-Pondoland Biodiversity Hotspot, South Africa, indicated that the entire community obtains some benefits from wetlands; most notably regulating ecosystem services. However, males were more likely to benefit from wetlands, which highlights a potential power imbalance. Respondents were more likely to blame others for wetland degradation, although there was no link between the damage-causing activities and benefits from wetlands. The high dependence on ecosystem services by community members, when combined with gender-based power imbalances and the propensity to blame others, could jeopardize the sustainable use of communal wetlands. Therefore, we describe how strong leadership could nurture a sustainable social–ecological system by integrating ecological information and social empowerment into a multi-level governance system.
Modified HEPES one-pot synthetic strategy for gold nanostars
Authors: Mulder Danielle Wingrove , Phiri Masauso Moses , Jordaan Anine , Vorster Barend Christiaan
Published: June 2019

Gold nanostars are being used more regularly in the biosensing field. Despite their useful attributes, there is still a need to optimize aspects of the synthesis and stability. The seedless, synthetic method comprising 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES) is a facile, rapid method; however, it produces heteromorphic nanostars. The modification of a HEPES method resulted in a silver-assisted, seedless gold nanostar synthesis method. The nanostars resulting from this method were monodispersed, multi-branched and approximately 37 ± 2 nm in diameter. It proved to be a repeatable method that produced homogeneous and robust nanostars. Once functionalized with polyvinylpyrrolidone 10 000, the new nanostars were observed to be stable in various environments such as salt, ionic strength and cell culture medium. In conclusion, the addition of the silver nitrate improved the morphology of the reported HEPES nanostars for the purpose of nanobiosensor development.
Piceatannol attenuates RANKL-induced osteoclast differentiation and bone resorption by suppressing MAPK, NF-κB and AKT signalling pathways and promotes Caspase3-mediated apoptosis of mature osteoclasts
Authors: Yan Liuliu , Lu Lulu , Hu Fangbin , Shetti Dattatrya , Wei Kun
Published: June 2019

Osteoclasts are multinuclear giant cells that have unique ability to degrade bone. The search for new medicines that modulate the formation and function of osteoclasts is a potential approach for treating osteoclast-related bone diseases. Piceatannol (PIC) is a natural organic polyphenolic stilbene compound found in diverse plants with a strong antioxidant and anti-inflammatory effect. However, the effect of PIC on bone health has not been scrutinized systematically. In this study, we used RAW264.7, an osteoclast lineage of cells of murine macrophages, to investigate the effects and the underlying mechanisms of PIC on osteoclasts. Here, we demonstrated that PIC treatment ranging from 0 to 40 µM strongly inhibited osteoclast formation and bone resorption in a dose-dependent manner. Furthermore, the inhibitory effect of PIC was accompanied by the decrease of osteoclast-specific genes. At the molecular level, PIC suppressed the phosphorylation of c-Jun N-terminal kinase (JNK), extracellular signal-regulated kinase (ERK1/2), NF-κB p65, IκBα and AKT. Besides, PIC promoted the apoptosis of mature osteoclasts by inducing caspase-3 expression. In conclusion, our results suggested that PIC inhibited RANKL-induced osteoclastogenesis and bone resorption by suppressing MAPK, NF-κB and AKT signalling pathways and promoted caspase3-mediated apoptosis of mature osteoclasts, which might contribute to the treatment of bone diseases characterized by excessive bone resorption.
Revisiting the simulation of quantum Turing machines by quantum circuits
Authors: Molina Abel , Watrous John
Published: June 2019

Yao's 1995 publication ‘Quantum circuit complexity’ in
Proceedings of the 34th Annual IEEE Symposium on Foundations of Computer Science
, pp. 352–361, proved that quantum Turing machines and quantum circuits are polynomially equivalent computational models:
t
≥
n
steps of a quantum Turing machine running on an input of length
n
can be simulated by a uniformly generated family of quantum circuits with size quadratic in
t
, and a polynomial-time uniformly generated family of quantum circuits can be simulated by a quantum Turing machine running in polynomial time. We revisit the simulation of quantum Turing machines with uniformly generated quantum circuits, which is the more challenging of the two simulation tasks, and present a variation on the simulation method employed by Yao together with an analysis of it. This analysis reveals that the simulation of quantum Turing machines can be performed by quantum circuits having depth linear in
t
, rather than quadratic depth, and can be extended to variants of quantum Turing machines, such as ones having multi-dimensional tapes. Our analysis is based on an extension of method described by Arright, Nesme and Werner in 2011 in
Journal of Computer and System Sciences
77
, 372–378. (
doi:10.1016/j.jcss.2010.05.004
), that allows for the localization of causal unitary evolutions.
Pollen-borne microbes shape bee fitness
Authors: Dharampal Prarthana S. , Carlson Caitlin , Currie Cameron R. , Steffan Shawn A.
Published: June 2019

Teeming within pollen provisions are diverse communities of symbiotic microbes, which provide a variety of benefits to bees. Microbes themselves may represent a major dietary resource for developing bee larvae. Despite their apparent importance in sustaining bee health, evidence linking pollen-borne microbes to larval health is currently lacking. We examined the effects of microbe-deficient diets on the fitness of larval mason bees. In a series of diet manipulations, microbe-rich maternally collected pollen provisions were replaced with increasing fractions of sterilized, microbe-deficient pollen provisions before being fed to developing larvae. Convergent findings from amino acid and fatty acid trophic biomarker analyses revealed that larvae derived a substantial amount of nutrition from microbial prey and occupied a significantly higher trophic position than that of strict herbivores. Larvae feeding on increasingly sterile diets experienced significant adverse effects on growth rates, biomass and survivorship. When completely deprived of pollen-borne microbes, larvae consistently exhibited marked decline in fitness. We conclude that microbes associated with aged pollen provisions are central to bee health, not only as nutritional mutualists, but also as a major dietary component. In an era of global bee decline, the conservation of such bee–microbe interactions may represent an important facet of pollinator protection strategies.
Prenatal development in pterosaurs and its implications for their postnatal locomotory ability
Authors: Unwin David Michael , Deeming D. Charles
Published: June 2019

Recent fossil finds in China and Argentina have provided startling new insights into the reproductive biology and embryology of pterosaurs, Mesozoic flying reptiles. Nineteen embryos distributed among four species representing three distinct clades have been described and all are assumed to be at, or near, term. We show here how the application of four contrasting quantitative approaches allows a more precise identification of the developmental status of embryos revealing, for the first time to our knowledge, the presence of middle and late developmental stages as well as individuals that were at term. We also identify a predicted relationship between egg size and shape and the developmental stage of embryos contained within. Small elongate eggs contain embryos at an earlier stage of development than larger rounder eggs which contain more fully developed embryos. Changes in egg shape and size probably reflect the uptake of water, consistent with a pliable shell reported for several pterosaurs. Early ossification of the vertebral column, limb girdles and principal limb bones involved some heterochronic shifts in appearance times, most notably of manus digit IV, and facilitated full development of the flight apparatus prior to hatching. This is consistent with a super-precocial flight ability and, while not excluding the possibility of parental care in pterosaurs, suggests that it was not an absolute requirement.
Regional climate affects salmon lice dynamics, stage structure and management
Authors: Hurford Amy , Wang Xiunan , Zhao Xiao-Qiang
Published: June 2019

Regional variation in climate can generate differences in population dynamics and stage structure. Where regional differences exist, the best approach to pest management may be region-specific. Salmon lice are a stage-structured marine copepod that parasitizes salmonids at aquaculture sites worldwide, and have fecundity, development and mortality rates that depend on temperature and salinity. We show that in Atlantic Canada and Norway, where the oceans are relatively cold, salmon lice abundance decreases during the winter months, but ultimately increases from year to year, while in Ireland and Chile, where the oceans are warmer, the population size grows monotonically without any seasonal declines. In colder regions, during the winter the stage structure is dominated by the adult stage, which is in contrast to warmer regions where all stages are abundant year round. These differences translate into region-specific recommendations for management: regions with slower population growth have lower critical stocking densities, and regions with cold winters have a seasonal dependence in the timing of follow-up chemotherapeutic treatments. Predictions of our salmon lice model agree with empirical data, and our approach provides a method to understand the effects of regional differences in climate on salmon lice dynamics and management.
The strategic reference gene: an organismal theory of inclusive fitness
Authors: Fromhage Lutz , Jennions Michael D.
Published: June 2019

How to define and use the concept of inclusive fitness is a contentious topic in evolutionary theory. Inclusive fitness can be used to calculate selection on a focal
gene
, but it is also applied to whole
organisms
. Individuals are then predicted to appear designed as if to maximize their inclusive fitness, provided that certain conditions are met (formally when interactions between individuals are ‘additive’). Here we argue that applying the concept of inclusive fitness to organisms is justified under far broader conditions than previously shown, but only if it is appropriately defined. Specifically, we propose that organisms should maximize the sum of their offspring (
including
any accrued due to the behaviour/phenotype of relatives), plus any effects on their relatives' offspring production, weighted by relatedness. By contrast, most theoreticians have argued that a focal individual's inclusive fitness should exclude any offspring accrued due to the behaviour of relatives. Our approach is based on the notion that long-term evolution follows the genome's ‘majority interest’ of building coherent bodies that are efficient ‘vehicles’ for gene propagation. A gene favoured by selection that reduces the propagation of unlinked genes at other loci (e.g. meiotic segregation distorters that lower sperm production) is eventually neutralized by counter-selection throughout the rest of the genome. Most phenotypes will therefore appear as if designed to maximize the propagation of any given gene in a focal individual and its relatives.
Overexpression of an antioxidant enzyme improves male mating performance after stress in a lek-mating fruit fly
Authors: Teets Nicholas M. , Dias Vanessa S. , Pierce Bailey K. , Schetelig Marc F. , Handler Alfred M. , Hahn Daniel A.
Published: June 2019

In many species, courtship displays are reliable signals of male quality, and current hypotheses suggest that these displays allow females to choose males with high cellular function. Environmental stressors generate excess reactive oxygen species (ROS) that impair cellular function, and thus antioxidant pathways that remove ROS are probably critical for preserving complex sexual behaviours. Here, we test the hypothesis that enhanced antioxidant activity in mitochondria preserves mating performance following oxidative stress. Using a transgenic approach, we directly manipulated mitochondrial antioxidant activity in the Caribbean fruit fly,Anastrepha suspensa,a lek-mating species with elaborate sexual displays and intense sexual selection that is also a model for sterile insect technique programmes. We generated seven transgenic lines that overexpress mitochondrial superoxide dismutase (MnSOD). Radiation is a severe oxidative stressor used to induce sterility for sterile insect programmes. After radiation treatment, two lines with intermediate MnSOD overexpression showed enhanced mating performance relative to wild-type males. These improvements in mating corresponded with reduced oxidative damage to lipids, demonstrating that MnSOD overexpression protects flies from oxidative stress at the cellular level. For lines with improved mating performance, overexpression also preserved locomotor activity, as indicated by a laboratory climbing assay. Our results show a clear link between oxidative stress, antioxidant capacity and male performance. Our work has implications for fundamentally understanding the role of antioxidants in sexual selection, and shows promise for using transgenic approaches to enhance the field performance of insects released for area-wide pest management strategies and improving performance of biological control agents in general.
Pair-bonding influences affective state in a monogamous fish species
Authors: Laubu Chloé , Louâpre Philippe , Dechaume-Moncharmont François-Xavier
Published: June 2019

In humans, affective states are a key component in pair-bonding, particularly in the early stage of a relationship. Pairing with a high-quality partner elicits positive affective states which, in turn, validate and reinforce the mate choice. Affective states thus strongly affect pair stability and future reproductive success. We propose generalizing the link between affective states and pair-bonding to encompass other monogamous species exhibiting biparental care, chiefly where the reproductive success of the pair critically depends on the coordination between partners. The convict cichlidAmatitlania siquiais a monogamous fish species that forms long-lasting pairs with strong cooperation between parents for parental care. In this species, we showed that females paired with their non-preferred male had lower reproductive success than those paired with their preferred male. We then transposed the judgement bias paradigm, previously used in other animal species, to assess objectively affective states in fishes. Females that were assigned their non-preferred partner exhibited pessimistic bias, which indicates a negative affective state. By contrast, females that were assigned their preferred partner did not exhibit changes in their affective state. Our results highlight that the influence of pair-bonding on affective states is not human-specific and can also be observed in non-human species.
Olfactory receptor repertoire size in dinosaurs
Authors: Hughes Graham M. , Finarelli John A.
Published: June 2019

The olfactory bulb (OB) ratio is the size of the OB relative to the cerebral hemisphere, and is used to estimate the proportion of the forebrain devoted to smell. In birds, OB ratio correlates with the number of olfactory receptor (OR) genes and therefore has been used as a proxy for olfactory acuity. By coupling OB ratios with known OR gene repertoires in birds, we infer minimum repertoire sizes for extinct taxa, including non-avian dinosaurs, using phylogenetic modelling, ancestral state reconstruction and comparative genomics. We highlight a shift in the scaling of OB ratio to body size along the lineage leading to modern birds, demonstrating variable OR repertoires present in different dinosaur and crown-bird lineages, with varying factors potentially influencing sensory evolution in theropods. We investigate the ancestral sensory space available to extinct taxa, highlighting potential adaptations to ecological niches. Through combining morphological and genomic data, we show that, while genetic information for extinct taxa is forever lost, it is potentially feasible to investigate evolutionary trajectories in extinct genomes.
Dissociation of disease phenotype and allele silencing in hypertrophic cardiomyopathy
Authors: Dainis Alexandra , Zaleta-Rivera Kathia , Ribeiro Alexandre , Chia Hao Chang Andrew , Shang Ching , Lan Feng , Burridge Paul W. , Wu Joseph C. , Chia Yu Chang Alex , Pruitt Beth L. , Wheeler Matthew , Ashley Euan
Published: June 2019

Allele-specific RNA silencing has been shown to be an effective therapeutic treatment in a number of diseases, including neurodegenerative disorders. Studies of allele-specific silencing in hypertrophic cardiomyopathy to date have focused on mouse models of disease. Here, we investigate two methods of allele-specific silencing, short hairpin RNA (shRNA) and antisense oligonucleotide (ASO) silencing, using a human induced pluripotent stem cell-derived cardiomyocyte (hiPSC-CM) model of disease. We used cellular micropatterning devices with traction force microscopy and automated video analysis to examine each strategy’s effects on contractile defects underlying disease. We find that shRNA silencing ameliorates contractile phenotypes of disease, reducing disease-associated increases in cardiomyocyte velocity, force, and power. We find that ASO silencing, while better able to target and knockdown a specific disease-associated allele, showed more modest improvements in contractile phenotypes. We find a dissociation between allelic-specificity and functional improvements between the two tested therapeutic strategies, suggesting a more complex method of allelic control underlying HCM-associated transcripts.

Author summary

Allele-specific silencing, whereby a therapeutic molecule is used to lower the expression of just one of the two copies or alleles of a gene, may be a potential therapeutic strategy in diseases caused by a single mutation. In this paper, we examine two such strategies in hypertrophic cardiomyopathy, a disease characterized by an overgrowth of the left-ventricular heart muscle as well as contractile dysfunction. We used a human cell model of disease, creating induced pluripotent stem cell derived cardiomyocytes from a patient with HCM caused by a single base pair change in just one allele of the gene MYH7. We used two strategies to silence the disease-associated copy of MYH7, both focused on reducing RNA expression from the mutated allele, as well as state-of-the-art biophysical techniques for measuring contractility. We found that one silencing strategy, which reduced expression of both the disease-associated and the healthy alleles of MYH7, showed great improvements in contractility between treated and untreated cells. Our second strategy, which silenced only the disease-associated copy of MYH7, showed more modest improvements in contractility. This suggests that the disease mechanism underlying this type of hypertrophic cardiomyopathy may be more complex than just presence or absence of the mutated RNA.
A high-quality genome assembly from short and long reads for the non-biting midge Chironomus riparius (Diptera)
Authors: Schmidt Hanno , Waldvogel Ann-Marie , Hellmann Sören Lukas , Feldmeyer Barbara , Hankeln Thomas , Pfenninger Markus
Published: June 2019

Background

Chironomus riparius is of great importance as a study species in various fields like ecotoxicology, molecular genetics, developmental biology and ecology. However, only a fragmented draft genome exists to date, hindering the recent rush of population genomic studies in this species.

Findings

Making use of 50 NGS datasets, we present a hybrid genome assembly from short and long sequence reads that make C. riparius’ genome one of the most contiguous Dipteran genomes published, the first complete mitochondrial genome of the species and the respective recombination rate as one of the first insect recombination rates at all.

Conclusions

The genome and associated resources will be highly valuable to the broad community working with dipterans in general and chironomids in detail. The estimated recombination rate will help evolutionary biologist gain a better understanding of commonalities and differences of genomic patterns in insects.
Cell-free prototyping of AND-logic gates based on heterogeneous RNA activators
Authors: Lehr François-Xavier , Hanst Maleen , Vogel Marc , Kremer Jennifer , Göringer H. Ulrich , Suess Beatrix , Koeppl Heinz
Published: June 2019

RNA-based devices controlling gene expression bear great promise for synthetic biology, as they offer many advantages like short response times and light metabolic burden compared to protein-circuits. However, little work has been done regarding their integration to multi-level regulated circuits. In this work, we combined a variety of small transcriptional activator RNAs (STARs) and toehold switches to build highly effective AND-gates. To characterise the components and their dynamic range, we used an Escherichia coli (E. coli) cell-free transcription-translation (TX-TL) system dispensed via nanoliter droplets. We analysed a prototype gate in vitro as well as in silico, employing parameterised ordinary differential equations (ODEs), where parameters were inferred via parallel tempering, a Markov chain Monte Carlo (MCMC) method. Based on this analysis, we created nine additional AND-gates and tested them in vitro. The functionality of the gates was found to be highly dependent on the concentration of the activating RNA for either the STAR or the toehold switch. All gates were successfully implemented in vivo, offering a dynamic range comparable to the level of protein circuits. This study shows the potential of a rapid prototyping approach for RNA circuit design, using cell-free systems in combination with a model prediction.

Abbreviations

TX-TL (transcription-translation), ODEs (ordinary differential equations), STARs (small transcriptional activator RNAs), MCMC (Markov chain Monte Carlo).
Staphylococcus epidermidismetabolic adaptation and biofilm formation in response to varying oxygen
Authors: Pedroza-Dávila Ulrik H. , Uribe-Alvarez Cristina , Morales-García Lilia , Espinoza-Simón Emilio , Muhlia-Almazán Adriana , Chiquete-Félix Natalia , Uribe-Carvajal Salvador
Published: June 2019

Staphylococcus epidermidisis a Gram-positive saprophytic bacterium found in the microaerobic/anaerobic layers of the skin. It becomes a health hazard when introduced across the skin by punctures or wounds.S. epidermidisforms biofilms in low O2environments. As oxygen concentrations ([O2]) decreased, the metabolism ofS. epidermidiswas modified ranging from fully aerobic to anaerobic. Respiratory activity increased at high [O2], while anaerobically grown cells exhibited the highest rate of fermentation. High aerobic metabolism coincided with high hydrogen peroxide-mediated damage. Remarkably, the rate of growth decreased at low [O2] even though the concentration of ATP was high. Under these conditions bacteria associated into biofilms. Then, in the presence of metabolic inhibitors, biofilm formation decreased. It is suggested that when [O2] is lowS. epidermidisaccumulates ATP in order to synthesize the proteins and polysaccharides needed to attach to surfaces and form biofilms.

Importance

Bacteria and humans coexist, establishing all kinds of relationships that may change from saprophytic to infectious as environmental conditions vary. S. epidermidis is saprophytic when living in the skin. Inside the organism it evokes a pathologic reaction and is thus rejected by the organism. Additionally it is forced to adapt to high oxygen concentrations, becoming vulnerable to reactive oxygen species, which may come from leukocyte attack. Avoiding both, high oxygen and leukocytes is a must for bacteria. Escaping from oxygen involves a clever response: whenever it finds a low oxygen environment it attaches to surfaces, associating into biofilms. Biofilms protectS. epidermidisagainst host cells. Understanding these responses is a must in order to develop treatments and prevent infection success.
Context information supports serial dependence of multiple visual objects across memory episodes
Authors: Fischer Cora , Czoschke Stefan , Peters Benjamin , Rahm Benjamin , Kaiser Jochen , Bledowski Christoph
Published: June 2019

Visual perception operates in an object-based manner, by integrating associated features via attention. Working memory allows a flexible access to a limited number of currently relevant objects, even when they are occluded or physically no longer present. Recently, it has been shown that we compensate for small changes of an object’s feature over memory episodes, which can support its perceptual stability. This phenomenon was termed ‘serial dependence’ and has mostly been studied in situations that comprised only a single relevant object. However, since we are typically confronted with situations where several objects have to be perceived and held in working memory, the central question of how we selectively create temporal stability of several objects has remained unsolved. As different objects can be distinguished by their accompanying context features, like their color or temporal position, we tested whether serial dependence is supported by the congruence of context features across memory episodes. Specifically, we asked participants to remember the motion directions of two sequentially presented colored dot fields per trial. At the end of a trial one motion direction was cued for continuous report either by its color (Experiment 1) or serial position (Experiment 2). We observed serial dependence, i.e., an attractive bias of currently toward previously memorized objects, between current and past motion directions that was clearly enhanced when items had the same color or serial position across trials. This bias was particularly pronounced for the context feature that was used for cueing and for the target of the previous trial. Together, these findings demonstrate that coding of current object representations depends on previous representations, especially when they share similar content and context features. Apparently the binding of content and context features is not completely erased after a memory episode, but it is carried over to subsequent episodes. As this reflects temporal dependencies in natural settings, the present findings reveal a mechanism that integrates corresponding bundles of content and context features to support stable representations of individualized objects over time.
Global analysis of Two Component System (TCS) member of chickpea and other legume genomes implicates its role in enhanced nodulation
Authors: Tiwari Manish , Yadav Manisha , Singh Baljinder , Pandey Vimal , Nawaz Kashif , Bhatia Sabhyata
Published: June 2019

Nodule organogenesis is governed primarily by phytohormone cytokinin. We observed the significant nodulation in chickpea at particular cytokinin concentration (2.5×10−7) which indicated the importance of cytokinin in nodule development. Cytokinin signaling is mediated through the Two Component System (TCS) which comprises of sensor histidine kinases (HKs), histidine phosphotransfer proteins (HPs), and response regulators (RRs). Therefore, we analyzed the interconnection of cytokinin with TCS molecules during root nodule development through global analysis of TCS candidates in legumes with special consideration to cytokinin receptor and Type-B RR member. We have conducted an in depth global analysis of TCS family members in chickpea and other legumes, Medicago and pigeon pea. Higher number of TCS genes were found in Medicago (96), followed by pigeonpea (75) and chickpea (67). A good correlation between TCS members with their corresponding total number of genes were observed in all three-legume species. Collinearity analysis of TCS revealed phylogenetically closer proximity of Cicer to Medicago followed by Glycine than Cajanus. Comprehensive analysis of 3-dimensional structure, genomic organisation and domain arrangement showed a conservation of TCS members within species. In depth investigation showed that HKs were mainly conserved among TCS members in legumes and non-legumes while divergence occurred at level of RRs. Further, Type-B RRs were functionally most diversified in RRs based on phylogeny, syntenic and transcript analysis. Few numbers of segmentally duplicated pair of TCS showed difference in their transcriptional regulation suggesting the functional evolution. For functional characterization the cre1 mutants of (Medicago) were complemented with chickpea cytokinin responsive HKs and nodulation deficient phenotype of mutants were restored. A synchronous cytokinin-induced expression of chickpea cytokinin receptor HKs and CaNIN provides strong relation of cytokinin signaling during nodulation. Furthermore, interesting potential candidate CaRR13 was selected to deduce the underlying molecular mechanism of nodulation, chickpea in specific and legumes in general.
Epithelium intrinsic vitamin A signaling co-ordinates pathogen clearance in the gut via IL-18
Authors: Iyer Namrata , Grizotte-Lake Mayara , Gordon Sarah R. , Palmer Ana C. S. , Calvin Crystle , Vaishnava Shipra
Published: June 2019

Intestinal epithelial cells (IECs) are at the forefront of host-pathogen interactions, coordinating a cascade of immune responses to confer protection against pathogens. Here we show that IEC-intrinsic vitamin A signaling restricts pathogen invasion early in the infection and subsequently activates immune cells to promote pathogen clearance. Mice blocked for retinoic acid receptor (RAR) signaling selectively in IECs (stopΔIEC) showed significantly higherSalmonellaburden in colonic tissues early in the infection associated with higher luminal and systemic loads of the pathogen at later stages. Higher susceptibility of stopΔIECmice correlated with attenuated mucosal interferon gamma (IFNγ) production by underlying immune cells. We found that, at homeostasis, the intestinal epithelium of stopΔIECmice produced significantly lower amounts of interleukin 18 (IL-18), a potent inducer of IFNγ. Regulation of IL-18 by vitamin A was also observed in a dietary model of vitamin A supplementation. IL-18 reconstitution in stopΔIECmice restored resistance toSalmonellaby promoting epithelial cell shedding to eliminate infected cells and limit pathogen invasion early in infection. Further, IL-18 augmented IFNγ production by underlying immune cells to restrict pathogen burden and systemic spread. Our work uncovers a critical role for vitamin A in coordinating a biphasic immune response toSalmonellainfection by regulating IL-18 production by IECs.

Author Summary

Epithelial cells line the intestinal lumen, forming a barrier between the body and dietary and microbial contents in the lumen. Apart from absorbing nutrients from diet, these epithelial cells help mediate a stable, symbiotic relationship between microbes in the gut and the immune cells. During infection, they help co-ordinate the immune response to counter the infection. How dietary micronutrients, such as vitamin A, inform epithelial cell function during infection is poorly understood. Using a model where epithelial cells in the gut cannot respond to vitamin A signals, we find that epithelial vitamin A signaling promotes resistance toSalmonellainfection. We show that, vitamin A increases the production of a key cytokine, interleukin 18, by epithelial cells. IL-18 promotes shedding of infected epithelial cells to reduce the pathogen invasion while also inducing the production of interferon gamma by immune cells to mediate pathogen clearance. Thus, epithelial cells dynamically respond to dietary vitamin A to regulate interleukin 18 production and potentiate resistance to infection.
Wampa is a dynein subunit required for axonemal assembly and male fertility inDrosophila
Authors: Bauerly Elisabeth , Yi Kexi , Gibson Matthew C.
Published: June 2019

Axonemal dyneins are motor proteins that form the inner and outer arms of the axoneme in cilia and flagella. Defects in dynein arms are the leading cause of primary ciliary dyskinesia (PCD), which is characterized by chronic respiratory infections, situs inversus, and sterility. Despite current understanding of pathological features associated with PCD, many of their causative genes still remain elusive. Here we analyze genetic requirements forwampa(wam), a previously uncharacterized component of the outer dynein arm that is essential for male fertility. In addition to a role in outer dynein arm formation, we uncovered additional requirements during spermatogenesis, including regulation of remodeling events for the mitochondria and the nucleus. Due to the conserved nature of axonemal dyneins and their essential role in both PCD and fertility, this study advances our understanding of the pathology of PCD, as well as the functional role of dyneins in axonemal formation and spermatogenesis.
Glucosinolate and phenylpropanoid biosynthesis are linked by proteasome-dependent degradation of PAL
Authors: Kim Jeongim , Zhang Xuebin , Pascuzzi Pete , Liu Chang-Jun , Chapple Clint
Published: June 2019

Plants produce several hundreds of thousands of secondary metabolites that are important for adaptation to various environmental conditions. Although different groups of secondary metabolites are synthesized through unique biosynthetic pathways, plants must orchestrate their production simultaneously. Phenylpropanoids and glucosinolates are two classes of secondary metabolites that are synthesized through apparently independent biosynthetic pathways. Genetic evidence has revealed that the accumulation of glucosinolate intermediates limits phenylpropanoid production in a Mediator Subunit 5 (MED5) dependent manner. To elucidate the molecular mechanism underlying this process, we analyzed the transcriptomes of a suite of glucosinolate-deficient mutants using RNAseq and identified mis-regulated genes that are rescued by the disruption of MED5. The expression of a group of Kelch Domain F-Box genes (KFBs) that function in PAL degradation is affected in glucosinolate biosynthesis mutants and the disruption of these KFBs restores phenylpropanoid deficiency, dwarfism and sterility in the mutants. Our study suggests that glucosinolate/phenylpropanoid metabolic crosstalk involves the transcriptional regulation of KFB genes that initiate the degradation of the enzyme phenylalanine ammonia-lyase, which catalyzes the first step of the phenylpropanoid biosynthesis pathway. Nevertheless, KFB mutant plants remain partially sensitive to glucosinolate pathway mutations, suggesting that other mechanisms that link the two pathways also exist.