bluuebunny/crossref_metadata_2025 huggingface dataset:
Sympathetic innervation directs Ankyrin G, voltage-gated Navand KCNQ1 channels to the neuro-cardiac junctions
Authors: Shcherbakova Olga G.
Published: November 2019

The sympathetic nervous system plays a central role in the cardiovascular response to acute stress by increasing heart rate and contractility. Despite the importance of functional connections between sympathetic nerves and cardiac myocytes, very little is known about the structural and functional organization of the neuro-cardiac synapses. Earlier, we demonstrated that specialized signaling domains are organized in cardiac myocytes at sites of contact with sympathetic neurons2. In the present study, we addressed the question if sympathetic innervation may affect localization of the cardiac ion channels. We have found that ankyrin G, scaffold protein involved in targeting ion channels and transporters, is localized at the postsynaptic sites in the cardiac myocytes innervated by sympathetic neurons. Consistent with the roles of ankyrin G in targeting Navchannels to specific domains in neurons and cardiac myocytes, we have observed an increased density of Navchannels at the neuro-cardiac junctions in co-cultures of cardiac myocytes and sympathetic neurons. We have also found that KCNQ1 channels are enriched at that sites. The increased density of Navand KCNQ1 channels at the sites of sympathetic innervation is likely to play a role in regulation of the cardiac excitability by sympathetic nervous system.
ThemicroRNA476a/RFL module regulates adventitious root formation through a mitochondria-dependent pathway inPopulus
Authors: Xu Changzheng , Tao Yuanxun , Fu Xiaokang , Guo Li , Xing Haitao , Li Chaofeng , Su HuiLi , Wang Xianqiang , Hu Jian , Fan Di , Chiang Vincent L. , Luo Keming
Published: November 2019

Adventitious root (AR) formation at the base of stem cuttings determines the efficiency of clonal propagation for woody plants. Many endogenous and environmental factors influence AR formation. However, our knowledge about the regulation of AR development by mitochondrial metabolism in plants is very limited. Here we identifiedPopulus-specificmiR476aas a novel regulator of wound-induced adventitious rooting via orchestrating mitochondrial homeostasis in poplar.MiR476aexhibited inducible expression during AR formation and directly targets severalRestorer of Fertility like(RFL) genes encoding mitochondrion-localized pentatricopeptide repeat proteins. Genetic modification ofmiR476-RFLexpression revealed themiR476/RFL-mediated dynamic regulation of mitochondrial homeostasis on AR formation in transgenic poplar. Furthermore, mitochondrial perturbation via exogenous chemical inhibitor validated that themiR476a/RFL-directed AR formation depended on mitochondrial regulation though modulating the auxin pathway. Our results established a miRNA-directed mitochondrion-auxin signaling cascade required for AR development, providing novel insights into the understanding of mitochondrial regulation on plant developmental plasticity.
Statistical power: implications for planning MEG studies
Authors: Chaumon Maximilien , Puce Aina , George Nathalie
Published: November 2019

Statistical power is key for robust, replicable science. Here, we systematically explored how numbers of trials and subjects affect statistical power in MEG sensor-level data. More specifically, we simulated “experiments” using the MEG resting-state dataset of the Human Connectome Project (HCP). We divided the data in two conditions, injected a dipolar source at a known anatomical location in the “signal condition”, but not in the “noise condition”, and detected significant differences at sensor level with classical paired t-tests across subjects, using amplitude, squared amplitude, and global field power (GFP) measures. Group-level detectability of these simulated effects varied drastically with anatomical origin. We thus examined in detail which spatial properties of the sources affected detectability, looking specifically at the distance from closest sensor and orientation of the source, and at the variability of these parameters across subjects. In line with previous single-subject studies, we found that the most detectable effects originate from source locations that are closest to the sensors and oriented tangentially with respect to the head surface. In addition, cross-subject variability in orientation also affected group-level detectability, boosting detection in regions where this variability was small and hindering detection in regions where it was large. Incidentally, we observed a considerable covariation of source position, orientation, and their cross-subject variability in individual brain anatomical space, making it difficult to assess the impact of each of these variables independently of one another. We thus also performed simulations where we controlled spatial properties independently of individual anatomy. These additional simulations confirmed the strong impact of distance and orientation and further showed that orientation variability across subjects affects detectability, whereas position variability does not. Importantly, our study indicates that strict unequivocal recommendations as to the ideal number of trials and subjects for any experiment cannot be realistically provided for neurophysiological studies and should be adapted according to the brain regions under study.
Manual dexterity of mice during food-handling involves the thumb and a set of fast basic movements
Authors: Barrett John M. , Tapies Martinna G. Raineri , Shepherd Gordon M. G.
Published: November 2019

The small first digit (D1) of the mouse’s hand resembles a volar pad, but its thumb-like anatomy suggests ethological importance for manipulating small objects. To explore this possibility, we recorded high-speed close-up video of mice eating seeds and other food items. Analyses of ethograms and automated tracking with DeepLabCut revealed multiple distinct microstructural features of food-handling. First, we found that mice indeed made extensive use of D1 for dexterous manipulations. In particular, mice used D1 to hold food with either of two grip types: a pincer-type grasp, or a “thumb-hold” grip, pressing with D1 from the side. Thumb-holding was preferentially used for handling smaller items, with the smallest items held between the two D1s alone. Second, we observed that mice cycled rapidly between two postural modes while feeding, with the hands positioned either at the mouth (oromanual phase) or resting below (holding phase). Third, we identified two highly stereotyped D1-related movements during feeding, including an extraordinarily fast (∼20 ms) “regrip” maneuver, and a fast (∼100 ms) “sniff” maneuver. Lastly, in addition to these characteristic simpler movements and postures, we also observed highly complex movements, including rapid D1-assisted rotations of food items and dexterous simultaneous double-gripping of two food fragments. Manipulation behaviors were generally conserved for different food types, and for head-fixed mice. Wild squirrels displayed a similar repertoire of D1-related movements. Our results define, for the mouse, a set of kinematic building-blocks of manual dexterity, and reveal an outsized role for D1 in these actions.
Estimating mutual information under measurement error
Authors: Ma Cong , Kingsford Carl
Published: November 2019

Mutual information is widely used to characterize dependence between biological signals, such as co-expression between genes or co-evolution between amino acids. However, measurement error of the biological signals is rarely considered in estimating mutual information. Measurement error is widespread and non-negligible in some cases. As a result, the distribution of the signals is blurred, and the mutual information may be biased when estimated using the blurred measurements. We derive a corrected estimator for mutual information that accounts for the distribution of measurement error. Our corrected estimator is based on the correction of the probability mass function (PMF) or probability density function (PDF, based on kernel density estimation). We prove that the corrected estimator is asymptotically unbiased in the (semi-) discrete case when the distribution of measurement error is known. We show that it reduces the estimation bias in the continuous case under certain assumptions. On simulated data, our corrected estimator leads to a more accurate estimation for mutual information when the sample size is not the limiting factor for estimating PMF or PDF accurately. We compare the uncorrected and corrected estimator on the gene expression data of TCGA breast cancer samples and show a difference in both the value and the ranking of estimated mutual information between the two estimators.
The Landscape of Mutations in Human Fumarate Hydratase
Authors: Shorthouse David , Hall Michael W J , Hall Benjamin A
Published: November 2019

Fumarate Hydratase (FH) is an enzyme of the citric acid (TCA) cycle that is responsible for reversibly catalysing the conversion between fumarate and malate. FH loss and subsequent buildup of the oncometabolite fumarate causes hereditary leiomyomatosis and renal cell carcinoma. We explore the mutational landscape of FH in silico, predict the functional effects of many already detected mutations, and categorise detected but un-characterised mutations in human populations. Using mutational energy predicting tools such as Rosetta and FoldX we accurately predict mutations and mutational hotspots with high disruptive capability. Furthermore, through performing molecular dynamics simulations we show that hinge regions of the protein can be stabilized or destabilized by mutations, with new mechanistic implications of the consequences on the binding affinity of the enzyme for its substrates. Finally, we categorise all potential mutations in FH into functional groups, and predict which known mutations in the human population are loss-of-function, and therefore predispose patients to papillary renal carcinoma – we validate our findings through analysis of metabolomics data of characterized cell lines.
Scalable Phylogenetic Profiling using MinHash Uncovers Likely Eukaryotic Sexual Reproduction Genes
Authors: Moi David , Kilchoer Laurent , Aguilar Pablo S. , Dessimoz Christophe
Published: November 2019

Phylogenetic profiling is a computational method to predict genes involved in the same biological process by identifying protein families which tend to be jointly lost or retained across the tree of life. Phylogenetic profiling has customarily been more widely used with prokaryotes than eukaryotes, because the method is thought to require many diverse genomes. There are now many eukaryotic genomes available, but these are considerably larger, and typical phylogenetic profiling methods require quadratic time or worse in the number of genes. We introduce a fast, scalable phylogenetic profiling approach entitled HogProf, which leverages hierarchical orthologous groups for the construction of large profiles and locality-sensitive hashing for efficient retrieval of similar profiles. We show that the approach outperforms Enhanced Phylogenetic Tree, a phylogeny-based method, and use the tool to reconstruct networks and query for interactors of the kinetochore complex as well as conserved proteins involved in sexual reproduction: Hap2, Spo11 and Gex1. HogProf enables large-scale phylogenetic profiling across the three domains of life, and will be useful to predict biological pathways among the hundreds of thousands of eukaryotic species that will become available in the coming few years. HogProf is available athttps://github.com/DessimozLab/HogProf.
Exposure to PM2.5 during pregnancy or lactation increases methylation while reducing the expression of Pdx1 and NEUROG3 in mouse pancreatic islets
Authors: Ataíde Lima Raquel Patricia , Boico Vitor Ferreira , Peruca Guilherme Francisco , Cruz Rodrigues Kellen Cristina da , Yariwake Victor Yuji , Neto Daisuke Hayashi , de Carvalho Costa Maria José , Rebelo Santos-Silva Junia Carolina , Anhê Gabriel Forato , Nascimento Saldiva Paulo Hilário , Veras Mariana Matera , de Oliveira Prada Patrícia
Published: November 2019

Air pollution is comprised of several substances, including particulate matter (PM). Exposure to air pollution may trigger alterations in DNA methylation thus modifying gene expression patterns. This phenomenon is likely to mediate the relationship between exposure to air pollution and adverse health effects. The purpose of this study was analyzing the effects of exposure to PM2.5 during pregnancy or lactation and whether it would cause multigenerational epigenetic alterations in the promoter region of the genes Pdx1 and NEUROG3 within mouse pancreatic islets. Our results show that maternal exposure to PM2.5 led to an elevation in blood glucose levels within the two following generations (F1 and F2). There was also an increase in DNA methylation in the aforementioned promoter regions accompanied by reduced gene expression in generations F1 and F2 upon F0 exposure to PM2.5 during pregnancy. These data suggest that maternal exposure to PM2.5 from air pollution, particularly during pregnancy, may lead to a multigenerational and lifelong negative impact on glucose homeostasis mediated by an increase in DNA methylation within the promoter region of the genes Pdx1 and NEUROG3 in pancreatic islets.
Marine deforestation leads to widespread loss of ecosystem function
Authors: Edwards Matthew S , Konar Brenda , Kim Ju-Hyoung , Gabara Scott , Sullaway Genoa , McHugh Tristin A , Spector Michael , Small Sadie L
Published: November 2019

Trophic interactions can result in changes to the abundance and distribution of habitat-forming species that dramatically reduce ecosystem health and functioning. Nowhere may this be as dramatic as in the coastal zone of the Aleutian Archipelago, where overgrazing by herbivorous sea urchins that began in the 1980s resulted in widespread deforestation of the region’s kelp forests. Here we show that this deforestation resulted in decreased macroalgal and invertebrate abundance and diversity, increased benthic irradiances, and reduced rates of gross primary production and respiration by the ecosystem. These opposing metabolic processes remain in balance, however, which resulted in little-to-no changes to net ecosystem production. These patterns were consistent across nine islands spanning more than 1000 kilometers of the archipelago. In light of the worldwide declines in kelp forests observed in recent decades, our findings suggest that marine deforestation profoundly affects the health of coastal ecosystems and how they function.

Significance statement

Widespread marine deforestation results in reduced biodiversity and primary productivity throughout more than 1000 km of the Aleutian Archipelago.
Polyploidy in the adultDrosophilabrain
Authors: Nandakumar Shyama , Grushko Olga , Buttitta Laura A.
Published: November 2019

Long-lived cells such as terminally differentiated postmitotic neurons and glia must cope with the accumulation of damage over the course of an animal’s lifespan. How long-lived cells deal with ageing-related damage is poorly understood. Here we show that polyploid cells accumulate in the ageing adult fly brain and that polyploidy protects against DNA damage-induced cell death. Multiple types of neurons and glia that are diploid at eclosion, become polyploid with age in the adultDrosophilabrain. The optic lobes exhibit the highest levels of polyploidy, associated with an elevated DNA damage response in this brain region with age. Inducing oxidative stress or exogenous DNA damage leads to an earlier onset of polyploidy, and polyploid cells in the adult brain are more resistant to DNA damage-induced cell death than diploid cells. Our results suggest polyploidy may serve a protective role for neurons and glia in ageingDrosophila melanogasterbrains.
The role of organizational climate in setting project goals
Authors: Zwikael Ofer , Meredith Jack R.
Published: November 2019

Purpose

Project goal setting, led by a project proposal development team, is an important operations process because effective goal setting aligned with the operations strategy can enhance project investment decision making, project success and thereby operations performance. The purpose of this paper is to argue that because of the strategic nature of this task, the organizational climate (OC) that the proposal development team works in is critical for the effectiveness of their goal setting.

Design/methodology/approach

The authors raise hypotheses regarding the role OC plays in enhancing the effectiveness of the support senior executives provide to project proposal teams. The authors test the hypotheses in a longitudinal survey of 200 managers in the USA.

Findings

Results show that a formal organizational process used by proposal development teams for setting project goals is highly effective and that an appropriate OC further intensifies the positive effect of such a process. However, a formal organizational process has no positive effect on effective goal setting if implemented in an environment with a poor OC.

Originality/value

The paper contributes to the literature by finding that a positive OC intensifies the already positive effect of organizational support. In practice, the creation of such a climate can enhance project goal setting, project success, and as a result, operations performance.
Susceptibility of rat immortalized neuronal cell line Rn33B expressing equine major histocompatibility class 1 to equine herpesvirus‐1 infection is differentiation dependent
Authors: Minato Erina , Kobayashi Atsushi , Aoshima Keisuke , Fukushi Hideto , Kimura Takashi
Published: November 2019

Equine herpesvirus‐1 (EHV‐1), which causes encephalomyelitis in horses, shows endotheliotropism in the central nervous system of horses, and generally does not infect neurons. However, little is known about the mechanism underlying the resistance of neuron to EHV‐1, due to the lack of convenient cell culture systems. In this study, we examined EHV‐1 infection in immortalized Rn33B rat neuronal cells, which differentiate into neurons when cultured under nonpermissive conditions. Because murine cell lines are resistant to EHV‐1 infections due to the lack of functional entry receptors for EHV‐1, we used an Rn33B‐derived cell line that stably expresses the equine MHC class 1 molecule, which acts as EHV‐1 entry receptor (Rn33B‐A68B2M cells). EHV‐1 infected undifferentiated Rn33B‐A68B2M cells more efficiently than differentiated cells, resulting in the production of progeny virus in the former but not in the latter. By contrast, both differentiated and undifferentiated cells infected with herpes simplex virus‐1 produced infectious viral progeny. While EHV‐1 infection induced stronger expression of IFN alpha gene in differentiated cells than in undifferentiated cells, downstream IFN responses, including phosphorylation of STAT1 (signal transducer and activator of transcription 1) and expression of IFN‐stimulated genes, were not activated regardless of whether cells were differentiated or not. These results suggest that neuronal differentiation of RN33B‐A68B2M cells reduced their susceptibility to EHV‐1, which is not due to different IFN responses. This culture system may be useful as an in vitro model for studying neuron‐specific resistance to EHV‐1, by investigating viral and host factors responsible for the difference in susceptibility between differentiated and undifferentiated cells.
The eukaryome: Diversity and role of microeukaryotic organisms associated with animal hosts
Authors: del Campo Javier , Bass David , Keeling Patrick J.
Published: November 2019

Awareness of the roles that host‐associated microbes play in host biology has escalated in recent years. However, microbiome studies have focused essentially on bacteria, and overall, we know little about the role of host‐associated eukaryotes outside the field of parasitology. Despite that, eukaryotes and microeukaryotes in particular are known to be common inhabitants of animals. In many cases, and/or for long periods of time, these associations are not associated with clinical signs of disease.

Unlike the study of bacterial microbiomes, the study of the microeukaryotes associated with animals has largely been restricted to visual identification or molecular targeting of particular groups. So far, since the publication of the influential Human Microbiome Project Consortium paper in 2012, few studies have been published dealing with the microeukaryotes using a high‐throughput barcoding ‘microbiome‐like’ approach in animals.

Nonetheless, microeukaryotes have an impact on the host physiology and lifestyle and also on the diversity and composition of the wider symbiotic community of bacteria and viruses. Beyond being parasites, microeukaryotes have many different roles in animals. For example, they directly interact with the host immune system in mammals; they have a key role on cellulose degradation, lignocellulose in xylophage termites and cockroaches; and they have an essential role in providing photosynthates to reef‐building corals.

Certain microeukaryotic lineages have diversified within hosts more than others. These cases of co‐evolution led to different forms of symbiosis: from mutualism (like Symbiodinium in corals or parabasalians in termites), to commensalism (Blastocystis in humans) or to strict parasitism (apicomplexans or microsporidians in a broad range of hosts). We will review the ecological context and the evolutionary mechanisms that ended up in these different symbiotic scenarios, across the taxonomic range of both symbionts and their metazoan hosts.

Host‐associated microeukaryotes have impacts at many levels, from individual animal health to ecosystems and to agroeconomy. Therefore, it is crucial to have a better understanding of their diversity and roles. Novel methodologies are being developed to access the eukaryotic fraction of the microbiome using high‐throughput methods. From ‐omics, to imaging and barcoding approaches biased against metazoans, these novel methodologies and strategies are helping us to increase and improve our knowledge of microeukaryotes in animal‐associated environments.

A free Plain Language Summary can be found within the Supporting Information of this article.
Can dynamic network modelling be used to identify adaptive microbiomes?
Authors: Garcia Joshua , Kao‐Kniffin Jenny
Published: November 2019

In recent times, interest has grown in understanding how microbiomes – the collection of microorganisms in a specific environment – influence the survivability or fitness of their plant and animal hosts. The profound diversity of bacterial and fungal species found in certain environments, such as soil, provides a large pool of potential microbial partners that can interact in ways that reveal patterns of associations linking host–microbiome traits developed over time. However, most microbiome sequence data are reported as a community fingerprint, without analysis of interaction networks across microbial taxa through time.

To address this knowledge gap, more robust tools are needed to account for microbiome dynamics that could signal a beneficial change to a plant or animal host. In this paper, we discuss applying mathematical tools, such as dynamic network modelling, which involves the use of longitudinal data to study system dynamics and microbiomes that identify potential alterations in microbial communities over time in response to an environmental change. In addition, we discuss the potential challenges and pitfalls of these methodologies, such as handling large amounts of sequencing data and accounting for random processes that influence community dynamics, as well as potential ways to address them.

Ultimately, we argue that components of microbial community interactions can be characterized through mathematical models to reveal insights into complex dynamics associated with a plant or animal host trait. The inclusion of interaction networks in microbiome studies could provide insights into the behaviour of complex communities in tandem with host trait modification and evolution.

A free Plain Language Summary can be found within the Supporting Information of this article.
Within‐individual trophic variability drives short‐term intraspecific trait variation in natural populations
Authors: Musseau Camille , Vincenzi Simone , Santoul Frédéric , Boulêtreau Stéphanie , Jesenšek Dusan , Crivelli Alain J.
Published: November 2019

Intraspecific trait variability (ITV) maintains functional diversity in populations and communities, and plays a crucial role in ecological and evolutionary processes such as trophic cascades or speciation. Furthermore, functional variation within a species and its populations can help buffer against harmful environmental changes. Trait variability within species can be observed from differences among populations, and between‐ and within individuals. In animals, ITV can be driven by ontogeny, the environment in which populations live and by within‐individual specialization or variation unrelated to growth. However, we still know little about the relative strength of these drivers in determining ITV variation in natural populations.

Here, we aimed to (a) measure the relative strength of between‐ and within‐individual effects of body size on ITV over time, and (b) disentangle the trophic changes due to ontogeny from other sources of variability, such as the environment experienced by populations and individual preferences at varying temporal and spatial scales.

We used as a model system the endangered marble trout Salmo marmoratus, a freshwater fish living in a restricted geographical area (<900 km2) that shows marked changes in diet through ontogeny. We investigated two trophic traits, trophic position and resource use, with stable isotopes (δ15N and δ13C), and followed over time 238 individually tagged marble trout from six populations to estimate the trophic changes between and within individuals through ontogeny at three different time‐scales (short term: 3 months, medium term: 1 year and long term: 2 years).

We found that the relative strength of between‐ and within‐individual effects of body size on trophic position and resource use change strongly over time. Both effects played a similar role in ITV over medium‐ and long‐term time‐scales, but within‐individual effects were significantly driving trophic variability over short‐term scales. Apart from ontogenetic shifts, individuals showed variability in trophic traits as big as the variability estimated between populations.

Overall, our results show how the relative strengths of ITV drivers change over time. This study evidences the crucial importance of considering effects of time‐scales on functional variability at individual, population and species levels.
Evidence based practice and knowledge translation: A survey of Australian occupational therapy practice with clients experiencing neurocognitive impairments
Authors: Nott Melissa T. , Barden Hannah L. H. , Chapparo Chris , Ranka Judy L.
Published: November 2019

Introduction

The clinical practice patterns and use of research evidence by Australian occupational therapists working with clients experiencing neurocognitive impairments has not been surveyed for nearly 10 years. This survey aimed to evaluate the current status of occupational therapy practice and evidence use and provide recommendations for ongoing evidence translation.

Methods

An online survey of occupational therapists working in Australia was conducted over four months targeting registered clinicians working with adults experiencing neurocognitive impairments.

Results

191 occupational therapists from a wide range of clinical practice areas, with a significant level of experience completed the survey. Functional retraining (n = 180, 94%), compensatory training (n = 173, 91%) and task/environmental modifications (n = 161, 84%) were the most commonly reported intervention techniques, while more targeted interventions such as context‐sensitive training (n = 54, 28%), positive behaviour supports (n = 42, 22%) and metacognitive strategy training (n = 37, 19%) were used less frequently. Half the respondents were aware of current research evidence and suggested a wide range of strategies supporting evidence translation. Traditional barriers of limited time, access and skills to interpret research were also reported.

Conclusion

Consistent with earlier surveys most occupational therapists continue to use a functional/compensatory approach to cognitive rehabilitation, with an increasing number of therapists using specialist cognitive interventions. The current challenge for occupational therapists is embedding specialist techniques into occupation‐based intervention. Knowledge translation and implementation strategies will be a critical component to achieving this.
Hypoperfusion in the posterior cingulate cortex is associated with lower bone mass density in elderly women with osteopenia and Alzheimer’s disease
Authors: Takano Yumi , Mutoh Tatsushi , Tatewaki Yasuko , Seki Toshiki , Yamamoto Shuzo , Odagiri Hayato , Arai Hiroyuki , Taki Yasuyuki
Published: November 2019

Accelerated bone loss is closely associated with Alzheimer's disease (AD), but the relationship between bone mineral density (BMD) and imaging markers of neurodegeneration remains uncertain. We examined the effect of low bone mass (osteopenia) on regional cerebral blood flow (rCBF) in patients with AD (n = 19) and non‐demented aging (n = 12). We enrolled 31 female outpatients diagnosed with osteopenia (age ≥ 65 years) who had both a single‐photon emission computed tomography brain scan and dual‐energy X‐ray absorptiometry bone scan taken at their initial investigation. We analyzed the relationship between osteopenia (−2.5 < T‐score < −1) and rCBF in 62 cortical areas measured using the stereotactic extraction estimation analysis on single‐photon emission computed tomography (SPECT) (mean Z‐scores). We found that the mean Z‐scores of 14 cerebral subregions, most of which are often affected early in AD, were significantly lower in the AD group than the non‐demented group (P < .001). The age‐stratified multivariate regression analysis showed that the decreased rCBF in the left posterior cingulate cortex (PCC) was an independent predictor of osteopenia (r = −0.395; P = .005). BMD and rCBF in the left PCC were significantly correlated in the overall population (r = −0.54; P = .001), as well as the AD group (r = −0.514; P = .02). These imaging data suggest that osteopenia may contribute to neurodegeneration of a brain network hub associated with AD.
Rapid divergent coevolution of Sinopotamon freshwater crab genitalia facilitates a burst of species diversification
Authors: YAO Fengxin , SHI Boyang , WANG Xiaoqi , PAN Da , BAI Ming , YAN Jie , CUMBERLIDGE Neil , SUN Hongying
Published: November 2019

One of the most striking radiations in brachyuran evolution is the considerable morphological diversification of the external reproductive structures of primary freshwater crabs: the male first gonopod (G1) and the female vulva (FV). However, the lack of quantitative studies, especially the lack of data on female genitalia, has seriously limited our understanding of genital evolution in these lineages. Here we examined 69 species of the large Chinese potamid freshwater crab genus Sinopotamon Bott, 1967 (more than 80% of the described species). We used a landmark‐based geometric morphometric approach to analyze variation in the shape of the G1 and FV, and to compare the relative degree of variability of the genitalia with non‐reproductive structures (the third maxillipeds). We found rapid divergent evolution of the genitalia among species of Sinopotamon when compared to non‐reproductive traits. In addition, the reconstruction of ancestral groundplans, together with plotting analyses, indicated that the FV show the most rapid divergence, and that changes in FV traits correlate with changes in G1 traits. Here we provide new evidence for coevolution between the male and female external genitalia of Sinopotamon that has likely contributed to rapid divergent evolution and an associated burst of speciation in this lineage.
Activation of insulin‐like growth factor‐1 receptor confers acquired resistance to osimertinib in non‐small cell lung cancer with EGFR T790M mutation
Authors: Hayakawa Daisuke , Takahashi Fumiyuki , Mitsuishi Yoichiro , Tajima Ken , Hidayat Moulid , Winardi Wira , Ihara Hiroaki , Kanamori Koichiro , Matsumoto Naohisa , Asao Tetsuhiko , Ko Ryo , Shukuya Takehito , Takamochi Kazuya , Hayashi Takuo , Suehara Yoshiyuki , Takeda Nakamura Ikuko , Ueno Toshihide , Kohsaka Shinji , Mano Hiroyuki , Takahashi Kazuhisa
Published: November 2019

Background

Osimertinib (AZD9291) is a third‐generation EGFR‐tyrosine kinase inhibitor (TKI) that selectively inhibits the activating EGFR mutation and T790M mutation, and is currently used globally to treat EGFR‐mutant non‐small cell lung cancer (NSCLC). However, acquired resistance to osimertinib is inevitable.

Methods

We established osimertinib‐resistant cells (PC9/T790M/AZDR and H1975/AZDR) derived from EGFR‐mutant NSCLC cells harboring T790M mutation, and investigated the mechanism of acquired resistance to osimertinib by whole‐exome sequencing and multiple phospho‐receptor tyrosine kinase (RTK) array. A tumor specimen from an EGFR‐mutant NSCLC patient with acquired resistance to osimertinib was also subjected to immunohistochemical analysis.

Results

Whole‐exome sequencing analysis demonstrated that genetic alterations, such as acquisition of EGFR C797S, loss of T790M mutation, MET amplification, or mutated KRAS, MEK, BRAF, PIK3CA, were not detected. Analysis of phospho‐RTK array revealed that insulin‐like growth factor‐1 receptor (IGF1R) was activated in PC9/T790M/AZDR and H1975/AZDR cells. Knockdown of IGF1R by siRNA as well as inhibition of IGF1R activation by linstinib (IGF1R inhibitor) significantly restored the sensitivity to osimertinib. Immunohistochemical analysis revealed that the expression level of phosphorylated IGF1R was higher in the tumor specimen from the EGFR‐mutant NSCLC patient with acquired resistance to osimertinib than in the specimen collected prior to the treatment.

Conclusions

IGF1R activation could occur following treatment with osimertinib in EGFR‐mutant NSCLC with T790M mutation, and might be one of the mechanisms underlying osimertinib resistance. Combined treatment of osimertinib and IGF1R inhibitor might be effective in overcoming the acquired resistance to osimertinib induced by IGF1R activation.

Key points

Significant findings of the study: Using osimertinib‐resistant cells, we found that IGF1R activation induced by osimertinib treatment in EGFR‐mutant NSCLC with T790M mutation is involved in resistance. Increased phosphorylation of IGF1R was observed in the tumor specimen from an EGFR‐mutant NSCLC patient with acquired osimertinib resistance.

What this study adds: IGF1R activation might be one of the mechanisms of osimertinib resistance. A combination therapy with osimertinib and an IGF1R inhibitor might be an optimal approach for overcoming the acquired resistance to osimertinib induced by IGF1R activation.
Horizontal and vertical distribution of mosquitoes (Diptera: Culicidae) in the rainforest of Maromizaha, Madagascar: implications for pathogen transmission to humans and animals
Authors: Tantely Luciano M , Randrianambinintsoa Fano J , Woog Friederike , Raharinirina Manou R , Ratsimbazafy Jonah , Boyer Sébastien , Girod Romain
Published: November 2019

The horizontal and vertical distribution of mosquito species was studied in Maromizaha rainforest, Madagascar. In November 2014, horizontal distribution was studied using light traps that were placed in four habitat types, ranging from degraded forest to primary rainforest. In November to December 2016, vertical distribution was studied using light traps placed near to the ground and elevated near the canopy. From the horizontal survey, 476 adults were collected:Uranotaenia(52.10%) andCulex(35.2%) were the most abundant genera. The highest numbers of mosquitoes were observed in the rainforest edge habitat, while the highest mosquito diversity was observed within primary rainforest. From the vertical survey, 276 adults were collected:Culexwas the most abundant genus and represented 75.70% of adults caught. Mosquitoes were more abundant in traps placed near the ground than those near the canopy. The highest species diversity was observed near the canopy. The higher abundance of mosquitoes at the forest edge agrees with the role of this zone as an ecotone between intact rainforest and the nearest human habitation. Increased mosquito abundance in lower strata might heighten their contact with particular vertebrate hosts. The presence of vectors in different habitats and in varying elevations likely influences the risk of pathogen transmission between animals and humans in this rainforest.
Phenotypic characterization of testicular immune cells expressing immune checkpoint molecules in wild‐type and pituitary adenylate cyclase‐activating polypeptide‐deficient mice
Authors: Meggyes Matyas , Lajko Adrienn , Fulop Balazs Daniel , Reglodi Dora , Szereday Laszlo
Published: November 2019

Problem

Pituitary adenylate cyclase‐activating polypeptide (PACAP) is a neuropeptide having several regulatory functions in the nervous system and in peripheral organs including those of the reproductive system. PACAP‐deficient male mice have several morphological, biochemical, behavioral defects and show disturbed signaling in spermatogenesis affecting fertility in PACAP KO mice. Reproductive functions such as fertility, mating, and maternal behaviors have been widely investigated, but no immune analyses are available regarding the testicular immune‐privileged environment in male PACAP‐deficient mice.

Method of Study

We performed detailed immunophenotyping of testicular immune cells and investigated the expression of TIM‐3 and PD‐1 Immune checkpoint molecules of immune cells together with the detection of galectin‐9 and perforin. We investigated the percentage of numerous immune cell populations in the testis of wild‐type and PACAP‐deficient mice.

Results

We demonstrated a significant increase in the frequency of testicular CD8+ T cells together with the decrease in Treg cell number obtained from PACAP KO mice compared with wild‐type mice. Investigating Immune checkpoint receptors, only PD‐1 showed a significantly decreased expression in CD8+ T cells in PACAP KO mice compared with wild‐type suggesting an impaired PD‐1/PD‐L1 pathway. Regarding TIM‐3 expression, we did not find any significant difference between the investigated groups.

Conclusion

We hypothesize that these local changes may result in an immune activation with disturbed testicular immunoregulation in PACAP KO mice; however, determining the exact function requires further investigations. Our data further support the view that besides a systemic immune tolerance, localized active immunosuppression is involved in the regulation of testicular immune privilege.
Is it possible to apply trial outcomes to a real‐world population? A novel approach to External Validity Analysis
Authors: Agresta Franca , Fois Romano , Garrett Claire , Rozen Genia , Polyakov Alex
Published: November 2019

Background

Translation of findings from randomised controlled trials (RCT), the foundation of evidence‐based medicine, into clinical practice requires an understanding of relationships between patient characteristics, treatment practices and outcomes. We propose a novel technique, External Validity Analysis (EVA), to evaluate applicability of findings from a large RCT, comparing baseline characteristics, interventions and outcomes between the RCT and a large clinical database.

Aim

To perform EVA of the findings of a randomised controlled trial (ESTHER‐1) to a population in an Australian clinic setting. To demonstrate this method, we evaluated the discordance in first cycle follicle‐stimulating hormone (FSH) exposure and outcomes between the two populations, to inform clinical practice.

Materials and Methods

In this retrospective, descriptive analysis, we compared practices and outcomes between the follitropin alfa ‘conventional’ dosing arm of the ESTHER‐1 trial and a selected comparable clinic subpopulation of patients who underwent controlled ovarian stimulation using FSH.

Results

Mean FSH exposure was 34% higher in the clinic subpopulation than in the trial subpopulation, resulting in higher average ovarian response without improving the likelihood of clinical pregnancy or live birth.

Conclusions

EVA allowed for the comparison of a trial population with a selected clinic population with similar characteristics. With respect to FSH consumption, this analysis revealed higher exposure to FSH in the clinic setting without a corresponding benefit. The comparison reveals population differences as well as the potential to improve clinical outcomes through a reappraisal of current practices and objectives in gonadotropin dose selection.
Risk factors for severe postpartum haemorrhage: A population‐based retrospective cohort study
Authors: Davey Mary‐Ann , Flood Margaret , Pollock Wendy , Cullinane Fiona , McDonald Susan
Published: November 2019

Background

Severe postpartum haemorrhage (PPH) is a serious clinical problem that is increasing in incidence.

Aim

To identify risk factors for severe PPH.

Materials and Methods

Population‐based retrospective cohort study of all women who gave birth in Victoria in 2009–2013 using the validated Victorian Perinatal Data Collection. Three multivariable logistic regression models estimated the adjusted risk of severe PPH. Adjusted odds ratios (aOR) and their 95% confidence intervals are reported. The primary outcome was severe PPH (estimated blood loss of ≥1500 mL).

Results

Severe PPH occurred in 1.4% of all births (n = 5122). Maternal characteristics significantly associated with severe PPH included: multiple pregnancy; older maternal age; overweight/obesity; first births. Other risk factors included placental complications, macrosomia, instrumental vaginal birth, third and fourth degree perineal lacerations, in‐labour caesarean section, birth at a gestation other than 37–41 weeks, duration of labour 12 to <24 h, and use of oxytocin infusions in labour. Planned pre‐labour caesarean section was associated with reduced odds of severe PPH. Severe PPH also occurred in 0.7% (n = 104) of women with none of the identified risk factors.

Conclusions

Numerous risk factors for severe PPH are identified but some cases are not modifiable or predictable. Limiting use of oxytocin infusions in labour to cases with clear indications, and strategies to prevent severe perineal lacerations would prevent some severe PPHs. Close surveillance of all women in the hours immediately following birth is crucial to detect and manage excessive blood loss and reduce severe PPH and associated morbidity.
Immune dysregulation increases the incidence of delayed‐type drug hypersensitivity reactions
Authors: Naisbitt Dean J. , Olsson‐Brown Anna , Gibson Andrew , Meng Xiaoli , Ogese Monday O. , Tailor Arun , Thomson Paul
Published: November 2019

Delayed‐type, T cell–mediated, drug hypersensitivity reactions are a serious unwanted manifestation of drug exposure that develops in a small percentage of the human population. Drugs and drug metabolites are known to interact directly and indirectly (through irreversible protein binding and processing to the derived adducts) with HLA proteins that present the drug‐peptide complex to T cells. Multiple forms of drug hypersensitivity are strongly linked to expression of a single HLA allele, and there is increasing evidence that drugs and peptides interact selectively with the protein encoded by the HLA allele. Despite this, many individuals expressing HLA risk alleles do not develop hypersensitivity when exposed to culprit drugs suggesting a nonlinear, multifactorial relationship in which HLA risk alleles are one factor. This has prompted a search for additional susceptibility factors. Herein, we argue that immune regulatory pathways are one key determinant of susceptibility. As expression and activity of these pathways are influenced by disease, environmental and patient factors, it is currently impossible to predict whether drug exposure will result in a health benefit, hypersensitivity or both. Thus, a concerted effort is required to investigate how immune dysregulation influences susceptibility towards drug hypersensitivity.
Parental understanding of relapsing idiopathic nephrotic syndrome—Where are the knowledge gaps?
Authors: Lo Cao Edward , Amir Noa , McKay Ashlene , Durkan Anne M.
Published: November 2019

Aim

To assess parental understanding of idiopathic nephrotic syndrome (INS) and its management, to enable targeted education in areas of deficit.

Methods

Families of children with at least one relapse of INS were interviewed, following a template covering key domains of (a) disease understanding, (b) management of INS and (c) access to information. Common trends and responses were identified and notable observations recorded.

Results

Twenty‐one parents were interviewed. The mean duration of INS was 4.4 years (range 0.5‐14.5 years), with a mean of two steroid‐sparing agents used. Although 90% parents self‐reported that they understood INS, only 29% could appropriately define relapse and 24% name potential complications. The management of INS was generally good, with most parents appropriately testing urine (81%) and managing relapses (90%). Unnecessary dietary restrictions were imposed on 57% during remission. The Internet was searched by 90% of parents for disease and drug information. Further information was desired in paper form (71%), hospital website (81%) and face‐to‐face workshop (90%), plus educational materials for schools.

Conclusion

Parents overestimated their understanding of INS; however, their management was generally well done. Parents desired more information and support in various forms.
Archaeological human hair in a burial context: Microscopical evaluation of samples from Iași, Romania (18th–19th centuries)
Authors: Petraru O.‐M. , Groza V.‐M. , Neagu A.‐N. , Bejenaru L.
Published: November 2019

Owing to its resistance to degradation, hair is an important bio‐sample with unique properties used to study post mortem decompositional changes. The present paper is a microscopical approach to preserved human scalp hair discovered at the 18th–19th‐century archaeological site of Iași, Romania. The hair fibre alterations were assessed using optical microscopy, scanning electron microscopy, image analysis and hair histological scores. External alterations showed a statistically significant heterogeneous degradation. Image analysis results of the internal degradation of hairs were correlated to external lesions. The results consider the implication of intrinsic biological factors in the post mortem degradation of human hair preserved in graves with comparable environmental conditions.