bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparing written and verbal delivery of a treatment regimen to women with overactive bladder: a randomized controlled trial
Authors: Shirreff Lindsay , Anderson Michelle , McDermott Colleen
Published: October 2019

Objective:

Overactive bladder is a common condition among aging women requiring a multifaceted treatment approach, which is usually communicated by physician to the patient in the clinic setting. The objective of this two-center, randomized controlled trial was to determine if a transcribed list of six management strategies for overactive bladder improves immediate and delayed retention of these recommendations compared with a traditional verbal discussion.

Methods:

Between March, 2015 and February, 2019, women newly diagnosed with overactive bladder were randomized to either the intervention group, where they received a transcribed list of six treatment recommendations, or to the control group, where the same six recommendations were communicated verbally by their physician. Participants in both groups were asked to recall treatment recommendations immediately after their appointment and 2 weeks later. A score out of 6 was assigned at each time point based on the number of recommendations participants could list. Scores at each point of recall were compared between groups.

Results:

Seventy-two women were recruited and randomized to either the written instruction (n = 34) or verbal discussion group (n = 38). Immediate total retention score was significantly better for women who received the transcribed list compared with those receiving verbal communication (P = 0.002). There was no difference in 2-week total information retention scores between groups.

Conclusions:

A written list of recommendations is a quality improvement initiative that can improve overactive bladder participants’ immediate retention of a suggested treatment regimen, but lacks impact 2 weeks later.
Speech Perception, Dichotic Listening, and Ear Advantage in Simultaneous Bilateral Cochlear Implanted Children
Authors: Koopmann Moritz , Lesinski-Schiedat Anke , Illg Angelika
Published: October 2019

Objective:

To study the development of dichotic listening, ear advantage, and speech perception in cochlear implant (CI) recipients using five audiometric tests.

Study Design:

Prospective cohort analysis.

Setting:

University Hospital.

Patients:

One hundred twenty one participants who received simultaneous bilateral CIs and had at least 12 months of regular bilateral CI use. Age at time of testing ranged from 4 to 18 years with a mean age of 9 years (standard deviation [SD]: 3.0). Mean duration of CI use was 7.073 years (SD: 2.86).

Intervention:

Bilateral simultaneous cochlear implantation.

Main Outcome Measure:

Goettinger and Freiburger monosyllabic word test, Hochmair, Schulz and Desoyer sentence (HSM) test in noise and in quiet conditions and the dichotic listening test by Uttenweiler were applied according to the childrens’ age. The results were evaluated using a two-sided t test for dependent samples.

Results:

In all tests applied, we could not show significant differences in performance between left and right CI and therefore could not demonstrate an ear advantage. Dichotic listening was challenging, only one subject produced results required for normal hearing subjects to pass the test. The older the CI recipients get and duration of CI use increases, the more results in all speech perception tests improve.

Conclusions:

Our results cannot lend further support to the existence of ear advantage in CI recipients. We do not recommend the Uttenweiler dichotic listening test to determine lateralization. Further research to gather more information on dichotic listening and ear advantage in CI recipients is necessary and should use consonant-vowel stimuli as more comparable stimuli.
Intraoperative Recording of Auditory Brainstem Responses for Monitoring of Floating Mass Transducer Coupling Efficacy During Revision Surgery—Proof of Concept
Authors: Fröhlich Laura , Rahne Torsten , Plontke Stefan K. , Oberhoffner Tobias , Dziemba Oliver , Gadyuchko Maria , Hoth Sebastian , Mir-Salim Parwis , Müller Alexander
Published: October 2019

Objective:

The objective of the study was to measure auditory brainstem responses elicited by stimulation via a semi-implantable active middle ear implant with an electromagnetically driven floating mass transducer to quantify the coupling efficacy (=vibroplasty in situ thresholds – bone conduction thresholds) in a patient during a revision surgery.

Patients:

One patient, reimplanted with an active middle ear implant in a revision surgery.

Intervention(s):

Diagnostic.

Main Outcome Measure(s):

Intraoperative auditory brainstem responses evoked by stimulation via an active middle ear implant in a calibrated set-up directly indicating the coupling efficacy magnitude (auditory brainstem response threshold = coupling efficacy), as well as pre- and postoperative bone conduction and vibroplasty in situ thresholds.

Results:

The intraoperative auditory brainstem response threshold was detected at 0 dB nHL, i.e., the magnitude of coupling efficacy was determined intraoperatively to be 0 dB. The actual postoperative coupling efficacy (=postoperative vibroplasty in situ – postoperative bone conduction thresholds) was –2.5 dB.

Conclusions:

The coupling efficacy determined intraoperatively was consistent with the postoperative coupling efficacy. The described method seems to be a promising tool to objectively quantify the magnitude of coupling efficacy in active middle ear implant surgeries.
68Ga–Prostate-Specific Membrane Antigen-11 PET/CT
Authors: Kunikowska Jolanta , Kuliński Radosław , Muylle Kristoff , Koziara Henryk , Królicki Leszek
Published: October 2019

Background

Glioblastoma multiforme (GBM) is the most common and most aggressive primary tumor of the brain. After initial therapy and total resection of GBM, 80% to 90% of recurrences occur at the surgical margins. Currently, limited data are available in the literature on the possible use of 68Ga–prostate-specific membrane antigen (PSMA-11) for diagnosis of recurrence in GBM patients. The aim was to assess the feasibility and potential of 68Ga-PSMA-11 PET/CT as a diagnostic procedure in patients with histologically confirmed of GBM and suspected recurrent disease on MRI.

Results

No radiopharmaceutical-related adverse events were noted. Characterization of recurrent disease with MRI included T2-weighted fast spin-echo images, fluid-attenuated inversion recovery and diffusion-weighted imaging sequences, and gadolinium enhanced T1-weighted images. Visual interpretation of PET showed increased accumulation of 68Ga-PSMA-11 in recurrent lesion detected by T1 contrast enhanced and diffusion-weighted imaging images in all patients with a median SUVmax of the tumor of 6.5 and an SUVmean of 3.5. The median tumor-to-background brain ratio and tumor-to-liver ratio obtained from 68Ga-PSMA-11 PET/CT were 96.7 and 0.8, respectively.

Conclusions

The extremely low background uptake in normal brain tissue and consequently high tumor-to-brain ratio make 68Ga-PSMA-11 PET/CT highly promising for diagnosis of recurrent disease in GBM patients. Although PSMA expression in recurrent GBM also opens a potential way for targeted peptide therapy with α/β-emitters as well as for prediction of treatment with antiangiogenic agents, the low tumor-to-liver ratio observed in the majority of patients in this study suggests a limited role of radiolabeled PSMA ligands for targeted radionuclide therapy of recurrent GBM.
Multi-modal communication: song sparrows increase signal redundancy in noise
Authors: Akçay Çağlar , Beecher Michael D.
Published: October 2019

Although the effects of anthropogenic noise on animal communication have been studied widely, most research on the effect of noise in communication has focused on signals in a single modality. Consequently, how multi-modal communication is affected by anthropogenic noise is relatively poorly understood. Here, we ask whether song sparrows (Melospiza melodia) show evidence of plasticity in response to noise in two aggressive signals in acoustic and visual modalities. We test two hypotheses: (i) that song sparrows will shift signalling effort to the visual modality (the multi-modal shift hypothesis) and (ii) that they will increase redundancy of their multi-modal signalling (the back-up signal hypothesis). We presented male song sparrows with song playback and a taxidermic mount with or without a low-frequency acoustic noise from a nearby speaker. We found that males did not switch their signalling effort to visual modality (i.e. wing waves) in response to the noise. However, the correlation between warbled soft songs and wing waves increased in the noise treatment, i.e. signals became more redundant. These results suggest that when faced with anthropogenic noise, song sparrows can increase the redundancy of their multi-modal signals, which may aid in the robustness of the communication system.
Force chains in cell–cell mechanical communication
Authors: Mann Amots , Sopher Ran S. , Goren Shahar , Shelah Ortal , Tchaicheeyan Oren , Lesman Ayelet
Published: October 2019

Force chains (FCs) are a key determinant of the micromechanical properties and behaviour of heterogeneous materials, such as granular systems. However, less is known about FCs in fibrous materials, such as the networks composing the extracellular matrix (ECM) of biological systems. Using a finite-element computational model, we simulated the contraction of a single cell and two nearby cells embedded in two-dimensional fibrous elastic networks and analysed the tensile FCs that developed in the ECM. The role of ECM nonlinear elasticity on FC formation was evaluated by considering linear and nonlinear, i.e. exhibiting ‘buckling’ and/or ‘strain-stiffening’, stress–strain curves. The effect of the degree of cell contraction and network coordination value was assessed. We found that nonlinear elasticity of the ECM fibres influenced the structure of the FCs, facilitating the transition towards more distinct chains that were less branched and more radially oriented than the chains formed in linear elastic networks. When two neighbouring cells contract, a larger number of FCs bridged between the cells in nonlinear networks, and these chains had a larger effective rigidity than the chains that did not reach a neighbouring cell. These results suggest that FCs function as a route for mechanical communication between distant cells and highlight the contribution of ECM fibre nonlinear elasticity to the formation of FCs.
Macro- and mesoscale pattern interdependencies in complex networks
Authors: Palazzi M. J. , Borge-Holthoefer J. , Tessone C. J. , Solé-Ribalta A.
Published: October 2019

Identifying and explaining the structure of complex networks at different scales has become an important problem across disciplines. At the mesoscale, modular architecture has attracted most of the attention. At the macroscale, other arrangements—e.g. nestedness or core–periphery—have been studied in parallel, but to a much lesser extent. However, empirical evidence increasingly suggests that characterizing a network with a unique pattern typology may be too simplistic, since a system can integrate properties from distinct organizations at different scales. Here, we explore the relationship between some of these different organizational patterns: two at the mesoscale (modularity and in-block nestedness); and one at the macroscale (nestedness). We show experimentally and analytically that nestedness imposes bounds to modularity, with exact analytical results in idealized scenarios. Specifically, we show that nestedness and modularity are interdependent. Furthermore, we analytically evidence that in-block nestedness provides a natural combination between nested and modular networks, taking structural properties of both. Far from a mere theoretical exercise, understanding the boundaries that discriminate each architecture is fundamental, to the extent that modularity and nestedness are known to place heavy dynamical effects on processes, such as species abundances and stability in ecology.
One-to-one correspondence without language
Authors: Koopman Sarah E. , Arre Alyssa M. , Piantadosi Steven T. , Cantlon Jessica F.
Published: October 2019

A logical rule important in counting and representing exact number is one-to-one correspondence, the understanding that two sets are equal if each item in one set corresponds to exactly one item in the second set. The role of this rule in children's development of counting remains unclear, possibly due to individual differences in the development of language. We report that non-human primates, which do not have language, have at least a partial understanding of this principle. Baboons were given a quantity discrimination task where two caches were baited with different quantities of food. When the quantities were baited in a manner that highlighted the one-to-one relation between those quantities, baboons performed significantly better than when one-to-one correspondence cues were not provided. The implication is that one-to-one correspondence, which requires intuitions about equality and is a possible building block of counting, has a pre-linguistic origin.
The interdependence of corporate reputation and ownership: a network approach to quantify reputation
Authors: Zhang Yan , Schweitzer Frank
Published: October 2019

We propose a novel way to measure the reputation of firms by using information about their ownership structure. Supported by the signalling theory, we argue that ownership relations channel reputation spillovers between shareholders and their invested companies. We model such reputation spillovers by means of a simple dynamics that runs on the ownership network, constructed from available databases. We focus on the core of the global ownership network with 1300 firms and 12 100 ownership links. Our method assigns an ownership-based reputation value to each firm, used to provide a quantitative reputation ranking. We compare our ranking with alternative rankings, to confirm that the top-ranked firms are correctly identified. We also demonstrate that our reputation measure does not correlate substantially with operating revenue or control and thus provides additional information about firms.
Cognitive and environmental interventions to encourage healthy eating: evidence-based recommendations for public health policy
Authors: Walker Lindsay A. , Chambers Christopher D. , Veling Harm , Lawrence Natalia S.
Published: October 2019

Policymakers are focused on reducing the public health burden of obesity. The UK average percentage of adults classified as obese is 26%, which is double that of the global average. Over a third of UK adults report using at least one weight management aid. Yet, many people still struggle to change their diet-related behaviour, despite having the awareness, intention and capability to do so. This ‘intention–behaviour gap’ may be because most existing dietary-choice interventions focus on individual decision-making, ignoring the effects of environmental cues on human behaviour. Behaviour change interventions that ‘nudge’ people into making healthier choices by modifying the food environment have been shown to be effective. However, this type of intervention is typically challenging for policymakers to implement for economic, ethical and public accessibility reasons. To overcome these concerns, policymakers should consider ‘boosting’ interventions. Boosting involves enhancing competences that help people make decisions consistent with their goals. Here, we outline cognitive training as a boosting intervention to tackle obesity. We synthesize the evidence for one type of cognitive training (go/no-go training) that may be effective at modifying food-related decisions and reducing body weight. We offer evidence-based recommendations for an obesity-focused Public Health Wales behaviour change programme.
Heritability and genetic correlations of personality, life history and morphology in the grey mouse lemur (Microcebus murinus)
Authors: Zablocki-Thomas Pauline B. , Herrel Anthony , Karanewsky Caitlin J. , Aujard Fabienne , Pouydebat Emmanuelle
Published: October 2019

The recent interest in animal personality has sparked a number of studies on the heritability of personality traits. Yet, how the sources variance these traits can be decomposed remains unclear. Moreover, whether genetic correlations with life-history traits, personality traits and other phenotypic traits exist as predicted by the pace-of-life syndrome hypothesis remains poorly understood. Our aim was to compare the heritability of personality, life-history and morphological traits and their potential genetic correlations in a small primate (Microcebus murinus). We performed an animal model analysis on six traits measured in a large sample of captive mouse lemurs (N= 486). We chose two personality traits, two life-history traits and two morphological traits to (i) estimate the genetic and/or environmental contribution to their variance, and (ii) test for genetic correlations between these traits. We found modest narrow-sense heritability for personality traits, morphological traits and life-history traits. Other factors including maternal effects also influence the sources of variation in life-history and morphological traits. We found genetic correlations between emergence latency on the one hand and radius length and growth rate on the other hand. Emergence latency was also genetically correlated with birth weight and was influenced by maternal identity. These results provide insights into the influence of genes and maternal effects on the partitioning of sources of variation in personality, life-history and morphological traits in a captive primate model and suggest that the pace-of-life syndrome may be partly explained by genetic trait covariances.
Lead ethyl dithiocarbamates: efficient single-source precursors to PbS nanocubes
Authors: Saah S. A. , Boadi N. O. , Adu-Poku D. , Wilkins C.
Published: October 2019

Lead ethyl dithiocarbamates have been successfully used as single-source precursors for the deposition of PbS using spin coating followed by annealing at moderate temperatures. The thin films were characterized using a powder X-ray diffractometer and were found to be face-centred cubic with the (200) plane being the most preferred orientation. Scanning electron microscopy images showed the formation of well-defined cubes. Optical band gaps of PbS thin films were estimated using Tauc plots as 0.72, 0.73 and 0.77 eV at annealing temperatures of 250, 300 and 400°C. These band gaps were all blue shifted from the bulk value of 0.41 eV. Energy-dispersive X-ray analysis was used to determine the composition of the thin films which showed an approximately 1 : 1 Pb to S ratio.
Usage frequency and lexical class determine the evolution of kinship terms in Indo-European
Authors: Rácz Péter , Passmore Sam , Sheard Catherine , Jordan Fiona M.
Published: October 2019

Languages do not replace their vocabularies at an even rate: words endure longer if they are used more frequently. This effect, which has parallels in evolutionary biology, has been demonstrated for the core vocabulary, a set of common, unrelated meanings. The extent to which it replicates in closed lexical classes remains to be seen, and may indicate how general this effect is in language change. Here, we use phylogenetic comparative methods to investigate the history of 10 kinship categories, a type of closed lexical class of content words, across 47 Indo-European languages. We find that their rate of replacement is correlated with their usage frequency, and this relationship is stronger than in the case of the core vocabulary, even though the envelope of variation is comparable across the two cases. We also find that the residual variation in the rate of replacement of kinship terms is related to genealogical distance of referent to kin. We argue that this relationship is the result of social changes and corresponding shifts in the entire semantic class of kinship terms, shifts typically not present in the core vocabulary. Thus, an understanding of the scope and limits of social change is needed to understand changes in kinship systems, and broader context is necessary to model cultural evolution in particular and the process of system change in general.
Local- versus broad-scale environmental drivers of continental
β
-diversity patterns in subterranean spider communities across Europe
Authors: Mammola Stefano , Cardoso Pedro , Angyal Dorottya , Balázs Gergely , Blick Theo , Brustel Hervé , Carter Julian , Ćurčić Srećko , Danflous Samuel , Dányi László , Déjean Sylvain , Deltshev Christo , Elverici Mert , Fernández Jon , Gasparo Fulvio , Komnenov Marjan , Komposch Christian , Kováč L'ubomír , Kunt Kadir Boğaç , Mock Andrej , Moldovan Oana Teodora , Naumova Maria , Pavlek Martina , Prieto Carlos E. , Ribera Carles , Rozwałka Robert , Růžička Vlastimil , Vargovitsh Robert S. , Zaenker Stefan , Isaia Marco
Published: October 2019

Macroecologists seek to identify drivers of community turnover (
β
-diversity) through broad spatial scales. However, the influence of local habitat features in driving broad-scale
β
-diversity patterns remains largely untested, owing to the objective challenges of associating local-scale variables to continental-framed datasets. We examined the relative contribution of local- versus broad-scale drivers of continental
β
-diversity patterns, using a uniquely suited dataset of cave-dwelling spider communities across Europe (35–70° latitude). Generalized dissimilarity modelling showed that geographical distance, mean annual temperature and size of the karst area in which caves occurred drove most of
β
-diversity, with differential contributions of each factor according to the level of subterranean specialization. Highly specialized communities were mostly influenced by geographical distance, while less specialized communities were mostly driven by mean annual temperature. Conversely, local-scale habitat features turned out to be meaningless predictors of community change, which emphasizes the idea of caves as the human accessible fraction of the extended network of fissures that more properly represents the elective habitat of the subterranean fauna. To the extent that the effect of local features turned to be inconspicuous, caves emerge as experimental model systems in which to study broad biological patterns without the confounding effect of local habitat features.
Generation of simian rotavirus reassortants with diverse VP4 genes using reverse genetics
Authors: Falkenhagen Alexander , Patzina-Mehling Corinna , Rückner Antje , Vahlenkamp Thomas W. , Johne Reimar
Published: October 2019

Species A rotaviruses (RVAs) are a major cause of gastroenteritis in animals and humans. Their genome consists of 11 segments of dsRNA, and reassortment events between animal and human strains can contribute to the high genetic diversity of RVAs. We used a plasmid-based reverse genetics system to investigate the reassortment potential of the genome segment encoding the viral outer capsid protein VP4, which is a major antigenic determinant, mediates viral entry and plays an important role in host cell tropism. We rescued reassortant viruses containing VP4 from porcine, bovine, bat, pheasant or chicken RVA strains in the backbone of simian strain SA11. The VP4 reassortants could be stably passaged in MA-104 cells and induced cytopathic effects. However, analysis of growth kinetics revealed marked differences in replication efficiency. Our results show that the VP4-encoding genome segment has a high reassortment potential, even between virus strains from highly divergent species. This can result in replication-competent reassortants with new genomic, growth and antigenic features.
Women in Science and Technology: An Indian scenario
Authors: Swarup Akanksha , Dey Tuli
Published: October 2019

The concept of treating women as equal to their male counterpart became a topic of political debate in Europe during the ‘age of enlightenment’ (18th Century). The battle towards equal voting rights took approximately 100 years to win, and went until the 19th Century. It was only around 1902-1920 that women got equal voting rights in prominent Western countries followed by others. Amidst the celebration of ‘women’s vote centenary’ throughout the world, the issue of equal rights to education and work is still waiting for the proper attention. Historically the presence of women in educational, technological and scientific fields remains mostly marginal. In this article, the current state of under-representation of women in the science and technology community is depicted, primarily highlighting the Indian scenario. It is observed that throughout India, and amongst the relatively developed countries of the world, the presence of women in highly prestigious Institutes and Universities remains negligible even in this day and age. The probable causes behind such inequality need to be analyzed, addressed and looked upon for remedial purposes.
Polarly localized EccE1 is required for ESX-1 function and stabilization of ESX-1 membrane proteins in Mycobacterium tuberculosis
Authors: Soler-Arnedo Paloma , Sala Claudia , Zhang Ming , Cole Stewart T. , Piton Jérémie
Published: October 2019

Mycobacterium tuberculosis is a slow-growing intracellular bacterium with the ability to induce host cell death and persist indefinitely in the human body. This pathogen uses the specialized ESX-1 secretion system to secrete virulence factors and potent immunogenic effectors required for disease progression. ESX-1 is a multi-subunit apparatus with a membrane complex that is predicted to form a pore in the cytoplasmic membrane. In M. tuberculosis this complex is composed of five membrane proteins: EccB1, EccCa1, EccCb1, EccD1, EccE1. In this study, we have characterized the membrane component EccE1 and found that deletion of eccE1 lowers the levels of EccB1, EccCa1 and EccD1 thereby abolishing ESX-1 secretion and attenuating M. tuberculosis ex vivo. Surprisingly, secretion of EspB was not affected by loss of EccE1. Furthermore, EccE1 was found to be a membrane- and cell-wall associated protein that needs the presence of other ESX-1 components to assemble into a stable complex at the poles of M. tuberculosis. Overall, this investigation provides new insights into the role of EccE1 and its localization in M. tuberculosis.

IMPORTANCE

Tuberculosis (TB), the world’s leading cause of death of humans from an infectious disease, is caused by the intracellular bacterium Mycobacterium tuberculosis. The development of successful strategies to control TB requires better understanding of the complex interactions between the pathogen and human host. We investigated the contribution of EccE1, a membrane protein, to the function of the ESX-1 secretion system, the major virulence determinant of M. tuberculosis. By combining genetic analysis of selected mutants with eukaryotic cell biology and proteomics, we demonstrate that EccE1 is critical for ESX-1 function, secretion of effector proteins and pathogenesis. Our research improves knowledge of the molecular basis of M. tuberculosis virulence and enhances our understanding of pathogenesis.
New roles for two-component system response regulators ofSalmonella entericaserovar Typhi during host cell interactions
Authors: Murret-Labarthe Claudie , Kerhoas Maud , Dufresne Karine , Daigle France
Published: October 2019

In order to survive external stresses, bacteria need to adapt quickly to changes in their environment. One adaptive mechanism is to coordinate and alter their gene expression by using two-component systems (TCS). TCS are composed of a sensor kinase that activates a transcriptional response regulator by phosphorylation. TCS are involved in motility, virulence, nutrient acquisition, and envelope stress in many bacteria. The pathogenic bacteriaSalmonella entericaserovar Typhi (S.Typhi) possess 30 TCSs, is specific to humans and causes typhoid fever. Here, we have deleted individually each of the 30 response regulators. We have determined their role during interaction with host cells (epithelial cells and macrophages). Deletion of most of the systems (24 out of 30) resulted in a significantly change during infection, either lower or higher than the wild-type strain. We have identified 32 new phenotypes associated with TCS ofS.Typhi. Some previously known phenotypes associated with TCSs inSalmonellawere also confirmed. We have also uncovered phenotypic divergence betweenSalmonellaserovars as distinct phenotypes betweenS.Typhi andS.Typhimurium were identified forcpxR. This highlight the importance of specifically studyingS.Typhi to understand its pathogenesis mechanisms and to develop strategies to potentially reduce typhoid infections.
Multiple Low Dose (MLD) therapy: an effective strategy to treat EGFR inhibitor-resistant NSCLC tumours
Authors: Fernandes Neto João M. , Nadal Ernest , Ooft Salo N , Bosdriesz Evert , Farre Lourdes , McLean Chelsea , Klarenbeek Sjoerd , Jurgens Anouk , Hagen Hannes , Wang Liqin , Felip Enriqueta , Martinez-Marti Alex , Voest Emile , Wessels Lodewyk F.A. , van Tellingen Olaf , Villanueva Alberto , Bernards René
Published: October 2019

Targeted cancer drugs often elicit powerful initial responses, but generally fail to deliver long-term benefit due to the emergence of resistant cells1,2. This is thought to be the consequence of strong selective pressure exerted on the cancer drug target by a Maximum Tolerated Dose (MTD) of a drug3–5. We hypothesized that partial inhibition of multiple components in the same oncogenic signalling pathway might add up to complete pathway inhibition, while at the same time decreasing the selective pressure on each individual component to acquire a resistance mutation. We report here testing of this Multiple Low Dose (MLD) model of drug administration in Epidermal Growth Factor Receptor (EGFR) mutant non-small cell lung cancer (NSCLC). We show that as little as 20% of the individual drug doses required for full inhibition of cell viability is sufficient to completely block MAPK signalling and proliferation when used in 3D (RAF+MEK+ERK inhibitors) or 4D (EGFR+RAF+MEK+ERK inhibitors) combinations. Importantly,EGFRmutant NSCLC cells treated with EGFR inhibitors at a high dose rapidly developed resistance in vitro, but the cells treated with 3D or 4D MLD therapy did not. Moreover, NSCLC cells that had gained resistance to high dose anti-EGFR therapies were still sensitive to MLD therapy. Using several animal models, including patient derived xenografts of NSCLC tumours that are resistant to EGFR inhibitors erlotinib and osimertinib6,7, we found durable responses to MLD therapy without associated toxicity. These data support the notion that partial inhibition of multiple components of cancer-activated signalling pathways is difficult to circumvent and suggest that MLD therapy could deliver clinical benefit. We propose that MLD strategy could be an effective treatment option for EGFR mutant NSCLC patients, especially those having acquired resistance to even third generation EGFR inhibitor therapy.
Genome-wide Analysis In Response to N and C Identifies New Regulators for root AtNRT2 Transporters
Authors: Ruffel Sandrine , Chaput Valentin , Przybyla-Toscano Jonathan , Fayos Ian , Ibarra Catalina , Moyano Tomas , Fizames Cécile , Tillard Pascal , O’Brien Jose Antonio , Gutiérrez Rodrigo A. , Gojon Alain , Lejay Laurence
Published: October 2019

In Arabidopsis thaliana, the High-Affinity Transport System (HATS) for root NO3- uptake depends mainly on four NRT2 transporters, namely NRT2.1, NRT2.2, NRT2.4 and NRT2.5. The HATS is the target of many regulations to coordinate nitrogen (N) acquisition with the N status of the plant and with carbon (C) assimilation through photosynthesis. At the molecular level, C and N signaling pathways have been shown to control gene expression of the NRT2 transporters. Although several regulators of these transporters have been identified in response to either N or C signals, the response of NRT2 genes expression to the interaction of these signals has never been specifically investigated and the underlying molecular mechanisms remain largely unknown. To address this question we used an original systems biology approach to model a regulatory gene network targeting NRT2.1, NRT2.2, NRT2.4 and NRT2.5 in response to N/C signals. Our systems analysis of the data highlighted the potential role of three putative transcription factors, TGA3, MYC1 and bHLH093. Functional analysis of mutants combined with yeast one hybrid experiments confirmed that all 3 transcription factors are regulators of NRT2.4 or NRT2.5 in response to N or C signals.

One sentence summary

Identification of three transcription factors involved in the regulation of NRT2s transporters using a systems biology approach and NRT2.1 as target gene in response to combinations of N/C treatments
Characterization ofC. difficilestrains isolated from companion animals and the associated changes in the host fecal microbiota
Authors: Thanissery R. , McLaren M.R. , Rivera A. , Reed Amber D. , Betrapally N.S. , Burdette T. , Winston J.A. , Jacob M. , Callahan B.J. , Theriot C.M.
Published: October 2019

Background

Clostridioides difficileis an enteric pathogen historically known to cause hospital associated (HA)-infections in humans. A major risk factor for CDI in humans is antibiotic usage as it alters the gut microbiota and there is a loss of colonization resistance againstC. difficile. In recent years there has been an increase in community associated (CA)-C. difficileinfection that does not have the same risk factors as HA-CDI. Potential sources of CA-CDI have been proposed and include animals, food, water, and the environment, however these sources remain poorly investigated. Here, we define the prevalence ofC. difficilestrains found in different companion animals (canines, felines, and equines) to investigate a potential zoonotic link.C. difficilestrains were identified by toxin gene profiling, fluorescent PCR ribotyping, and antimicrobial susceptibility testing. 16s rRNA gene sequencing was done on animal feces to investigate the relationship between the presence ofC. difficileand the gut microbiota in different hosts.

Results

Here, we show thatC. difficilewas recovered from 20.9% of samples (42/201), which included 33 canines, 2 felines, and 7 equines. Over 69% (29/42) of the isolates were toxigenic and belonged to 14 different ribotypes, with overlap between HA- and CA-CDI cases in humans. The presence ofC. difficileresults in a shift in the fecal microbial community structure in both canines and equines. Commensal ClostridiaC. hiranoniswas negatively associated withC. difficilein canines. Further experimentation showed a clear antagonistic relationship between the two strainsin vitro, suggesting that commensalClostridiamight play a role in colonization resistance againstC. difficilein different hosts.

Conclusions

In this study we investigated a potentially important source ofC. difficiletransmission: the companion animal population.C. difficilecarriage was common in dogs, cats, and horses.C. difficileisolates from companion animals included many of the same ribotypes known to cause HA- and CA-CDI in humans, and had similar antimicrobial resistance profiles as those isolated from human populations. These data contribute to our understanding of non-hospital exposure toC. difficilein the human population and suggest new avenues for reducingC. difficileprevalence in companion animals and, perhaps, thereby reducing CA-CDI in humans.
Transcriptomic signature of rapidly evolving immune genes in a highland fish
Authors: Tong Chao , Li Miao , Zhao Kai
Published: October 2019

Recent genome-wide studies have begun to elucidate the genomic basis of hypoxia, long-term cold and high saline and alkaline adaptation in highland fish, and a number of key genes contributed to its highland adaptation were identified. An increasing number of studies indicated that immune genes of Tibetan endemic fish species underwent positive selection towards functional shift, while the insight into immune gene repertoire of Tibetan highland fishes from genome-wide studies has largely lagged behind. In this study, we performed one of the first comparative genomics study in particular focusing on the signatures of immune genes in a highland fish, Gymnocypris przewalskii based on immune-relevant tissue transcriptome assemblies. We identified seven putative rapidly evolving immune genes with elevated molecular evolutionary rate (dN/dS) relative to lowland fish species. Using tissue-transcriptome data, we found most of rapidly evolving immune genes were broadly expressed in head-kidney, spleen, gills and skin tissues, which significantly enriched for complement activation and inflammatory response processes. In addition, we found a set of complement activation related genes underwent accelerated evolution and showed consistently repressed expression patterns in response to parasite Ichthyophthirius multifiliis infection. Moreover, we detected a number of immune genes involved in adaptive immune system exhibited distinct signature of upregulated expression patterns after parasite infection. Taken together, this study provided putative transcriptomic signatures of rapidly evolving immune genes, and will gain the insight into Schizothoracine fish adaptation to high-altitude extreme aquatic environments including diversified pathogen challenge.
Identification of a missense ARSA mutation in metachromatic leukodystrophy and its potential pathogenic mechanism
Authors: Guo Liyuan , Jin Bo , Zhang Yidan , Wang Jing
Published: October 2019

Background

The most common type of metachromatic leukodystrophy (MLD) is an inherited lysosomal disorder caused by recessive mutations in ARSA. The biological process of MLD disease caused by candidate pathogenic mutations in the ARSA gene remains unclear.

Methods

We used whole-exome sequencing (WES) and Sanger sequencing to identify the pathogenic mutation in a Chinese family. Literature review and protein three-dimensional structure prediction were performed to analyse the potential pathogenesis of the identified mutations. Overexpression cell models of wild-type and mutated ARSA genes were constructed to obtain expression profiles, and weighted gene co-expression network analysis (WGCNA), hub gene detection and protein-protein interaction (PPI) analysis were carried out to compare the biological changes caused by candidate pathogenic mutations.

Results

We identified an ARSA c.925G>A homozygous mutation from a Chinese late-infantile MLD patient, the first report of this mutation in Asia. According to the literature and protein structure analysis, three mutations of c.925G (c.925G>A, c.925G>T, c.925G>C) in the ARSA gene were pathogenic. The transcriptome of four ARSA overexpression cell models (c.925G, c.925G>A, c.925G>T, c.925G>C) were analysed by WGCNA, Hub genes and PPI complexes.RNA-seq and bioinformatics results indicate that the mutations at c.925G cause comprehensive molecular changes related to energy metabolism, ion binding, vesicle transport and transport.

Conclusion

We identified a pathogenic mutation, ARSA homozygosity c.925G>A, from a Chinese MLD family. All three mutations of c.925G in the ARSA gene are pathogenic and may cause disease by dysregulating the molecular processes of ion binding, vesicle transport and ion transport.
Dasatinib Plus Quercetin on Uterine Age-Related Dysfunction and Fibrosis in Mice
Authors: Cavalcante Marcelo B. , Saccon Tatiana D. , Nunes Allancer D. C. , Kirkland James L. , Tchkonia Tamara , Schneider Augusto , Masternak Michal M.
Published: October 2019

Female reproductive function is negatively impacted by age. Animal and human studies show that fibrosis of the uterus contributes to gestational outcomes. Collagen deposition in the myometrial and endometrial layers is the main change related to uterine aging. Senolytic therapies are a potential option for reducing diseases and health complications related to aging. We investigated effects of aging and the senolytic drug combination of dasatinib plus quercetin (D+Q) on uterine fibrosis. A total of 40 mice, 20 young females (03-months) and 20 old females (18-months), were analyzed. Young (Y) and old (O) animals were divided into groups of 10 mice, with one treatment (T) group (YT and OT) and another control (C) group (YC and OC). Comparative analysis ofPi3k/Akt1/mTorand p53 gene expression among the 4 groups was performed to test effects of age and treatment on collagen deposition in uterine tissue. Uterine levels of microRNAs (miR34a, miR34b, miR34c, miR146a, miR449a, miR21a, miR126a, and miR181b) were evaluated. Aging promoted downregulation of genes of thePi3k/Akt1/mTorsignaling pathway (p=0.005, p=0.031, and p=0.028, respectively) as well as a reduction in expression of miR34c (p=0.029), miR126a (p=0.009), and miR181b (p=0.007). D+Q treatment increased p53 gene expression (p=0.041) and decreased levels of miR34a (p=0.016). Our results demonstrate a role for thePi3k/Akt1/mTorsignaling pathway in uterine aging and suggest for the first time a possible anti-fibrotic effect in the uterus of D+Q senolytic therapy.
The impact of respiratory gating on improving volume measurement of murine lung tumors in micro-CT imaging
Authors: Blocker S. J. , Holbrook M. D. , Mowery Y. M. , Sullivan D. C. , Badea C. T.
Published: October 2019

Small animal imaging has become essential in evaluating new cancer therapies as they are translated from the preclinical to clinical domain. However, preclinical imaging faces unique challenges that emphasize the gap between mouse and man. One example is the difference in breathing patterns and breath-holding ability, which can dramatically affect tumor burden assessment in lung tissue. As part of a co-clinical trial studying immunotherapy and radiotherapy in sarcomas, we are using micro-CT of the lungs to detect and measure metastases as a metric of disease progression. To effectively utilize metastatic disease detection as a metric of progression, we have addressed the impact of respiratory gating during micro-CT acquisition on improving lung tumor detection and volume quantitation. Accuracy and precision of lung tumor measurements with and without respiratory gating were studied by performing experiments with in vivo images, simulations, and a pocket phantom. When performing test-retest studies in vivo, the variance in volume calculations was 5.9% in gated images and 15.8% in non-gated images, compared to 2.9% in post-mortem images. Sensitivity of detection was examined in images with simulated tumors, demonstrating that reliable sensitivity (true positive rate (TPR) ≥ 90%) was achievable down to 1.0 mm3 lesions with respiratory gating, but was limited to ≥ 8.0 mm3 in non-gated images. Finally, a clinically-inspired “pocket phantom” was used during in vivo mouse scanning to aid in refining and assessing the gating protocols. Application of respiratory gating techniques reduced variance of repeated volume measurements and significantly improved the accuracy of tumor volume quantitation in vivo.
Towards implementation of AI in New Zealand national screening program: Cloud-based, Robust, and Bespoke
Authors: Xie Li , Yang Song , Squirrell David , Vaghefi Ehsan
Published: October 2019

Convolutional Neural Networks (CNN)s have become a prominent method of AI implementation in medical classification tasks. Grading Diabetic Retinopathy (DR) has been at the forefront of the development of AI for ophthalmology. However, major obstacles remain in the generalization of these CNN’s onto real-world DR screening programs. We believe these difficulties are due to use of 1) small training datasets (<5,000 images), 2) private and ‘curated’ repositories, 3) offline CNN implementation methods, while 4) relying on accuracy measured as area under the curve (AUC) as the sole measure of CNN performance.

To address these issues, the public EyePACS Kaggle Diabetic Retinopathy dataset was uploaded onto Microsoft Azure™ cloud platform. Two CNNs were trained as a “Quality Assurance”, and a “Classifier”. The “Classifier” CNN performance was then tested both on ‘un-curated’ as well as the ‘curated’ test set created by the “Quality Assessment” CNN. Finally, the sensitivity of the “Classifier” CNNs was boosted post-training using two post-training techniques.

Our “Classifier” CNN proved to be robust, as its performance was similar on ‘curated’ and ‘uncurated’ sets. The implementation of ‘cascading thresholds’ and ‘max margin’ techniques led to significant improvements in the “Classifier” CNN’s sensitivity, while also enhancing the specificity of other grades.
Does training method matter?: Evidence for the negative impact of aversive-based methods on companion dog welfare
Authors: Vieira de Castro Ana Catarina , Fuchs Danielle , Pastur Stefania , de Sousa Liliana , Olsson I Anna S
Published: October 2019

There is a growing number of dogs kept as companion animals, and the methods by which they are trained range broadly from those using mostly positive punishment and negative reinforcement (aversive-based methods) to those using primarily positive reinforcement (reward-based methods). Although the use of aversive-based methods has been strongly criticized for negatively affecting dog welfare, these claims do not find support in solid scientific evidence. Previous research on the subject lacks companion dog-focused research, investigation of the entire range of aversive-based techniques (beyond shock-collars), objective measures of welfare, and long-term welfare studies. The aim of the present study was to perform a comprehensive evaluation of the short- and long-term effects of aversive- and reward-based training methods on companion dog welfare. Ninety-two companion dogs were recruited from three reward-based (Group Reward, n=42) and four aversive-based (Group Aversive, n=50) dog training schools. For the short-term welfare assessment, dogs were video recorded for three training sessions and six saliva samples were collected, three at home (baseline levels) and three after the training sessions (post-training levels). Video recordings were then used to examine the frequency of stress-related behaviors (e.g., lip lick, yawn) and the overall behavioral state of the dog (e.g., tense, relaxed), and saliva samples were analyzed for cortisol concentration. For the long-term welfare assessment, dogs performed a cognitive bias task. Dogs from Group Aversive displayed more stress-related behaviors, spent more time in tense and low behavioral states and more time panting during the training sessions, showed higher elevations in cortisol levels after training and were more ‘pessimistic’ in the cognitive bias task than dogs from Group Reward. These findings indicate that the use of aversive-based methods compromises the welfare of companion dogs in both the short- and the long-term.
Comprehensive fitness maps of Hsp90 show widespread environmental dependence
Authors: Flynn Julia M. , Rossouw Ammeret , Cote-Hammarlof Pamela A. , Fragata Ines , Mavor David , Hollins Carl , Bank Claudia , Bolon Daniel N.A.
Published: October 2019

Gene-environment interactions have long been theorized to influence molecular evolution. However, the environmental dependence of most mutations remains unknown. Using deep mutational scanning, we engineered yeast with all 44,604 single codon changes encoding 14,160 amino acid variants in Hsp90 and quantified growth effects under standard conditions and under five stress conditions. To our knowledge these are the largest determined comprehensive fitness maps of point mutants. The growth of many variants differed between conditions, indicating that environment can have a large impact on Hsp90 evolution. Multiple variants provided growth advantages under individual conditions, however these variants tended to exhibit growth defects in other environments. The diversity of Hsp90 sequences observed in extant eukaryotes preferentially contains variants that supported robust growth under all tested conditions. Rather than favoring substitutions in individual conditions, the long-term selective pressure on Hsp90 may have been that of fluctuating environments, leading to robustness under a variety of conditions.