bluuebunny/crossref_metadata_2025 huggingface dataset:
Therapeutic Advances in the Management of Smoldering Myeloma
Authors: Khan Rafiullah , Zahid Umar , Kollu Vidya , Jahan Nusrat , Ali McBride , Tricot Guido , Anwer Faiz
Published: December 2019

Background:

The International Myeloma Working Group has defined smoldering multiple myeloma (SMM) as the presence of 10%–60% plasma cells in the bone marrow and M-protein (IgG, IgA) ≥3 g/dL without end-organ damage (an increased calcium level, renal failure, anemia, and destructive bone lesions).

Areas of Uncertainty:

Patients considered to have SMM should not have any myeloma-defining events or amyloidosis. Different risks factors classify SMM into low-, intermediate-, or high-risk categories. The rate of progression from SMM to symptomatic myeloma is ∼10% per year during the first 5 years of diagnosis. SMM requires frequent follow-up ∼every 3 months during the first 5 years as compared to monoclonal gammopathy of undermined significance, which usually requires follow-up every 6–12 months after the first year of diagnosis.

Data Sources:

A literature search was performed from electronic bibliographic databases: MEDLINE (Ovid SP/PubMed), EMBASE, the Cochrane Library (Cochrane Database of Systematic Reviews), and Cochrane Central Register of Controlled Trials and from annual meeting abstracts from inception to May 2017.

Therapeutic Advances:

This review presents the literature and available data that support or do not support early treatment of high-risk SMM (HR-SMM) and provides evidence-based recommendations for management of SMM patients. Despite emerging data recommending early treatment of HR-SMM, we predict the SMM category may disappear in the near future and patients will be diagnosed with either multiple myeloma or monoclonal gammopathy of undermined significance.

Conclusions:

Success with early therapy trials for HR-SMM is largely due to patients meeting current criteria for multiple myeloma that may have been classified as SMM and, therefore, benefitted from therapy. Based on current practices and the literature, SMM should be managed with close follow-up. Based on available data, we suggest SMM to only be treated in clinical trial settings.
A Prospective, Randomized Cross‐over Trial of 2 Low‐profile Gastrostomy Buttons to Determine Family Preference
Authors: Abdelhadi Ruba A. , Dekonenko Charlene , Dorman Robert M. , Oyetunji Tolulope A. , St. Peter Shawn D.
Published: December 2019

Low‐profile gastrostomy balloon buttons are often used in the pediatric population. We conducted a prospective, randomized crossover trial to determine family preference comparing MIC‐KEY (tube A) and MiniONE (tube B) buttons. Patients were randomized to tube A and tube B at placement. At 2 months, patients were given the opposite button. At 4 months, parents indicated their preferred button. A standardized assessment tool was used to assess gastrostomy site skin complications and device malfunction. One hundred fifty‐eight patients were randomized, 79 each to receive tube A or tube B first. Sixty‐eight with tube A and 60 with tube B completed their first follow‐up. Sixty‐five with tube A and 43 with tube B completed crossover, 69% of whom preferred tube B (P < 0.001). Including those who preferred their first button and declined to switch at 2 months, 91 of 127 (72%) kept tube B, demonstrating a strong preference for tube B.
Divergent Perspectives on the Use of the Edmonton Symptom Assessment System (Revised) in Palliative Care
Authors: Schick-Makaroff Kara , Sawatzky Richard
Published: December 2019

The Edmonton Symptom Assessment System (Revised) (ESAS-r) contains 9 questions pertaining to symptoms/well-being. It is a standardized patient-reported assessment instrument, but inconsistently used in palliative care. Thus, a problem exists in knowledge translation regarding routine use of the ESAS-r in palliative practice. The objective was to understand clinicians' perspectives on the use of the ESAS-r in palliative care in hospitals and at home. Qualitative focus groups (n = 14 with 46 clinicians) and interviews (n = 24) elicited views regarding use of the ESAS-r in palliative practice. Interpretive description was used as a general approach to this qualitative analysis focused on understanding clinicians' views. Palliative clinicians presented multiple perspectives of the ESAS-r pertaining to their (1) underlying values, (2) disparate purposes, and (3) incommensurate responses toward use in daily practice. Benefits and challenges supported diversity within these themes, highlighting divergence among perspectives and complexity of integrating a standardized tool in patient care. Integration of the ESAS-r in palliative care requires (1) educational support for developing competence; (2) consideration of clinicians' existing, heterogeneous beliefs regarding the use of standardized assessment instruments; and (3) Consultation with multidisciplinary practitioners about optimal ways that ESAS-r results can be used in a person-centered approach to palliative care.
Auditory Verbal Hallucinations in Psychosis
Authors: Mitropoulos George B.
Published: December 2019

Auditory verbal hallucinations (AVHs) are considered as hallmark symptoms of psychosis, more specifically of schizophrenia. A substantial body of evidence indicates that AVHs can be attributed to a disorganization of overall speech capacity in psychotic subjects. AVHs are associated with activation of cortical areas of the brain that are related to speech production and perception; “voices” in deaf patients seem to be about the message rather than the sound of it; the content of AVHs is often related to that of delusional ideas; the internal or external location of AVHs makes little diagnostic difference; AVHs are often related to the patient's subvocal speech, having identical content with that, and they have been theorized as a misattribution of inner speech (i.e., the patient's own thoughts) to external sources. The aforementioned evidence comes close to certain long-standing insights mainly of the French psychiatric (de Clérambault) and psychoanalytical (Lacan) school, according to which, 1) the outside world is perceived through normal language function, 2) a language disorder is central to schizophrenic phenomena, and 3) AVHs represent a fragmentation and autonomization of speech (thought) function in schizophrenic patients (de Clérambault: “hallucinations think”). Today, several authors agree that 1) operationalized definitions have led to an oversimplification of psychopathology, and 2) a more theoretically informed understanding and an integration of different levels of explanation of psychotic phenomena is needed. Thus, psychotic AVHs should be investigated beyond their narrow classification as disordered perceptions, in the wider context of formal thought disorder and disordered language capacity.
Psychometric Properties of an Indian Translation of the Vision-related Activity Limitation Item Bank in Cataract
Authors: Gothwal Vijaya K. , Muthineni Vani V. , Khadka Jyoti , Lamoureux Ecosse L. , Pesudovs Konrad
Published: December 2019

SIGNIFICANCE

The Indian translated and culturally adapted version of the vision-related activity limitation (VRAL) item bank is a validated instrument to assess the difficulty in performing daily activities by cataract patients and can also be used to capture self-reported changes in ability to perform daily activities after cataract surgery.

PURPOSE

The purpose of this study was to document (a) translation, cross-cultural adaptation of VRAL item bank into an Indian language, and (b) its validation using Rasch analysis in a South Indian cataract population.

METHODS

At the first stage, a translated Indian version of VRAL item bank was produced using recommended procedures. At the second stage, Rasch analysis was performed to investigate its psychometric properties in 787 cataract patients (mean age, 58.2 years; mean ± SD visual acuity [logMAR], 1.19 ± 0.96 at baseline in eye for surgery) including comparison with the original version.

RESULTS

Post-translation equivalence of meaning was achieved, but some English phrases required cross-cultural adaptation. Subsequently, all items were appropriate for the Indian culture, and VRAL item bank demonstrated excellent measurement precision (7.39). Dimensionality assessment suggested that VRAL construct may contain other dimensions such as self-care and visual search, and mobility. Self-care and visual search formed a unidimensional measure but was highly correlated with main VRAL dimension, and the removal of its items weakened precision of the main VRAL dimension measurement. Taken together, evidence favored retaining self-care and visual search items in a larger VRAL item bank. Mobility subscale lacked adequate measurement precision, so it was not examined further; again, items were retained in VRAL scale because they strengthened its measurement properties. Majority of items (99%) did not demonstrate notable differential item functioning (>1.0 logit) by presenting visual acuity (median, 0.20 logMAR) in the better-seeing eye.

CONCLUSIONS

Items in the translated Indian VRAL item bank measure the same construct as the English version and fulfilled the psychometric requirements for use in cataract patients.
Primary Care Quality Improvement Metrics and National Committee on Quality Assurance Medical Home Recognition for Children With Medical Complexity
Authors: Lail Jennifer , Fields Elise , Paolella Alyssa , Schoettker Pamela J.
Published: December 2019

Introduction:

The Complex Care Center at Cincinnati Children’s Hospital Medical Center developed and implemented a set of evidence-based clinical process measures of immunization delivery, preventive and chronic condition laboratory screening, and behavioral health medication surveillance for use in the primary care setting.

Methods:

Improvement activities focused on 4 measures across 4 domains mandated by the National Committee on Quality Assurance for patient-centered medical home recognition. Interventions were implemented in phases from January 2017 to October 2018. The goal was the improvement in immunizations, preventive lead screening, vitamin D testing in chronic conditions, and behavioral health medication surveillance. Preventative lipid screening in the entire population and thyroid-stimulating hormone levels in patients with Down syndrome were also measured.

Results:

The offering and the completion of an immunization bundle increased from a mean of 61.0% to a mean of 83.7% of patients. Eligible patients with documented lead surveillance increased from 61.2% to 96.5%. Patients with documented 25-hydroxy vitamin D levels increased from 72.2% to 87.8%. The percentage of patients metabolically monitored while taking an atypical antipsychotic continued at 92.0%.

Conclusions:

Using quality improvement education, data measurement/feedback, electronic medical record optimization/decision support, and care gap identification with planned care, the Complex Care Center demonstrated improved reliability in needed immunization delivery and laboratory screenings for a heterogeneous primary care population of children with medical complexity. As the numbers of children with medical complexity rise, so does the importance of reliable processes and relevant measures for quality in their unique care delivery systems.
Epidemiological Analysis of Venous Malformation of the Orbit
Authors: Bonavolontà Paola , Fossataro Federica , Attanasi Federica , Clemente Lidia , Iuliano Adriana , Bonavolontà Giulio
Published: December 2019

Orbital venous malformation (OVM) is one of the most common orbital mass of adults, accounting for approximately 5% to 15% of all vascular abnormalities in the central nervous system and representing 9% of orbital lesions. Clinical presentation is variable from asymptomatic cases to symptomatic ones. The purpose of the authors’ work is to analyze OVM incidence and prevalence in a cohort of patients referred over the last 40 years to the Orbital Unit, tertiary center for orbital diseases.

Records of 224 patients diagnosed with CVM in a 40-year period were retrospectively reviewed extracting prevalence/year and incidence/year based on data obtained from Eurostat population statistics. Data were aggregate and analyzed with a Microsoft Excel (Microsoft Corporation, Redmond, WA) spread sheet.

The incidence rate was measured as the number of new cases of OVM observed in Orbital Unit, a tertiary center. Incidence was about 1 case out (0.94) every 10 million people. The incidence rate was measured also as the number of new cases of OVM observed in Campania, considering in the latter case patients residents in this region (112 patients). Incidence was less than 1 case out (0.58) every 10 million people.

The prevalence rate was measured as the proportion of individuals with OVM observed in our Orbital Unit and is equal to 5%. This indicator resulted to increase from 1977 to 2017.

The management of OVM is still under discussion, but in agreement with data present in the literature the authors still believe that the surgical indication is only for symptomatic lesions.
First case report on pyogenic tenosynovitis in the hand caused by Paenibacillus sp.
Authors: Saito Mateus , Paulos Renata G. , Oliveira Priscila R.D. de , Barros Thiago F. dos S. , Kim So Yeon , Rezende Marcelo R. de , Lima Ana L.L.M. , Junior Rames M.
Published: December 2019

Bacteria from the genus Paenibacillus are widely present in places like soil and water, but rarely cause infections in humans. A 23-year-old female individual with her right hand with no other symptoms was admitted in the emergency room. Her physical examination was compatible with infectious tenosynovitis and surgical drainage was performed with intense synovitis but no purulent drainage. Culture analysis was positive for Paenibacillus sp. This is the first case description of pyogenic tenosynovitis caused by Paenibacillus. Even though rare, this report is important to cause awareness in health professionals on cases caused by uncommon pathogens.
Grief, Stress, Trauma, and Support During the Organ Donation Process
Authors: Dicks Sean G. , Burkolter Nadia , Jackson Lyndall C. , Northam Holly L. , Boer Douglas P. , van Haren Frank M.P.
Published: December 2019

The organ donation process is complex and stressful for the family of the potential donor and members of the multidisciplinary team who may experience grief, ethical dilemmas, vicarious trauma, or compassion fatigue. Several studies each explore the role of a specific healthcare group and the impact of inhospital processes on group members. We conducted a systematic literature search to identify such studies and a qualitative synthesis to consolidate findings and highlight features of the interaction and relationships between role players. Our results suggest that, while healthcare professionals have different roles, attitudes, and views, the experience of stressors and interdisciplinary tension is common. Nevertheless, staff are united by the goal of caring for the patient and family. We therefore propose that, while focusing on bereavement care and other aspects of the family’s experience, staff can find other shared goals and develop understanding, trust, empathy, and respect for each other’s positions, thereby improving functioning in the complex adaptive system that forms at this time. Education and training can equip staff to facilitate anticipatory mourning, family-led activities, and a meaningful parting from their relative, assisting families with their grief and increasing staff members’ efficacy, confidence, and interdisciplinary teamwork. Knowledge of systems thinking and opportunities to share ideas and experiences will enable staff to appreciate each other’s roles, while supportive mentors, self-care strategies, and meaningful feedback between role players will foster healthy adjustment and shared learning. A focus on psychosocial outcomes such as family satisfaction with the process, collaboration within the multidisciplinary team, and reduction in the role stress of healthcare professionals will contribute to family well-being as well as personal and professional growth for staff.
Toxic Optic Neuropathy From Quinine Overdose
Authors: Freund Paul R. , Wright Tom , Margolin Edward A.
Published: December 2019

A 45-year-old man presented with longstanding poor vision in both eyes. His medical history was significant for a remote overdose of quinine. After the ingestion, he fell into a coma and on awakening was not able to see light out of both eyes. Several days later, his central vision began to gradually recover and continued to improve over the span of several months. Presently, he had 20/20 visual acuity in both eyes with severely constricted peripheral visual fields. There were bilateral iris transillumination defects, and both optic nerves were diffusely pale with attenuated vasculature and inner retinal thinning on ocular coherence tomography. We present a patient with the stereotypical findings and natural history of quinine toxicity, a rare and not widely known cause of toxic optic neuropathy and retinopathy.
Studying language in context using the temporal generalization method
Authors: Fyshe Alona
Published: December 2019

The temporal generalization method (TGM) is a data analysis technique that can be used to test if the brain’s representation for particular stimuli (e.g. sounds, images) is maintained, or if it changes as a function of time (King J-R, Dehaene S. 2014 Characterizing the dynamics of mental representations: the temporal generalization method.Trends Cogn. Sci.18, 203–210. (doi:10.1016/j.tics.2014.01.002)). The TGM involves training models to predict the stimuli or condition using a time window from a recording of brain activity, and testing the resulting models at all possible time windows. This is repeated for all possible training windows to create a full matrix of accuracy for every combination of train/test window. The results of a TGM indicate when brain activity patterns are consistent (i.e. the trained model performs well even when tested on a different time window), and when they are inconsistent, allowing us to track neural representations over time. The TGM has been used to study the representation of images and sounds during a variety of tasks, but has been less readily applied to studies of language. Here, we give an overview of the method itself, discuss how the TGM has been used to analyse two studies of language in context and explore how the TGM could be applied to further our understanding of semantic composition.

This article is part of the theme issue ‘Towards mechanistic models of meaning composition’.
Modelling meaning composition from formalism to mechanism
Authors: Martin Andrea E. , Baggio Giosuè
Published: December 2019

Human thought and language have extraordinary expressive power because meaningful parts can be assembled into more complex semantic structures. This partly underlies our ability to compose meanings into endlessly novel configurations, and sets us apart from other species and current computing devices. Crucially, human behaviour, including language use and linguistic data, indicates that composing parts into complex structures does not threaten the existence of constituent parts as independent units in the system: parts and wholes exist simultaneously yet independently from one another in the mind and brain. This independence is evident in human behaviour, but it seems at odds with what is known about the brain's exquisite sensitivity to statistical patterns: everyday language use is productive and expressive precisely because it can go beyond statistical regularities. Formal theories in philosophy and linguistics explain this fact by assuming that language and thought arecompositional: systems of representations that separate a variable (orrole) from its values (fillers), such that the meaning of a complex expression is a function of the values assigned to the variables. The debate on whether and how compositional systems could be implemented in minds, brains and machines remains vigorous. However, it has not yet resulted in mechanistic models of semantic composition: how, then, are the constituents of thoughts and sentences put and held together? We review and discuss current efforts at understanding this problem, and we chart possible routes for future research.

This article is part of the theme issue ‘Towards mechanistic models of meaning composition’.
The meaning-making mechanism(s) behind the eyes and between the ears
Authors: Hagoort Peter
Published: December 2019

In this contribution, the following four questions are discussed: (i) where is meaning?; (ii) what is meaning?; (iii) what is the meaning of mechanism?; (iv) what are the mechanisms of meaning? I will argue that meanings are in the head. Meanings have multiple facets, but minimally one needs to make a distinction between single word meanings (lexical meaning) and the meanings of multi-word utterances. The latter ones cannot be retrieved from memory, but need to be constructed on the fly. A mechanistic account of the meaning-making mind requires an analysis at both a functional and a neural level, the reason being that these levels are causally interdependent. I will show that an analysis exclusively focusing on patterns of brain activation lacks explanatory power. Finally, I shall present an initial sketch of how the dynamic interaction between temporo-parietal areas and inferior frontal cortex might instantiate the interpretation of linguistic utterances in the context of a multimodal setting and ongoing discourse information.

This article is part of the theme issue ‘Towards mechanistic models of
meaning composition’
Sheaving—a universal construction for semantic compositionality
Authors: Phillips Steven
Published: December 2019

Semantic compositionality—the way that meanings of complex entities obtain from meanings of constituent entities and their structural relations—is supposed to explain certain concomitant cognitive capacities, such as systematicity. Yet, cognitive scientists are divided on mechanisms for compositionality: e.g. a language of thought on one side versus a geometry of thought on the other. Category theory is a field of (meta)mathematics invented to bridge formal divides. We focus on sheaving—a construction at the nexus of algebra and geometry/topology, alluding to an integrative view, to sketch out a category theory perspective on the semantics of compositionality. Sheaving is a universal construction for making inferences from local knowledge, where meaning is grounded by the underlying topological space. Three examples illustrate how topology conveys meaning, in terms of the inclusion relations between the open sets that constitute the space, though the topology is not regarded as the only source of semantic information. In this sense, category (sheaf) theory provides a general framework for semantic compositionality.

This article is part of the theme issue ‘Towards mechanistic models of meaning composition’.
Structured sequence processing and combinatorial binding: neurobiologically and computationally informed hypotheses
Authors: Calmus Ryan , Wilson Benjamin , Kikuchi Yukiko , Petkov Christopher I.
Published: December 2019

Understanding how the brain forms representations of structured information distributed in time is a challenging endeavour for the neuroscientific community, requiring computationally and neurobiologically informed approaches. The neural mechanisms for segmenting continuous streams of sensory input and establishing representations of dependencies remain largely unknown, as do the transformations and computations occurring between the brain regions involved in these aspects of sequence processing. We propose a blueprint for a neurobiologically informed and informing computational model of sequence processing (entitled: Vector-symbolic Sequencing of Binding INstantiating Dependencies, or VS-BIND). This model is designed to support the transformation of serially ordered elements in sensory sequences into structured representations of bound dependencies, readily operates on multiple timescales, and encodes or decodes sequences with respect to chunked items wherever dependencies occur in time. The model integrates established vector symbolic additive and conjunctive binding operators with neurobiologically plausible oscillatory dynamics, and is compatible with modern spiking neural network simulation methods. We show that the model is capable of simulating previous findings from structured sequence processing tasks that engage fronto-temporal regions, specifying mechanistic roles for regions such as prefrontal areas 44/45 and the frontal operculum during interactions with sensory representations in temporal cortex. Finally, we are able to make predictions based on the configuration of the model alone that underscore the importance of serial position information, which requires input from time-sensitive cells, known to reside in the hippocampus and dorsolateral prefrontal cortex.

This article is part of the theme issue ‘Towards mechanistic models of meaning composition’.
Training neural networks to encode symbols enables combinatorial generalization
Authors: Vankov Ivan I. , Bowers Jeffrey S.
Published: December 2019

Combinatorial generalization—the ability to understand and produce novel combinations of already familiar elements—is considered to be a core capacity of the human mind and a major challenge to neural network models. A significant body of research suggests that conventional neural networks cannot solve this problem unless they are endowed with mechanisms specifically engineered for the purpose of representing symbols. In this paper, we introduce a novel way of representing symbolic structures in connectionist terms—the vectors approach to representing symbols (VARS), which allows training standard neural architectures to encode symbolic knowledge explicitly at their output layers. In two simulations, we show that neural networks not only can learn to produce VARS representations, but in doing so they achieve combinatorial generalization in their symbolic and non-symbolic output. This adds to other recent work that has shown improved combinatorial generalization under some training conditions, and raises the question of whether specific mechanisms or training routines are needed to support symbolic processing.

This article is part of the theme issue ‘Towards mechanistic models of meaning composition’.
AlphaFamImpute: high accuracy imputation in full-sib families from genotype-by-sequencing data
Authors: Whalen Andrew , Gorjanc Gregor , Hickey John M
Published: December 2019

AlphaFamImpute is an imputation package for calling, phasing, and imputing genome-wide genotypes in outbred full-sib families from single nucleotide polymorphism (SNP) array and genotype-by-sequencing (GBS) data. GBS data is increasingly being used to genotype individuals, especially when SNP arrays do not exist for a population of interest. Low-coverage GBS produces data with a large number of missing or incorrect naïve genotype calls, which can be improved by identifying shared haplotype segments between full-sib individuals. Here we present AlphaFamImpute, an algorithm specifically designed to exploit the genetic structure of full-sib families. It performs imputation using a two-step approach. In the first step it phases and imputes parental genotypes based on the segregation states of their offspring (that is, which pair of parental haplotypes the offspring inherited). In the second step it phases and imputes the offspring genotypes by detecting which haplotype segments the offspring inherited from their parents. With a series of simulations we find that AlphaFamImpute obtains high accuracy genotypes, even when the parents are not genotyped and individuals are sequenced at less than 1x coverage.

Availability and implementation

AlphaFamImpute is available as a Python package from the AlphaGenes website,http://www.AlphaGenes.roslin.ed.ac.uk/AlphaFamImpute.

Contact

awhalen@roslin.ed.ac.uk

Supplementary information

A complete description of the methods is available in the supplementary information.
Compartment and cell type-specific hypoxia responses in the developingDrosophilabrain
Authors: Baccino-Calace Martin , Prieto Daniel , Cantera Rafael , Egger Boris
Published: December 2019

Environmental factors such as the availability of oxygen are instructive cues to regulate stem cell maintenance and differentiation. We used a genetically encoded biosensor to monitor the hypoxic state of neural cells in the larval brain ofDrosophila. The biosensor reveals brain compartment and cell type specific levels of hypoxia. The values correlate with differential tracheolation that is observed throughout development between the central brain and the optic lobe. Neural stem cells in both compartments show the strongest hypoxia response while intermediate progenitors, neurons and glial cells reveal weaker responses. We demonstrate that the distance between a cell and the next closest tracheole is a good predictor of the hypoxic state for that cell. Our model concludes that oxygen availability is the major factor controlling the hypoxia response in the developingDrosophilabrain but cell intrinsic and cell-type specific factors contribute to modulate the response in an unexpected manner.
An Extended Primer Grip of Picornavirus Polymerase Facilitates Sexual RNA Replication Mechanisms
Authors: Kempf Brian J. , Watkins Colleen L. , Peersen Olve B. , Barton David J
Published: December 2019

Picornaviruses have both asexual and sexual RNA replication mechanisms. Asexual RNA replication mechanisms involve one parental template whereas sexual RNA replication mechanisms involve two or more parental templates. Because sexual RNA replication mechanisms counteract ribavirin-induced error catastrophe, we selected for ribavirin-resistant poliovirus to identify polymerase residues that facilitate sexual RNA replication mechanisms. We used serial passage in ribavirin, beginning with a variety of ribavirin-sensitive and ribavirin-resistant parental viruses. Ribavirin-sensitive virus contained an L420A polymerase mutation while ribavirin-resistant virus contained a G64S polymerase mutation. A G64 codon mutation (G64Fix) was used to inhibit emergence of G64S-mediated ribavirin resistance. Revertants (L420) or pseudo-revertants (L420V, L420I) were selected from all independent lineages of L420A, G64FixL420A and G64S L420A parental viruses. Ribavirin-resistant G64S mutations were selected in two independent lineages and novel ribavirin-resistance mutations were selected in the polymerase in other lineages (M299I, M323I, M392V, T353I). The structural orientation of M392, immediately adjacent to L420 and the polymerase primer grip region, led us to engineer additional polymerase mutations into poliovirus (M392A, M392L & M392V and K375R & R376K). L420A revertants and pseudorevertants (L420V, L420I) restored efficient sexual RNA replication mechanisms, confirming that ribavirin-induced error catastrophe coincides with defects in sexual RNA replication mechanisms. Viruses containing M392 mutations (M392A, M392L & M392V) and primer grip mutations (K375R & R376K) exhibited divergent RNA recombination, ribavirin sensitivity and biochemical phenotypes, consistent with changes in the fidelity of RNA synthesis. We conclude that an extended primer grip of the polymerase, including L420, M392, K375 & R376, contributes to the fidelity of RNA synthesis and to efficient sexual RNA replication mechanisms.

IMPORTANCE

Picornaviruses have both asexual and sexual RNA replication mechanisms. Sexual RNA replication shapes picornavirus species groups, contributes to the emergence of vaccine-derived polioviruses and counteracts error catastrophe. Can viruses distinguish between homologous and non-homologous partners during sexual RNA replication? We implicate an extended primer grip of the viral polymerase in sexual RNA replication mechanisms. By sensing RNA sequence complementarity near the active site, the extended primer grip of the polymerase has the potential to distinguish between homologous and non-homologous RNA templates during sexual RNA replication.
Stretchable Composite Acoustic Transducer for Wearable Monitoring of Vital Signs
Authors: Cotur Yasin , Kasimatis Michael , Kaisti Matti , Olenik Selin , Georgiou Charis , Güder Firat
Published: December 2019

We report a highly flexible, stretchable, and mechanically robust low-cost soft composite consisting of silicone polymers and water (or hydrogels). When combined with conventional acoustic transducers, the materials reported enable high performance real-time monitoring of heart and respiratory patterns over layers of clothing (or furry skin of animals) without the need for direct contact with the skin. Our approach enables an entirely new method of fabrication that involves encapsulation of water and hydrogels with silicones and exploits the ability of sound waves to travel through the body. The system proposed outperforms commercial, metal-based stethoscopes for the auscultation of the heart when worn over clothing and is less susceptible to motion artefacts. We have tested the system both with human and furry animal subjects (i.e.dogs), primarily focusing on monitoring the heart, however, we also present initial results on monitoring breathing. Our work is especially important because it is the first demonstration of a stretchable sensor that is suitable for use with furry animals and do not require shaving of the animal for data acquisition.
Cell-specific exon methylation and CTCF binding in neurons regulates calcium ion channel splicing and function
Authors: Soto Eduardo Javier Lopez , Lipscombe Diane
Published: December 2019

Cell-specific alternative splicing modulates myriad cell functions and this process is disrupted in disease. The mechanisms governing alternative splicing are known for relatively few genes and typically focus on RNA splicing factors. In sensory neurons, cell-specific alternative splicing of the presynaptic voltage-gated calcium channelCacna1bgene modulates opioid sensitivity. How this splicing is regulated has remained unknown. We find that cell-specific exon DNA hypomethylation permits binding of CTCF, the master regulator of chromatin structure in mammals, which, in turn, controls splicing in noxious heat-sensing nociceptors.

Hypomethylation of an alternative exon specifically in nociceptors allows for CTCF binding, and expression of CaV2.2 channels with increased opioid sensitivity. Following nerve injury, exon methylation is increased, and splicing is disrupted. Our studies define the molecular mechanisms of cell-specific alternative splicing of a functionally validated exon in normal and disease states – and reveal a potential target for the treatment of chronic pain.

Highlights

The molecular basis of cell-specific splicing of a synaptic calcium channel gene.

Splicing controlled by cell-specific exon hypomethylation and CTCF binding.

Peripheral nerve injury disrupts exon hypomethylation and splicing.

Targeted demethylation of exon by dCAS9-TET modifies alternative splicing.

GRAPHICAL ABSTRACT

Cell-specific epigenetic modifications in a synaptic calcium ion channel gene controls cell-specific splicing in normal and neuropathic pain.

In naïve animals, in most neurons,Cacna1be37a locus is hipermethylated (5-mC) and CTCF does not bind this locus. During splicing, e37a is skipped andCacna1bmRNAs include e37b. In contrast, inTrpv1-lineage neurons,Cacna1be37a locus is hypomethylated and is permissive for CTCF binding. CTCF promotes e37a inclusion and bothCacna1be37a and e37b mRNAs are expressed. E37a confers strong sensitivity to the Cav2.2 channel to inhibition by μ-opioid receptors (μOR). Morphine is more effective at inhibiting e37a-containing Cav2.2 channels.After peripheral nerve injurythat results in pathological pain, methylation level ofCacna1be37a locus is increased, CTCF binding is impaired, andCacna1be37a mRNA levels are decreased. This disrupted splicing pattern is associated with reduced efficacy of morphinein vivo.
Discovery, optimization, and cellular activities of 2-(aroylamino)cinnamamide derivatives against colon cancer cells
Authors: Omar Abdelsattar M. , Elhaggar Radwan S. , Safo Martin K. , Abdelghany Tamer M. , Ahmed Mostafa H. , Boothello Rio , Patel Bhaumik B. , Abdel-Bakky Mohamed S. , El-Araby Moustafa E.
Published: December 2019

Curcumin andtrans-cinnamaldehyde are acrolein-based Michael acceptor compounds that are commonly found in domestic condiments, and known to cause cancer cell deathviaredox mechanisms. Based on the structural features of these compounds we designed and synthesized several 2-cinnamamido-N-substituted-cinnamamide (bis-cinnamamide) compounds. One of the derivatives, (Z)-2-[(E)-cinnamamido]-3-phenyl-N-propylacrylamide (1512)showed a moderate antiproliferative potency (HT116 cell line inhibition of 32.0 µM ± 2.6) with proven cellular activities leading to apoptosis. Importantly,1512exhibited good selectivity toxicity on cancer cells over noncancerous cells (IC50of C-166 cell lines >100 µM), and low cancer cell resistance at 100 µM dose (growth rate 10.1±1.1%). We subsequently carried out structure activity relationship studies with1512. Derivatives with electron rich moiety at the aryl ring of the 2-aminocinnamaide moiety exhibited strong antiproliferative action while electron withdrawing groups caused loss of activity. Our most promising compound,4112[(Z)-3-(1H-indol-3-yl)-N-propyl-2-[(E)-3-(thien-2-yl)propenamido)propenamide] killed cancer cells at IC50= 0.89 ± 0.04 µM (Caco-2), 2.85 ± 1.5 (HCT-116) and 1.65 ± 0.07 (HT-29), while exhibiting much weaker potency on C-166 and BHK normal cell lines (IC50= 71 ± 5.12 and 77.6 ± 6.2 µM, respectively). Cellular studies towards identifying the compounds mechanism of cytotoxic activities revealed that apoptotic induction occurs in part due to oxidative stress. Importantly, the compounds showed inhibition of cancer stem cells that are critical for maintaining the potential for self-renewal and stemness. The results presented here show discovery of Michael addition compounds that potently kill cancer cells by a defined mechanism, with minimal effect on normal noncancerous cell.
Stochastic dynamics of extra-chromosomal DNA
Authors: Pichugin Yuriy , Huang Weini , Werner Benjamin
Published: December 2019

Nuclear extra-chromosomal DNA (ecDNA) is highly prevalent in human tumours. ecDNA amplifications can promote accessible chromatin, oncogen over-expression and imply a worse clinical prognosis. Yet, little is known about the evolutionary process of ecDNA in human cancers. Here, we develop the theoretical foundation of the ecDNA somatic evolutionary process combining mathematical, computational and experimental approaches. We show that random ecDNA segregation leads to unintuitive dynamics even if ecDNA is under very strong positive selection. Patterns of inter- and intra-tumour ecDNA and chromosomal heterogeneity differ markedly and standard approaches are not directly applicable to quantify ecDNA evolution. We show that evolutionary informed modelling leads to testable predictions on how to distinguish positively selected from neutral ecDNA dynamics. Our predictions describe the dynamics of circular amplicons in GBM39 cell line experiments, suggesting a 300% fitness increase due to circular extra-chromosomalEGFRvIIIamplifications. Our work lies the basis for further studies to quantitate ecDNA somatic evolutionary processes.
Induced aneuploidy disrupts MCF10A acini formation and CCND1 expression
Authors: Waschow Marcel , Wang Qi , Saary Paul , Klein Corinna , Aschenbrenner Sabine , Jechow Katharina , Maier Lorenz , Tirier Stephan , Schoell Brigitte , Chudoba Ilse , Dietz Christian , Dreidax Daniel , Jauch Anna , Sprick Martin , Herrmann Carl , Eils Roland , Conrad Christian
Published: December 2019

Abnormal karyotypes, namely aneuploidy, can be detected in nearly all cancer entities at different grades. The impact of these altering mutations on epigenetic regulation, especially on promoter-enhancer interactions are not well understood. Here, we applied a 3D model of MCF10A cells in a high-content screen to measure induced aneuploidy by RNA interference of 82 mitotic genes associated with aneuploidy and breast cancer. Perturbation of ESPL1 and TOP2A expression led to increased mitotic instability and subsequent aneuploidy and polylobed nuclei. During acinus formation these polylobed cells disrupted proper acinus rotation inhibiting the development of a hollow lumen and a polarized outer cell layer. Further, gene expression profiling identified upregulated CCND1 among other breast cancer related genes. We show that acquisition of aneuploidy affects the morphogenesis of MCF10A acini and expression of cancer relevant genes. By conducting 4C chromosome capturing experiments we linked the alteration of interactions of the promoter region to CCND1 upregulation.
Gene regulatory networks associated with lateral root and nodule development in soybean
Authors: Smita Shuchi , Kiehne Jason , Adhikari Sajag , Zeng Erliang , Ma Qin , Subramanian Senthil
Published: December 2019

Legume plants such as soybean produce two major types of root lateral organs, lateral roots and root nodules. A robust computational framework was developed to predict potential gene regulatory networks (GRNs) associated with root lateral organ development in soybean. A genome-scale expression dataset was obtained from soybean root nodules and lateral roots and subjected to biclustering using QUBIC. Biclusters (BCs) and transcription factor (TF) genes with enriched expression in lateral root tissues were converged using different network inference algorithms to predict high confident regulatory modules that are repeatedly retrieved in different methods. The ranked combination of results from all different network inference algorithms into one ensemble solution identified 21 GRN modules of 182 co-regulated genes networks potentially involved in root lateral organ development stages in soybean. The pipeline correctly predicted previously known nodule- and LR-associated TFs including the expected hierarchical relationships. The results revealed high scorer AP2, GRF5, and C3H co-regulated GRN modules during early nodule development; and GRAS, LBD41, and ARR18 co-regulated GRN modules late during nodule maturation. Knowledge from this work supported by experimental validation in the future is expected to help determine key gene targets for biotechnological strategies to optimize nodule formation and enhance nitrogen fixation.
Are teams experiencing relationship conflicts destined to fail
Authors: Yuan Ling , Yu Yue , Liu Pan
Published: December 2019

Purpose

The purpose of this study is to find ways to mitigate the negative consequences of relationship conflict under the situation that while the negative role of team relationship conflict has been underscored in prior literature, few studies try to alleviate it. With the development of positive psychology, a stream focusing on the role of emotion in conflict management emerges. First, the authors want to explore the mediating role of members’ work engagement in the association between relationship conflict and members’ job performance. Moreover, they want to explore contingent roles of perceived team leader’s emotional intelligence and members’ emotion regulation strategies (i.e. cognitive reappraisal and expressive suppression) in moderating the effect of relationship conflict on members’ work engagement.

Design/methodology/approach

Using a data set of 363 individuals working in 73 teams in service sectors, the authors empirically examined the cross-level model with hierarchical linear model.

Findings

Relationship conflict was negatively related to members’ job performance while members’ work engagement mediated this relationship. Moreover, perceived team leader’s emotional intelligence mitigated the negative effect of relationship conflict on members’ work engagement, while members’ expressive suppression strategy intensified the negative effect.

Originality/value

The authors address the void of the cross-level mediating process by examining the role of individual work engagement that mediates relationship conflict and individual job performance. The individual work engagement is highlighted in this study for the hope of serving as the basis of finding effective moderators to alleviate the negative relationship conflict–performance relationship by mitigating the decrease of work engagement. Moreover, the claim that the role of emotion from different status subjects varies in regulating the effect of relationship conflict contributes to the development of positive psychology by combining emotion with conflict management.
Network, reputation, VC-financing: SME in Zhongguancun and Silicon Valley
Authors: Trunina Anna , Liu Xielin , Hafeez Muhammad , Chen Jian , Sarker Swati Anindita
Published: December 2019

Purpose

This paper aims to investigate if the collaboration intensity of the company with local and international stakeholders facilitates the attracting of venture capital (VC) financing. The reputation of the company was incorporated as a factor, which can potentially influence investment decision-making. The study also aims to make a cross-national comparison of new ventures financing in two innovation regions – Chinese Zhongguancun and American Silicon Valley.

Design/methodology/approach

Quantitative methodology involving data gathered from 176 venture-backed as well as non-venture backed SME located in Chinese Zhongguancun and American Silicon Valley was applied. The data has been gathered through a survey. A logistic regression model has been adopted to test the hypotheses and explore relationships among concerned variables.

Findings

The results spotlight that collaboration intensity with the company’s domestic stakeholders could enhance the attractiveness of the company for external investments. Collaboration intensity with foreign stakeholders increases the likelihood of acquiring financial support only for Chinese companies. For American companies, the reputation of their stakeholders did not show a significant effect. However, positive reputation acquired from the Chinese company’s stakeholders enhances the chance of getting funding and moderates the investment effect of collaboration intensity with domestic stakeholders.

Originality/value

This paper unfolds that the network strength and the reputation of the SME could play the role in getting VC investment. The results are shown in two different contexts (Silicon Valley in the USA and Zhongguancun in China), characterizing the completely different cultural, legal, institutional and operating environments.
A reflection on borrowing from western economics
Authors: Fang Fuqian
Published: December 2019

Purpose

Western economics came into being with the rise of the capitalist market economy. It had a nature of duality beginning from its birth: the justificativeness of providing theoretical pillars for the capitalist market economy system and the scientificity of revealing the internal relations and operating rules of the capitalist market economy. The paper aims to discuss this issue.

Design/methodology/approach

However, after the 1830s, this justificativeness gradually evolved into vulgarity. Since the 1930s, modern western mainstream economics has mainly explored the general market economy on the assumption that the capitalist system remains unchanged, and many outcomes of such research are positive and beneficial.

Findings

Political economy of socialism with Chinese characteristics, at the present stage, is mainly a Chinese socialist market economics. It is guided by the Marxist political economy and rooted in the great practice of China’s reform and opening up and socialist modernization.

Originality/value

According to political complexion, western economic theories can be divided into political economic theory, mainstream economic theory and basic economic theory. By subjecting these theories to what we term “elimination,” “transformation” and “transplantation” surgeries, respectively, we can absorb and accommodate their beneficial elements in building a political economy of socialism with Chinese characteristics, which in turn is conducive to the development and prosperity of such an economy.