bluuebunny/crossref_metadata_2025 huggingface dataset:
Investigating a unique partial eclipse in the high-mass X-ray binary IGR J16393−4643 with Swift-XRT
Authors: Kabiraj Sanhita , Islam Nazma , Paul Biswajit
Published: November 2019

The orbital profile of the high-mass X-ray binary IGR J16393−4643 shows a dip in its X-ray intensity, which was previously interpreted as an eclipse. Unlike most eclipsing HMXBs, where the X-ray eclipses are about two orders of magnitude fainter compared to the out-of-eclipse emission, this particular eclipse-like feature is narrow and partial, casting doubt if it is indeed an eclipse. To further investigate the nature of this low-intensity orbital phase, we use a large number of observations with Swift-XRT, covering the entire orbital phase. The soft X-ray observations also show this low-intensity phase, which is about 30 % of the intensity during rest of the orbit. We also carried out orbital-phase-resolved spectroscopy to compare the change in the spectral parameters inside and outside of this low-intensity state. The results indicate that this low-intensity state might not be an eclipse, as previously thought but absorption in the stellar corona. We have also provided the inclination angle of the binary for grazing eclipse caused by the stellar corona.
Statistical properties of magnetar bursts and FRB 121102
Authors: Cheng Yingjie , Zhang G Q , Wang F Y
Published: November 2019

In this paper, we present statistics of soft gamma repeater (SGR) bursts from SGR J1550−5418, SGR 1806−20, and SGR 1900+14 by adding new bursts from Kırmızıbayrak et al. detected with the Rossi X-ray Timing Explorer. We find that the fluence distributions of magnetar bursts are well described by power-law functions with indices 1.84, 1.68, and 1.65 for SGR J1550−5418, SGR 1806−20, and SGR 1900+14, respectively. The duration distributions of magnetar bursts also show power-law forms. Meanwhile, the waiting time distribution can be described by a non-stationary Poisson process with an exponentially growing occurrence rate. These distributive features indicate that magnetar bursts can be regarded as a self-organizing critical process. We also compare these distributions with the repeating fast radio burst (FRB) 121102. The statistical properties of repeating FRB 121102 are similar with magnetar bursts, combining with the large required magnetic field (B ≥ 1014 G) of neutron star for FRB 121102, which indicates that the central engine of FRB 121102 may be a magnetar.
Outflows from inflows: the nature of Bondi-like accretion
Authors: Waters Tim , Aykutalp Aycin , Proga Daniel , Johnson Jarrett , Li Hui , Smidt Joseph
Published: November 2019

The classic Bondi solution remains a common starting point both for studying black hole growth across cosmic time in cosmological simulations and for smaller scale simulations of active galactic nuclei (AGN) feedback. In nature, however, there will be inhomogeneous distributions of rotational velocity and density along the outer radius (Ro) marking the sphere of influence of a black hole. While there have been many studies of how the Bondi solution changes with a prescribed angular momentum boundary condition, they have all assumed a constant density at Ro. In this Letter, we show that a non-uniform density at Ro causes a meridional flow and due to conservation of angular momentum, the Bondi solution qualitatively changes into an inflow–outflow solution. Using physical arguments, we analytically identify the critical logarithmic density gradient |$\partial \ln \rho/\partial \theta$| above which this change of the solution occurs. For realistic Ro, this critical gradient is less than 0.01 and tends to 0 as Ro → ∞. We show using numerical simulations that, unlike for solutions with an imposed rotational velocity, the accretion rate for solutions under an inhomogeneous density boundary condition remains constant at nearly the Bondi rate $\dot{M}_\mathrm{ B}$, while the outflow rate can greatly exceed $\dot{M}_\mathrm{ B}$.
Promises and Perils of Artificial Intelligence in Neurosurgery
Authors: Panesar Sandip S , Kliot Michel , Parrish Rob , Fernandez-Miranda Juan , Cagle Yvonne , Britz Gavin W
Published: November 2019

Artificial intelligence (AI)-facilitated clinical automation is expected to become increasingly prevalent in the near future. AI techniques may permit rapid and detailed analysis of the large quantities of clinical data generated in modern healthcare settings, at a level that is otherwise impossible by humans. Subsequently, AI may enhance clinical practice by pushing the limits of diagnostics, clinical decision making, and prognostication. Moreover, if combined with surgical robotics and other surgical adjuncts such as image guidance, AI may find its way into the operating room and permit more accurate interventions, with fewer errors. Despite the considerable hype surrounding the impending medical AI revolution, little has been written about potential downsides to increasing clinical automation. These may include both direct and indirect consequences. Directly, faulty, inadequately trained, or poorly understood algorithms may produce erroneous results, which may have wide-scale impact. Indirectly, increasing use of automation may exacerbate de-skilling of human physicians due to over-reliance, poor understanding, overconfidence, and lack of necessary vigilance of an automated clinical workflow. Many of these negative phenomena have already been witnessed in other industries that have already undergone, or are undergoing “automation revolutions,” namely commercial aviation and the automotive industry. This narrative review explores the potential benefits and consequences of the anticipated medical AI revolution from a neurosurgical perspective.
Diagnosis and Management of Osteomyelitis Associated With Stage 4 Pressure Ulcers: Report of a Query to the Emerging Infections Network of the Infectious Diseases Society of America
Authors: Kaka Anjum S , Beekmann Susan E , Gravely Amy , Filice Gregory A , Polgreen Philip M , Johnson James R
Published: November 2019

Background

Few studies exist to guide the management of patients with stage 4 pressure ulcers with possible underlying osteomyelitis. We hypothesized that infectious disease (ID) physicians would vary widely in their approach to such patients.

Methods

The Emerging Infections Network distributed a 10-question electronic survey in 2018 to 1332 adult ID physicians in different practice settings to determine their approach to such patients.

Results

Of the 558 respondents (response rate: 42%), 17% had managed no such patient in the past year. Of the remaining 464 respondents, 60% usually felt confident in diagnosing osteomyelitis; the strongest clinical indicator of osteomyelitis reported was palpable or visible bone at the ulcer base. Approaches to diagnosing osteomyelitis in patients with visible and palpable bone varied: 41% of respondents would assume osteomyelitis, 27% would attempt pressure off-loading first, and 22% would perform diagnostic testing immediately. Preferred tests for osteomyelitis were bone biopsy (for culture and histopathology) and magnetic resonance imaging. Respondents differed widely on favored route(s) (intravenous, oral, or both) and duration of antimicrobial therapy but would treat longer in the absence, vs presence, of full surgical debridement (P < .001). Overall, 62% of respondents opined that osteomyelitis under stage 4 pressure ulcers is usually or almost always treated excessively, and most (59%) suggested multiple topics for future research.

Conclusions

Regarding osteomyelitis underlying stage 4 pressure ulcers, ID physicians reported widely divergent diagnostic and treatment approaches. Most of the reported practice is not supported by the available evidence, which is quite limited and of low quality.
Privatizing Police Discretion—‘Private Security Criminal Investigations’ in Sweden
Authors: Stiernstedt Peter
Published: November 2019

This article highlights the commodification of private security criminal investigations in Sweden. Today, the reach of the private security industry extends to almost all responsibilities traditionally reserved for the police. Regulation is constantly trying to catch up with the ever-changing scope and nature of private security. When looking at private security industry regulation in the European Union, Sweden enjoys one of the most comprehensive frameworks. There are however gaps and private security criminal investigation is one which, if left unchecked, could possibly lead to a dangerous commodification of justice and decreasing trust in the police. In this article, these issues are explored through interviews with a number of stakeholders. The interviews reveal that the potential danger lies in circumstances whereby police are, for various reasons, forced to turn down investigations. Citizens and organizations alike then have the opportunity to proceed with the investigation through a private security service provider. Presented with a complete substratum for prosecution, the police are incentivized to proceed. Thus, police discretion as to whether or not to proceed with an investigation is effectively for sale. The article consequently calls for a revision of Swedish private security regulation.
Explanation of detailed spectral properties of fast radio bursts by the axion star model
Authors: Iwazaki Aiiichi
Published: November 2019

We have proposed a generation mechanism for non-repeating (repeating) fast radio bursts (FRBs): They arise by axion star collisions with neutron stars (accretion disks of galactic black holes). The axion star, as a coherent state of axions with mass $m_a$, generates a homogeneous electric field oscillating with frequency $m_a/2\pi$ under strong magnetic fields. The field makes electrons oscillate coherently and emit coherent dipole radiation (FRBs). The radiation stops when the oscillations are disturbed by the thermalization of the oscillating energies. Thus, the duration of the FRB is determined by the time scale of the thermalization. We show that it can be shorter than $1$ ms. The line spectra of the dipole radiation are broadened by the thermal effects. The thermally broadened spectra have the feature that the bandwidths $\delta\nu$ are proportional to their center frequencies $\nu_{\rm c}$: $\delta\nu \propto \nu_{\rm c}$. Because the accretion disks can orbit with relativistic velocities, the radiation is Doppler shifted. This leads to the presence of various center frequencies ($\nu_{\rm c}=600 \, \text{MHz} \sim 7$ GHz) in repeating FRB 121102. On the other hand, non-repeating FRBs do not show such a variety in the center frequencies. They come from the surfaces of neutron stars whose motions are non-relativistic. The Doppler shift also makes the duration of bursts with higher frequencies become shorter. Because the magnetic fields of the neutron stars are stronger than those of the accretion disks, the peak flux densities of non-repeating FRBs are larger than those of repeating FRB 121102. They also lead to wide bandwidths of non-repeating FRBs, which cover the full extent of the receiver frequency range. The spectral features of the recently discovered new repeating FRB 180814.J0422+75 are coincident with our general analyses of the repeating FRB 121102.
Soothing the emotional brain: modulation of neural activity to personal emotional stimulation by social touch
Authors: Kraus Jakub , Frick Andreas , Roman Robert , Jurkovičová Lenka , Mareček Radek , Mikl Michal , Brázdil Milan , Fredrikson Mats
Published: November 2019

Social touch may modulate emotions, but the neurobehavioral correlates are poorly understood. Here, we investigated neural responses to a picture of a deceased close person and if neural activity and connectivity are modulated by social touch from one’s romantic partner. Using functional magnetic resonance imaging, we found altered reactivity in several brain areas including the anterior cingulate cortex (ACC) and the anterior insula in response to the personal picture compared to a picture of an unfamiliar person. Hand holding with the romantic partner, compared to being alone, reduced reactivity in the ACC and cerebellum and provided subjective comfort. To separate physical touch from the emotional effect of partner presence, we evaluated hand holding with the partner relative to a stranger and found reduced reactivity in the anterior insula. Connectivity between the anterior insula and the ACC was reduced during partner touch, and the connectivity strength was negatively related to attachment security, with higher reported partner security associated with weaker connectivity. Overall, holding hands with one’s partner attenuates reactivity in emotional brain areas and reduces between-region connectivity.
Slimming One’s Way to a Better Self? Weight Loss Clubs and Women in Britain, 1967–1990
Authors: Moseley Katrina-Louise
Published: November 2019

Following the arrival of Weight Watchers UK in 1967, slimming clubs expanded rapidly in Britain in the late 1960s and early 1970s. Initially aimed at, and founded by, women, these organizations were complex emotional spaces in which female entrepreneurship and homosociality would unfold. Looking afresh at the relationship between women and commercialized weight loss, this article provides the first detailed study of the rise of the slimming club in mid-to-late-twentieth-century Britain. Slimming clubs proved lucrative business opportunities for some women; moreover, as homosocial spaces intersecting with women’s everyday lives, they had the potential to be emotionally and psychologically empowering. A history of these organizations thus complicates feminist critiques of the slimming industry. This article draws on a variety of historical sources to piece together this forgotten history, including contemporary slimming guides, newspaper ‘before-and-after’ features, and oral history interviews with industry professionals and former slimming club members. Though members recognized that the commercial promise of transformation was shot through with contradictions, simultaneously, slimming clubs sparked enjoyment in being in the female body and provided a space away from domesticity.
MicroRNA‐206 regulates cell proliferation by targeting G6PD in skeletal muscle
Authors: Jiang Aiwen , Dong Chao , Li Bojiang , Zhang Zengkai , Chen Yujun , Ning Caibo , Wu Wangjun , Liu* Honglin
Published: November 2019

Skeletal muscle is a major component of body mass and plays a central role in the control of whole‐body metabolism in humans and animals. Therefore, elucidation of the underlying mechanisms of skeletal growth and development are expected to lead to the discovery of novel genes and pathways related to muscle disease. miR‐206, a skeletal muscle‐specific microRNA, plays a crucial role in myogenesis; however, miR‐206 is known to function in myogenic differentiation, whether or not it affects muscle cells' proliferation, and the underlying mechanisms are unknown. In this study, we investigated the effect of miR‐206 on muscle cell proliferation and differentiation, as well as its effect on myofiber type conversion using mouse C2C12 myoblasts. The results showed that overexpression of miR‐206 inhibited cell proliferation and promoted muscle cell differentiation, but it did not affect myofiber type conversion. Intriguingly, we found that overexpression of miR‐206 suppressed muscle cell proliferation and induced cell cycle arrest in G0/G1 phase by inhibiting the glucose‐6‐phosphate dehydrogenase (G6PD) gene. Taken together, we demonstrated that the miR‐206‐G6PD pathway suppresses muscle cell proliferation, and these findings may facilitate the treatment of muscle diseases.—Jiang, A., Dong, C., Li, B., Zhang, Z., Chen, Y., Ning, C., Wu, W., Liu, H. MicroRNA‐206 regulates cell proliferation by targeting G6PD in skeletal muscle. FASEB J. 33, 14083‐14094 (2019). www.fasebj.org
The human mitochondrial 12S rRNA m4C methyltransferase METTL15 is required for proper mitochondrial function
Authors: Chen Hao , Shi Zhennan , Guo Jiaojiao , Chang Kao-jung , Chen Qianqian , Yao Conghui , Haigis Marcia C. , Shi Yang
Published: November 2019

Mitochondrial DNA (mtDNA) gene expression is coordinately regulated pre- and post-transcriptionally, and its perturbation can lead to human pathologies. Mitochondrial ribosomal RNAs (mt-rRNAs) undergo a series of nucleotide modifications following release from polycistronic mitochondrial RNA (mtRNA) precursors, which is essential for mitochondrial ribosomal biogenesis. Cytosine N4 methylation (m4C) at position 839 of the 12S small subunit (SSU) mt-rRNA was identified decades ago, however, its biogenesis and function have not been elucidated in details. Here we demonstrate that human Methyltransferase Like 15 (METTL15) is responsible for 12S mt-rRNA methylation at C839 (m4C839) both in vivo and in vitro. We tracked the evolutionary history of RNA m4C methyltransferases and revealed the difference in substrates preference between METTL15 and its bacterial ortholog rsmH. Additionally, unlike the very modest impact on ribosome upon loss of m4C methylation in bacterial SSU rRNA, we found that depletion of METTL15 specifically causes severe defects in mitochondrial ribosome assembly, which leads to an impaired translation of mitochondrial protein-coding genes and a decreased mitochondrial respiration capacity. Our findings point to a co-evolution of methylatransferase specificities and modification patterns in rRNA with differential impact on prokaryotic ribosome versus eukaryotic mitochondrial ribosome.
In Vivo Neuroregeneration to Treat Ischemic Stroke in Adult Non-Human Primate Brains through NeuroD1 AAV-based Gene Therapy
Authors: Ge Long-Jiao , Yang Fu-Han , Feng Jie , Chen Nan-Hui , Jiang Min , Wang Jian-Hong , Hu Xin-Tian , Chen Gong
Published: November 2019

Stroke is a leading cause of death and disability but most of the clinical trials have failed in the past, despite our increasing understanding of the molecular and pathological mechanisms underlying stroke. While many signaling pathways have been identified in the aftermath of stroke, the majority of current approaches are focusing on neural protection rather than neuroregeneration. In this study, we report an in vivo neural regeneration approach to convert brain internal reactive astrocytes into neurons through ectopic expression of a neural transcription factor NeuroD1 in adult non-human primate (NHP) brains following ischemic stroke. We demonstrate that NeuroD1 AAV-based gene therapy can convert reactive astrocytes into neurons with high efficiency (90%), but astrocytes are never depleted in the NeuroD1-expressed areas, consistent with the proliferative capability of astrocytes. The NeuroD1-mediated in vivo astrocyte-to-neuron (AtN) conversion in monkey cortex following ischemic stroke increased local neuronal density, reduced reactive microglia, and surprisingly protected parvalbumin interneurons in the converted areas. The NeuroD1 gene therapy showed a broad time window, from 10 days to 30 days following ischemic stroke, in terms of exerting its neuroregenerative and neuroprotective effects. The cortical astrocyte-converted neurons also showed Tbr1+ cortical neuron identity, similar to our earlier findings in rodent animal models. Unexpectedly, NeuroD1 expression in converted neurons showed a significant decrease after 6 months of viral infection, suggesting a potential self-regulatory mechanism of NeuroD1 in adult mature neurons of NHPs. These results suggest that in vivo cell conversion through NeuroD1-based gene therapy may be an effective approach to regenerate new neurons in adult primate brains for tissue repair.
Regeneration of dorsal spinal cord neurons after injury viain situNeuroD1-mediated astrocyte-to-neuron conversion
Authors: Puls Brendan , Ding Yan , Zhang Fengyu , Pan Mengjie , Lei Zhuofan , Pei Zifei , Jiang Mei , Bai Yuting , Forsyth Cody , Metzger Morgan , Rana Tanvi , Zhang Lei , Ding Xiaoyun , Keefe Matthew , Cai Alice , Redilla Austin , Lai Michael , He Kevin , Li Hedong , Chen Gong
Published: November 2019

Spinal cord injury (SCI) often leads to impaired motor and sensory functions, partially because the injury-induced neuronal loss cannot be easily replenished through endogenous mechanisms.In vivoneuronal reprogramming has emerged as a novel technology to regenerate neurons from endogenous glial cells by forced expression of neurogenic transcription factors. We have previously demonstrated successful astrocyte-to-neuron conversion in mouse brains with injury or Alzheimer’s disease by overexpressing a single neural transcription factorNeuroD1via retroviruses. Here we demonstrate regeneration of dorsal spinal cord neurons from reactive astrocytes after SCI via adeno-associated virus (AAV), a more clinically relevant gene delivery system. We find thatNeuroD1converts reactive astrocytes into neurons in the dorsal horn of stab-injured spinal cord with high efficiency (∼95%). Interestingly,NeuroD1-converted neurons in the dorsal horn mostly acquire glutamatergic neuronal subtype, expressing spinal cord-specific markers such as Tlx3 but not brain-specific markers such as Tbr1, suggesting that the astrocytic lineage and local microenvironment affect the cell fate of conversion. Electrophysiological recordings show that theNeuroD1-converted neurons can functionally mature and integrate into local spinal cord circuitry by displaying repetitive action potentials and spontaneous synaptic responses. We further show thatNeuroD1-mediated neuronal conversion can occur in the contusive SCI model, allowing future studies of evaluating this reprogramming technology for functional recovery after SCI. In conclusion, this study may suggest a paradigm shift for spinal cord repair usingin vivoastrocyte-to-neuron conversion technology to generate functional neurons in the grey matter.
OCTAD: an open workplace for virtually screening therapeutics targeting precise cancer patient groups using gene expression features
Authors: Zeng Billy , Glicksberg Benjamin S. , Newbury Patrick , Xing Jing , Liu Ke , Wen Anita , Chow Caven , Chen Bin
Published: November 2019

One approach to precision medicine is to discover drugs that target molecularly defined diseases. Voluminous cancer patient gene expression profiles have been accumulated in public databases, enabling the creation of a cancer-specific expression signature. By matching this signature to perturbagen-induced gene expression profiles from large drug libraries, researchers can prioritize small molecules that present high potency to reverse expression of signature genes for further experimental testing of their efficacy. This approach has proven to be an efficient and cost-effective way to identify efficacious drug candidates. However, the success of this approach requires multiscale procedures, imposing significant challenges to many labs. Therefore, we present OCTAD: an open workplace for virtually screening compounds targeting precise cancer patient groups using gene expression features. We release OCTAD as a web portal and standalone R workflow to allow experimental and computational scientists to easily navigate the tool. In this work, we describe this tool and demonstrate its potential for precision medicine.
Human glial progenitor cells effectively remyelinate the demyelinated adult brain
Authors: Windrem Martha , Schanz Steven , Zou Lisa , Chandler-Militello Devin , Kuypers Nicholas J. , Mariani John N. , Goldman Steven A.
Published: November 2019

Human glial progenitor cells (hGPCs) can completely myelinate the brains of congenitally hypomyelinated shiverer mice, rescuing the phenotype and extending or normalizing the lifespan of these mice. We asked if implanted hGPCs might be similarly able to broadly disperse and remyelinate the diffusely and/or multicentrically-demyelinatedadultCNS. In particular, we asked if fetal hGPCs could effectively remyelinate both congenitally hypomyelinated adult axons,andaxons acutely demyelinated in adulthood, using adultshiverermice and cuprizone-demyelinated mice, respectively. We found that hGPCs broadly infiltrate the adult CNS after callosal injection, and robustly myelinate congenitally-unmyelinated axons in adultshiverer. Moreover, implanted hGPCs similarly remyelinated denuded axons after cuprizone demyelination, whether they were delivered prior toorafter initial cuprizone demyelination. Extraction and FACS of hGPCs from cuprizone-demyelinated brains in which they had been resident, followed by RNA-seq of the isolated human hGPCs, revealed their activation of transcriptional programs indicating their initiation of oligodendrocyte differentiation and myelination. These data indicate the ability of transplanted hGPCs to disperse throughout the adult CNS, to myelinate dysmyelinated regions encountered during their parenchymal colonization, and to also be recruited as myelinating oligodendrocytes at later points in life, upon demyelination-associated demand.
ER stress drives ER-to-Golgi trafficking of ATF6 by blocking its membrane insertion
Authors: Xu Jia , Meng Xianbin , Wu Fang , Deng Haiteng , Fu Suneng
Published: November 2019

Regulated ER-to-Golgi trafficking is a fundamental cellular process that enables ER-resident transcription factors to sense perturbations in the ER environment and activates transcriptional programs that restore ER and cellular homeostasis. Current models suggest sensor activation is initiated by dissociation from its ER-resident binding partners. Here we challenge this model by demonstrating that the unfolded protein sensor ATF6 is sorted to the Golgi as a newly synthesized peripheral membrane protein beyond the reach of its ER retainer, and translocon inhibition alone is sufficient to drive ATF6 activation. We identify ATF6 transmembrane domain and its C-terminus as the intrinsic factors that control membrane insertion efficiency and stress sensing capacity, and the BAG6 complex as the receptor that triages ATF6 between membrane insertion and Golgi sorting. Besides ATF6, we show that translocon inhibition expedites the activation of the cholesterol sensor SREBP2, and the catalytic domain of Golgi-bound S1P that processes both ATF6 and SREBP2 resides in the cytosol. Therefore, we propose an alternative, sensing-by-synthesis model, in which transcription factors are continuously synthesized, and perturbations to the ER environment are quantitatively sensed by the fraction of sensors that fail to be properly incorporated into ER membrane and sorted to Golgi for activation.
The BELT and phenoSEED platforms: shape and colour phenotyping of seed samples
Authors: Halcro Keith , McNabb Kaitlin , Lockinger Ashley , Socquet-Juglard Didier , Bett Kirstin E , Noble Scott D
Published: November 2019

Background

Seed analysis is currently a bottleneck in phenotypic analysis of seeds. Measurements are slow and imprecise with potential for bias to be introduced when gathered manually. New acquisition tools were requested to improve phenotyping efficacy with an emphasis on obtaining colour information.

Results

A portable imaging system (BELT) supported by image acquisition and analysis software (phenoSEED) was created for small-seed optical analysis. Lentil (Lens culinaris L.) phenotyping was used as the primary test case. Seeds were loaded into the system and all seeds in a sample were automatically and individually imaged to acquire top and side views as they passed through an imaging chamber. A Python analysis script applied a colour calibration and extracted quantifiable traits of seed colour, size and shape. Extraction of lentil seed coat patterning was implemented to further describe the seed coat. The use of this device was forecasted to eliminate operator biases, increase the rate of acquisition of traits, and capture qualitative information about traits that have been historically analyzed by eye.

Conclusions

Increased precision and higher rates of data acquisition compared to traditional techniques will help breeders to develop more productive cultivars. The system presented is available as an open-source project for academic and non-commercial use.
Machine learning of stochastic gene network phenotypes
Authors: Park Kyemyung , Prüstel Thorsten , Lu Yong , Tsang John S.
Published: November 2019

A recurrent challenge in biology is the development of predictive quantitative models because most molecular and cellular parameters have unknown values and realistic models are analytically intractable. While the dynamics of the system can be analyzed via computer simulations, substantial computational resources are often required given uncertain parameter values resulting in large numbers of parameter combinations, especially when realistic biological features are included. Simulation alone also often does not yield the kinds of intuitive insights from analytical solutions. Here we introduce a general framework combining stochastic/mechanistic simulation of reaction systems and machine learning of the simulation data to generate computationally efficient predictive models and interpretable parameter-phenotype maps. We applied our approach to investigate stochastic gene expression propagation in biological networks, which is a contemporary challenge in the quantitative modeling of single-cell heterogeneity. We found that accurate, predictive machine-learning models of stochastic simulation results can be constructed. Even in the simplest networks existing analytical schemes generated significantly less accurate predictions than our approach, which revealed interesting insights when applied to more complex circuits, including the extensive tunability of information propagation enabled by feedforward circuits and how even single negative feedbacks can utilize stochastic fluctuations to generate robust oscillations. Our approach is applicable beyond biology and opens up a new avenue for exploring complex dynamical systems.
Using artificial intelligence on dermatology conditions in Uganda: A case for diversity in training data sets for machine learning
Authors: Kamulegeya Louis Henry , Okello Mark , Bwanika John Mark , Musinguzi Davis , Lubega William , Rusoke Davis , Nassiwa Faith , Börve Alexander
Published: November 2019

Introduction

Artificial intelligence (AI) in healthcare has gained momentum with advances in affordable technology that has potential to help in diagnostics, predictive healthcare and personalized medicine. In pursuit of applying universal non-biased AI in healthcare, it is essential that data from different settings (gender, age and ethnicity) is represented. We present findings from beta-testing an AI-powered dermatological algorithm called Skin Image Search, by online dermatology company First Derm on Fitzpatrick 6 skin type (dark skin) dermatological conditions.

Methods

123 dermatological images selected from a total of 173 images retrospectively extracted from the electronic database of a Ugandan telehealth company, The Medical Concierge Group (TMCG) after getting their consent. Details of age, gender and dermatological clinical diagnosis were analyzed using R on R studio software to assess the diagnostic accuracy of the AI app along disease diagnosis and body part. Predictability levels of the AI app was graded on a scale of 0 to 5, where 0-no prediction made and 1-5 demonstrating reducing correct prediction.

Results

76 (62%) of the dermatological images were from females and 47 (38%) from males. The 5 most reported body parts were; genitals (20%), trunk (20%), lower limb (14.6%), face (12%) and upper limb (12%) with the AI app predicting a diagnosis in 62% of image body parts uploaded. Overall diagnostic accuracy of the AI app was low at 17% (21 out of 123 predictable images) with varying predictability levels correctness i.e. 1-8.9%, 2-2.4%, 3-2.4%, 4-1.6%, 5-1.6% with performance along individual diagnosis highest with dermatitis (80%).

Conclusion

There is a need for diversity in the image datasets used when training dermatology algorithms for AI applications in clinical decision support as a means to increase accuracy and thus offer correct treatment across skin types and geographies.
Foxi1inactivation rescues loss of principal cell fate selection inHes1-deficient kidneys but does not ensure maintenance of principal cell gene expression
Authors: Mukherjee Malini , DeRiso Jennifer , Janga Madhusudhana , Fogarty Eric , Surendran Kameswaran
Published: November 2019

The distal nephron and collecting duct segments of the mammalian kidney consist of intercalated cell types intermingled among principal cell types. Notch signaling ensures that a sufficient number of cells select a principal instead of an intercalated cell fate. However, the precise mechanisms by which Notch signaling patterns the distal nephron and collecting duct cell fates is unknown. Here we observed thatHes1, a direct target of Notch signaling pathway, is required within the mouse developing collecting ducts for repression ofFoxi1expression, an essential intercalated cell specific transcription factor. Interestingly, inactivation ofFoxi1inHes1-deficient collecting ducts rescues the deficiency in principal cell fate selection, overall urine concentrating deficiency, and reduces the occurrence of hydronephrosis. However,Foxi1inactivation does not rescue the reduction in expression of all principal cell genes in the Hes1-deficient kidney collecting duct cells that select the principal cell fate. Additionally, suppression of Notch/Hes1 signaling in mature principal cells reduces principal cell gene expression without activatingFoxi1. We conclude that Hes1 is a Notch signaling target that is essential for normal patterning of the collecting ducts with intermingled cell types by repressingFoxi1, and for maintenance of principal cell gene expression independent of repressingFoxi1.
Retinoic acid organizes the vagus motor topographic map via spatiotemporal regulation of Hgf/Met signaling
Authors: Isabella Adam J. , Barsh Gabrielle R. , Stonick Jason A. , Moens Cecilia B.
Published: November 2019

The topographic map, in which the positions of neuron cell bodies correspond with the positions of their synaptic targets, is a major organizational motif in the nervous system. To understand how topographic axon targeting is controlled during development, we examine the mechanism underlying topographic innervation of the pharyngeal arches by the vagus motor nerve in zebrafish. We reveal that Retinoic Acid organizes the topographic map by specifying anterior-posterior identity in post-mitotic vagus motor neurons. We then show that chemoattractant signaling between hepatocyte growth factor (Hgf) and the Met receptor is required for pharyngeal arch innervation by the vagus motor nerve. Finally, we find that Retinoic Acid controls the spatiotemporal dynamics of Hgf/Met signaling to coordinate axon targeting with the developmental progression of the pharyngeal arches and show that experimentally altering the timing of Hgf/Met signaling is sufficient to redirect axon targeting and disrupt the topographic map. These findings establish a new mechanism of topographic map development in which regulation of chemoattractant signaling in both space and time guides axon targeting.
A genome-wide almanac of co-essential modules assigns function to uncharacterized genes
Authors: Wainberg Michael , Kamber Roarke A. , Balsubramani Akshay , Meyers Robin M. , Sinnott-Armstrong Nasa , Hornburg Daniel , Jiang Lihua , Chan Joanne , Jian Ruiqi , Gu Mingxin , Shcherbina Anna , Dubreuil Michael M. , Spees Kaitlyn , Snyder Michael P. , Kundaje Anshul , Bassik Michael C.
Published: November 2019

A central remaining question in the post-genomic era is how genes interact to form biological pathways. Measurements of gene dependency across hundreds of cell lines have been used to cluster genes into ‘co-essential’ pathways, but this approach has been limited by ubiquitous false positives. Here, we develop a statistical method that enables robust identification of gene co-essentiality and yields a genome-wide set of functional modules. This almanac recapitulates diverse pathways and protein complexes and predicts the functions of 102 uncharacterized genes. Validating top predictions, we show thatTMEM189encodes plasmanylethanolamine desaturase, the long-sought key enzyme for plasmalogen synthesis. We also show thatC15orf57binds the AP2 complex, localizes to clathrin-coated pits, and enables efficient transferrin uptake. Finally, we provide an interactive web tool for the community to explore the results (coessentiality.net). Our results establish co-essentiality profiling as a powerful resource for biological pathway identification and discovery of novel gene functions.
The α1 subunit of the Na,K-ATPase acts upstream of PI(4,5)P2 facilitating unconventional secretion of Fibroblast Growth Factor 2 from tumor cells
Authors: Legrand Cyril , Saleppico Roberto , Sticht Jana , Lolicato Fabio , Müller Hans-Michael , Wegehingel Sabine , Dimou Eleni , Steringer Julia P. , Ewers Helge , Vattulainen Ilpo , Freund Christian , Nickel Walter
Published: November 2019

Fibroblast Growth Factor 2 (FGF2) is a tumor cell survival factor that is exported from cells by an unconventional secretory pathway. This process is based on direct translocation of FGF2 across the plasma membrane. FGF2 membrane translocation depends on PI(4,5)P2-induced formation of membrane-inserted FGF2 oligomers followed by extracellular trapping of FGF2 at the outer leaflet mediated by cell surface heparan sulfate proteoglycans. Beyond the well-characterized core mechanism of FGF2 membrane translocation, the Na,K-ATPase has been proposed to play a so far unknown role in unconventional secretion of FGF2. Here, we define a direct physical interaction of FGF2 with a subdomain of the cytoplasmic part of the α1 subunit of the Na,K-ATPase. Employing NMR spectroscopy and molecular dynamics simulations, we identified two lysine residues on the molecular surface of FGF2 that are shown to be essential for its interaction with α1. In intact cells, the corresponding lysine-to-glutamate variants of FGF2 were characterized by inefficient secretion and reduced recruitment to the inner plasma membrane leaflet as shown by single molecule TIRF microscopy. Our findings suggest that α1 acts upstream of PI(4,5)P2 facilitating efficient membrane translocation of FGF2 to the cell surface of tumor cells.
Preparing Feeder Cell Cultures to Support Hybridoma Growth
Authors: Greenfield Edward A.
Published: November 2019

Feeder layer plates are prepared with cells that provide the appropriate growth factors to support the growth of hybridoma cells until they can expand in number and provide their own. Good feeder cells should have properties that allow them to be selected against during the future growth of the hybridomas. Peritoneal macrophages, myeloma cells, splenocytes, and MRC-5 cells (a human lung fibroblast line) are the most common feeder layer cells used in hybridoma fusions. Methods for their preparation are described here.
Crystal structures of theBacillus subtilisprophage lytic cassette proteins XepA and YomS
Authors: Freitag-Pohl Stefanie , Jasilionis Andrius , Håkansson Maria , Svensson L. Anders , Kovačič Rebeka , Welin Martin , Watzlawick Hildegard , Wang Lei , Altenbuchner Josef , Płotka Magdalena , Kaczorowska Anna Karina , Kaczorowski Tadeusz , Nordberg Karlsson Eva , Al-Karadaghi Salam , Walse Björn , Aevarsson Arnthór , Pohl Ehmke
Published: November 2019

As part of the Virus-X Consortium that aims to identify and characterize novel proteins and enzymes from bacteriophages and archaeal viruses, the genes of the putative lytic proteins XepA fromBacillus subtilisprophage PBSX and YomS from prophage SPβ were cloned and the proteins were subsequently produced and functionally characterized. In order to elucidate the role and the molecular mechanism of XepA and YomS, the crystal structures of these proteins were solved at resolutions of 1.9 and 1.3 Å, respectively. XepA consists of two antiparallel β-sandwich domains connected by a 30-amino-acid linker region. A pentamer of this protein adopts a unique dumbbell-shaped architecture consisting of two discs and a central tunnel. YomS (12.9 kDa per monomer), which is less than half the size of XepA (30.3 kDa), shows homology to the C-terminal part of XepA and exhibits a similar pentameric disc arrangement. Each β-sandwich entity resembles the fold of typical cytoplasmic membrane-binding C2 domains. Only XepA exhibits distinct cytotoxic activityin vivo, suggesting that the N-terminal pentameric domain is essential for this biological activity. The biological and structural data presented here suggest that XepA disrupts the proton motive force of the cytoplasmatic membrane, thus supporting cell lysis.
Does directors’ experience positively moderate the impact of board busyness on firm efficiency? Evidence from Asia-Pacific
Authors: Tan Khar Mang , Bany-Ariffin A.N. , Kamarudin Fakarudin , Abdul Rahim Norhuda
Published: November 2019

Purpose

The purpose of this paper is to examine the impact of board busyness on firm efficiency in the context of directors’ experience, specifically on directors’ experience that moderates the impact of board busyness on firm efficiency. Directors’ experience is examined by exploring both depth (board tenure) and breadth (number of former listed directorship) of experience.

Design/methodology/approach

This paper employs data envelopment analysis (DEA) to examine firm efficiency. Then, fixed effect panel regression analysis is applied to test the direct and moderating effect based on a sample of firms in the selected Asia-Pacific countries.

Findings

Significant positive evidence for the moderating effect of directors’ experience on the impact of board busyness on firm efficiency is documented.

Practical implications

Findings are essential for managers, country policymakers and potential investors as inputs to improve the current company practices, laws and policies through the notion that directors’ experience does enable the busy board to contribute to improved firm efficiency.

Originality/value

This paper contributes to the debated perspectives on board busyness by providing initial evidence that directors’ experience positively moderates the impact of board busyness on firm efficiency.
The importance of cross-border cooperation in the quality assurance of TNE
Authors: Trifiro Fabrizio
Published: November 2019

Purpose

The purpose of this paper is to provide evidence on the importance of cross-border cooperation in the quality assurance of transnational education (TNE) by offering a comparative overview of how TNE is quality assured by both sending and receiving countries. Through this comparative analysis, it will be possible to appreciate the diversity of approaches to TNE. The paper also shows that for the foreseeable future, progress towards effective and effiicient quality assurance of TNE cannot rest on the hope of developing an internationally agreed framework, but it must rest on strengthening cooperation between quality assurance agencies operating within different national frameworks.

Design/methodology/approach

This paper looks at four key sending countries of TNE, the UK, Australia, the USA and Germany, considering the main drivers for out-going TNE, its main features and how it is quality assured. It then considers the same aspects from the perspective of receiving countries of TNE, looking at four key receiving locations, China, Dubai, Singapore and Hong Kong. It also offers an overview of some recent international initiatives aimed at fostering cross-border cooperation in the quality assurance of TNE.

Findings

In the backdrop of this overview of different approaches to TNE, this paper will conclude that for the foreseeable future it is not possible to develop an internationally agreed view and approach to TNE and its quality assurance. This conclusion allows the author to focus on the importance of cross-border cooperation amongst quality assurance agencies in sending and receiving countries for the effective and efficient quality assurance of TNE.

Originality/value

This is the first comparative study of different countries’ approaches to TNE and its quality assurance, taking into account both sending and receiving countries. It allows pointing to the key different features in different countries’ approaches and illustrates how these often relate to the underlining national strategic priorities and drivers for TNE (either in-bound or out-bound). It also allows the international community to realise that in the absence of a viable shared and agreed international framework for the regulation and quality assurance of TNE, it is of paramount importance to focus efforts on inter-agency cross-border cooperation in order to ensure that TNE continues to be of good quality and relevant to the respective communities.
From co-discovery to co-capture: co-innovation in themusic business
Authors: Saragih Harriman Samuel , Simatupang Togar , Sunitiyoso Yos
Published: November 2019

Purpose

Previous work has asserted that the co-innovation process in the music business is composed of four stages, i.e. co-discovery, co-creation, co-delivery and co-capture. This study aims to re-examine and validate this proposed conceptualisation by gathering and interviewing additional respondents, specifically academics and professional event organisers, who were not formerly involved. By gaining more insight from different stakeholders, this study expects to gain more reliable results regarding the proposed concept derived from the previous study.

Design/methodology/approach

This study uses the case study method by carrying out qualitative interview data collection from 11 respondents. Narrative analysis is used in examining the findings. Pattern matching is used as the basis of the analysis using the proposed conceptualisation from co-discovery to co-capture of co-innovation as the rival analysis to the empirical findings discovered in this study. This paper also discusses how the validity and reliability of the qualitative analysis carried out are ensured.

Findings

This study supports the notion that the co-innovation process in the music industry follows the four stages of co-discovery, co-creation, co-delivery and co-capture. The respondents, from different professional backgrounds, interviewed in this study indicated and validated that the proposed framework aligns with their actual practices, expectations and realities, along with their specific roles in the music industry’s ecosystems.

Practical implications

The results of this study can be used as a reference in developing guidelines or policies for co-innovation practices in the music business, which previous studies have not explored, e.g. focusing only on preconditions for positive collaboration, open license and music for co-creation or discussions that are merely conceptual.

Originality/value

This study validates the co-innovation process in the music business proposed by the previous works, which integrates the value chain thinking concept within the analysis.