bluuebunny/crossref_metadata_2025 huggingface dataset:
Psychiatric Neuroethics
Authors: Glannon Walter
Published: February 2019

This book is an analysis and discussion of questions at the intersection of psychiatry, neuroscience, philosophy, and law that have arisen from advances in psychiatric research and clinical psychiatric practice in the last 30 years. Are psychiatric disorders diseases of the brain, caused by dysfunctional neural circuits and neurotransmitters? What role do genes, neuroendocrine and neuroimmune interactions, and a person’s response to the environment play in the development of these disorders? How do different explanations of the etiology and pathophysiology of mental illness influence diagnosis, prognosis, and decisions about treatment? How do psychiatric disorders affect consciousness and agency? Could the presumed salutary effects of neural interventions for pathological thought and behavior change one’s mental states in undesirable ways? What are the social justice issues regarding access to treatment and experimental and innovative interventions for treatment-refractory conditions? What are the obligations of clinicians and researchers to patients and research subjects in psychiatry? Could the interests of society in preventing recidivism and public harm override the cognitive liberty of criminal offenders with a psychiatric disorder to refuse a therapeutic intervention in the brain? Would it be rational for a person with a chronic treatment-resistant disorder to request euthanasia or assisted suicide to end his suffering? Could psychiatric disorders be predicted and prevented? The book examines these questions in a comprehensive, systematic, and thematically integrated way. It is written for a multidisciplinary audience, including psychiatrists, neurologists, neurosurgeons, philosophers, psychologists, legal theorists, and informed lay readers.
Introduction
Authors: Glannon Walter
Published: February 2019

This Introduction describes the book as an analysis and discussion of questions at the intersection of psychiatry, philosophy and law that have arisen from advances in psychiatric research and practice in the last 30 years. After pointing out the extent to which mental illness constitutes the global burden of disease, it outlines a paradigm for major psychiatric conditions as diseases of the brain and mind consisting in a biopsychosocial model in which the DSM-5 and RDoC are complementary frameworks. The Introduction explains psychiatric disorders as disorders of consciousness, memory and will, examines invasive and non-invasive treatments for them, how these treatments affect autonomous agency and the obligations of researchers to subjects participating in psychiatric research. In addition, it explores ethical and legal issues in brain interventions for psychopathy, arguments for and against euthanasia and assisted suicide for psychiatric disorders and how to prevent them.
Prediction and prevention
Authors: Glannon Walter
Published: February 2019

This chapter considers reasons for and against intervening with psychotropic drugs during the prodromal phase of disease. It also discusses how the identification of biomarkers for psychiatric disorders in childhood or adolescence might predict who would be at risk of developing these disorders. Biomarkers could indicate which interventions could reduce this risk or eliminate it altogether. But there are questions about their predictive value. Abnormal neuroimmune and neuroendocrine interactions may disrupt normal rates of synaptic pruning and myelination in childhood and adolescence and increase the risk of schizophrenia and other disorders with an onset in adolescence or early adulthood. Immune-modulating drugs could reverse this process, but require careful weighing of potential benefits and risks. The chapter also discusses different interventions before birth that might prevent people from having a psychiatric disorder after birth.
Epilogue: Psychiatry, neuroscience, philosophy
Authors: Glannon Walter
Published: February 2019

This Epilogue summarizes the main points of the book's eight chapters. It emphasizes a biopsychosocial model for understanding, treating and possibly psychiatric disorders. It also points out that major forms of mental illness are disorders of this brain as well as disorders of the mind and the person relations to others and the world. Advances in neuroscience may lead to better explanations of the pathophysiology of psychiatric disorders and their philosophical implications. But these advances may not completely account for the experience of living with these disorders. Given the global burden of disease from mental illness, it should receive priority in medical research over other types of disease to improve the quality of life of the people affected by it.
The Life of Dr Helen Boyle (1869−1957)
Authors: Subotsky Fiona
Published: February 2019

This chapter presents a profile of Dr Helen Boyle. Having trained at the London School of Medicine for Women from 1890, qualifying in 1893 with the Scottish triple qualification, becoming licentiate of the Royal College of Physicians of Edinburgh, the Royal College of Surgeons of Edinburgh, and the Royal Faculty of Physicians and Surgeons of Glasgow. In 1894 she achieved her MD in Brussels with distinction. She started the Lewes Road Dispensary for Women and Children in Brighton which in 1905 became the Lady Chichester for the Treatment of Early Mental Disorders, the first of its kind.
Dame Fiona Caldicott
Authors: Kennet Katherine , Caldicott Fiona
Published: February 2019

This chapter presents a profile of Dame Fiona Caldicott. Dame Fiona is the first woman to be President of the Royal College of Psychiatrists, has been Principal of Somerville College, the University of Oxford, and is the pioneer behind the Caldicott Principles. These principles are used throughout the National Health Service (NHS) to guide confidentiality in the age of newly computerized data.
Dora Black
Authors: Verma Rashmi
Published: February 2019

This chapter presents a profile of Dora Black, who has held posts including NHS Consultant Child and Adolescent Psychiatrist; Founder, Director and Child and Adolescent Psychiatry Consultant of the Traumatic Stress Clinic in London (the first of its kind for children in the United Kingdom); Vice-Chairwoman of Cruse Bereavement Care; a founder member and Chairwoman of the Institute of Family Therapy, 1989–92, the largest family therapy organization in the United Kingdom; Chief Psychiatric Consultant, Rhodes Farm Clinic, 1991–2001; Director of The Children’s Trauma Service, Royal Free Hospital; and Consultant Child and Adolescent Psychiatrist, Royal Free Hospital.
Helen Green Allison (1923–2011)
Authors: Mounty Jane
Published: February 2019

This chapter presents a profile of Helen Green Allison, who founded the Society for Autistic Children (SAC) in the United Kingdom (later renamed National Society for Autistic Children), and researched the effects of bereavement in autistic adults. She later received an MBE for her achievements.
The Disappeared
Authors: Wills Emily
Published: February 2019

This chapter presents a poem entitled ‘The Disappeared’.
Neurological emergencies
Authors: Ramrakha Punit S. , Moore Kevin P. , Sam Amir H.
Published: February 2019

This chapter discusses neurological emergencies, including coma, limb weakness, acute dizziness, acute loss of vision, painful red eye, acute bacterial meningitis, acute viral encephalitis, head injury, raised intracranial pressure (ICP), intracranial space-occupying lesion, haemorrhage (intracerebral, extradural, subdural, subarachnoid), status epilepticus (tonic–clonic), stroke, cerebral infarction syndromes, brainstem stroke, cerebellar stroke, transient ischaemic attacks (TIAs), confusional states and delirium, acute alcohol withdrawal, neuromuscular respiratory failure, myasthenic crises, spinal cord compression, Guillain–Barré syndrome (GBS), botulism, tetanus, the Glasgow Coma Scale (GCS), examination of brainstem function, and brain death.
Dermatological emergencies
Authors: Ramrakha Punit S. , Moore Kevin P. , Sam Amir H.
Published: February 2019

This chapter discusses dermatological emergencies, including cutaneous drug reactions, erythroderma, urticaria and angio-oedema, autoimmune bullous disease, eczema herpeticum, herpes zoster, generalized pustular psoriasis, and Stevens–Johnson syndrome and toxic epidermal necrolysis.
Adenocarcinoma identified to be ALK fusion positive
Authors: Juan Oscar , Popat Sanjay
Published: February 2019

This case study looks at Adenocarcinoma identified to be ALK fusion positive, and provides questions with model answers.
Non-resolving bilateral consolidation diagnosed as invasive mucinous adenocarcinoma with a lepidic predominant pattern (previously known as bronchoalveolar carcinoma) on biopsy
Authors: Januszewski Adam , Popat Sanjay
Published: February 2019

This case study looks at Non-resolving bilateral consolidation diagnosed as invasive mucinous adenocarcinoma with lepidic predominant pattern (previously known as bronchoalveolar carcinoma) on biopsy, and provides questions with model answers.
Lung carcinoid tumour
Authors: Gennatas Spyros , Popat Sanjay
Published: February 2019

This case study looks at Lung carcinoid tumour, and provides questions with model answers.
Drop metastasis
Authors: Ho Andrew , Singer Julian
Published: February 2019

This case study looks at Drop Metastasis, and provides questions with model answers.
Stereotactic radiotherapy
Authors: Sritharan Kobika , Singer Julian
Published: February 2019

This case study looks at Stereotactic radiotherapy, and provides questions with model answers.
Preoperative assessment and fitness for surgery: T2N0M0 left hilar squamous cell carcinoma in a female with severe COPD
Authors: Hayward Martin , Patrini Davide
Published: February 2019

This case study looks at Preoperative assessment and fitness for surgery- T2N0 M0 Left hilar squamous cell carcinoma in lady with severe COPD, and provides questions with model answers.
Immunotherapy is associated with improved survival and decreased neurologic death after SRS for brain metastases from lung and melanoma primaries
Authors: Lanier Claire M , Hughes Ryan , Ahmed Tamjeed , LeCompte Michael , Masters Adrianna H , Petty William J , Ruiz Jimmy , Triozzi Pierre , Su Jing , O’Neill Stacy , Watabe Kuonosuke , Cramer Christina K , Laxton Adrian W , Tatter Stephen B , Wang Ge , Whitlow Christopher , Chan Michael D
Published: February 2019

Background

The effect of immunotherapy on brain metastasis patients remains incompletely understood. Our goal was to evaluate its effect on survival, neurologic death, and patterns of failure after stereotactic radiosurgery (SRS) without prior whole-brain radiation therapy (WBRT) in patients with lung and melanoma primaries metastatic to the brain.

Methods

We performed a retrospective analysis of 271 consecutive lung or melanoma patients treated with upfront SRS for brain metastases between 2013 and 2018. Of these patients, 101 (37%) received immunotherapy and 170 (63%) did not. Forty-three percent were treated with nivolumab. Thirty-seven percent were treated with pembrolizumab. Fifteen percent were treated with ipilimumab. One percent were treated with a combination of nivolumab and ipilimumab. One percent were treated with atezolizumab. Three percent were treated with another immunotherapy regimen. Survival was estimated by the Kaplan–Meier method and cumulative incidences of neurologic death, and local and distant brain failure were estimated using death as a competing risk.

Results

The median overall survival (OS) of patients treated with immunotherapy vs without was 15.9 (95% CI: 13.3 to 24.8) vs 6.1 (95% CI: 5.1 to 8.8) months (P < .01). The 1-year cumulative incidence of neurologic death was 9% in patients treated with immunotherapy vs 23% in those treated without (P = .01), while nonneurologic death was not significantly different (29% vs 41%, P = .51). Median brain metastasis velocity (BMV) did not differ between groups, and rates of salvage SRS and WBRT were similar.

Conclusions

The use of immunotherapy in patients with lung cancer or melanoma metastatic to the brain treated with SRS is associated with improved OS and decreased incidence of neurologic death.
Willingness to Participate in Passive Mobile Data Collection
Authors: Keusch Florian , Struminskaya Bella , Antoun Christopher , Couper Mick P , Kreuter Frauke
Published: February 2019

The rising penetration of smartphones now gives researchers the chance to collect data from smartphone users through passive mobile data collection via apps. Examples of passively collected data include geolocation, physical movements, online behavior and browser history, and app usage. However, to passively collect data from smartphones, participants need to agree to download a research app to their smartphone. This leads to concerns about nonconsent and nonparticipation. In the current study, we assess the circumstances under which smartphone users are willing to participate in passive mobile data collection. We surveyed 1,947 members of a German nonprobability online panel who own a smartphone using vignettes that described hypothetical studies where data are automatically collected by a research app on a participant’s smartphone. The vignettes varied the levels of several dimensions of the hypothetical study, and respondents were asked to rate their willingness to participate in such a study. Willingness to participate in passive mobile data collection is strongly influenced by the incentive promised for study participation but also by other study characteristics (sponsor, duration of data collection period, option to switch off the app) as well as respondent characteristics (privacy and security concerns, smartphone experience).
Cortical zeta-inhibitory peptide injection reduces local sleep need
Authors: Carroll Caitlin M , Hsiang Harrison , Snyder Sam , Forsberg Jade , Dash Michael B
Published: February 2019

Local sleep need within cortical circuits exhibits extensive interregional variability and appears to increase following learning during preceding waking. Although the biological mechanisms responsible for generating sleep need are unclear, this local variability could arise as a consequence of wake-dependent synaptic plasticity. To test whether cortical synaptic strength is a proximate driver of sleep homeostasis, we developed a novel experimental approach to alter local sleep need. One hour prior to light onset, we injected zeta-inhibitory peptide (ZIP), a pharmacological antagonist of protein kinase Mζ, which can produce pronounced synaptic depotentiation, into the right motor cortex of freely behaving rats. When compared with saline control, ZIP selectively reduced slow-wave activity (SWA; the best electrophysiological marker of sleep need) within the injected motor cortex without affecting SWA in a distal cortical site. This local reduction in SWA was associated with a significant reduction in the slope and amplitude of individual slow waves. Local ZIP injection did not significantly alter the amount of time spent in each behavioral state, locomotor activity, or EEG/LFP power during waking or REM sleep. Thus, local ZIP injection selectively produced a local reduction in sleep need; synaptic strength, therefore, may play a causal role in generating local homeostatic sleep need within the cortex.
Genetic lesioning of histamine neurons increases sleep–wake fragmentation and reveals their contribution to modafinil-induced wakefulness
Authors: Yu Xiao , Ma Ying , Harding Edward C , Yustos Raquel , Vyssotski Alexei L , Franks Nicholas P , Wisden William
Published: February 2019

Acute chemogenetic inhibition of histamine (HA) neurons in adult mice induced nonrapid eye movement (NREM) sleep with an increased delta power. By contrast, selective genetic lesioning of HA neurons with caspase in adult mice exhibited a normal sleep–wake cycle overall, except at the diurnal start of the lights-off period, when they remained sleepier. The amount of time spent in NREM sleep and in the wake state in mice with lesioned HA neurons was unchanged over 24 hr, but the sleep–wake cycle was more fragmented. Both the delayed increase in wakefulness at the start of the night and the sleep–wake fragmentation are similar phenotypes to histidine decarboxylase knockout mice, which cannot synthesize HA. Chronic loss of HA neurons did not affect sleep homeostasis after sleep deprivation. However, the chronic loss of HA neurons or chemogenetic inhibition of HA neurons did notably reduce the ability of the wake-promoting compound modafinil to sustain wakefulness. Thus, part of modafinil’s wake-promoting actions arise through the HA system.
Clinical and laboratory-induced colistin-resistance mechanisms in Acinetobacter baumannii
Authors: Boinett Christine J. , Cain Amy K. , Hawkey Jane , Do Hoang Nhu Tran , Khanh Nhu Nguyen Thi , Thanh Duy Pham , Dordel Janina , Campbell James I. , Lan Nguyen Phu Huong , Mayho Matthew , Langridge Gemma C. , Hadfield James , Chau Nguyen Van Vinh , Thwaites Guy E. , Parkhill Julian , Thomson Nicholas R. , Holt Kathryn E. , Baker Stephen
Published: February 2019

The increasing incidence and emergence of multi-drug resistant (MDR)

Acinetobacter baumannii

has become a major global health concern. Colistin is a historic antimicrobial that has become commonly used as a treatment for MDR

A. baumannii

infections. The increase in colistin usage has been mirrored by an increase in colistin resistance. We aimed to identify the mechanisms associated with colistin resistance in

A. baumannii

using multiple high-throughput-sequencing technologies, including transposon-directed insertion site sequencing (TraDIS), RNA sequencing (RNAseq) and whole-genome sequencing (WGS) to investigate the genotypic changes of colistin resistance in

A. baumannii
. Using TraDIS, we found that genes involved in drug efflux (adeIJK), and phospholipid (mlaC, mlaF and mlaD) and lipooligosaccharide synthesis (lpxC and lpsO) were required for survival in sub-inhibitory concentrations of colistin. Transcriptomic (RNAseq) analysis revealed that expression of genes encoding efflux proteins (adeI, adeC, emrB, mexB and macAB) was enhanced in in vitro generated colistin-resistant strains. WGS of these organisms identified disruptions in genes involved in lipid A (lpxC) and phospholipid synthesis (mlaA), and in the baeS/R two-component system (TCS). We additionally found that mutations in the pmrB TCS genes were the primary colistin-resistance-associated mechanisms in three Vietnamese clinical colistin-resistant

A. baumannii

strains. Our results outline the entire range of mechanisms employed in

A. baumannii

for resistance against colistin, including drug extrusion and the loss of lipid A moieties by gene disruption or modification.
Design of a comprehensive microfluidic and microscopic toolbox for the ultra-wide spatio-temporal study of plant protoplasts development and physiology
Authors: Sakai K. , Charlot F. , Le Saux T. , Bonhomme S. , Nogué F. , Palauqui J.C. , Fattaccioli J.
Published: February 2019

Background

One of the main features of plant cells is their strong plasticity, and their propensity to regenerate an organism from a single cell. Plant protoplasts are basic plant cells units in which the pecto-cellulosic cell wall has been removed, but the plasma membrane is intact. One of the main features of plant cells is their strong plasticity, which in some species, can be very close from what is defined as cell totipotency. Methods and differentiation protocols used in plant physiology and plant biology usually involve macroscopic vessels and containers that make difficult, for example, to follow the fate of the same protoplast all along its full development cycle, but also to perform continuous studies of the influence of various gradients in this context. These limits have hampered the precise study of regeneration processes.

Results

Herein, we present the design of a comprehensive, physiologically relevant, easy-to-use and low-cost microfluidic and microscopic setup for the monitoring of Physcomitrella patens (P. patens) growth and development on a long-term basis. The experimental solution we developed is made of two parts (i) a microfluidic chip composed of a single layer of about a hundred flow-through microfluidic traps for the immobilization of protoplasts, and (ii) a low-cost, light-controlled, custom-made microscope allowing the continuous recording of the moss development in physiological conditions.

We validated the experimental setup with three proofs of concepts: (i) the kinetic monitoring of first division steps and cell wall regeneration, (ii) the influence of the photoperiod on growth of the protonemata, and (iii) finally the induction of leafy buds using a phytohormone, cytokinin.

Conclusions

We developed the design of a comprehensive, physiologically relevant, easy-to-use and low-cost experimental setup for the study of P. patens development in a microfluidic environment. This setup allows imaging of P. patens development at high resolution and over long time periods.
Fine-scale family structure shapes influenza transmission risk in households: insights from a study of primary school students in Matsumoto city, 2014/15
Authors: Endo Akira , Uchida Mitsuo , Kucharski Adam J. , Funk Sebastian
Published: February 2019

Background

Households are important settings for the transmission of seasonal influenza. Previous studies found that the per-person risk of within-household transmission decreases with household size. However, more detailed heterogeneities driven by household composition and contact patterns have not been studied.

Methods

We employed a mathematical model which accounts for infections both from outside and within the household. The model was applied to citywide primary school surveillance data of seasonal influenza in 2014/15 season in Matsumoto city, Japan. We compared a range of models to estimate the structure of household transmission.

Results

Familial relationship and household composition strongly influenced the transmission patterns of seasonal influenza in households. Children had substantially high risk of infection from outside the household (up to 20%) compared with adults (1-3%). Intense transmission was observed within-generation (between children/parents/grandparents) and also between mother and child, with transmission risks typically ranging around 5-20% depending on the pair and household composition.

Conclusions

We characterised heterogeneity in household transmission patterns of influenza. Children were identified as the largest source of secondary transmission, with family structure influencing infection risk. This suggests that vaccinating children would have stronger secondary effects on transmission than would be assumed without taking into account transmission patterns within the household.
A Brownian ratchet model explains the biased sidestepping movement of single-headed kinesin-3 KIF1A
Authors: Mitra A. , Suñé M. , Diez S. , Sancho J. M. , Oriola D. , Casademunt J.
Published: February 2019

The kinesin-3 motor KIF1A is involved in long-ranged axonal transport in neurons. In order to ensure vesicular delivery, motors need to navigate the microtubule lattice and overcome possible roadblocks along the way. The single-headed form of KIF1A is a highly diffusive motor that has been shown to be a prototype of Brownian motor by virtue of a weakly-bound diffusive state to the microtubule. Recently, groups of single-headed KIF1A motors were found to be able to sidestep along the microtubule lattice, creating left-handed helical membrane tubes when pulling on giant unilamellar vesicles in vitro. A possible hypothesis is that the diffusive state enables the motor to explore the microtubule lattice and switch protofilaments, leading to a left-handed helical motion. Here we study microtubule rotation driven by single-headed KIF1A motors using fluorescene-interference contrast (FLIC) microscopy. We find an average rotational pitch of ≃ 1.4 μm which is remarkably robust to changes in the gliding velocity, ATP concentration and motor density. Our experimental results are compared to stochastic simulations of Brownian motors moving on a two-dimensional continuum ratchet potential, which quantitatively agree with the FLIC experiments. We find that single-headed KIF1A sidestepping can be explained as a consequence of the intrinsic handedness and polarity of the microtubule lattice in combination with the diffusive mechanochemical cycle of the motor.
An actin-based protrusion originating from a podosome-enriched region initiates macrophage fusion
Authors: Faust James J. , Balabiyev Arnat , Heddleston John M. , Podolnikova Nataly P. , Page Baluch D. , Chew Teng-Leong , Ugarova Tatiana P.
Published: February 2019

Macrophage fusion resulting in the formation of multinucleated giant cells occurs in a variety of chronic inflammatory diseases, yet the mechanism responsible for initiating macrophage fusion is unknown. Here, we used live cell imaging to show that actin-based protrusions at the leading edge initiate macrophage fusion. Phase contrast video microscopy demonstrated that in the majority of events, short protrusions (3 ± 1 μm) between two closely apposed cells initiated fusion, but occasionally we observed long protrusions (16 ± 7 μm). Using macrophages isolated from LifeAct mice and imaging with lattice light sheet microscopy, we further found that fusion-competent actin-based protrusions formed at sites enriched in podosomes. Inducing fusion in mixed populations of GFP- and mRFP-LifeAct macrophages showed rapid spatial overlap between GFP and RFP signal at the site of fusion. Cytochalasin B strongly reduced fusion and when rare fusion events occurred, protrusions were not observed. Fusion of macrophages deficient in Wiskott-Aldrich syndrome protein and Cdc42, key molecules involved in the formation of actin-based protrusions and podosomes, was also impaired bothin vitroandin vivo. Finally, inhibiting the activity of the Arp2/3 complex decreased fusion and podosome formation. Together these data indicate that an actin-based protrusion formed at the leading edge initiates macrophage fusion.
Outcome of radial scar/complex sclerosing lesion associated with epithelial proliferations with atypia diagnosed on breast core biopsy – Results from a multicentric UK based study
Authors: Rakha Emad , Beca Francisco , D'Andrea Mariangela , Abbas Areeg , Petrou-Nunn William , Shaaban Abeer M , Kandiyil Aneeshya , Smith Samantha , Menon Sindhu , Elsheikh Somaia , ElSayed Maysa E , Lee Andrew H S , Sharma Nisha
Published: February 2019

AIMS: The clinical significance of radial scar/complex sclerosing lesion (RS/CSL) with high risk lesions (epithelial atypia) diagnosed on needle core biopsy (NCB) is not well defined. We aimed at assessing the upgrade rate to carcinoma in-situ (DCIS) and invasive on the surgical excision specimen in a large cohort of RS/CSL associated with atypia.
METHODS: 161 women with NCB diagnosis of a RS/CSL with atypia and follow-up histology were studied. Histological findings including different forms of the atypical lesions and final histological outcome in the excision specimens were retrieved and analysed and the upgrade rate for malignancy and invasive carcinoma calculated.
RESULTS: 76% of the cases were associated with an atypical ductal hyperplasia (ADH) whereas lobular neoplasia was seen in 24%. On final histology 38 cases were malignant (overall upgrade rate of 25%); 12 invasive and 27 DCIS. The upgrade differed according to the type of atypia and was highest for ADH (35%). When associated with lobular neoplasia the upgrade rate was 12%. The upgrade rates variability was also considerably lower and showing less variability when considering the upgrade to invasive carcinoma alone.
CONCLUSION: The upgrade rate for ADH diagnosed on NCB with RS is similar to that of ADH without RS and therefore should be managed similarly. RS associated with LN is less frequently associated with malignant outcome. Most lesions exhibiting some degree of atypia showed similar upgrade rate to invasive carcinoma. Management of RS should be based on the concurrent atypical lesion.
AMMISOFT for AMMI Analysis with Best Practices
Authors: Gauch Hugh G. , Moran David R.
Published: February 2019

The Additive Main effects and Multiplicative Interaction (AMMI) model has been used extensively for analysis of multi-environment yield trials for two main purposes: understanding complex genotype-by-environment interactions and increasing accuracy. A 2013 paper in Crop Science presented a protocol for AMMI analysis with best practices, which has four steps: (i) analysis of variance, (ii) model diagnosis, (iii) mega-environment delineation, and (iv) agricultural recommendations. This preprint announces free open-source software, called AMMISOFT, which makes it easy to implement this protocol and thereby to accelerate crop improvement.
Experimental Evolution of the Megaplasmid pMPPla107 in Pseudomonas stutzeri Enables Identification of Genes Contributing to Sensitivity to an Inhibitory Agent
Authors: Smith Brian A. , Dougherty Kevin , Clark Meara , Baltrus David A.
Published: February 2019

Horizontally transferred elements such as plasmids can, at times, burden host cells with various metabolic and fitness costs. Our previous work demonstrated that acquisition of the Pseudomonas syringae megaplasmid pMPPla107 causes sensitivity to a growth inhibiting substance that is produced in cultures during growth under standard laboratory conditions. After 500 generations of laboratory passage of P. stutzeri lines containing pMPPla107, two out of six independent lines displayed resistance to this inhibitory agent. We therefore sequenced the genomes of isolates from each independent evolutionary line to identify the genetic basis of this resistance phenotype through comparative genomics. Our analysis demonstrates that two different compensatory mutations on the megaplasmid ameliorate the sensitivity phenotype: 1) a large deletion of approximately 368kb in pMPPla107 and 2) a SNP in the gene we name skaA for Supernatant Killing Activity. These results provide further evidence that costs associated with horizontal gene transfer can be compensated through single mutational events and emphasize the power of experimental evolution and resequencing to better understand the genetic basis of evolved phenotypes.
EEG-based Prediction of Cognitive Load in Intelligence Tests
Authors: Friedman Nir , Fekete Tomer , Gal Ya’akov (Kobi) , Shriki Oren
Published: February 2019

Measuring and assessing the cognitive load associated with different tasks is crucial for many applications, from the design of instructional materials to monitoring the mental wellbeing of aircraft pilots. The goal of this paper is to utilize EEG to infer the cognitive workload of subjects during intelligence tests. We chose the well established advanced progressive matrices test, an ideal work-frame because it presents problems at increasing levels of difficulty, and has been rigorously validated in past experiments. We train classic machine learning models using basic EEG measures as well as measures of network connectivity and signal complexity. Our findings demonstrate that cognitive load can be well predicted using these features, even for a low number of channels. We show that by creating an individually tuned neural network for each subject, we can improve prediction compared to a general model and that such models are robust to decreasing the number of available channels as well.
GWAS hints at pleiotropic roles forFLOWERING LOCUS Tin flowering time and yield-related traits in canola
Authors: Raman Harsh , Raman Rosy , Qiu Yu , Yadav Avilash Singh , Sureshkumar Sridevi , Borg Lauren , Maheswaran Rohan , Wheeler David , Owens Ollie , Menz Ian , Balasubramanian Sureshkumar
Published: February 2019

Transition to flowering at the right time is critical for local adaptation and to maximize seed yield in canola, which is an important oilseed crop. There is extensive variation among canola varieties in flowering time. However, our understanding of underlying genes and their role in canola productivity is still limited. We reveal natural variation in flowering time and response to photoperiod in a diverse GWAS panel (up to 368 accessions) of canola and identify associated SNPs across multiple experiments. Complementary QTL and eQTL mapping studies were also conducted in an Australian doubled haploid (DH) population for flowering time and other grain yield related traits. We show that several associations that were repeatedly detected across experiments map in the vicinity ofFLOWERING LOCUS T(FT) paralogues and its known transcriptional regulators. QTL mapping study in a DH population detected consistent genomic regions close toFTparalogs.FTsequences vary between accessions andFTexpression in field and controlled environment grown plants was correlated with flowering time.FTparalogs displayed association not only with flowering time, but also with plant emergence, shoot biomass and grain yield. Our findings suggest thatFTparalogs not only modulate flowering time but also modulate yield-related productivity traits in canola.

Highlight

The genetic association, eQTL and expression analyses suggest thatFTparalogs have multifaceted roles in canola flowering time, plant development and productivity traits.
Novel hepatitis D-like agents in vertebrates and invertebrates
Authors: Chang Wei-Shan , Pettersson John H.-O. , Le Lay Callum , Shi Mang , Lo Nathan , Wille Michelle , Eden John-Sebastian , Holmes Edward
Published: February 2019

Hepatitis delta virus (HDV) is the smallest known RNA virus and encodes a single protein. Until recently, HDV had only been identified in humans, where it is strongly associated with co-infection with hepatitis B virus (HBV). However, the recent discovery of HDV-like viruses in metagenomic samples from birds and snakes suggests that this virus has a far longer evolutionary history. Herein, using additional meta-transcriptomic data, we show that highly divergent HDV-like viruses are also present in fish, amphibians and invertebrates. Notably, the novel viruses identified here share HDV-like genomic features such as a small genome size of ~1.7kb in length, circular genomes, and self-complementary, unbranched rod-like structures. Coiled-coil domains, leucine zippers, conserved residues with essential biological functions and isoelectronic points similar to those in the human hepatitis delta virus antigens (HDAgs) were also identified in the putative non-human HDAgs. Notably, none of these novel HDV-like viruses were associated with hepadnavirus infection, supporting the idea that the HDV-HBV association may be specific to humans. Collectively, these data not only broaden our understanding of the diversity and host range of HDV in non-human species, but shed light on its origin and evolutionary history.
Early migration of precursor neurons initiates cellular and functional regeneration after spinal cord injury in zebrafish
Authors: Vandestadt Celia , Vanwalleghem Gilles C. , Castillo Hozana Andrade , Li Mei , Schulze Keith , Khabooshan Mitra , Don Emily , Anko Minna-Liisa , Scott Ethan K. , Kaslin Jan
Published: February 2019

Zebrafish have a remarkable capacity to regenerate following spinal cord (SC) injury but the responsible cellular events are not well understood. We used in vivo imaging and genetics to pin-point specific cellular processes controlling SC regeneration in zebrafish. We identified two temporally and mechanistically distinct phases of cellular regeneration in the SC. The initial phase relies on migration of precursor neurons to the injury, enabling rapid functional recovery, and activation of quiescent neural progenitor cells (NPCs). A second phase of regenerative neurogenesis compensates for both the lost tissue and cells depleted due to precursor neuron migration. We propose a critical role of precursor neurons recruitment in initiating neuronal circuit recovery and buying sufficient time for regenerative neurogenesis to take place. Taken together, our data suggests an unanticipated role of precursor cell recruitment in driving neural repair and functional recovery during the regenerative response.

Graphical Abstract
NMR Mapping of Disordered Segments from a Viral Scaffolding Protein Encapsulated in a 23 MDa Procapsid Complex
Authors: Whitehead Richard D. , Teschke Carolyn M. , Alexandrescu Andrei T.
Published: February 2019

Scaffolding proteins are requisite for the capsid shell assembly of many tailed dsDNA bacteriophages, some archaeal viruses, herpesviruses, and adenoviruses. Despite their importance, no high-resolution structural information is available for scaffolding proteins within capsids. Here we use the inherent size limit of NMR to identify mobile segments of the phage P22 scaffolding protein in solution and when incorporated into a ~23 MDa procapsid complex. Free scaffolding protein gives NMR signals from both the N and C-terminus. When scaffolding protein is incorporated into P22 procapsids, NMR signals from the C-terminal helix-turn-helix (HTH) domain disappear due to binding to the procapsid interior. Signals from the N-terminal domain persist, indicating this segment retains flexibility when bound to procapsids. The unstructured character of the N-terminus coupled with its high content of negative charges, is likely important for the dissociation and release of scaffolding protein, during the genome packaging step accompanying phage maturation.

Graphical Abstract

Scaffolding protein (SP) nucleates the assembly of phage P22 coat proteins into an icosahedral capsid structure that envelops the viral genome. NMR spectra of free SP show signals from the N-terminus (red) and a helix-turn-helix domain at the C-terminus (blue). When SP is incorporated into empty phage P22 procapsids to form a 23 MDa complex, the subset of signals from the N-terminal 40 residues persist indicating this segment is disordered. The unfolded nature of the N-terminus coupled with its negatively charged character, is important for the functional requirement of SP to exit the capsid as it becomes packaged with its genome.
Cell non-autonomous interactions during non-immune stromal progression in the breast tumor microenvironment
Authors: Utama Raditya , Bastian Anja , Sadagopan Narayanan , Jin Ying , Antoniou Eric , Gao Qing , Huang Yinghui J. , Gopalakrishna-Pillai Sailesh , Lee Peter P. , Atwal Gurinder S.
Published: February 2019

The breast tumor microenvironment of primary and metastatic sites is a complex milieu of differing cell populations, consisting of tumor cells and the surrounding stroma. Despite recent progress in delineating the immune component of the stroma, the genomic expression landscape of the non-immune stroma (NIS) population and their role in mediating cancer progression and informing effective therapies are not well understood. Here we obtained 52 cell-sorted NIS and epithelial tissue samples across 37 patients from i) normal breast, ii) normal breast adjacent to primary tumor, iii) primary tumor, and iv) metastatic tumor sites. Deep RNA-seq revealed diverging gene expression profiles as the NIS evolves from normal to metastatic tumor tissue, with intra-patient normal-primary variation comparable to inter-patient variation. Significant expression changes between normal and adjacent normal tissue support the notion of a cancer field effect, but extended out to the NIS. Most differentially expressed protein-coding genes and lncRNAs were found to be associated with pattern formation, embryogenesis, and the epithelial-mesenchymal transition. We validated the protein expression changes of a novel candidate gene, C2orf88, by immunohistochemistry staining of representative tissues. Significant mutual information between epithelial ligand and NIS receptor gene expression, across primary and metastatic tissue, suggests a unidirectional model of molecular signaling between the two tissues. Furthermore, survival analyses of 827 luminal breast tumor samples demonstrated the predictive power of the NIS gene expression to inform clinical outcomes. Together, these results highlight the evolution of NIS gene expression in breast tumors and suggest novel therapeutic strategies targeting the microenvironment.
Nutrient transporter translocation to the plasma membrane via a Golgi-independent unconventional route
Authors: Bouris Vangelis , Martzoukou Olga , Amillis Sotiris , Diallinas George
Published: February 2019

Nutrient transporters are believed to traffic from their site of synthesis, the ER, to the plasma membrane, through the Golgi, using the conventional vesicular trafficking pathway. However, here we report that the UapA purine transporter in Aspergillus nidulans, follows a Golgi-independent, unconventional new route, which does not involve key Rab GTPases, AP adaptors, microtubules or endosomes, but is dependent on functional COPII, clathrin heavy chain (ClaH) and actin. The role of ClaH in transporter secretion is shown to be unrelated to that performing, together with Rab11/AP-1, at the Golgi, and is seemingly due to an effect in actin network functioning. Our findings are discussed within the frame of a model that rationalizes why the trafficking mechanism uncovered herein might hold true for transporters in higher organisms.

One Sentence Summary

Fungal transporters use a non-polar, COPII- and actin-dependent, route for subcellular traffic to the cell membrane.
Functional analysis of evolutionary human methylated regions in schizophrenia patients
Authors: Banerjee Niladri , Polushina Tatiana , Stavrum Anne-Kristin , Steen Vidar Martin , Le Hellard Stephanie
Published: February 2019

Background

Recent studies have implicated variations in DNA methylation in the aetiology of schizophrenia. Genome-wide scans in both brain and blood report differential methylated regions (DMRs) and positions (DMPs) between patients with schizophrenia and healthy controls. Previously, we reported that DMRs where human specific methylation (hDMR) has occurred over evolutionary time are enriched for schizophrenia-associated markers (SCZ_hDMR). However, it is unknown whether these human specific DMRs show variable methylation in patients with schizophrenia.

Methods

Using publicly available data, we investigate if human specific DMRs that harbour genetic variants associated with schizophrenia are differentially methylated between cases and controls.

Results

We find statistically significant (p < 1e-4) methylation difference in schizophrenia associated human specific DMRs (SCZ hDMR) between brain samples of cases and controls. However, we fail to find evidence of similar differences in methylation in blood samples.

Conclusion

Regions that are evolutionarily important for human species and that are associated with schizophrenia, also show difference in methylation variation in the brain in patients with schizophrenia.
Microtubules stabilize intercellular contractile force transmission during tissue folding
Authors: Ko Clint S. , Tserunyan Vardges , Martin Adam C.
Published: February 2019

During development, forces transmitted between cells are critical for sculpting epithelial tissues. Actomyosin contractility in the middle of the cell apex (medioapical) can change cell shape (e.g., apical constriction), but can also result in force transmission between cells via attachments to adherens junctions. How actomyosin networks maintain attachments to adherens junctions under tension is poorly understood. Here, we discovered that microtubules stabilize actomyosin intercellular attachments in epithelia duringDrosophilamesoderm invagination. First, we used live imaging to show a novel arrangement of the microtubule cytoskeleton during apical constriction: medioapical, non-centrosomal Patronin (CAMSAP) foci formed by actomyosin contraction organizes an apical microtubule network. Microtubules were required for mesoderm invagination but were not necessary for apical contractility or adherens junction assembly. Instead, microtubules promoted the stable connection between medioapical actomyosin and adherens junctions. These results define a role for coordination between actin and microtubule cytoskeletal systems in intercellular force transmission and tissue morphogenesis.
Machine-learning to Improve Prediction of Mortality following Acute Myocardial Infarction: An Assessment in the NCDR-Chest Pain-Myocardial Infarction Registry
Authors: Khera Rohan , Haimovich Julian , Hurley Nate , McNamara Robert , Spertus John A , Desai Nihar , Masoudi Frederick A. , Huang Chenxi , Normand Sharon-Lise , Mortazavi Bobak J. , Krumholz Harlan M
Published: February 2019

Introduction

Accurate prediction of risk of death following acute myocardial infarction (AMI) can guide the triage of care services and shared decision-making. Contemporary machine-learning may improve risk-prediction by identifying complex relationships between predictors and outcomes.

Methods and Results

We studied 993,905 patients in the American College of Cardiology Chest Pain-MI Registry hospitalized with AMI (mean age 64 ± 13 years, 34% women) between January 2011 and December 2016. We developed and validated three machine learning models to predict in-hospital mortality and compared the performance characteristics with a logistic regression model. In an independent validation cohort, we compared logistic regression with lasso regularization (c-statistic, 0.891 [95% CI, 0.890-0.892]), gradient descent boosting (c-statistic, 0.902 [0.901-0.903]), and meta-classification that combined gradient descent boosting with a neural network (c-statistic, 0.904 [0.903-0.905]) with traditional logistic regression (c-statistic, 0.882 [0.881-0.883]). There were improvements in classification of individuals across the spectrum of patient risk with each of the three methods; the meta-classifier model – our best performing model - reclassified 20.9% of individuals deemed high-risk for mortality in logistic regression appropriately as low-to-moderate risk, and 8.2% of deemed low-risk to moderate-to-high risk based consistent with the actual event rates.

Conclusions

Machine-learning methods improved the prediction of in-hospital mortality for AMI compared with logistic regression. Machine learning methods enhance the utility of risk models developed using traditional statistical approaches through additional exploration of the relationship between variables and outcomes.
Determinants of Self-referral among Outpatients at Referral Hospitals in East Wollega, Western Ethiopia
Authors: Geta Edosa Tesfaye , Belete Yibeltal Siraneh , Yesuf Elias Ali
Published: February 2019

Background

Patient self-referral is a condition when patients refer themselves to higher level health facilities without having to see anyone else first or without being told to refer themselves by health professional. Despite the expansion in the number of health facilities, it has been seen when patients routinely accessed referral hospitals. The study aims to determine the magnitude and identify determinants of outpatient self-referral at referral hospitals.

Methods

Facility based cross sectional study design was used to collect data from December 01- 30; 2017.The sample size was determined by using single population proportion formula. Data entry and analysis were made using SPSS version 20. Descriptive statistics of frequency, bivariate and multivariate logistic regression were performed.

Results

A total of 404 outpatients were included making response rate 96.8%. Among 391 outpatients interviewed 330(84.4%) were self-referred.

The factors significantly associated with outpatient self-referral were referral information (AOR and 95%CI=0.324(0.150-0.696), illness severity (AOR and 95% CI=3.496(1.473-8.297), confidence of patients to get providers (AOR and 95 CI=3.027(1.510-6.070), availability of laboratory (AOR and 95%CI=4.966(2.199-11.216) and drugs (AOR and 95%CI=2.366(1.013-5.526) and quality of services (AOR and 95%CI=2.996(1.418-6.328).

Conclusion

The proportion of outpatients’ self-referral was high and that associated with referral information, patient confidence to get health care providers, severity of illness, availability of laboratory and drugs, and quality of services. There should be monitoring system of referral linkage of health facilities at all levels and the health facilities should create awareness in the community about referral linkages of health facilities.