bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical handover from emergency medical services to the trauma team: A gap analysis
Authors: Javidan Arshia P. , Nathens Avery B. , Tien Homer , da Luz Luis T.
Published: October 2020

Objectives

There has been limited evaluation of handover from emergency medical services (EMS) to the trauma team. We sought to characterize these handover practices to identify areas of improvement and determine if handover standardization might be beneficial for trauma team performance.

Methods

Data were prospectively collected over a nine-week period by a trained observer at a Canadian level one trauma centre. A randomized scheduled was used to capture a representative breadth of handovers. Data collected included outcome measures such as duration of handover, structure of the handover, and information shared, process measures such as questions and interruptions from the trauma team, and perceptions of the handover from nurses, trauma team leaders and EMS according to a bidirectional Likert scale.

Results

79 formal verbal handovers were observed. Information was often missing regarding airway (present 22%), breathing (54%), medications (59%), and allergies (54%). Handover structure lacked consistency beyond the order of identification and mechanism of injury. Of all questions asked, 35% were questioning previously given information. The majority of handovers (61%) involved parallel conversations between team members while EMS was speaking. There was a statistically significant disparity between the self-evaluation of EMS handovers and the perceived quality determined by nurses and trauma team leaders.

Conclusions

We have identified the need to standardize handover due to poor information content, a lack of structure and active listening, information repetition, and discordant expectations between team members. These data will guide the development of a co-constructed framework integrating the perspectives of all team members.
Air medical transport myths
Authors: MacDonald Russell D. , Lewell Michael , Moore Sean , Pan Andy , Peddle Michael , Sawadsky Bruce
Published: October 2020

The role of air medical and land-based critical care transport services is not always clear amongst traditional emergency medical service providers or hospital-based health care practitioners. Some of this is historical, when air medical services were in their infancy and their role within the broader health care system was limited. Despite their evolution within the regionalized health care system, some myths remain regarding air medical services in Canada. The goal is to clarify several commonly held but erroneous beliefs regarding the role, impact, and practices in air medical transport.
Quality of abdominal ultrasound image acquisition by novice practitioners following a minimal training session on healthy volunteers
Authors: Waterman Bradley , Van Aarsen Kristine , Lewell Michael , Myslik Frank , Peddle Michael , Doran Sean
Published: October 2020

Background

Point of care ultrasound (POCUS) is an essential tool for physicians to guide treatment decisions in both hospital and prehospital settings. Despite the potential patient care and system utilization benefits of prehospital ultrasound, the financial burden of a “hands-on” training program for large numbers of paramedics remains a barrier to implementation. In this study, we conducted a prospective, observational, double-blinded study comparing paramedics to emergency physicians in their ability to generate usable abdominal ultrasound images after a 1-hour didactic training session.

Methods

Canadian aeromedical critical care paramedics were compared against emergency medicine physicians in their ability to generate adequate abdominal ultrasound images on five healthy volunteers. Quality of each scan was evaluated by a trained expert in POCUS who was blinded to the identity of the participant using a 5-point Likert scale and using the standardized QUICk Focused Assessment with Sonography in Trauma (FAST) assessment tool.

Results

Fourteen Critical care paramedics and four emergency department (ED) physicians were voluntarily recruited. Of paramedics, 57% had never used ultrasound before, 36% has used ultrasound without formal training, and 7% had previous training. Physicians had a higher proportion of usable scans compared with paramedics (100% v. 61.4%, Δ38.6%; 95% confidence interval, 19.3–50.28).

Conclusions

Paramedics were not able to produce images of interpretable quality at the same frequency when compared with emergency medicine physicians. However, a 61.4% usable image rate for paramedics following a short 1-hour didactic training session is promising for future studies, which could incorporate a short hands-on tutorial while remaining cost-effective.
Sex Differences in Endovascular Treatment for Stroke: A Population-based Analysis
Authors: Zerna Charlotte , Rogers Edwin , Rabi Doreen M. , Demchuk Andrew M. , Kamal Noreen , Mann Balraj , Jeerakathil Tom , Buck Brian , Shuaib Ashfaq , Rempel Jeremy , Menon Bijoy K. , Goyal Mayank , Hill Michael D.
Published: October 2020

Background:

Acute ischemic stroke may affect women and men differently. We aimed to evaluate sex differences in outcomes of endovascular treatment (EVT) for ischemic stroke due to large vessel occlusion in a population-based study in Alberta, Canada.

Methods and Results:

Over a 3-year period (April 2015–March 2018), 576 patients fit the inclusion criteria of our study and constituted the EVT group of our analysis. The medical treatment group of the ESCAPE trial had 150 patients. Thus, our total sample size was 726. We captured outcomes in clinical routine using administrative data and a linked database methodology. The primary outcome of our study was home-time. Home-time refers to the number of days that the patient was back at their premorbid living situation without an increase in the level of care within 90 days of the index stroke event. In adjusted analysis, EVT was associated with an increase of 90-day home-time by an average of 6.08 (95% CI −2.74–14.89, p-value 0.177) days in women compared to an average of 11.20 (95% CI 1.94–20.46, p-value 0.018) days in men. Further analysis revealed that the association between EVT and 90-day home-time in women was confounded by age and onset-to-treatment time.

Conclusions:

We found a nonsignificant nominal reduction of 90-day home-time gain for women compared to men in this province-wide population-based study of EVT for large vessel occlusion, which was only partially explained by confounding.
The Impact of Japanese Labels on the Perceived Relevance of Lean Production Practices in a Russian Bank
Authors: Yakubovich Valery , Lup Daniela
Published: October 2020

We investigate how the relevance of the Lean Production System (LPS) as perceived by employees of a Russian bank depends on whether LPS practices are labeled with transliterated original Japanese words or translated Russian words. Building on organizational translation scholarship contextualized to Russia, we formulate hypotheses about the mechanism through which labels affect the perceived relevance of practices. The results of an experimental study situated in a Russian bank show that transliterated Japanese labels have a negative impact on the perceived relevance of LPS practices by Russian employees. Further analysis reveals that this negative perception is fully mediated by the label's semantic fit, that is, the extent to which the label complies with the linguistic codes of the Russian language. Specifically, we find that, on average, the transliterated Japanese labels have a lower semantic fit than the translated Russian labels, and this difference in semantic fit explains the Japanese labels’ lower relevance as perceived by the bank's employees. By unpacking the causal effect of the labels used for management practices on the practices’ perceived relevance, this study advances our understanding of how organizations could influence employees’ acceptance of foreign management practices.
Victims of the Pandemic? European Far-Right Parties and COVID-19
Authors: Wondreys Jakub , Mudde Cas
Published: October 2020

It has become received wisdom that the pandemic has “exposed” the political incompetence of far-right parties in government and that far-right parties in opposition have become its (first) “victims.” This is largely based on the generalization of one or two individual cases—most notably US president Donald Trump—who is the exception rather than the rule. This article provides a comparative analysis of far-right responses to the COVID-19 pandemic within the European Union. Based on theoretical insights from previous research, we expect the responses to reflect the main ideology and the internal heterogeneity of the contemporary far right as well as to show the increasing mainstreaming of its positions. We analyze four different, but related, aspects: (1) the narratives about COVID-19 from far-right parties; (2) the proposed solutions of far-right parties; (3) the electoral consequences of the pandemic for far-right parties; and (4) the success of far-right parties in dealing with the pandemic. Finally, in the discussion we shortly look ahead at the possible consequences of a highly likely second outbreak of COVID-19.
Analysis of population functional connectivity data via multilayer network embeddings
Authors: Wilson James D. , Baybay Melanie , Sankar Rishi , Stillman Paul , Popa Abbie M.
Published: October 2020

Population analyses of functional connectivity have provided a rich understanding of how brain function differs across time, individual, and cognitive task. An important but challenging task in such population analyses is the identification of reliable features that describe the function of the brain, while accounting for individual heterogeneity. Our work is motivated by two particularly important challenges in this area: first, how can one analyze functional connectivity data over populations of individuals, and second, how can one use these analyses to infer group similarities and differences. Motivated by these challenges, we model population connectivity data as a multilayer network and develop the multi-node2vec algorithm, an efficient and scalable embedding method that automatically learns continuous node feature representations from multilayer networks. We use multi-node2vec to analyze resting state fMRI scans over a group of 74 healthy individuals and 60 patients with schizophrenia. We demonstrate how multilayer network embeddings can be used to visualize, cluster, and classify functional regions of the brain for these individuals. We furthermore compare the multilayer network embeddings of the two groups. We identify significant differences between the groups in the default mode network and salience network—findings that are supported by the triple network model theory of cognitive organization. Our findings reveal that multi-node2vec is a powerful and reliable method for analyzing multilayer networks. Data and publicly available code are available at https://github.com/jdwilson4/multi-node2vec.
Artistic Taste-Making at the Sharjah Biennial
Authors: Ammagui Nada
Published: October 2020

This poster investigates the role that the Sharjah Biennial (SB), an international art showcase in the United Arab Emirates, plays in the development of a local artistic and cultural taste. It argues that the SB contributes to the molding of local aesthetic values through its selection of curatorial themes, artists, artworks, and, especially, venues. Using field visits, interviews, and archival research informed by sociological and anthropological theories on aesthetics, the author shows that organizers of public art exhibitions and programs are in a key position to shape the art to which people are exposed and how this, in turn, creates a public valuation of aesthetics. This project fills a gap in contemporary biennial literature by shedding light on the pivotal roles of art events in shaping societal aesthetic values.
The remote neuro-otology assessment – managing dizziness in the coronavirus disease 2019 era
Authors: Murdin L , Saman Y , Rea P
Published: October 2020

Background

Coronavirus disease 2019 and other factors have driven interest in conducting remote consultations, but there has been little research on this topic in neuro-otology. With suitable preparation, neuro-otology patients with dizziness can have remote assessments that include elements of neuro-otological physical examination, with tailored management and onward pathways arranged.

Methods

This paper reports experience with remote consultation in over 700 neuro-otology patient consultations and suggests a systematic approach, illustrated by a clinical case report and data on 100 consultations.

Conclusion

Remote consultations can play a role in neuro-otology clinics. Further research is needed to establish patient acceptability, diagnostic accuracy, safety and efficiency of remote models of care for this patient group.
Multidimensional Iterative Filtering: a new approach for investigating plasma turbulence in numerical simulations
Authors: Papini Emanuele , Cicone Antonio , Piersanti Mirko , Franci Luca , Hellinger Petr , Landi Simone , Verdini Andrea
Published: October 2020

Turbulent space and astrophysical plasmas exhibit a complex dynamics, which involves nonlinear coupling across different temporal and spatial scales. There is growing evidence that impulsive events, such as magnetic reconnection instabilities, lead to a spatially localized enhancement of energy dissipation, thus speeding up the energy transfer at small scales. Capturing such a diverse dynamics is challenging. Here, we employ the Multidimensional Iterative Filtering (MIF) method, a novel technique for the analysis of non-stationary multidimensional signals. Unlike other traditional methods (e.g. based on Fourier or wavelet decomposition), MIF does not require any previous assumption on the functional form of the signal to be identified. Using MIF, we carry out a multiscale analysis of Hall-magnetohydrodynamic (HMHD) and hybrid particle-in-cell (HPIC) numerical simulations of decaying plasma turbulence. The results assess the ability of MIF to spatially identify and separate the different scales (the MHD inertial range, the sub-ion kinetic and the dissipation scales) of the plasma dynamics. Furthermore, MIF decomposition allows localized current structures to be detected and their contribution to the statistical and spectral properties of turbulence to be characterized. Overall, MIF arises as a very promising technique for the study of turbulent plasma environments.
Preliminary experimental scaling of the helical mirror confinement effectiveness
Authors: Sudnikov Anton V. , Beklemishev Aleksey D. , Inzhevatkina Anna A. , Ivanov Ivan A. , Postupaev Vladimir V. , Burdakov Aleksandr V. , Glinskiy Vladimir V. , Kuklin Konstantin N. , Rovenskikh Andrey F. , Ustyuzhanin Viktor O.
Published: October 2020

The paper presents experimental results from the SMOLA device that is the first facility with a helical mirror section of the magnetic field. This device is built in the Budker Institute of Nuclear Physics for the verification of the helical mirror confinement idea that is the recently introduced technique of the active control of axial losses from a confinement zone. Theory predicts that with rotating plasma, a helical mirror will provide suppression of the axial plasma flow and, simultaneously, density pinching to the axis. Experiments demonstrated that plasma density at the exit from the transport section is suppressed with activation of the helical field, the effect is significant and highly reproducible. The most pronounced effect is observed on the plasma periphery, where the mirror ratio is the highest. The integral suppression ratio reaches 2–2.5 in the discussed experiments. Experimental results are compared with simplified theoretical estimates. The integral suppression ratio matches the simple theoretical estimates even if the transversal diffusion is neglected.
The Cognitive Difficulties Scale (CDS): Psychometric Characteristics in a Clinical Referral Sample
Authors: Gass Carlton S. , Patten Brooke , Penate Ailyn , Rhodes Alice
Published: October 2020

Objective:

To evaluate the psychometric characteristics of the Cognitive Difficulties Scale (CDS), a 39-item Likert-type self-report instrument that requires a fifth grade reading level. The CDS is a popular instrument that has been shown to predict cognitive decline in older persons.

Method:

Participants were 512 consecutive outpatient referrals (71% women, mean age 60.6, and education 14.6 years) for a neuropsychological examination in a memory disorders clinic as part of a broader neurodiagnostic workup for cognitive decline. A principal components analysis was followed by a varimax rotation (Kaiser). Factor scores were investigated in relation to multiple internal and external criteria including demographics, Cronbach’s alpha, Digit Span, and Wechsler Memory Scale-IV Logical Memory (LM) and Visual Reproduction (VR), and Minnesota Multiphasic Personality Inventory (MMPI)-2 measures of depression, anxiety, somatic preoccupations, and thought disturbance.

Results:

Six dimensions of cognitive complaint emerged accounting for 64% of the variance: attention/concentration, praxis, prospective memory, speech problems, memory for people’s names, and temporal orientation. The factors showed good internal consistency (alphas > .850). Correlations with Digit Span, LM, and VR were all nonsignificant. CDS scores were associated with MMPI-2 measures of anxiety, depression, somatic preoccupation, and thought disturbance. Percentiles and T-scores were derived for raw scores on the CDS and its six component subscales.

Conclusion:

The CDS is a multidimensional measure of subjective cognitive complaints that provides clinicians with a psychometrically sound basis for deriving a profile with six subscale scores. The test has clinical utility and is a potentially useful tool in research involving age-related cognitive changes and meta-cognition.
The impact of a Stress Control course delivered in partnership with a sports organisation on mental health outcomes in a general population
Authors: Hayes Jennifer , Crowley Rosarie , O’Brien Yvonne , Hannon Geraldine , Hennessey Emma , O’Connell Laura , Twomey Deirdre , Berry David , Harrington Janas , McCarthy Pearse
Published: October 2020

Mental health problems have a significant impact globally in terms of social and economic costs. Increasing access to and uptake of mental health interventions (particularly by men) remains a challenge for service providers. The current study sought to examine the efficacy of a delivering a Stress Control intervention in partnership with a community sporting organisation (the Gaelic Athletic Assocaition, GAA) in ameliorating mental health difficulties in a general population. Measures of anxiety, depression and quality of life were administered before and after the delivery of the 6-week programme. A focus group was conducted afterwards to gather qualitative data on participants’ experiences of the intervention. Statistically significant decreases in depression scores were found following attendance at the course: t (94) = 3.14, p = .002, with a large effect size (0.5) (n = 95). There was an increase in the number of male attendees compared with clinic-based courses. Thematic analysis of the focus group data revealed a number of key themes including increased accessibility in terms of the scale and context of the delivery of the course. Delivering large-scale psychoeducational courses like Stress Control in partnership with the GAA represents a promising avenue for increasing access (for males in particular) to an effective intervention for improving mental health outcomes

Key learning aims

(1)

To gain an understanding of the impact of delivering a large-scale psychological intervention in partnership with a community sports organisation on accessibility and stigma reduction for participants.

(2)

To become aware of the potential benefits of considering non-clinic-based locations in running public mental health interventions.

(3)

To understand the key role of the normalisation of the experience of common mental health problems and the impact on intervention uptake.
¡A LaHuelga!Secondary Students, School Strikes, and the Power of Educational Activism in 1970s Nicaragua
Authors: Rueda Claudia
Published: October 2020

The year 1976 was a violent one in Nicaragua. In an effort to quash the Sandinista guerrillas, the dictator Anastasio Somoza Debayle had declared a state of siege, suspending constitutional guarantees, muzzling the press, and unleashing the Guardia Nacional. Despite the dangers of dissent, thousands of students across the country walked off their secondary school campuses that year to protest poor funding, inept teachers, and oppressive administrators. This article examines this series of strikes to uncover the ways in which teenagers managed to organize their schools and communities in spite of the repression that marked the final years of the Somoza regime. Analyzing student documents, Ministry of Education records, and newspaper reports, this article argues that in the context of a decades-long dictatorship, student demands for more democratic schools opened a relatively safe pathway for cross-generational activism that forced concessions from the Somoza regime. By the 1970s, secondary schools had come to reflect the state's authoritarianism and mismanagement, and widespread educational deficiencies brought students and parents together in a joint project to demand better schools. Battles over the quality of education, thus, showcased the power of an organized citizenry and laid the groundwork for the revolutionary mobilizations that were to come.
Estimating the Spread in Future Fine Dust Concentrations in the Southwest United States
Authors: Brey Steven J. , Pierce Jeffrey R. , Barnes Elizabeth A. , Fischer Emily V.
Published: October 2020

This work examines how environmental variables previously shown to be correlated with dust emissions (temperature, vapor pressure deficit, relative humidity, precipitation, soil moisture, wind speed, and leaf area index [LAI]) explain historical variability in observed fine dust concentrations in the southwestern United States. We quantify fine dust concentrations in the U.S. Southwest dust season, March through July 1995 through 2015, using fine iron measurements from the Interagency Monitoring of Protected Visual Environments network as a dust proxy. We use Coupled Model Intercomparison Project Phase 5 (CMIP5) output to estimate how environmental variables that drive dust concentrations may change in the future. The majority of CMIP5 models that simulate LAI, a quantity anticorrelated with dust concentrations, show increasing LAI in the Southwest United States in the 21st century. Based on linear estimates of how dust concentrations respond to changes in LAI, increases in LAI could result in reduced dust concentrations in the future. However, when environmental variables are selected objectively using lasso regression, LAI is not selected in favor of other variables. When using a linear combination of objectively selected environmental variables, we estimate that future Southwest dust season concentrations will increase by 0.24 μg m−3 (12%) by the end of the 21st century for RCP 8.5. This estimated increase in fine dust concentration is driven by decreases in relative humidity, precipitation, and soil moisture and buffered by decreased wind speeds.
Disseminating Scientific Results in the Age of Rapid Communication
Authors: Kondragunta Shobha , Crisp David , Zehner Claus
Published: October 2020

Modernizing the peer review process and clarifying how to use and understand open data are two essential ways to make sure our science is accurate and accurately presented.
Slow Slip and Inter‐transient Locking on the Nicoya Megathrust in the Late and Early Stages of an Earthquake Cycle
Authors: Xie Surui , Dixon Timothy H. , Malservisi Rocco , Jiang Yan , Protti Marino , Muller Cyril
Published: October 2020

We analyzed continuous GPS data collected from 2002–2020 to characterize slow slip events (SSEs) in and near the Nicoya Peninsula, Costa Rica. These data are bisected by the 5 September 2012 Mw 7.6 earthquake. The displacement time series contain multiple signals, including plate convergence, plate interface locking, coseismic and postseismic deformation, seasonal oscillations, SSEs, and noise. GPS‐measured coseismic and postseismic displacements associated with the Mw 7.6 earthquake are modeled and removed by a step function plus multiple timescale relaxation processes with four characteristic times: 11, 94, 470, and 1,865 days. Seasonal oscillations are eliminated using a multichannel singular spectrum analysis (M‐SSA). Ten major SSEs (Mw > 6.6) are observed in the remaining time series, with a constant recurrence interval of 21.7 ± 2.6 months. SSEs occur in both shallow (~10 km) and deep (~35 km) portions of the plate interface, but the latter last longer and have larger magnitudes. There is minimum to no slow slip in the Mw 7.6 seismic rupture area and a persistent slow slip patch beneath the Nicoya Gulf entrance. Despite strong earthquake‐related stress perturbations, the inter‐SSE locking status on the megathrust is very similar between the late and early stages of the earthquake cycle and includes locked patches that ruptured in the 2012 earthquake or continue to rupture via SSEs. Some locked patches offshore south of the Nicoya Peninsula did not rupture in 2012, do not participate in SSEs, and may be indicative of supercycle behavior, that is, strain accumulation over several seismic cycles. These areas warrant heightened monitoring.
Epigenome-wide analysis reveals functional modulators of drug sensitivity and post-treatment survival in chronic lymphocytic leukaemia
Authors: Barrow Timothy M. , Nakjang Sirintra , Lafta Fadhel , Bilotkach Kateryna , Woodhouse Laura , Junge Gesa , Tudhope Susan J. , Wallis Jonathan P. , Marr Helen , Marshall Scott , Bown Nick , Willmore Elaine , Strathdee Gordon
Published: October 2020

Background

Chronic lymphocytic leukaemia (CLL) patients display a highly variable clinical course, with progressive acquisition of drug resistance. We sought to identify aberrant epigenetic traits that are enriched following exposure to treatment that could impact patient response to therapy.

Methods

Epigenome-wide analysis of DNA methylation was performed for 20 patients at two timepoints during treatment. The prognostic significance of differentially methylated regions (DMRs) was assessed in independent cohorts of 139 and 163 patients. Their functional role in drug sensitivity was assessed in vitro.

Results

We identified 490 DMRs following exposure to therapy, of which 31 were CLL-specific and independent of changes occurring in normal B-cell development. Seventeen DMR-associated genes were identified as differentially expressed following treatment in an independent cohort. Methylation of the HOXA4, MAFB and SLCO3A1 DMRs was associated with post-treatment patient survival, with HOXA4 displaying the strongest association. Re-expression of HOXA4 in cell lines and primary CLL cells significantly increased apoptosis in response to treatment with fludarabine, ibrutinib and idelalisib.

Conclusion

Our study demonstrates enrichment for multiple CLL-specific epigenetic traits in response to chemotherapy that predict patient outcomes, and particularly implicate epigenetic silencing of HOXA4 in reducing the sensitivity of CLL cells to therapy.
Impaired autophagy increases susceptibility to endotoxin-induced chronic pancreatitis
Authors: Xia L. , Xu Z. , Zhou X. , Bergmann F. , Grabe N. , Büchler M. W. , Neoptolemos J. P. , Hackert T. , Kroemer G. , Fortunato F.
Published: October 2020

Chronic pancreatitis (CP) is associated with elevated plasma levels of bacterial lipopolysaccharide (LPS) and we have demonstrated reduced acinar cell autophagy in human CP tissue. Therefore, we investigated the role of autophagy in experimental endotoxin-induced pancreatic injury and aimed to identify LPS in human CP tissue. Pancreatic Atg7-deficient mice were injected with a single sub-lethal dose of LPS. Expression of autophagy, apoptosis, necroptosis, and inflammatory markers was determined 3 and 24 h later utilizing immunoblotting and immunofluorescence. The presence of LPS in pancreatic tissue from mice and from patients and healthy controls was determined using immunohistochemistry, immunoblots, and chromogenic assay. Mice lacking pancreatic autophagy exhibited local signs of inflammation and were particularly sensitive to the toxic effect of LPS injection as compared to control mice. In response to LPS, Atg7Δpan mice exhibited enhanced vacuolization of pancreatic acinar cells, increase in TLR4 expression coupled to enhanced expression of NF-κΒ, JNK, and pro-inflammatory cytokines by acinar cells and enhanced infiltration by myeloid cells (but not Atg7F/F controls). Cell death was enhanced in Atg7Δpan pancreata, but only necroptosis and trypsin activation was further amplified following LPS injection along with elevated pancreatic LPS. The presence of LPS was identified in the pancreata from all 14 CP patients examined but was absent in the pancreata from all 10 normal controls. Altogether, these results support a potential role for metabolic endotoxemia in the pathogenesis of CP. Moreover, the evidence also supports the notion that autophagy plays a major cytoprotective and anti-inflammatory role in the pancreas, and blunting metabolic endotoxemia-induced CP.
Prevention of mitochondrial impairment by inhibition of protein phosphatase 1 activity in amyotrophic lateral sclerosis
Authors: Choi So Yoen , Lee Ju-Hyun , Chung Ah-Young , Jo Youhwa , Shin Joo-ho , Park Hae-Chul , Kim Hyun , Lopez-Gonzalez Rodrigo , Ryu Jae Ryun , Sun Woong
Published: October 2020

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease caused by progressive loss of motor neurons (MNs) and subsequent muscle weakness. These pathological features are associated with numerous cellular changes, including alteration in mitochondrial morphology and function. However, the molecular mechanisms associating mitochondrial structure with ALS pathology are poorly understood. In this study, we found that Dynamin-related protein 1 (Drp1) was dephosphorylated in several ALS models, including those with SOD1 and TDP-43 mutations, and the dephosphorylation was mediated by the pathological induction of protein phosphatase 1 (PP1) activity in these models. Suppression of the PP1-Drp1 cascade effectively prevented ALS-related symptoms, including mitochondrial fragmentation, mitochondrial complex I impairment, axonal degeneration, and cell death, in primary neuronal culture models, iPSC-derived human MNs, and zebrafish models in vivo. These results suggest that modulation of PP1-Drp1 activity may be a therapeutic target for multiple pathological features of ALS.
The GEF Trio controls endothelial cell size and arterial remodeling downstream of Vegf signaling in both zebrafish and cell models
Authors: Klems Alina , van Rijssel Jos , Ramms Anne S. , Wild Raphael , Hammer Julia , Merkel Melanie , Derenbach Laura , Préau Laetitia , Hinkel Rabea , Suarez-Martinez Irina , Schulte-Merker Stefan , Vidal Ramon , Sauer Sascha , Kivelä Riikka , Alitalo Kari , Kupatt Christian , van Buul Jaap D. , le Noble Ferdinand
Published: October 2020

Arterial networks enlarge in response to increase in tissue metabolism to facilitate flow and nutrient delivery. Typically, the transition of a growing artery with a small diameter into a large caliber artery with a sizeable diameter occurs upon the blood flow driven change in number and shape of endothelial cells lining the arterial lumen. Here, using zebrafish embryos and endothelial cell models, we describe an alternative, flow independent model, involving enlargement of arterial endothelial cells, which results in the formation of large diameter arteries. Endothelial enlargement requires the GEF1 domain of the guanine nucleotide exchange factor Trio and activation of Rho-GTPases Rac1 and RhoG in the cell periphery, inducing F-actin cytoskeleton remodeling, myosin based tension at junction regions and focal adhesions. Activation of Trio in developing arteries in vivo involves precise titration of the Vegf signaling strength in the arterial wall, which is controlled by the soluble Vegf receptor Flt1.
Sensitivity enhancement of homonuclear multidimensional NMR correlations for labile sites in proteins, polysaccharides, and nucleic acids
Authors: Novakovic Mihajlo , Kupče Ēriks , Oxenfarth Andreas , Battistel Marcos D. , Freedberg Darón I. , Schwalbe Harald , Frydman Lucio
Published: October 2020

Multidimensional TOCSY and NOESY are central experiments in chemical and biophysical NMR. Limited efficiencies are an intrinsic downside of these methods, particularly when targeting labile sites. This study demonstrates that the decoherence imparted on these protons through solvent exchanges can, when suitably manipulated, lead to dramatic sensitivity gains per unit time in the acquisition of these experiments. To achieve this, a priori selected frequencies are encoded according to Hadamard recipes, while concurrently subject to looped selective inversion or selective saturation procedures. Suitable processing then leads to protein, oligosaccharide and nucleic acid cross-peak enhancements of ≈200–1000% per scan, in measurements that are ≈10-fold faster than conventional counterparts. The extent of these gains will depend on the solvent exchange and relaxation rates of the targeted sites; these gains also benefit considerably from the spectral resolution provided by ultrahigh fields, as corroborated by NMR experiments at 600 MHz and 1 GHz. The mechanisms underlying these experiments’ enhanced efficiencies are analyzed on the basis of three-way polarization transfer interplays between the water, labile and non-labile protons, and the experimental results are rationalized using both analytical and numerical derivations. Limitations as well as further extensions of the proposed methods, are also discussed.
An all-photonic focal-plane wavefront sensor
Authors: Norris Barnaby R. M. , Wei Jin , Betters Christopher H. , Wong Alison , Leon-Saval Sergio G.
Published: October 2020

Adaptive optics (AO) is critical in astronomy, optical communications and remote sensing to deal with the rapid blurring caused by the Earth’s turbulent atmosphere. But current AO systems are limited by their wavefront sensors, which need to be in an optical plane non-common to the science image and are insensitive to certain wavefront-error modes. Here we present a wavefront sensor based on a photonic lantern fibre-mode-converter and deep learning, which can be placed at the same focal plane as the science image, and is optimal for single-mode fibre injection. By measuring the intensities of an array of single-mode outputs, both phase and amplitude information on the incident wavefront can be reconstructed. We demonstrate the concept with simulations and an experimental realisation wherein Zernike wavefront errors are recovered from focal-plane measurements to a precision of 5.1 × 10−3 π radians root-mean-squared-error.
Clonal evolution of acute myeloid leukemia revealed by high-throughput single-cell genomics
Authors: Morita Kiyomi , Wang Feng , Jahn Katharina , Hu Tianyuan , Tanaka Tomoyuki , Sasaki Yuya , Kuipers Jack , Loghavi Sanam , Wang Sa A. , Yan Yuanqing , Furudate Ken , Matthews Jairo , Little Latasha , Gumbs Curtis , Zhang Jianhua , Song Xingzhi , Thompson Erika , Patel Keyur P. , Bueso-Ramos Carlos E. , DiNardo Courtney D. , Ravandi Farhad , Jabbour Elias , Andreeff Michael , Cortes Jorge , Bhalla Kapil , Garcia-Manero Guillermo , Kantarjian Hagop , Konopleva Marina , Nakada Daisuke , Navin Nicholas , Beerenwinkel Niko , Futreal P. Andrew , Takahashi Koichi
Published: October 2020

Clonal diversity is a consequence of cancer cell evolution driven by Darwinian selection. Precise characterization of clonal architecture is essential to understand the evolutionary history of tumor development and its association with treatment resistance. Here, using a single-cell DNA sequencing, we report the clonal architecture and mutational histories of 123 acute myeloid leukemia (AML) patients. The single-cell data reveals cell-level mutation co-occurrence and enables reconstruction of mutational histories characterized by linear and branching patterns of clonal evolution, with the latter including convergent evolution. Through xenotransplantion, we show leukemia initiating capabilities of individual subclones evolving in parallel. Also, by simultaneous single-cell DNA and cell surface protein analysis, we illustrate both genetic and phenotypic evolution in AML. Lastly, single-cell analysis of longitudinal samples reveals underlying evolutionary process of therapeutic resistance. Together, these data unravel clonal diversity and evolution patterns of AML, and highlight their clinical relevance in the era of precision medicine.
Synaptic vesicle traffic is supported by transient actin filaments and regulated by PKA and NO
Authors: Chenouard Nicolas , Xuan Feng , Tsien Richard W.
Published: October 2020

Synaptic vesicles (SVs) can be pooled across multiple synapses, prompting questions about their dynamic allocation for neurotransmission and plasticity. We find that the axonal traffic of recycling vesicles is not supported by ubiquitous microtubule-based motility but relies on actin instead. Vesicles freed from synaptic clusters undergo ~1 µm bouts of active transport, initiated by nearby elongation of actin filaments. Long distance translocation arises when successive bouts of active transport were linked by periods of free diffusion. The availability of SVs for active transport can be promptly increased by protein kinase A, a key player in neuromodulation. Vesicle motion is in turn impeded by shutting off axonal actin polymerization, mediated by nitric oxide-cyclic GMP signaling leading to inhibition of RhoA. These findings provide a potential framework for coordinating post-and pre-synaptic strength, using retrograde regulation of axonal actin dynamics to mobilize and recruit presynaptic SV resources.
Single-cell derived tumor organoids display diversity in HLA class I peptide presentation
Authors: Demmers Laura C. , Kretzschmar Kai , Van Hoeck Arne , Bar-Epraïm Yotam E. , van den Toorn Henk W. P. , Koomen Mandy , van Son Gijs , van Gorp Joost , Pronk Apollo , Smakman Niels , Cuppen Edwin , Clevers Hans , Heck Albert J. R. , Wu Wei
Published: October 2020

Tumor heterogeneity is a major cause of therapeutic resistance. Immunotherapy may exploit alternative vulnerabilities of drug-resistant cells, where tumor-specific human leukocyte antigen (HLA) peptide ligands are promising leads to invoke targeted anti-tumor responses. Here, we investigate the variability in HLA class I peptide presentation between different clonal cells of the same colorectal cancer patient, using an organoid system. While clone-specific differences in HLA peptide presentation were observed, broad inter-clone variability was even more prevalent (15–25%). By coupling organoid proteomics and HLA peptide ligandomics, we also found that tumor-specific ligands from DNA damage control and tumor suppressor source proteins were prominently presented by tumor cells, coinciding likely with the silencing of such cytoprotective functions. Collectively, these data illustrate the heterogeneous HLA peptide presentation landscape even within one individual, and hint that a multi-peptide vaccination approach against highly conserved tumor suppressors may be a viable option in patients with low tumor-mutational burden.
Antibody-mediated disruption of the SARS-CoV-2 spike glycoprotein
Authors: Wrobel Antoni G. , Benton Donald J. , Hussain Saira , Harvey Ruth , Martin Stephen R. , Roustan Chloë , Rosenthal Peter B. , Skehel John J. , Gamblin Steven J.
Published: October 2020

The CR3022 antibody, selected from a group of SARS-CoV monoclonal antibodies for its ability to cross-react with SARS-CoV-2, has been examined for its ability to bind to the ectodomain of the SARS-CoV-2 spike glycoprotein. Using cryo-electron microscopy we show that antibody binding requires rearrangements in the S1 domain that result in dissociation of the spike.
Dual mRNA therapy restores metabolic function in long-term studies in mice with propionic acidemia
Authors: Jiang Lei , Park Ji-Sun , Yin Ling , Laureano Rodrigo , Jacquinet Eric , Yang Jinsong , Liang Shi , Frassetto Andrea , Zhuo Jenny , Yan Xinhua , Zhu Xuling , Fortucci Steven , Hoar Kara , Mihai Cosmin , Tunkey Christopher , Presnyak Vlad , Benenato Kerry E. , Lukacs Christine M. , Martini Paolo G. V. , Guey Lin T.
Published: October 2020

Propionic acidemia/aciduria (PA) is an ultra-rare, life-threatening, inherited metabolic disorder caused by deficiency of the mitochondrial enzyme, propionyl-CoA carboxylase (PCC) composed of six alpha (PCCA) and six beta (PCCB) subunits. We herein report an enzyme replacement approach to treat PA using a combination of two messenger RNAs (mRNAs) (dual mRNAs) encoding both human PCCA (hPCCA) and PCCB (hPCCB) encapsulated in biodegradable lipid nanoparticles (LNPs) to produce functional PCC enzyme in liver. In patient fibroblasts, dual mRNAs encoded proteins localize in mitochondria and produce higher PCC enzyme activity vs. single (PCCA or PCCB) mRNA alone. In a hypomorphic murine model of PA, dual mRNAs normalize ammonia similarly to carglumic acid, a drug approved in Europe for the treatment of hyperammonemia due to PA. Dual mRNAs additionally restore functional PCC enzyme in liver and thus reduce primary disease-associated toxins in a dose-dependent manner in long-term 3- and 6-month repeat-dose studies in PA mice. Dual mRNAs are well-tolerated in these studies with no adverse findings. These studies demonstrate the potential of mRNA technology to chronically administer multiple mRNAs to produce large complex enzymes, with applicability to other genetic disorders.
5-FU promotes stemness of colorectal cancer via p53-mediated WNT/β-catenin pathway activation
Authors: Cho Yong-Hee , Ro Eun Ji , Yoon Jeong-Su , Mizutani Tomohiro , Kang Dong-Woo , Park Jong-Chan , Il Kim Tae , Clevers Hans , Choi Kang-Yell
Published: October 2020

5-Fluorouracil (5-FU) remains the first-line treatment for colorectal cancer (CRC). Although 5-FU initially de-bulks the tumor mass, recurrence after chemotherapy is the barrier to effective clinical outcomes for CRC patients. Here, we demonstrate that p53 promotes WNT3 transcription, leading to activation of the WNT/β-catenin pathway in ApcMin/+/Lgr5EGFP mice, CRC patient-derived tumor organoids (PDTOs) and patient-derived tumor cells (PDCs). Through this regulation, 5-FU induces activation and enrichment of cancer stem cells (CSCs) in the residual tumors, contributing to recurrence after treatment. Combinatorial treatment of a WNT inhibitor and 5-FU effectively suppresses the CSCs and reduces tumor regrowth after discontinuation of treatment. These findings indicate p53 as a critical mediator of 5-FU-induced CSC activation via the WNT/β-catenin signaling pathway and highlight the significance of combinatorial treatment of WNT inhibitor and 5-FU as a compelling therapeutic strategy to improve the poor outcomes of current 5-FU-based therapies for CRC patients.
Decarboxylative thiolation of redox-active esters to free thiols and further diversification
Authors: Cao Tianpeng , Xu Tianxiao , Xu Ruting , Shu Xianli , Liao Saihu
Published: October 2020

Thiols are important precursors for the synthesis of a variety of pharmaceutically important sulfur-containing compounds. In view of the versatile reactivity of free thiols, here we report the development of a visible light-mediated direct decarboxylative thiolation reaction of alkyl redox-active esters to free thiols based on the abundant carboxylic acid feedstock. This transformation is applicable to various carboxylic acids, including primary, secondary, and tertiary acids as well as natural products and drugs, forging a general and facile access to free thiols with diverse structures. Moreover, the direct access to free thiols affords an advantage of rapid in situ diversification with high efficiency to other important thiol derivatives such as sulfide, disulfide, thiocyanide, thioselenide, etc.
Completing asthma action plans by screen-sharing in video-consultations: practical insights from a feasibility assessment
Authors: Hamour Omer , Smyth Eve , Pinnock Hilary
Published: October 2020

Supported self-management is a vital component of routine asthma care. Completion of an agreed personalised asthma action plan is integral to implementation of this care, and traditionally this requires a face-to-face consultation. We aimed to assess the practical feasibility and potential utility of using screen-sharing technologies to complete asthma action plans remotely. Assisted by people with diverse technological ability and using a range of devices, we tested the technological feasibility of completing action plans in remote consultations using two leading video-conference systems. We used a semi-structured topic guide to check functionality and lead feedback discussions. Themes were interpreted using the Model for ASsessment of Telemedicine applications (MAST). Discussions with ten participants (age 20–74 years) revealed that screen-sharing was practical on most devices. Joint editing of an action plan (as was possible with Zoom) was considered to encourage participation and improve communication. Attend Anywhere had less functionality than Zoom, but the NHS badging was reassuring. Most participants appreciated the screen-sharing and considered it enabled a meaningful discussion about their action plan. Online shared completion of action plans is feasible with only a few (potentially remediable) practical problems. These findings suggest this may be a fruitful approach for further study—made more urgent by the imperative to develop remote consultations in the face of a global pandemic.
Experimental creation of multi-photon high-dimensional layered quantum states
Authors: Hu Xiao-Min , Xing Wen-Bo , Zhang Chao , Liu Bi-Heng , Pivoluska Matej , Huber Marcus , Huang Yun-Feng , Li Chuan-Feng , Guo Guang-Can
Published: October 2020

Quantum entanglement is one of the most important resources in quantum information. In recent years, the research of quantum entanglement mainly focused on the increase in the number of entangled qubits or the high-dimensional entanglement of two particles. Compared with qubit states, multipartite high-dimensional entangled states have beneficial properties and are powerful for constructing quantum networks. However, there are few studies on multipartite high-dimensional quantum entanglement due to the difficulty of creating such states. In this paper, we experimentally prepared a multipartite high-dimensional state $$\left|{\Psi }_{442}\right\rangle =\frac{1}{2}(\left|000\right\rangle +\left|110\right\rangle +\left|221\right\rangle +\left|331\right\rangle )$$

Ψ

442

=

1

2

(

000

+

110

+

221

+

331

)

by using the path mode of photons. We obtain the fidelity F = 0.854 ± 0.007 of the quantum state, which proves a real multipartite high-dimensional entangled state. Finally, we use this quantum state to demonstrate a layered quantum network in principle. Our work highlights another route toward complex quantum networks.