bluuebunny/crossref_metadata_2025 huggingface dataset:
Engineering macroscale cell alignment through coordinated toolpath design using support-assisted 3D bioprinting
Authors: Lee Jia Min , Yeong Wai Yee
Published: July 2020

Aligned cells provide direction-dependent mechanical properties that influence biological and mechanical function in native tissues. Alignment techniques such as casting and uniaxial stretching cannot fully replicate the complex fibre orientation of native tissue such as the heart. In this study, bioprinting is used to direct the orientation of cell alignment. A 0°–90° grid structure was printed to assess the robustness of the support-assisted bioprinting technique. The variation in the angles of the grid pattern is designed to mimic the differences in fibril orientation of native tissues, where angles of cell alignment vary across the different layers. Through bioprinting of a cell–hydrogel mixture, C2C12 cells displayed directed alignment along the longitudinal axis of printed struts. Cell alignment is induced through firstly establishing structurally stable constructs (i.e. distinct 0°–90° structures) and secondly, allowing cells to dynamically remodel the bioprinted construct. Herein reports a method of inducing a macroscale level of controlled cell alignment with angle variation. This was not achievable both in terms of methods (i.e. conventional alignment techniques such as stretching and electrical stimulation) and magnitude (i.e. hydrogel features with less than 100 µm features).
Data-driven nonlinear aeroelastic models of morphing wings for control
Authors: Fonzi N. , Brunton S. L. , Fasel U.
Published: July 2020

Accurate and efficient aeroelastic models are critically important for enabling the optimization and control of highly flexible aerospace structures, which are expected to become pervasive in future transportation and energy systems. Advanced materials and morphing wing technologies are resulting in next-generation aeroelastic systems that are characterized by highly coupled and nonlinear interactions between the aerodynamic and structural dynamics. In this work, we leverage emerging data-driven modelling techniques to develop highly accurate and tractable reduced-order aeroelastic models that are valid over a wide range of operating conditions and are suitable for control. In particular, we develop two extensions to the recent dynamic mode decomposition with control (DMDc) algorithm to make it suitable for flexible aeroelastic systems: (1) we introduce a formulation to handle algebraic equations, and (2) we develop an interpolation scheme to smoothly connect several linear DMDc models developed in different operating regimes. Thus, the innovation lies in accurately modelling the nonlinearities of the coupled aerostructural dynamics over multiple operating regimes, not restricting the validity of the model to a narrow region around a linearization point. We demonstrate this approach on a high-fidelity, three-dimensional numerical model of an airborne wind energy system, although the methods are generally applicable to any highly coupled aeroelastic system or dynamical system operating over multiple operating regimes. Our proposed modelling framework results in real-time prediction of nonlinear unsteady aeroelastic responses of flexible aerospace structures, and we demonstrate the enhanced model performance for model predictive control. Thus, the proposed architecture may help enable the widespread adoption of next-generation morphing wing technologies.
Effect of porous layer on the Faraday instability in viscous liquid
Authors: Samanta Arghya
Published: July 2020

A linear stability analysis of a viscous liquid on a vertically oscillating porous plane is performed for infinitesimal disturbances of arbitrary wavenumbers. A time-dependent boundary value problem is derived and solved based on the Floquet theory along with the complex Fourier series expansion. Numerical results show that the Faraday instability is dominated by the subharmonic solution at high forcing frequency, but it responds harmonically at low forcing frequency. The unstable regions corresponding to both subharmonic and harmonic solutions enhance with the increasing value of permeability and yields a destabilizing effect on the Faraday instability. Further, the presence of porous layer makes faster the transition process from subharmonic instability to harmonic instability in the wavenumber regime. In addition, the first harmonic solution shrinks gradually and becomes an unstable island, and ultimately disappears from the neutral curve if the porous layer thickness is increased. In contrast, the first and second subharmonic solutions coalesce, and the onset of Faraday instability is dominated by the subharmonic solution. In a special case, the study of Faraday instability of a viscous liquid on a porous substrate can be replaced by a study of Faraday instability of a viscous liquid on a slippery substrate when the permeability of the porous substrate is very low. Further, the Faraday instability can be destabilized by introducing a slip effect at the bottom plane.
Locally adaptive activation functions with slope recovery for deep and physics-informed neural networks
Authors: Jagtap Ameya D. , Kawaguchi Kenji , Em Karniadakis George
Published: July 2020

We propose two approaches of locally adaptive activation functions namely, layer-wise and neuron-wise locally adaptive activation functions, which improve the performance of deep and physics-informed neural networks. The local adaptation of activation function is achieved by introducing a scalable parameter in each layer (layer-wise) and for every neuron (neuron-wise) separately, and then optimizing it using a variant of stochastic gradient descent algorithm. In order to further increase the training speed, an activation slope-basedslope recoveryterm is added in the loss function, which further accelerates convergence, thereby reducing the training cost. On the theoretical side, we prove that in the proposed method, the gradient descent algorithms are not attracted to sub-optimal critical points or local minima under practical conditions on the initialization and learning rate, and that the gradient dynamics of the proposed method is not achievable by base methods with any (adaptive) learning rates. We further show that the adaptive activation methods accelerate the convergence by implicitly multiplying conditioning matrices to the gradient of the base method without any explicit computation of the conditioning matrix and the matrix–vector product. The different adaptive activation functions are shown to induce different implicit conditioning matrices. Furthermore, the proposed methods with the slope recovery are shown to accelerate the training process.
Pleural empyema due to Salmonella in a patient with bronchogenic carcinoma: the first case report from a cancer hospital in Egypt
Authors: Samir Abdelhafiz Ahmed , Wassef Mona , Alorabi Mohamed
Published: July 2020

Background.

Salmonella

species are motile, Gram-negative facultative anaerobic bacilli, which belong to the family

Enterobacteriaceae

. The most common clinical presentations of

Salmonella

infection are gastroenteritis and enteric fever. Detection of

Salmonella

organisms in empyema is very rare.

Case presentation. We report the case of a 66-year-old female patient with bronchogenic carcinoma who developed empyema, and

Salmonella

was identified from the culture of pleural fluid. After antimicrobial therapy and other therapeutic measures, including the insertion of an intercostal tube, oxygen supplementation, frequent suction of respiratory secretions, and chest physiotherapy, the patient's condition improved. To the best of our knowledge, this is the first case to be reported in Egypt.

Conclusions. Our case sheds light on the role of

Salmonella

in immunocompromised patients in general and cancer patients in specific. We recommend further study of this role, since it may lead to a better understanding of the pathogenicity of this organism in these patients.
Bradyrhizobium archetypum sp. nov., Bradyrhizobium australiense sp. nov. and Bradyrhizobium murdochi sp. nov., isolated from nodules of legumes indigenous to Western Australia
Authors: Helene Luisa Caroline Ferraz , Klepa Milena Serenato , O’Hara Graham , Hungria Mariangela
Published: July 2020

The genus

Bradyrhizobium

is considered as the probable ancestor lineage of all rhizobia, broadly spread in a variety of ecosystems and with remarkable diversity. A polyphasic study was performed to characterize and clarify the taxonomic position of eight bradyrhizobial strains isolated from indigenous legumes to Western Australia. As expected for the genus, the 16S rRNA gene sequences were highly conserved, but the results of multilocus sequence analysis with four housekeeping genes (dnaK, glnII, gyrB and recA) confirmed three new distinct clades including the following strains: (1) WSM 1744T, WSM 1736 and WSM 1737; (2) WSM 1791T and WSM 1742; and (3) WSM 1741T, WSM 1735 and WSM 1790. The highest ANI values of the three groups in relation to the closest type strains were 92.4, 92.3 and 93.3 %, respectively, below the threshold of species circumscription. The digital DNA–DNA hybridization analysis also confirmed new species descriptions, with less than 52 % relatedness with the closest type strains. The phylogeny of the symbiotic gene nodC clustered the eight strains into the symbiovar retamae, together with seven

Bradyrhizobium

type strains, sharing from 94.2–98.1 % nucleotide identity (NI), and less than 88.7 % NI with other related strains and symbiovars. Morpho-physiological, phylogenetics, genomic and symbiotic traits were determined for the new groups and our data support the description of three new species, Bradyrhizobium archetypum sp. nov., Bradyrhizobium australiense sp. nov. and Bradyrhizobium murdochi sp. nov., with WSM 1744T (=CNPSo 4013T=LMG 31646T), WSM 1791T (=CNPSo 4014T=LMG 31647T) and WSM 1741T (=CNPSo 4020T=LMG 31651T) designated as type strains, respectively.
The 3A protein of coxsackievirus B3 acts as a viral suppressor of RNA interference
Authors: Mu Jingfang , Zhang Haobo , Li Tao , Shu Ting , Qiu Yang , Zhou Xi
Published: July 2020

RNA interference (RNAi) is a potent antiviral defence mechanism in eukaryotes, and numerous viruses have been found to encode viral suppressors of RNAi (VSRs). Coxsackievirus B3 (CVB3) belongs to the genus Enterovirus in the family Picornaviridae, and has been reported to be a major causative pathogen for viral myocarditis. Despite the importance of CVB3, it is unclear whether CVB3 can also encode proteins that suppress RNAi. Here, we showed that the CVB3 nonstructural protein 3A suppressed RNAi triggered by either small hairpin RNAs (shRNAs) or small interfering RNAs (siRNAs) in mammalian cells. We further uncovered that CVB3 3A interacted directly with double-stranded RNAs (dsRNAs) and siRNAs in vitro. Through mutational analysis, we found that the VSR activity of CVB3 3A was significantly reduced by mutations of D24A/L25A/L26A, Y37A/C38A and R60A in conserved residues. In addition, the 3A protein encoded by coxsackievirus B5 (CVB5), another member of Enterovirus, also showed VSR activity. Taken together, our findings showed that CVB3 3A has in vitro VSR activity, thereby providing insights into the pathogenesis of CVB3 and other enteroviruses.
Hantavirus infection in type I interferon receptor-deficient (A129) mice
Authors: Dowall Stuart D. , Graham Victoria A. , Aram Marilyn , Findlay-Wilson Stephen , Salguero Francisco J. , Emery Kirsty , Hewson Roger
Published: July 2020

Type I interferon receptor knockout mice (strain A129) were assessed as a disease model of hantavirus infection. A range of infection routes (intramuscular, intraperitoneal and intranasal) were assessed using minimally passaged Seoul virus (strain Humber). Dissemination of virus to the spleen, kidney and lung was observed at 5 days after intramuscular and intraperitoneal challenge, which was resolved by day 14. In contrast, intranasal challenge of A129 mice demonstrated virus tropism to the lung, which was maintained to day 14 post-challenge. These data support the use of the A129 mouse model for future infection studies and the in vivo evaluation of interventions.
Genomic analyses of Staphylococcus aureus clonal complex 45 isolates does not distinguish nasal carriage from bacteraemia
Authors: Roe Chandler , Stegger Marc , Lilje Berit , Johannesen Thor Bech , Ng Kim Lee , Sieber Raphael N. , Driebe Elizabeth , Engelthaler David M. , Andersen Paal Skytt
Published: July 2020

Staphylococcus aureus

is a colonizing opportunistic pathogen and a leading cause of bloodstream infection with high morbidity and mortality.

S. aureus

carriage frequency is reportedly between 20 and 40 % among healthy adults, with

S. aureus

colonization considered to be a risk factor for

S. aureus

bacteraemia. It is unknown whether a genetic component of the bacterium is associated with

S. aureus

bacteraemia in comparison to nasal carriage strains. Previous association studies primarily focusing on the clinical outcome of an

S. aureus

infection have produced conflicting results, often limited by study design challenged by sample collections and the clonal diversity of

S. aureus

. To date, no study has investigated whether genomic features separate nasal carriage isolates from

S. aureus

bacteraemia isolates within a single clonal lineage. Here we have investigated whether genomic features, including single-nucleotide polymorphisms (SNPs), genes, or kmers, distinguish

S. aureus

nasal carriage isolates from bacteraemia isolates that all belong to the same clonal lineage [clonal complex 45 (CC45)] using whole-genome sequencing (WGS) and a genome-wide association (GWA) approach. From CC45, 100 isolates (50 bacteraemia and 50 nasal carriage, geographically and temporally matched) from Denmark were whole-genome sequenced and subjected to GWA analyses involving gene copy number variation, SNPs, gene content, kmers and gene combinations, while correcting for lineage effects. No statistically significant association involving SNPs, specific genes, gene variants, gene copy number variation, or a combination of genes was identified that could distinguish bacteraemia isolates from nasal carriage isolates. The presented results suggest that all

S. aureus

nasal CC45 isolates carry the potential to cause invasive disease, as no core or accessory genome content or variations were statistically associated with invasiveness.
Endocrine disrupting chemicals and COVID-19 relationships: a computational systems biology approach
Authors: Wu Qier , Coumoul Xavier , Grandjean Philippe , Barouki Robert , Audouze Karine
Published: July 2020

Background

Patients at high risk of severe forms of COVID-19 frequently suffer from chronic diseases, but other risk factors may also play a role. Environmental stressors, such as endocrine disrupting chemicals (EDCs), can contribute to certain chronic diseases and might aggravate the course of COVID-19.

Objectives

To explore putative links between EDCs and COVID-19 severity, an integrative systems biology approach was constructed and applied.

Methods

As a first step, relevant data sets were compiled from major data sources. Biological associations of major EDCs to proteins were extracted from the CompTox database. Associations between proteins and diseases known as important COVID-19 comorbidities were obtained from the GeneCards and DisGeNET databases. Based on these data, we developed a tripartite network (EDCs-proteins-diseases) and used it to identify proteins overlapping between the EDCs and the diseases. Signaling pathways for common proteins were then investigated by over-representation analysis.

Results

We found several statistically significant pathways that may be dysregulated by EDCs and that may also be involved in COVID-19 severity. The Th17 and the AGE/RAGE signaling pathways were particularly promising.

Conclusions

Pathways were identified as possible targets of EDCs and as contributors to COVID-19 severity, thereby highlighting possible links between exposure to environmental chemicals and disease development. This study also documents the application of computational systems biology methods as a relevant approach to increase the understanding of molecular mechanisms linking EDCs and human diseases, thereby contributing to toxicology prediction.
The Linkage among Sea Transportation, Trade Liberalization and Industrial Development in the context of Carbon Dioxide Emissions: An Empirical Investigation from China
Authors: Kalaycı Salih , Özden Cihan
Published: July 2020

The major goal of this paper is to focus on the existing literature regarding the linkage between maritime, trade liberalization and industrial development in the context of CO2by using econometrical model. In this context, it is attempted to reveal the effects of independent variables on CO2(dependent variable) for China from 1980 to 2013 (annual data) by implementing Phillips-Perron (PP), Zivot-Andrews unit root tests, FMOLS, DOLS, CCR, ARDL and GMM methods. According to results of FMOLS, DOLS and CCR models there is a long-term stable relationship between sea transportation, trade liberalization, industrial development and carbon dioxide emissions which is proved empirically. Similarly, Short term ARDL estimation results reveal that the main determinants of CO2in the short-run are changed in industrial development and maritime transport at 1% significance level. Table 6 summarizes the short-term ARDL results and the findings regarding the error correction model. According to Table 6, error correction model works in order to reach short-run adjustment. In the short term, approximately 78% of shocks in industrial development, maritime transport and trade liberalization are compensated within a period of time and the system is re-established in the long term. China produced half of the 1.2 million electric media used worldwide; the government directs its attention to the rehabilitation and reuse of all these lithium-ion batteries. Large-scale production of biofuels can still be several years away. Crude oil might be very difficult to promote alternative fuels on a national scale unless crude oil prices surge so high as to become unaffordable. Authorities underline: China will become the world’s number one economy. Now renewable energy will be more important, which should be encouraged to use by government on transportation so as to reduce the CO2emissions. However, China can be leader excess oil use for transport if they want to dominate the economy worldwide.
In vitrohydroxyapatite formation of a TTCP and DCPA based dentine desensitiser
Authors: Duminis Tomas , Shahid Saroash , Hill Robert , Gillam David , D’Onofrio Alessia
Published: July 2020

This manuscript has been withdrawn by the authors as it was submitted and made public without the full consent of all the authors. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.
Atlas55+: Brain Functional Atlas of Resting-state Networks for Late Adulthood
Authors: Doucet Gaelle E. , Labache Loic , Thompson Paul M. , Joliot Marc , Frangou Sophia ,   the Alzheimer’s Disease Neuroimaging Initiative
Published: July 2020

Currently, several human brain functional atlases are used to define the spatial constituents of the resting-state networks (RSNs). However, the only brain atlases available are derived from samples of young adults. As brain networks are continuously reconfigured throughout life, the lack of brain atlases derived from older populations may influence RSN results in late adulthood. To address this gap, the aim of the study was to construct a reliable brain atlas derived only from older participants. We leveraged resting-state functional MRI data from three cohorts of healthy older adults (total N=563; age=55-95years) and a younger-adult cohort (N=128; age=18-35 years). We identified the major RSNs and their subdivisions across all older-adult cohorts. We demonstrated high spatial reproducibility of these RSNs with an average spatial overlap of 67%. Importantly, the RSNs derived from the older-adult cohorts were spatially different from those derived from the younger-adult cohort (p=2.3×10−3). Lastly, we constructed a novel brain atlas, called Atlas55+, which includes the consensus of the major RSNs and their subdivisions across the older-adult cohorts. Thus, Atlas55+ provides a reliable age-appropriate template for RSNs in late adulthood and is publicly available. Our results confirm the need for age-appropriate functional atlases for studies investigating aging-related brain mechanisms.
An interactive meta-analysis of MRI biomarkers of myelin
Authors: Mancini Matteo , Karakuzu Agah , Cohen-Adad Julien , Cercignani Mara , Nichols Thomas , Stikov Nikola
Published: July 2020

Several MRI measures have been proposed as in vivo biomarkers of myelin, each with applications ranging from plasticity to pathology. Despite the availability of these myelin-sensitive modalities, specificity and sensitivity have been a matter of discussion. Debate about which MRI measure is the most suitable for quantifying myelin is still ongoing. In this study, we performed a systematic review of published quantitative validation studies to clarify how different these measures are when compared to the underlying histology. We analysed the results from 43 studies applying meta-analysis tools, controlling for study sample size and using interactive visualization (https://neurolibre.github.io/myelin-meta-analysis). We report the overall estimates and the prediction intervals for the coefficient of determination and find that MT and relaxometry-based measures exhibit the highest correlations with myelin content. We also show which measures are, and which measures are not statistically different regarding their relationship with histology.
Teladorsagia circumcincta1,6 bisphosphate aldolase: molecular and biochemical characterisation, structure analysis and recognition by immune hosts
Authors: Umair S. , Bouchet C.L.G. , Palevich N. , Knight J.S. , Simpson H.V.
Published: July 2020

A 1095 bp full length cDNA encodingTeladorsagia circumcinctaaldolase (TciALDO) was cloned, expressed inEscherichia coli,the recombinant protein purified and its kinetic properties determined. A phylogenetic tree was constructed using helminth aldolase sequences. The predicted protein consisted of 365 amino acids and was present as a single band of about 44 kDa on SDS-PAGE. Multiple alignments of the protein sequence ofTciALDO with homologues from other helminths showed that the greatest similarity (93%) to the aldolases ofHaemonchus contortusandDictyocaulus viviparus, 82-86% similarity to the other nematode sequences and 68-71% similarity to cestode and trematode enzymes. Substrate binding sites and conserved regions were identified and were completely conserved in other homologues. At 25 °C, the optimum pH forTciALDO activity was pH 7.5, the Vmaxwas 432 ± 23 nmoles.min−1.mg−1protein and the apparent Kmfor the substrate fructose 1,6-bisphosphate was 0.24 ± 0.01 μM (mean ± SEM, n = 3). Antibodies in both serum and saliva from field-immune, but not nematode-naïve, sheep recognised recombinantTciALDO in enzyme-linked immunosorbent assays. The recognition of the recombinant protein by antibodies generated by exposure of sheep to native aldolase indicates similar antigenicity of the two proteins.
SARS-CoV-2 infects cells following viral entry via clathrin-mediated endocytosis
Authors: Bayati Armin , Kumar Rahul , Francis Vincent , McPherson Peter S.
Published: July 2020

With more than 51 million cases and 1.3 million deaths, and with the resulting social upheaval, the COVID-19 pandemic presents one of the greatest challenges ever to human society. It is thus vital to fully understand the biology of SARS-CoV-2, the causative agent of COVID-19. SARS-CoV-2 uses its spike glycoprotein to interact with the cell surface as a first step in the infection process. Using purified spike glycoprotein and lentivirus pseudotyped with spike glycoprotein, we now demonstrate that following engagement with the plasma membrane, SARS-CoV-2 undergoes rapid clathrin-mediated endocytosis. This suggests that transfer of viral RNA to the cell cytosol occurs from the lumen of the endosomal system, and importantly clathrin-heavy chain knockdown, which blocks clathrin-mediated endocytosis, reduces viral infectivity. This discovery reveals important new information about the basic biology of SARS-CoV-2 infectivity.
CHEST DRAIN AEROSOL GENERATION IN COVID-19 AND EMISSION REDUCTION USING A SIMPLE ANTI-VIRAL FILTER
Authors: Duffy Clodagh , Kidd Andrew C. , Francis Sarah , Tsim Selina , McNaughton Laura , Ferguson Katie , Ferguson Jenny , Rodgers Gary , McGroarty Claire , Sayer Robin , Blyth Kevin G.
Published: July 2020

Introduction

The COVID-19 pandemic has been characterised by significant in-hospital virus transmission and deaths among healthcare workers. Sources of in-hospital transmission are not fully understood, with special precautions currently reserved for procedures previously shown to generate aerosols (particles <5 microns). Pleural procedures are not currently considered AGPs, reflecting a lack of data in this area.

Methods

An underwater seal chest drain bottle (R54500, Rocket Medical UK) was set up inside a 60-litre plastic box and connected via an airtight conduit to a medical air supply. A multichannel particle counter (TSI Aerotrak 9310 Aerosol Monitor) was placed inside the box, allowing measurement of particle count/cubic foot (pc/ft3) within six channel sizes: 0.3-0.5, 0.5-1, 1-3, 3-5, 5-10 and >10 microns. Stabilised particle counts at 1, 3 and 5 L/min were compared by Wilcoxon signed rank test; p-values were Bonferroni-adjusted. Measurements were repeated with a simple anti-viral filter, designed using repurposed materials by the study team, attached to the drain bottle. The pressure within the bottle was measured to assess any effect of the filter on bottle function.

Results

Aerosol emissions increased with increasing air flow, with the largest increase observed in smaller particles (0.3-3 microns). Concentration of the smallest particles (0.3-0.5 microns) increased from background levels by 700, 1400 and 2500 pc/ft3 at 1, 3 and 5 L/min, respectively. However, dispersion of particles of all sizes was effectively prevented by use of the viral filter at all flow rates. Use of the filter was associated with a maximum pressure rise of 0.3 cm H2O after 24hours of flow at 5 L/min, suggesting minimal impact on drain function.

Conclusion

A bubbling chest drain is a source of aerosolised particles, but emission can be prevented using a simple anti-viral filter. These data should be considered when designing measures to reduce in-hospital spread of SARS-CoV-2.
Comparison of the COVID-19 infection risks by close contact and aerosol transmission
Authors: Zhang Xiaole , Wang Jing
Published: July 2020

A comprehensive understanding of the transmission routes of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is of great importance for the effective control of the spread of Corona Virus Disease 2019 (COVID-19). Human-to-human transmission by close contact where large respiratory droplets play a significant role has been established as the main transmission route. At the same time the transmission by small aerosol is getting increasing attention. There is no distinct boundary between droplets and aerosol in nature so it is natural to investigate the infection risk due to aerosol. Here, we utilized a newly developed dose-response relation, combined with a box model for the exposure estimation, to quantitatively evaluate the infection risk of SARS-CoV-2 through aerosol transmission and compared with the risk due to close contact. The results indicated that the median infection risk via aerosol transmission was about 3.7×10−5 (95% confidence interval: 3.5×10−6 to 4.4×10−4) for one hour of exposure in a room with the size of 10 m (width)×10 m (length)×3 m (height) with one infected individual in it. The risk was more than three orders of magnitude lower than the risk at short distance, about 12.8% within 1 m, based on a meta-analysis. A simple exponential regression model Risk=10−0.90×D+0.10 (D<=5 m) could be utilized to characterize the magnitude of infection risk in the considered scenario based on the distance D from the infected individual. With prolonged exposure duration and large exposed population, the infection caused by aerosol transmission could be considerable, thus it is necessary to be cautious for the potential aerosol transmission risk in such situations.
Identification of Patterns in Epidemic Cycles and Methods for Estimating Their Duration: COVID-19 Case Study1
Authors: de Carvalho Eduardo Atem , de Carvalho Rogerio Atem
Published: July 2020

This paper presents several epidemic cycles of COVID-19 that have practically ended in countries, states and cities and normalize them through simple and well-known numerical methods. It is evident that there is a practically universal pattern between them, in a triangular shape. It is also possible to find similar cycles with very close scales and thus use cases with cycles already closed to predict the end of the cycles still in progress. Three methods are presented and discussed and the case of the city of Rio de Janeiro, Brazil, is presented in more detail.
Low SARS-CoV-2 sero-prevalence based on anonymized residual sero-survey before and after first wave measures in British Columbia, Canada, March-May 2020
Authors: Skowronski Danuta M , Sekirov Inna , Sabaiduc Suzana , Zou Macy , Morshed Muhammad , Lawrence David , Smolina Kate , Ahmed May A , Galanis Eleni , Fraser Mieke N , Singal Mayank , Naus Monika , Patrick David M , Kaweski Samantha E , Mill Christopher , Reyes Romina C , Kelly Michael T , Levett Paul N , Petric Martin , Henry Bonnie , Krajden Mel
Published: July 2020

Background

The province of British Columbia (BC) has been recognized for successful SARS-CoV-2 control, with surveillance data showing amongst the lowest case and death rates in Canada. We estimate sero-prevalence for two periods flanking the start (March) and end (May) of first-wave mitigation measures in BC.

Methods

Serial cross-sectional sampling was conducted using anonymized residual sera obtained from an outpatient laboratory network, including children and adults in the Greater Vancouver Area (population ∼3 million) where community attack rates were expected to be highest. Screening used two chemiluminescent immuno-assays for spike (S1) and nucleocapsid antibodies. Samples sero-positive on either screening assay were assessed by a third assay targeting the S1 receptor binding domain plus a neutralization assay. Age-standardized sero-prevalence estimates were based on dual-assay positivity. The May sero-prevalence estimate was extrapolated to the source population to assess surveillance under-ascertainment, quantified as the ratio of estimated infections versus reported cases.

Results

Serum collection dates spanned March 5-13 and May 15-27, 2020. In March, two of 869 specimens were dual-assay positive, with age-standardized sero-prevalence of 0.28% (95%CI=0.03-0.95). Neither specimen had detectable neutralizing antibodies. In May, four of 885 specimens were dual-assay positive, with age-standardized sero-prevalence of 0.55% (95%CI=0.15-1.37%). All four specimens had detectable neutralizing antibodies. We estimate ∼8 times more infections than reported cases.

Conclusions

Less than 1% of British Columbians had been infected with SARS-CoV-2 when first-wave mitigation measures were relaxed in May 2020. Our findings indicate successful suppression of community transmission in BC, but also substantial residual susceptibility. Further sero-survey snapshots are planned as the pandemic unfolds.

Key points

Cross-sectional sampling of anonymized residual sera at the start and end of first-wave mitigation measures in British Columbia, Canada shows SARS-CoV-2 sero-prevalence below 1% throughout the winter-spring 2020. Findings indicate successful suppression of community transmission but also substantial residual susceptibility.
Connecting in COVID 19: Neurology tele-follow-up experience
Authors: Vibha Deepti , Srivastava MV Padma , Prasad Kameshwar , Tripathi Manjari , Srivastava Achal Kumar , Bhatia Rohit , Singh Mamta Bhushan , Vishnu VY , Rajan Roopa , Singh Rajesh Kumar , Gupta Anu , Das Animesh , Elavarasi A , Divya MR , Ramanujam Bhargavi , Shariff A
Published: July 2020

Introduction

The lockdown due to COVID-19 pandemic led to temporary closure of routine hospital services. This prompted the initiation of teleconsult follow-up in our department. The study outlines the experience of tele-follow-up at a tertiary care teaching hospital in India, and the perspective of neurologists about this novel approach.

Methods

The tele-follow-up was started from 26th March 2020. Data of follow up appointments was provided by the medical record section. The faculty and senior residents conducted the tele-follow-up. Communication was made via voice calls. The data for initial ten days was analyzed to find the utility and experience of the new service.

Results

In the initial ten working days, data of 968 patients was provided for tele-follow-up. A successful communication was made in 50.3% patients (contact with patients: 27.7% and family members 22.6%). The phone numbers which were not contactable/invalid/not available constituted 36.8% of the data. A total of 35 faculty and residents conducted the tele-follow-up. The utility of tele-follow-up was perceived as good by 71.4% of neurologists. Majority of neurologists (71.4%) observed that >90% of patients were continuing medications. Patients outside the city constituted 50-75% of the list. The survey revealed that all neurologists felt the need to continue tele-follow-up for far off stable patients post lock down and resumption of regular outpatient services.

Conclusion

The survey established the feasibility and utility of teleconsult for follow up of patients with neurological diseases who were attending the regular outpatient services before the lock down.
Pharmacokinetics and pharmacodynamics of inhaled antipseudomonal bacteriophage therapy in mice
Authors: Chow Michael Y.T. , Chang Rachel Yoon Kyung , Li Mengyu , Wang Yuncheng , Lin Yu , Morales Sandra , McLachlan Andrew J , Kutter Elizabeth , Li Jian , Chan Hak-Kim
Published: July 2020

Inhaled bacteriophage (phage) therapy is a potential alternative to conventional antibiotic therapy to combat multidrug-resistant (MDR)Pseudomonas aeruginosainfections. However, pharmacokinetics (PK) and pharmacodynamics (PD) of phages are fundamentally different to antibiotics and the lack of understanding potentially limits optimal dosing. The aim of this study was to investigate thein vivoPK and PD profiles of antipseudomonal phage PEV31 delivered by pulmonary route in mice. BALB/c mice were administered phage PEV31 at doses of 107and 109PFU by the intratracheal route. Mice (n= 4) were sacrificed at 0, 1, 2, 4, 8 and 24 h post-treatment and various tissues (lungs, kidney, spleen and liver), bronchoalveolar lavage and blood were collected for phage quantification. In a separate study, mice (n= 4) were treated with PEV31 (109PFU) or PBS at 2 h post-inoculation with MDRP. aeruginosa. Infective PEV31 and bacteria were enumerated from the lungs. In the phage only study, PEV31 titer gradually decreased in the lungs over 24 hours with a half-life of approximately 8 h for both doses. In the presence of bacteria, PEV31 titer increased by almost 2-log10in the lungs at 16 h. Furthermore, bacterial growth was suppressed in the PEV31-treated group, while the PBS-treated group showed exponential growth. Some phage-resistant colonies were observed from the lung homogenates sampled at 24 h post-phage treatment. These colonies had a different antibiogram to the parent bacteria. This study provides evidence that pulmonary delivery of phage PEV31 in mice can reduce the MDR bacterial burden.
Cerebrospinal fluid (CSF) boosts metabolism and virulence expression factors inAcinetobacter baumannii
Authors: Martinez Jasmine , Razo-Gutierrez Chelsea , Le Casin , Courville Robert , Pimentel Camila , Liu Christine , Fuang Sammie E. , Vila Alejandro J. , Shahrestani Parvin , Jimenez Veronica , Tolmasky Marcelo E. , Becka Scott A. , Papp-Wallace Krisztina M. , Bonomo Robert A. , Soler-Bistue Alfonso , Sieira Rodrigo , Ramirez Maria Soledad
Published: July 2020

In a recent report by the Centers for Disease Control and Prevention (CDC), multidrug resistant (MDR)Acinetobacter baumanniiis a pathogen described as an “urgent threat”. Infection with this bacterium manifests as different diseases such as community and nosocomial pneumonia, bloodstream infections, endocarditis, urinary tract, wound infections, burn infections, skin and soft tissue infections, and meningitis. In particular, nosocomial meningitis, a common complication of neurosurgery caused by extensively-drug resistant (XDR)A. baumannii, is extremely challenging to manage. Therefore, it is necessary to identify signals, such as exposure to cerebrospinal fluid (CSF), that trigger expression of virulence factors that are associated with the successful establishment and progress of this infection. While a hypervirulentA. baumanniistrain did not show changes in its transcriptome when incubated in the presence of CSF, a low-virulence isolate showed significant differences in gene expression and phenotypic traits. Exposure to 4% CSF caused increased expression of virulence factors such as fimbriae, pilins, and iron chelators, and virulence as determined in various model systems. Furthermore, although CSF’s presence did not enhance bacterial growth, it was associated with an increase of expression of genes encoding transcription, translation, and the ATP synthesis machinery. Experiments to identify the active CSF component pointed to human serum albumin (HSA).

Importance

Acinetobacter baumannii, notorious for its multidrug resistant phenotype, overcomes nutrient deprived and desiccated conditions through its metabolic flexibility, pathogenic and physiological adaptability. Although this pathogen is commonly associated with respiratory infections, there have been a considerable amount of cases ofA. baumanniibacterial meningitis. These infections are usually post-neurological surgery complications associated with high mortality rates ranging from 40 to 70%. This work describes interactions that may occur duringA. baumanniiinfection of human cerebrospinal fluid (CSF).A. baumannii’sdisplays capabilities to persist and thrive in a nutrient-limited environment, which also triggers the expression of virulence factors. This work also further exploresA. baumannii’sutilization of an essential component within CSF to trigger enhanced expression of genes associated with its pathoadaptibility in this environment.
Action Imagery and Observation in Neurorehabilitation for Parkinson’s Disease (ACTION-PD): development and pilot randomised controlled trial of a user-informed home training intervention to improve everyday functional actions
Authors: Bek Judith , Holmes Paul S. , Craig Chesney E. , Franklin Zoë C. , Sullivan Matthew , Webb Jordan , Crawford Trevor J. , Vogt Stefan , Gowen Emma , Poliakoff Ellen
Published: July 2020

Background

Parkinson’s disease (PD) causes difficulties with everyday manual activities, but few studies have addressed these therapeutically. Training with action observation (AO) and motor imagery (MI) can significantly improve performance in healthy individuals, particularly when these techniques are applied simultaneously (AO+MI). Both AO and MI have shown promising effects in PD, but previous studies have used these separately. This article describes the development and pilot testing of an intervention combining AO+MI and physical practice to improve functional manual actions in PD.

Methods

The home-based intervention, delivered using a tablet computer app, was iteratively designed by an interdisciplinary team including people with PD, and further developed through focus groups and initial testing. The intervention was then tested in a six-week randomised controlled trial (ISRCTN 11184024) of 10 participants with mild to moderate PD (6 intervention; 4 treatment as usual).

Results and Conclusions

Usage and qualitative data provided preliminary evidence of acceptability and usability, indicating that a feasibility RCT is warranted. Exploratory analyses suggested potential improvements in manual actions. The importance of personalisation, choice, and motivation was highlighted, as well as the need to facilitate engagement in motor imagery. The findings also have broader relevance for AO+MI interventions in PD and other populations.
PD-1-induced T cell exhaustion is controlled by a Drp1-dependent mechanism
Authors: Simula Luca , Cancila Valeria , Antonucci Ylenia , Colamatteo Alessandra , Procaccini Claudio , Matarese Giuseppe , Tripodo Claudio , Campello Silvia
Published: July 2020

PD-1 signalling downregulates the T cell response, promoting an exhausted state in tumor-infiltrating T cells, through mostly unveiled molecular mechanisms. Drp1-dependent mitochondrial fission plays a crucial role to sustain T cell motility, proliferation, survival and glycolytic engagement and, interestingly, such processes are exactly those inhibited by PD-1 in tumor-infiltrating T cells. Here we show that the signature of PD-1posCD8+T cells infiltrating MC38-derived murine tumor mass is having downregulated Drp1 activity and more fused mitochondria, compared to PD-1negcounterparts. Also, PD-1poslymphocytic elements infiltrating human colon cancer rarely express active Drp1. Mechanistically, PD-1 signalling directly prevents mitochondria fragmentation following T cell stimulation by downregulating Drp1 phosphorylation on Ser616, via regulation of the ERK1/2 and mTOR pathways. In addition, downregulation of Drp1 activity in tumor-infiltrating PD-1posCD8+ T cells seems to be a mechanism exploited by PD-1 signalling to reduce motility and proliferation of these cells. Overall, our data indicate that the modulation of Drp1 activity in tumor-infiltrating T cells may become a valuable target to ameliorate the anti-cancer immune response in future immunotherapy approaches.
COVID-19 infection and attributable mortality in UK care homes: Cohort study using active surveillance and electronic records (March-June 2020)
Authors: Dutey-Magni Peter F , Williams Haydn , Jhass Arnoupe , Rait Greta , Lorencatto Fabiana , Hemingway Harry , Hayward Andrew , Shallcross Laura
Published: July 2020

Background

Epidemiological data on COVID-19 infection in care homes are scarce. We analysed data from a large provider of long-term care for older people to investigate infection and mortality during the first wave of the pandemic.

Methods

Cohort study of 179 UK care homes with 9,339 residents and 11,604 staff.We used manager-reported daily tallies to estimate the incidence of suspected and confirmed infection and mortality in staff and residents. Individual-level electronic health records from 8,713 residents were used to model risk factors for confirmed infection, mortality, and estimate attributable mortality.

Results

2,075/9,339 residents developed COVID-19 symptoms (22.2% [95% confidence interval: 21.4%; 23.1%]), while 951 residents (10.2% [9.6%; 10.8%]) and 585 staff (5.0% [4.7%; 5.5%]) had laboratory-confirmed infections. The incidence of confirmed infection was 152.6 [143.1; 162.6] and 62.3 [57.3; 67.5] per 100,000 person-days in residents and staff respectively. 121/179 (67.6%) care homes had at least one COVID-19 infection or COVID-19-related death. Lower staffing ratios and higher occupancy rates were independent risk factors for infection.

217/607 residents with confirmed infection died (case-fatality rate: 35.7% [31.9%; 39.7%]). Mortality in residents with no direct evidence of infection was two-fold higher in care homes with outbreaks versus those without (adjusted HR 2.2 [1.8; 2.6]).

Conclusions

Findings suggest many deaths occurred in people who were infected with COVID-19, but not tested. Higher occupancy and lower staffing levels were independently associated with risks of infection. Protecting staff and residents from infection requires regular testing for COVID-19 and fundamental changes to staffing and care home occupancy.
SARS-CoV-2 Infection Depends on Cellular Heparan Sulfate and ACE2
Authors: Clausen Thomas Mandel , Sandoval Daniel R. , Spliid Charlotte B. , Pihl Jessica , Painter Chelsea D. , Thacker Bryan E. , Glass Charles A. , Narayanan Anoop , Majowicz Sydney A. , Zhang Yang , Torres Jonathan L. , Golden Gregory J. , Porell Ryan , Garretson Aaron F. , Laubach Logan , Feldman Jared , Yin Xin , Pu Yuan , Hauser Blake , Caradonna Timothy M. , Kellman Benjamin P. , Martino Cameron , Gordts Philip L.S.M. , Leibel Sandra L. , Chanda Summit K. , Schmidt Aaron G. , Godula Kamil , Jose Joyce , Corbett Kevin D. , Ward Andrew B. , Carlin Aaron F. , Esko Jeffrey D.
Published: July 2020

We show that SARS-CoV-2 spike protein interacts with cell surface heparan sulfate and angiotensin converting enzyme 2 (ACE2) through its Receptor Binding Domain. Docking studies suggest a putative heparin/heparan sulfate-binding site adjacent to the domain that binds to ACE2. In vitro, binding of ACE2 and heparin to spike protein ectodomains occurs independently and a ternary complex can be generated using heparin as a template. Contrary to studies with purified components, spike protein binding to heparan sulfate and ACE2 on cells occurs codependently. Unfractionated heparin, non-anticoagulant heparin, treatment with heparin lyases, and purified lung heparan sulfate potently block spike protein binding and infection by spike protein-pseudotyped virus and SARS-CoV-2 virus. These findings support a model for SARS-CoV-2 infection in which viral attachment and infection involves formation of a complex between heparan sulfate and ACE2. Manipulation of heparan sulfate or inhibition of viral adhesion by exogenous heparin may represent new therapeutic opportunities.
Mapping endothelial functional phenotype in cancer by unveiling the kinase and phosphatase drivers
Authors: Gadish Or , Edelman Elazer R.
Published: July 2020

Endothelial cells (EC) are state-dependent regulators of the tumor ecosystem: quiescent ECs promote homeostasis; proliferative ECs stimulate tumor growth. Tumors, in turn, promote pro-tumorigenic EC phenotype. We studied functional and phosphorylative transformations on EC state in cancer. Quiescent HUVECs cultured in breast cancer cell-conditioned media displayed marked elongation and impaired wound healing. Quantitative mass spectrometry identified phosphorylative regulators of this dysfunctional transformation. Growth factor receptor kinases showed decreased, rather than increased activity, suggesting that EC regulation in tumors can arise other than from classic growth-factor-mediated angiogenesis alone. Of the 152 kinases and phosphatases across 62 families, six were chosen for functional validation using pharmacologic inhibitors. Inhibiting Akt and Ptp1b restored EC regulatory state, warranting further investigation as therapeutic targets; Src inhibition, however, promoted the dysfunctional phenotype, suggesting caution for Src inhibitors as EC-regulating therapies. Mapping phosphorylative drivers reveals complex relationships between EC phenotype, transformation, and regulation, and may shed light on how existing cancer-targeting inhibitors affect tumor endothelium. Data are available via ProteomeXchange with identifier PXD020333.